Congenital and Hereditary Hypoparathyroidism

Genetic causes of parathyroid hormone insufficiency: isolated, syndromic, autoimmune and calcium-sensing forms

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

Related entities, covered here only from the parathyroid perspective: 22q11.2 deletions and duplications, pseudohypoparathyroidism and disorders of PTH-PTHrP signalling, familial hypocalciuric hypercalcaemia and the loss-of-function forms of CASR, autoimmune polyendocrinopathy type 1 and the Kenny-Caffey, osteocraniostenosis and Sanjad-Sakati syndromes.

In France, the diagnosis and treatment of all entities in this table are framed by the national diagnosis and care protocol (PNDS, French National Diagnosis and Care Protocol) of the Haute Autorité de Santé dedicated to hypoparathyroidism, published in April 2025 and written by the reference centre for rare disorders of calcium and phosphate metabolism, which covers acquired and genetic forms at all ages, excludes disorders of PTH-PTHrP signalling, which have their own protocol, and does not detail the overall treatment of associated syndromes, such as autoimmune polyendocrinopathy type 1, 22q11.2 deletion, Kearns-Sayre syndrome and HDR syndrome [12].

1. Introduction

Hypoparathyroidism is the clinical state in which the parathyroid hormone secreted by the parathyroid glands is insufficient to maintain the calcium concentration of the extracellular fluid or, less frequently, in which the circulating hormone cannot act optimally on target tissues, and it is expressed biochemically as hypocalcaemia with hyperphosphataemia in the presence of normal renal function [1]. This definition, which Garfield and Karaplis set out in their 2001 review of the causes and clinical forms of the disease, remains the basis of current criteria, which require documented hypocalcaemia with undetectable, low or inappropriately normal intact parathyroid hormone on at least two occasions two weeks apart [27]. The set of genetic causes brought together here differs from postsurgical hypoparathyroidism — which is the most common form in absolute terms — in three characteristics with practical consequences: the age at presentation is usually neonatal or paediatric, the defect is permanent from the outset and not recoverable, and identification of the gene alters surveillance of other organs, the familial recurrence risk and, in several entities, the therapeutic target itself.

1.1 Historical overview of the familial forms

The clinical history of hereditary hypoparathyroidism begins with descriptions of familial clustering that preceded by decades any possibility of molecular confirmation. Sutphin, Albright and McCune described, in 1943, five cases of idiopathic hypoparathyroidism associated with moniliasis, three of them in siblings, in what would later be recognised as autoimmune polyendocrinopathy type 1 [1]. Chaptal and colleagues described in 1960 familial hypoparathyroidism in the children of consanguineous parents, and Bronsky, Kiamko and Waldstein reported in 1968 two siblings who developed idiopathic hypoparathyroidism at 11 and 21 years, citing six other previously published families with more than one affected member [1]. Peden published in 1960 a Missouri family with several males affected by neonatal idiopathic hypoparathyroidism following an X-linked pattern, and proposed that most early-onset familial cases were of this type, with the autosomal pattern associated with later onset [5]. Whyte and Weldon studied in 1981 a second family from the same region with X-linked isolated hypoparathyroidism of neonatal or infantile onset, and Whyte, Kim and Kosanovich demonstrated in 1986, at the autopsy of a member of the Peden family who died in adolescence in a road traffic accident, that careful dissection of the thyroid, the cervical tissues, the space between the trachea and the oesophagus and the retro-oesophageal space revealed no parathyroid tissue — that is, that the basis of the disease was agenesis of the glands [5]. Mumm and colleagues showed in 1997, by comparing the sequence of the mitochondrial DNA D-loop, that the two apparently unrelated Missouri families, both of which had migrated from Kentucky in the 1880s, shared the same maternal lineage and therefore the same genetic defect, in an early example of the use of mitochondrial markers to establish common ancestry in an X-linked disease [5].

Ahn, Antonarakis, Kronenberg, Igarashi and Levine published in 1986 the study that defined familial isolated hypoparathyroidism as an entity, applying strict criteria to eight families with 23 affected people: absence of a demonstrable anatomical cause, absence of candidiasis and of autoimmune polyglandular failure, absence of antithyroid and antiadrenal autoantibodies, absence of developmental defects suggesting branchial pouch dysgenesis and undetectable or subnormal immunoreactive parathyroid hormone [1]. Inheritance was compatible with autosomal dominance in five families and with autosomal recessiveness in three, and one of the dominant families and two of the recessive ones were also compatible with X-linked inheritance. In none of the 23 affected people was there absence of the PTH gene or abnormal restriction patterns; in four families, affected siblings inherited different PTH alleles, which excluded the gene in those families, while in two concordance was observed between the disease and specific alleles. The work therefore showed that familial isolated hypoparathyroidism was genetically heterogeneous before any gene was known.

The syndrome combining hypoparathyroidism, sensorineural deafness and kidney disease was described by Barakat and colleagues in 1977, in two brothers with steroid-resistant nephrosis, progressive renal failure and death at 5 and 8 years, who also had deafness and hypoparathyroidism; at autopsy, the parathyroids were absent in one child and hypoplastic in the other, and male twins from another family with similar findings died at 3 years with fibrotic parathyroids and thickened glomerular basement membranes [28]. Bilous and colleagues described in 1992 two brothers and two daughters of one of them with the same combination, documenting that the hearing deficit was bilateral, symmetrical, affected all frequencies with slight predominance at high frequencies and did not appear progressive, and that urography showed small, irregular kidneys with compressed collecting systems, consistent with bilateral renal dysplasia [28]. Because the two sets of families differed in their pattern of transmission, Barakat suggested in 1997 that the mode of inheritance would not distinguish two diseases and that the disease might result from different variants of the same gene, a hypothesis that the identification of GATA3 confirmed.

The history of the forms with skeletal dysplasia has an unresolved nomenclature problem. Kenny and Linarelli described in 1966 a dwarfism with cortical thickening of the tubular bones, and Caffey published in 1967 congenital stenosis of the medullary spaces of the tubular bones and calvaria in two proportionate dwarfs — mother and son — with transient hypocalcaemic tetany [29]. Majewski, Rosendahl, Ranke and Nolte characterised the syndrome in 1981 as a rare type of growth deficiency with tubular stenosis, transient hypoparathyroidism and refractive anomalies, and Fanconi, Fischer and Wieland documented in 1986 idiopathic hypoparathyroidism in two patients and abnormal parathyroid hormone in one [29]. Sanjad, Sakati and Abu-Osba presented in 1988, in an abstract, and published in 1991, based on 12 Saudi infants, a distinct entity with congenital hypoparathyroidism, seizures, growth failure and dysmorphism, later named Sanjad-Sakati syndrome, in which all had severe intrauterine and postnatal growth restriction, nine with symptoms in the neonatal period, hypocalcaemia with hyperphosphataemia and very low concentrations of immunoreactive parathyroid hormone, none with congenital heart disease and with normal cellular immunity in the five tested [19]. Richardson and Kirk had described in 1990 eight children from seven consanguineous marriages with height, weight and head circumference below minus two standard deviations, an identical facies with deep-set eyes, depressed nasal bridge with beaked nose, long philtrum, thin upper lip, micrognathia and large floppy ear lobes, medullary stenosis and other skeletal defects in seven of the eight and reduced T-lymphocyte subsets in the four tested [19].

1.2 Milestones of molecular discovery

The order in which the genes were identified explains the current architecture of the classification. Pollak, Brown, Seidman and colleagues demonstrated in 1993 that variants of the calcium-sensing receptor caused familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism [30], and in 1994 identified, in a family with at least 16 affected members over four generations, a CASR missense variant responsible for autosomal dominant hypocalcaemia, explicitly formulating the hypothesis that, unlike the mild hypercalcaemia caused by variants that reduce receptor activity, mild hypocalcaemia would be caused by a variant that activates it inappropriately at subnormal calcium concentrations — as was already known for other G protein-coupled receptors; Xenopus oocytes expressing the mutant receptor showed a greater increase in inositol 1,4,5-trisphosphate in response to calcium than those expressing the normal receptor [7]. Pearce and colleagues sequenced CASR in 1996 in probands from six families with hypercalciuric hypocalcaemia and identified heterozygous missense variants in five, cosegregating with hypocalcaemia and absent from 55 controls, with transfection studies in HEK293 cells confirming that the mutant receptors were active at lower extracellular calcium concentrations than normal [7]. Baron and colleagues identified in the same year activating variants in two families with autosomal dominant hypoparathyroidism and in an infant girl with severe sporadic disease, and explained the two consequences of the mechanism: because the receptor negatively regulates calcium reabsorption by renal cells, its activation causes hypercalciuria even with low serum calcium, and because it takes part in a negative feedback loop on parathyroid function, its activation is accompanied by hypoparathyroidism [7].

Arnold, Kronenberg, Levine and colleagues identified in 1990, in one of Ahn's families, a heterozygous point variant in the coding region of the signal peptide of the PTH gene, now written NM_000315.4:c.52T>C, NP_000306.1:p.(Cys18Arg) [1, 31]. Parkinson and Thakker identified in 1992 a splice donor site variant of the same gene in the homozygous state in two sisters and a brother, children of first cousins, which established the existence of a recessive form [1]. Sunthornthepvarakul, Churesigaew and Ngowngarmratana described in 1999 a signal peptide variant in a child with neonatal hypocalcaemic seizures, born to consanguineous parents, with serum calcium of 1.5 mmol/l (normal 2.0 to 2.5) and phosphate of 3.6 mmol/l (normal 0.9 to 1.5); two younger sisters and a niece later presented with neonatal hypocalcaemic seizures, with undetectable intact parathyroid hormone during severe hypocalcaemia, and only affected members were homozygous, with heterozygous parents, confirming recessive inheritance [1].

Ding, Buckingham and Levine identified in 2001, in the proband of an extended family from Central America, homozygosity for a large intragenic deletion of GCM2, with the non-consanguineous, asymptomatic parents heterozygous and haplotype analysis revealing genotypes shared over 5 cM around the gene, suggesting a founder effect with homozygosity by descent; they concluded that homozygous loss of function of GCM2 impairs normal parathyroid embryology [4]. Baumber and colleagues found in 2005, in a five-generation consanguineous Pakistani family, homozygosity for the missense variant NM_004752.4:c.140G>T, NP_004743.1:p.(Arg47Leu), which destroys DNA-binding activity [4, 31], and Thomée and colleagues identified in the same year, in two siblings of Moroccan first-cousin parents, homozygosity for a missense variant in the GCM DNA-binding domain, in one case with residual parathyroid hormone secretion — an important observation because it shows that GCM2 can cause hypoparathyroidism with detectable parathyroid hormone [4]. Bowl and colleagues identified in 2010 four different homozygous variants in eight families from the Indian subcontinent, and Mannstadt and colleagues demonstrated in 2008 that heterozygous frameshift variants in the last exon of GCM2 cause a dominant form, with well-expressed mutant proteins that dose-dependently inhibit the transactivation capacity of the normal protein in luciferase assays [4].

Van Esch and colleagues defined in 2000, by deletion mapping in two patients with HDR syndrome, a 200 kb critical region containing GATA3, and identified in a search in three other probands a nonsense variant and two intragenic deletions predicted to cause loss of function, confirmed by absent DNA binding by the mutant protein; they concluded that GATA3 is essential for the embryonic development of the parathyroids, the auditory system and the kidneys and that haploinsufficiency causes the human syndrome [28]. Before this, Hasegawa and colleagues had located the gene in 1997 in the 10pter-p13 region from a Japanese girl with a de novo 10p13 deletion, and Lichtner and colleagues concluded in 2000, by comparison with patients with a DiGeorge phenotype associated with 10p monosomy, that hemizygosity of a proximal region causes heart defects and T-lymphocyte deficiency, whereas that of a more distal region causes hypoparathyroidism, sensorineural deafness and renal dysplasia [28].

Parvari and colleagues identified in 2002 TBCE as the gene responsible for hypoparathyroidism-retardation-dysmorphism syndrome and for autosomal recessive Kenny-Caffey syndrome, finding in all patients of Middle Eastern ancestry the same homozygous 12 base-pair deletion, now written NM_003193.5:c.155_166del, NP_003184.1:p.(Ser52_Gly55del) [19, 31]; Kelly and colleagues had already mapped Sanjad-Sakati syndrome in 2000 to 1q42-q43, with a maximum lod score of 4.12 at marker D1S235 and a 1 cM candidate region, noting that Kenny-Caffey syndrome type 1 mapped to the same region and suggesting that they were allelic, if not the same condition [19]. Unger, Gorna, Le Bechec and colleagues demonstrated in 2013 that FAM111A variants cause hypoparathyroidism and abnormal skeletal development, establishing the gene-disease relationship simultaneously for dominant Kenny-Caffey syndrome and for osteocraniostenosis [17, 29]. Nesbit, Hannan, Thakker and colleagues identified in 2013 GNA11 variants in hypercalcaemia and hypocalcaemia, with functional analysis in HEK293 cells stably expressing the calcium-sensing receptor demonstrating that the mutant proteins induce increased sensitivity to changes in extracellular calcium, similar to that of CASR gain-of-function variants; Mannstadt and colleagues identified in the same year, in a four-generation family with linkage to 19p13.3 and a lod score of 3.0, the variant NM_002067.5:c.178C>T, NP_002058.2:p.(Arg60Cys) [31, 32]. Bowl, Nesbit, Thakker and colleagues characterised in 2005, in the Peden family, a gene-free deletion of 23 to 25 kb, replaced by an insertion of about 340 kb from 2p25 that contains a segment of the SNTG2 gene without an open reading frame, with the telomeric breakpoint about 67 kb downstream of SOX3; expression of Sox3 in developing parathyroid tissue of mouse embryos between days 10.5 and 15.5 post coitum supported a position effect on that gene as the mechanism of X-linked hypoparathyroidism [5].

1.3 Nomenclature and reclassifications

Three nomenclature problems run through this area and should be made explicit before the literature is used. The first is that of the Kenny-Caffey syndromes. The condition described by Sanjad and Sakati differs from that of Kenny and Caffey in having microcephaly, intellectual disability and recessive inheritance, and the authors of the bone dysplasia atlas consider that the OMIM listing of the dominant form as "Kenny-Caffey type 2" (127000) and of Sanjad-Sakati syndrome as "Kenny-Caffey type 1" (244460) perpetuates an error they hope to see corrected [29]. The 2023 nosology of genetic skeletal disorders adopted designations that resolve the ambiguity in genetic terms, calling the FAM111A form "Kenny-Caffey syndrome, dominant, FAM111A-related" and the TBCE form "Sanjad-Sakati syndrome, recessive, TBCE-related" [33]. The systematic review of 205 patients with genetically confirmed Kenny-Caffey syndrome added a finding that reverses clinical intuition: in TBCE disease intellectual disability is the typical feature, present in 74 of 80 patients, whereas the osteosclerotic bone changes that give the syndrome its name are uncommon — medullary stenosis in 7 of 46 and cortical thickening in 1 of 18 — and are, by contrast, the hallmark of FAM111A disease, with 27 of 28 and 16 of 20 [22].

The second problem is the designation of autosomal dominant hypocalcaemia. Thakker noted in 2001 that patients with CASR gain-of-function variants, who have generally asymptomatic hypocalcaemia with hypercalciuria and parathyroid hormone in the lower half of the normal range, had often been diagnosed as having hypoparathyroidism because of the insensitivity of the parathyroid hormone assays then available, and proposed the designation "autosomal dominant hypercalciuric hypocalcaemia" precisely because treatment with vitamin D to correct hypocalcaemia in these patients causes hypercalciuria, nephrocalcinosis and renal impairment, which requires them to be separated from the other forms of hypoparathyroidism [7]. The 2025 European guideline goes further and observes that in autosomal dominant hypocalcaemia the parathyroid glands are preserved and what is altered is the calcium set point, so that the entity is not, strictly speaking, a hypoparathyroidism [34]. The practical consequence is that, although the two forms appear in the same Orphanet entry for familial isolated hypoparathyroidism because they share the biochemical phenotype, the treatment is different.

The third problem is the aetiological attribution of non-surgical hypoparathyroidism. The Second International Workshop explicitly recommends avoiding the label "autoimmune hypoparathyroidism" in patients without autoimmune polyendocrinopathy type 1, because there is no definitive test that establishes it [27]. In parallel, the historical designation "idiopathic hypoparathyroidism" has been progressively emptied by the yield of genetic panels: in a Chinese cohort of 173 patients with childhood-onset hypoparathyroidism, the combination of next-generation sequencing targeted to 15 candidate genes with TBX1 dosage analysis identified a genetic defect in 27.7% of patients, and 16 of the 26 cases of DiGeorge syndrome diagnosed there — 61.5% — had gone unrecognised for lack of obvious clinical clues before testing [35].

1.4 Precise definition of the entities in this article

The article covers, as a class, the genetic causes of parathyroid hormone insufficiency, organised by mechanism. The isolated forms comprise familial isolated hypoparathyroidism type 1, due to PTH variants that prevent the synthesis, processing or biological activity of the hormone; type 2, due to loss of function or a dominant-negative effect of GCM2, which is the master regulator of gland development — and in neither of the two does the gene name determine the mode of transmission, because both PTH and GCM2 have documented dominant and recessive forms, depending on the variant; and the X-linked form, due to a rearrangement at Xq27.1 with a position effect on SOX3, whose anatomical basis is parathyroid agenesis. The calcium-sensing forms comprise autosomal dominant hypocalcaemia type 1, due to gain of function of CASR, with or without the Bartter type V phenotype, and type 2, due to gain of function of GNA11, the G protein that couples the receptor to phospholipase C-beta. The syndromic developmental forms comprise HDR syndrome, due to GATA3 haploinsufficiency; the hypoparathyroidism of 22q11.2 deletions and of TBX1 point variants, which acts upstream of the formation of the thymus and parathyroids from the third pharyngeal pouch; the FAM111A-related dysplasias, at the two ends of the spectrum of Kenny-Caffey syndrome and osteocraniostenosis; the recessive TBCE syndromes, Kenny-Caffey type 1 and Sanjad-Sakati; and lymphoedema-hypoparathyroidism syndrome, with no gene yet identified. The monogenic autoimmune form is autoimmune polyendocrinopathy type 1, due to failure of AIRE-dependent central tolerance. The mitochondrial forms arise in cytopathies with large mitochondrial DNA deletions, particularly Kearns-Sayre syndrome, and in the disease associated with the m.3243A>G variant. The 2025 European guideline includes, in its table of genetic aetiologies of hypoparathyroidism, other entities in which hypoparathyroidism is a finding within a dominant multisystem picture and which are therefore covered here in the differential diagnosis and not as entities in their own right: DiGeorge syndrome 2, due to partial monosomy of 10p14; CHARGE syndrome, due to CHD7 variants; Kabuki syndrome, due to KMT2D variants; Pearson syndrome, due to a large single mitochondrial DNA deletion; mitochondrial trifunctional protein and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiencies, due to HADHA and HADHB variants; medium-chain acyl-CoA dehydrogenase deficiency, due to ACADM variants; and Smith-Lemli-Opitz syndrome, due to DHCR7 variants [34]. Finally, primary hypomagnesaemia with secondary hypocalcaemia, due to TRPM6 variants, enters this article as an obligatory mimic, because severe hypomagnesaemia blocks the synthesis and release of parathyroid hormone and makes the picture biochemically indistinguishable from true hypoparathyroidism, although reversible with magnesium replacement [36].

2. Molecular Genetics and Pathophysiology

2.1 The parathyroid hormone axis and the points where genetics interrupts it

Parathyroid hormone is the main endocrine regulator of extracellular calcium and phosphate. The PTH gene, at 11p15.3, encodes pre-pro-parathyroid hormone, processed by the parathyroid chief cells into the 84-amino-acid hormone; this acts through the PTH1R receptor and raises serum calcium by mobilising bone through the RANKL/OPG axis, increasing distal tubular calcium reabsorption through the TRPV5 channel, reducing proximal tubular phosphate reabsorption and inducing renal 1-alpha-hydroxylase CYP27B1, which generates 1,25-dihydroxyvitamin D [37]. Calcium sensing is performed by the receptor encoded by the CASR gene, at 3q13.33-q21.1, a dimeric family C G protein-coupled receptor expressed in the parathyroid chief cells and the renal tubule, which reads the extracellular ionised calcium concentration and sets the set point: a rise suppresses parathyroid hormone secretion and increases urinary calcium excretion [30]. The receptor is also expressed in the collecting duct, where it protects against hypercalciuria-mediated nephrocalcinosis by favouring urinary acidification and water excretion, which explains why loss of this protective effect worsens the renal consequences of its overactivation [30]. Coupling of the receptor to phospholipase C-beta, which generates inositol trisphosphate and diacylglycerol, is mediated by the alpha-11 subunit of heterotrimeric G proteins, encoded by the GNA11 gene at 19p13.3 [8].

Genetics interrupts this axis at five distinct points, and the distinction is what organises differential diagnosis and treatment. The first is gland formation, impaired in the absence of the transcription factors required for development of the third and fourth pharyngeal pouches. The second is hormone synthesis or structure. The third is sensor calibration, shifted downwards by gain-of-function variants of CASR and GNA11, so that the hormone is suppressed at calcium concentrations that should stimulate it. The fourth is immune destruction of the already formed gland. The fifth is bioenergetic or metabolic failure of the parathyroid cell, in mitochondrial cytopathies and in severe hypomagnesaemia. The latter deserves to be separated from the others because the defect is not parathyroid: severe hypomagnesaemia blocks the synthesis or release of parathyroid hormone and, in its presence, administration of parathyroid hormone cannot raise serum calcium, so that the hypocalcaemia results from low parathyroid hormone combined with some form of end-organ resistance [36].

2.2 Failures of gland development

GCM2, at 6p24.2, encodes a nuclear transcription factor with a conserved GCM DNA-binding motif at the amino terminus, which acts as the master regulator of parathyroid development and of parathyroid hormone gene expression [38]. The predicted protein has 506 amino acids and contains, in addition to the GCM motif, a PEST-type sequence and a nuclear targeting sequence, and the 3' untranslated region of the transcript contains two messenger RNA instability domains, which suggests that these transcripts are unstable in vivo; reverse transcription amplification detected expression in kidney and fetal brain [39]. A negative observation important for the interpretation of laboratory results comes from analysis of genomic DNA from 17 affected members of 10 families with isolated hypoparathyroidism and from 10 sporadic patients, in which nine single-nucleotide changes were identified — three in the 5' untranslated region and six in exon 5 — leading to non-synonymous changes: the variant proteins had normal size, nuclear localisation and transactivation function when expressed in HEK293 cells, the alleles did not segregate with the disease and many of the substitutions were present in DNA from unrelated normal individuals, so they were polymorphisms; the authors concluded that GCM2 variants appear to be an uncommon cause of isolated hypoparathyroidism, although the variety of polymorphisms suggests that variant alleles may have a role in determining parathyroid function [39]. The direction of the variant's effect entirely determines the phenotype: loss-of-function alleles impair gland formation and hormone production and cause familial isolated hypoparathyroidism, whereas activating alleles clustered in a C-terminal inhibitory domain promote parathyroid cell proliferation and cause familial isolated hyperparathyroidism, listed as hyperparathyroidism 4 (OMIM 617343) [38]. The most informative experimental demonstration comes from the animal model: Gcm2-deficient mice have no parathyroid glands but, unlike mice deficient in the parathyroid hormone receptor, are viable and fertile and have only a mildly abnormal bone phenotype, with hypocalcaemia, hyperphosphataemia and increased urinary calcium excretion without renal failure; despite the absence of glands, they have serum parathyroid hormone concentrations identical to those of normal animals, as do parathyroidectomised normal animals, and expression and ablation studies identified the thymus, where the homologue Gcm1 is expressed, as an additional, regulatable source of parathyroid hormone [4]. The finding suggests the existence of an auxiliary calcium-regulating mechanism in the absence of parathyroids, whose human relevance has not been established.

X-linked hypoparathyroidism illustrates the concept of position effect. The linkage region at Xq26-q27 contains only three genes — ATP11C, U7snRNA and SOX3 — and sequencing of all three revealed no changes [5]. Detailed characterisation identified a gene-free deletion of 23 to 25 kb, replaced by an insertion of about 340 kb originating from 2p25 containing a segment of the SNTG2 gene without an open reading frame, with the telomeric breakpoint about 67 kb downstream of SOX3 and the centromeric breakpoint within a repetitive sequence [5]. The probable consequence is altered SOX3 expression through a position effect, a hypothesis supported by the demonstration, by in situ hybridisation, of Sox3 expression in developing parathyroid tissue of mouse embryos between days 10.5 and 15.5 post coitum. The practical implication is direct: in a male with isolated hypoparathyroidism of neonatal onset and a family history compatible with X-linked transmission, sequencing of the candidate genes will be normal and only analysis of structural rearrangements of Xq27.1 finds the cause.

GATA3, at 10p14, encodes a dual zinc finger transcription factor of the GATA family that binds the consensus motif AGATAG, including the enhancers of the T-cell receptor alpha and delta chains; it drives differentiation of type 2 helper T lymphocytes, coordinates transcriptional activation of macrophages and IL-33-dependent metabolic reprogramming, and is required for normal development of the parathyroids, inner ear and kidney [40]. A single functional copy is not sufficient, so heterozygous loss of function or deletion causes HDR syndrome; the ClinGen dosage curation assigns GATA3 haploinsufficiency the highest level of evidence, with a score of 3 [40]. The defect is therefore one of dosage of a developmental transcription factor and not enzymatic, and the downstream clinical consequence is failure of parathyroid hormone secretion with hypocalcaemia, added to structural maldevelopment of the cochlea and kidney. A finding that complicates this simple reading is the observation of Bernardini and colleagues, in a 14-month-old girl with the triad associated with psychomotor delay, facial dysmorphism, bilateral cleft lip and palate, tetralogy of Fallot and cutaneous syndactyly of the toes, in whom array comparative genomic hybridisation identified a 6.5 Mb deletion of 10p15.3-p15.1 and simultaneously a 1.9 Mb duplication of 10p15.1-p14 that included GATA3 and adjacent regions, both de novo, with real-time PCR confirmation of the two-fold increase in copy number and no sequence change; the authors suggested that both deletion and duplication of GATA3 may lead to a similar phenotype [28]. The HDR critical region maps distal to the DiGeorge syndrome region at 10p13-p14, and hemizygosity of a proximal region of 10p causes heart defects and T-lymphocyte deficiency whereas that of a more distal region causes hypoparathyroidism, deafness and renal dysplasia, which makes HDR a contiguous gene syndrome when it results from a terminal deletion [28].

TBX1, at 22q11.21, encodes a T-box developmental regulator that drives pharyngeal arch segmentation, development of the cardiac outflow tract and formation of the craniofacial musculature, and acts upstream of the formation of the thymus and parathyroids from the third pharyngeal pouch; it is considered the main contributor to the cardiac, palatal, thymic and parathyroid manifestations of the 22q11.2 deletion [41]. The molecular mechanism is not only loss of function: truncating variants remove the nuclear localisation signal and the transactivation domain, but three missense variants act through gain of function, possibly by stabilising the complex between the dimer and DNA, and produce the same phenotype, so that both insufficient and excessive TBX1 activity are pathogenic [41]. A 5' untranslated region variant that doubles translation efficiency has been described as a possible functional equivalent of a gene duplication. The ClinGen dosage curation assigns isolated TBX1 only haploinsufficiency level 1, with little evidence of dosage pathogenicity, and triplosensitivity 0, in the review of 11 June 2024, which means that an isolated heterozygous deletion or a truncating TBX1 variant should not be assumed to be fully penetrant [41]. The 22q11.2 deletion is a contiguous gene syndrome and the full phenotype is not a monogenic TBX1 disease; loss of TBX1 is linked mainly to the heart defects, and proximal deletions that include it to lower CD3 and CD4 counts [41].

FAM111A, at 11q12.1, encodes a cell cycle-regulated nuclear trypsin-like serine protease that binds single-stranded DNA and cleaves covalent DNA-protein crosslinks during DNA synthesis — including topoisomerase 1 adducts and PARP1-DNA complexes trapped by PARP inhibitors —, protecting replication forks from stalling; it has a PIP box, is required for PCNA loading at replication sites and promotes S-phase entry, and restricts SV40 polyomavirus and vaccinia virus, partly by disorganising the nuclear pore complex through its proteolytic activity [33]. It is expressed in bone and parathyroid glands [17]. The disease mechanism is stated as unknown by the GeneReviews chapter, which records the proposal of a dominant gain of function, with the supporting argument being negative: no deletions or truncating variants have been described in individuals with osteocraniostenosis or Kenny-Caffey syndrome, and null alleles exist in reference population databases; all associated variants are substitutions or deletions of a single amino acid, and experimental work showed that the proteolytic activity of FAM111 impairs cellular fitness and that this effect is amplified by the gain-of-function variants observed in human disease [17, 33]. The practical consequences are two: a truncating variant or a whole-gene deletion found on a panel does not have the evidence base of the described missense variants, and the biochemical deficit actually treated is downstream and endocrine — primary hypoparathyroidism with hypocalcaemia and hyperphosphataemia — and not the protease abnormality.

TBCE, at 1q42.3, encodes tubulin folding cofactor E, which acts in the second step of the folding pathway, capturing beta-tubulin from the cofactor D complex and, with cofactor C, releasing polymerisation-competent alpha-beta heterodimers; it also regulates heterodimer dissociation and maintains the neuronal microtubule network and the mitotic spindle [22]. Loss of function reduces polymerised alpha-tubulin, delays microtubule repolymerisation after nocodazole washout and produces disorganised mitotic spindles in patient fibroblasts, with TBCE protein reduced in a manner consistent with rapid degradation of the mutant product [22]. The endocrine consequence is congenital aplasia or hypoplasia of the parathyroids, with parathyroid hormone deficiency, hypocalcaemia and hyperphosphataemia, and the neurological consequence is failure to maintain the neuronal microtubule network. Padidela and colleagues added in 2009 a dimension extending beyond the parathyroid: in six children from four unrelated Middle Eastern families, all homozygous for the founder allele, brain imaging showed hypoplasia of the anterior pituitary, infundibulum and corpus callosum, reduced white matter volume, delayed myelination and dilated lateral ventricles; four of five tested had low growth hormone and subnormal cortisol responses to glucagon, all six had low plasma IGF1 and the three males had features suggestive of hypogonadotrophic hypogonadism, despite satisfactory testosterone responses to chorionic gonadotrophin [19]. The authors proposed that TBCE has a role in the development of the anterior pituitary, corpus callosum and white matter, in addition to the parathyroids.

The 2025 French protocol places the X-linked hypoparathyroidism rearrangement at Xq27.3, both in the text and in the synoptic table of causes, whereas OMIM, which describes the original molecular characterisation, places it at Xq27.1, the cytoband where SOX3 lies; the OMIM location is kept here, as it is that of the primary source [5, 12]. The same protocol describes GCM2 as having two successive functions: in fetal life, embryogenesis and maintenance of parathyroid cells; later, regulation of parathyroid hormone synthesis through control of calcium-sensing receptor expression [12].

2.3 Defects of the hormone itself

Pathogenic PTH variants cause familial isolated hypoparathyroidism 1, with three molecular mechanisms described: impaired synthesis or processing, as with signal peptide variants that block translocation; induction of parathyroid cell apoptosis by a misfolded product; and secretion of a complete but biologically inactive parathyroid hormone molecule [37]. The apoptotic mechanism has been demonstrated experimentally: in HEK293 cells transfected with pre-pro-parathyroid hormone cDNA carrying the p.(Cys18Arg) variant, the expressed mutant hormone was retained inside the cell, predominantly in the endoplasmic reticulum, with consequent apoptosis and marked overexpression of the reticulum stress response proteins BIP and PERK and of the pro-apoptotic transcription factor CHOP; in the presence of the pharmacological chaperone 4-phenylbutyric acid, intracellular accumulation decreased and normal secretion was restored, which led the authors to propose endoplasmic reticulum stress-induced cell death as the mechanism of autosomal dominant hypoparathyroidism [1]. The third mechanism has a diagnostic consequence of the first order: measured parathyroid hormone may be high and the child wrongly labelled as having pseudohypoparathyroidism [37]. Nusynowitz and Klein described in 1973 a 20-year-old student with hypocalcaemia, hyperphosphataemia, chronic tetany and cataracts, with normal to high immunoreactive parathyroid hormone concentrations and a demonstrated renal response to exogenous parathyroid hormone, and proposed a defect in the conversion of pro-parathyroid hormone into the active form; when Ahn and colleagues restudied the family in 1986, the proband showed markedly reduced or absent plasma parathyroid hormone in assays specific for the mid-region or carboxyl terminus despite symptomatic hypocalcaemia, and an affected son also had low parathyroid hormone, so that the case became an example of autosomal dominant hypoparathyroidism [1]. The resolution of this scenario is a parathyroid hormone 1-34 infusion test with measurement of nephrogenous cyclic AMP: an intact nephrogenous response distinguishes a bioinactive hormone variant from true pseudohypoparathyroidism [37].

2.4 Altered calibration of the calcium sensor

CASR produces three clinically distinct diseases, the confusion of which causes real harm. Heterozygous loss of function causes familial hypocalciuric hypercalcaemia type 1, with lifelong mild to moderate hypercalcaemia, mild hypermagnesaemia, normal or mildly raised parathyroid hormone and inappropriately low urinary calcium excretion, mostly asymptomatic; biallelic loss of function causes neonatal severe hyperparathyroidism, with serum calcium typically between 3.5 and 5.0 mmol/l against a normal range of about 2.10 to 2.55, bone demineralisation with fractures, respiratory distress and failure to thrive, and death without treatment; and gain of function causes autosomal dominant hypocalcaemia type 1 [30]. More than 150 loss-of-function variants are catalogued, more than 85% of them missense, and more than 70 gain-of-function variants, about 95% missense [30]. The first two diseases belong to the group of familial hypocalciuric hypercalcaemia and neonatal hyperparathyroidism; here the third mechanism is what matters. Gain of function lowers the set point, so that parathyroid hormone is suppressed with normal calcium and the kidney wastes calcium, producing hypocalcaemia with hypercalciuria [30]. A subgroup with particularly marked activation also has the phenotype of Bartter syndrome type V, with hypokalaemic alkalosis, renal salt wasting, hyperreninaemia and hyperaldosteronism [30]. The relationship between the degree of activation and the Bartter phenotype has been quantified: the four CASR variants described with hypocalcaemia and Bartter features were all strongly activating, with a median effective concentration below 1.5 mmol/l, whereas the other variants causing autosomal dominant hypocalcaemia without Bartter had values between 1.5 and 3 mmol/l [7]. The variant NM_000388.4:c.374T>C, NP_000379.3:p.(Leu125Pro), identified de novo in a boy with severe hypocalcaemia and Bartter phenotype, was more potent than any previously described gain-of-function variant, with a median effective concentration about one third of normal, and the authors proposed that it reduces sodium chloride reabsorption in the cortical thick ascending limb of the loop of Henle sufficiently to cause renal salt wasting with secondary hyperaldosteronism and hypokalaemia [7, 31]. An animal model corroborates the extrarenal dimension of the phenotype: the Nuf mouse, identified by opaque flecks in the lens nucleus in a screen for ocular mutants, shows ectopic calcification, hypocalcaemia, hyperphosphataemia, cataracts and inappropriately reduced plasma parathyroid hormone, due to an activating missense variant in the murine orthologue of CASR; ectopic calcification and cataract formation were milder in heterozygotes, which the authors interpreted as requiring these abnormalities to be sought in patients with activating variants [7].

GNA11 produces two germline disorders with opposite mechanisms, both autosomal dominant. Heterozygous loss of function makes the receptor pathway less sensitive to extracellular calcium and causes familial hypocalciuric hypercalcaemia type 2, and gain of function makes it more sensitive and causes autosomal dominant hypocalcaemia type 2 [8]. Both entities are rare: probably causal GNA11 variants were found in less than 1% of more than 1200 probands tested for hyper- or hypocalcaemia [8]. In a family with the variant NM_002067.5:c.179G>T, NP_002058.2:p.(Arg60Leu), affected members lacked the hypercalciuria and hypomagnesaemia typical of CASR-related autosomal dominant hypocalcaemia, and had short stature, with mild postnatal growth failure without evidence of growth hormone deficiency and significantly shorter stature than unaffected relatives [8, 31, 32]. This dissociation is clinically useful, because it suggests that hypercalciuria is not obligatory in autosomal dominant hypocalcaemia type 2 and that the decision to restrict treatment must be made with the patient's own urinary data.

One aspect of GNA11 requires explicit separation in counselling: post-zygotic mosaic activating variants cause cutis marmorata telangiectatica congenita, and Orphanet lists somatic GNA11 in phakomatosis pigmentovascularis of the cesioflammea and cesiomarmorata types, in diffuse capillary malformation with overgrowth and in anastomosing haemangioma; somatic variants at codon 209 occur in 32% of primary uveal melanomas, 57% of metastases and 7% of blue naevi [8]. These variants are acquired: a germline variant causing familial hypocalciuric hypercalcaemia type 2 or autosomal dominant hypocalcaemia type 2 does not imply a risk of uveal melanoma, and a tumour result at codon 209 says nothing about calcium disorders.

2.5 Autoimmune destruction of the gland

AIRE, at 21q22.3, encodes the autoimmune regulator, a chromatin-binding transcriptional regulatory protein expressed mainly by medullary thymic epithelial cells. It interacts selectively with histone H3 unmethylated at lysine 4, unphosphorylated at threonine 3 and unmethylated at arginine 2 — thus acting as a sensor of the H3 modification state — and induces the expression of thousands of tissue-restricted self-antigens, normally confined to peripheral organs, which are presented on MHC class I and II molecules to thymocytes traversing the medulla, so that autoreactive clones are eliminated by negative selection [42]. It also regulates the differentiation of the medullary thymic epithelial cells themselves, the medullary accumulation of dendritic cells and the development of regulatory T lymphocytes through the chemokine XCL1, and the production of CCR4 and CCR7 ligands that coordinates thymocyte maturation and migration [42]. Loss of this function allows autoreactive T lymphocytes to escape, which infiltrate organs and drive autoimmune destruction.

The downstream effector mechanism is now defined. Patients have excessive interferon gamma responses in blood and in all autoimmunity-affected tissues examined, with increased CXCL9 and phosphorylated STAT1, and Aire-deficient mice show the same pattern; ablation of the Ifng gene or blockade of JAK-STAT signalling in these animals normalises the interferon gamma response and prevents T-lymphocyte infiltration and organ damage [42]. The parathyroid autoantigen has been identified as NALP5, also called NLRP5, and autoantibodies against it accompany the hypoparathyroidism of the syndrome [42, 43]. Antibodies against the calcium-sensing receptor may also affect parathyroid function, but there is currently no clinically validated reference assay to measure them, so testing for them is not a test usable in practice and their role requires further research [43]. The endocrine consequence is autoimmune destruction of the glands: parathyroid failure with hypocalcaemia and inappropriately low parathyroid hormone, adrenocortical failure with glucocorticoid and mineralocorticoid deficiency, gonadal failure and, less frequently, type 1 diabetes and hypothyroidism, added to a functional defect of antifungal immunity that allows chronic mucocutaneous candidiasis [42].

Two molecular particularities have direct diagnostic consequences. The first is the deep intronic founder variant NM_000383.4:c.1504-818G>A, which causes the disease by activating a cryptic splice site and including a 109 base-pair pseudoexon with a frameshift; it was found in 17 of 104 patients studied prospectively, 16%, belonging to 14 families without biallelic exonic or flanking intronic variants, 15 of them of Puerto Rican ancestry, and it is not covered by exome sequencing or by current panels, requiring genome sequencing or a targeted assay [42]. The second is the existence of monoallelic dominant-negative missense variants in the PHD1, PHD2 or SAND domains, which cause milder, later-onset disease with the second allele normal, so that the report of a single heterozygous AIRE variant is not automatically a carrier state [42].

2.6 Mitochondrial and metabolic forms

Hypoparathyroidism arises in mitochondrial cytopathies with large mitochondrial DNA deletions, particularly Kearns-Sayre syndrome, where it is part of a set of endocrine abnormalities of which the most common are diabetes mellitus and hypogonadism, with amenorrhoea and delayed puberty, while hypoparathyroidism, thyroid abnormalities and hyperaldosteronism are less frequent [44]. The presumed mechanism is bioenergetic failure of the secretory cell, and the clinical observation that most supports this reading is the constant association with renal tubular dysfunction and hypomagnesaemia: an 18-year-old girl was described with hypoparathyroidism and renal tubular dysfunction associated with inappropriate hyperexcretion of magnesium and potassium, and another hypoparathyroid patient presented at five years with recurrent episodes of carpopedal spasm due to persistent hypomagnesaemia and hypocalcaemia with increased fractional urinary excretion of magnesium and calcium [44]. Four unrelated children with Kearns-Sayre syndrome presented first with hypoparathyroidism and deafness, and hypocalcaemic tetany was well controlled with low doses of 1,25-dihydroxycolecalciferol, with hypomagnesaemia in two of three patients [44]. Renal tubular acidosis is another manifestation, with possible glycosuria and generalised aminoaciduria, and some presentations have resembled Bartter or Lowe syndrome [44].

Primary hypomagnesaemia with secondary hypocalcaemia is caused by biallelic variants of TRPM6, a gene expressed in the intestine and in distal tubule cells, which encodes an ion channel for magnesium; the primary defect is impaired intestinal uptake, and a lowered renal threshold causing significant renal leak contributes and generally prevents serum magnesium from fully normalising during supplementation [36]. About 40 variants have been identified. Because severe hypomagnesaemia blocks the synthesis or release of parathyroid hormone and, in its presence, administration of parathyroid hormone does not raise serum calcium, the hypocalcaemia is secondary to low parathyroid hormone combined with end-organ resistance [36]. This is why measuring magnesium at the same time as calcium and parathyroid hormone is not a refinement but an obligatory step: hypomagnesaemic hypocalcaemia mimics the biochemical picture of genetic hypoparathyroidism but resolves rapidly with magnesium replacement, unlike the persistent hypocalcaemia of the parathyroid forms [22].

2.7 Variant spectrum and normalisation of nomenclature

The literature in this area widely uses historical protein residue notations, without transcript or version, which requires explicit conversion. The following table brings together the most cited variants, with Human Genome Variation Society (HGVS) notation validated in VariantValidator against the MANE (Matched Annotation from NCBI and EMBL-EBI) transcript and the GRCh38 reference genome.

Three nomenclature notes follow from this validation [31]. The historical notation "C18R" for PTH refers to the same residue as the MANE transcript notation, because both number the pre-pro-hormone including the signal peptide, so in this case there is no numbering shift. For FAM111A, the MANE Select transcript is NM_001312909.2 and not NM_022074.4 used by GeneReviews and the founding literature, although the numbering at cDNA and protein level is identical in both, and version NM_022074.5, which appears in some citations, does not exist. The GNA11 LRG_1111 record is in pending status, so the reference sequence of that record may still change, which does not affect RefSeq-based notation. Three entities in this article have no possible HGVS notation with the available sources and should be described rather than written as a variant: the intragenic deletion of about 8 kb of exons 1 to 4 of GCM2 in the Central American family, the 2 base-pair deletion in exon 2 of GATA3 described by Ferraris in 2009 and the Xq27.1 deletion-insertion with 2p25.3 in X-linked hypoparathyroidism, whose breakpoints were characterised by cytogenetic techniques and not at nucleotide level.

Comparison between the causal attribution of the primary sources and the aggregate ClinVar classification reveals discordances that should be declared in the report and in the conversation with the family, and not resolved by omission. The GCM2 variant NM_004752.4:c.187G>A, p.(Gly63Ser), described as causal in the homozygous state in two Moroccan siblings, has conflicting classifications in ClinVar; GNA11 NM_002067.5:c.542G>A, p.(Arg181Gln), listed by OMIM as causing autosomal dominant hypocalcaemia type 2, is classified as of uncertain significance; the deep intronic AIRE variant, despite functional demonstration of pseudoexon inclusion, has conflicting classifications; the dominant AIRE variant p.(Gly228Trp) has no assigned classification, so its pathogenicity rests on the functional literature; and NM_000383.4:c.1336T>G, p.(Cys446Gly), one of the dominant AIRE variants, is classified as of uncertain significance, with the evidence coming from functional and animal model studies [45]. The GATA3 variant p.(Cys288Tyr), described in a 52-year-old Japanese man with HDR syndrome and membranoproliferative glomerulonephritis and identified in four other affected relatives over three generations, has no ClinVar record; the notation NM_001002295.2:c.863G>A can be deduced unambiguously from the protein designation, because cysteine and tyrosine differ only at the second base of the codon, and was confirmed in VariantValidator, but should be presented as inferred and not as the published notation [28, 31, 45]. Two numbering pitfalls add to this: the GCM2 variant NM_004752.4:c.1400del has no ClinVar record, and the dominant AIRE variants have different numbering in the murine and human models — p.(Val303Met), p.(Cys313Tyr) and p.(Cys442Gly) in the mouse correspond to p.(Val301Met), p.(Cys311Tyr) and p.(Cys446Gly) in humans —, so direct transposition of numbers from the model to the patient is an error. For TBX1, the 2026 publication describing hypoparathyroidism with a point variant without 22q11.2 deletion uses transcript NM_080647, which is not MANE Select; the same genomic change is written NM_001379200.1:c.1036G>C, p.(Asp346His) on the MANE transcript, and the variant itself was classified as likely pathogenic by one laboratory in 2020 and as of uncertain significance by another in 2026, a discordance that the authors of the report point out [45, 46].

2.8 Inheritance, penetrance and expressivity

Two entities in this article have two documented inheritance patterns in the same gene, and both should be recorded. For PTH, OMIM lists phenotype 146200 as autosomal dominant and autosomal recessive, depending on the variant: signal peptide variants with endoplasmic reticulum retention and an apoptotic effect segregate dominantly, and splice site variants and some signal peptide variants in the homozygous state in consanguineous families segregate recessively [1]. For GCM2, most families are recessive, due to biallelic loss-of-function alleles that abolish DNA binding or transactivation, but a minority are dominant, due to last-exon frameshift alleles that act as dominant negatives and inhibit the normal protein; OMIM lists phenotype 618883 as dominant and recessive, whereas UniProt and most GenCC submitters record it only as recessive, a divergence that should be declared when interpreting a laboratory report [4, 38].

Expressivity is markedly variable in practically all entities, and intrafamilial variability is the rule rather than the exception. In autosomal dominant hypocalcaemia type 1, in a three-generation family with an activating variant, all affected members had marked hypocalcaemia, but some untreated cases had seizures in infancy while others were largely asymptomatic from birth to adulthood [7]. In a Japanese family with severe autosomal dominant hypocalcaemia, the proband presented with a seizure on the sixth day of life and the older brother and mother had seizures and tetany, but other members had no seizures despite severe hypocalcaemia [7]. In a three-generation Japanese family with the activating variant p.(Ser820Phe), five of six patients were asymptomatic and only one had a history of seizures [7]. In HDR syndrome, expressivity varied between and within families in the Japanese series of nine families, and of two families without detected GATA3 abnormalities one had typical features and the other atypical features, with retinitis pigmentosa and severe growth failure added to the triad [28]. In the FAM111A spectrum, GeneReviews states that there is no established genotype-phenotype correlation and that the genotype does not predict Kenny-Caffey syndrome rather than osteocraniostenosis, which must be stated clearly when the variant is found prenatally [17].

2.9 Allelic disorders and modifiers

Each gene in this article has allelic disorders whose confusion alters treatment. For CASR, the two directions of effect produce opposite diseases, and treating one as if it were the other causes predictable iatrogenic harm [30]. For GCM2, the same gene causes hypoparathyroidism through loss of function and familial isolated hyperparathyroidism through gain of function, the latter with earlier onset and a more aggressive course than sporadic primary hyperparathyroidism in the published series, including described parathyroid carcinoma [38]. For GNA11, loss of function causes familial hypocalciuric hypercalcaemia type 2 and gain of function autosomal dominant hypocalcaemia type 2 [8]. For FAM111A, Kenny-Caffey syndrome and osteocraniostenosis are allelic and may be considered a family of skeletal dysplasias, with similar phenotypes but very different severity [47]. For TBCE, three distinct entities that should not be merged: Sanjad-Sakati syndrome, Kenny-Caffey syndrome type 1 and a progressive encephalopathy with amyotrophy and optic atrophy (OMIM 617207) without hypoparathyroidism, described in six individuals from four unrelated families from an area of southern Italy carrying the hypomorphic allele c.464T>A, p.(Ile155Asn) [22]. For TBX1, in addition to the syndromic forms, congenital athymia with haploinsufficiency has been described, and rare functional variants occur in a small fraction of cases of non-syndromic tetralogy of Fallot [41]. For GATA3, phenotypic expansion continues to be described: Meiss and colleagues reported in 2026 a 10-year-old girl with a pathogenic deletion of about 1.45 Mb encompassing the whole gene who presented with bilateral sensorineural deafness, a renal cyst and oligoarticular juvenile idiopathic arthritis, mentioning a previous HDR patient with psoriatic juvenile idiopathic arthritis, which raises, without establishing, a susceptibility to early-onset autoimmune arthritis [40]. The GeneReviews chapter on FAM111A explicitly states that no phenotypes are known to be associated with germline variants of this gene beyond those described in the article, which is a useful negative when the gene appears on a broad panel [33].

3. Clinical Spectrum and Manifestations by System

3.1 What hypocalcaemia does, by age

The predominant manifestations are those of hypocalcaemia. In the acute setting there is neuromuscular irritability, with perioral paraesthesiae, tingling of the fingers and toes and spontaneous or latent tetany, and there may be generalised tonic-clonic seizures and laryngeal spasm [1]. In the chronic setting, hypocalcaemia may be asymptomatic and become apparent only after routine tests, or manifest with mild neuromuscular irritability, basal ganglia calcification, extrapyramidal disorders, cataracts, alopecia, abnormal dentition, coarse brittle hair, intellectual disability or personality changes [1]. Biochemically, there is low serum calcium and raised serum phosphorus with normal renal function; immunoreactive parathyroid hormone is low or undetectable, except in parathyroid hormone resistance, where it may be at the upper limit of normal or raised; circulating 1,25-dihydroxyvitamin D is usually low or low-normal; 24-hour urinary calcium excretion is reduced, nephrogenous cyclic AMP is low and renal tubular phosphorus reabsorption is increased [1].

In the newborn and infant, the picture is dominated by neonatal tetany, carpopedal spasm, tremor, laryngospasm with stridor and hypocalcaemic seizures [37]. In the older child and adolescent, perioral and acral paraesthesiae, muscle cramps, Chvostek and Trousseau signs and QT interval prolongation predominate [37]. Presentation in adulthood occurs and should not be attributed by default to an acquired autoimmune cause: two patients with isolated sporadic hypoparathyroidism, one severely symptomatic since infancy and the other with mild symptoms at 18 years, had de novo CASR gain-of-function variants, and the authors explicitly concluded that even patients presenting in adulthood without affected relatives should not be assumed to have an autoimmune aetiology [7]. Age at onset has quantified discriminatory value: in the Chinese cohort of 173 patients with childhood-onset hypoparathyroidism, the age at onset of patients with a variant found was significantly earlier than that of the others, with a median and interquartile range of 2.8 years (0.1 to 9.6) versus 13.0 years (8.8 to 15.0), with p below 0.001 [35].

The 2025 French protocol adds four elements of natural history with direct application to the genetic forms. The first is that, in children, there are two periods of high risk of symptomatic hypocalcaemia, because calcium requirements rise with rapid growth: early childhood, up to 2 years, and puberty, with its growth spurt; fever also increases requirements and can decompensate a hitherto stable and unrecognised hypoparathyroidism [12]. The second is that congenital forms do not necessarily become apparent in the neonatal period: hypocalcaemia may become symptomatic later in childhood or in adulthood, when environmental factors add up, and paucisymptomatic forms are discovered incidentally on a routine test, often years late; in women, pregnancy may be the circumstance of discovery [12]. The third is the range of non-specific chronic manifestations: in addition to paraesthesiae, tetany, cramps, diffuse pain, exercise fatigability and QT interval prolongation, the protocol describes a sensation of brain fog, attention and school performance problems, depression, anxiety, sleep disturbance, memory loss, agitation and irritability in adults and older children, and a sensation of "internal vibrations" reported by some patients [12]. The fourth is dental chronology: enamel hypoplasia only arises if hypocalcaemia is present during mineralisation, which is prenatal for the deciduous teeth and postnatal for the permanent ones, so that the pattern of lesions dates the onset of hypocalcaemia; it results in greater susceptibility to caries and post-eruptive wear and, more rarely, in hypodontia, microdontia and short roots, and any orthodontic treatment requires specific monitoring [12].

The radiological signs are not pathognomonic and are subjective. The absence of remodelling due to lack of parathyroid hormone produces thick cortices in the long bones and increased trabecular length; in children, dense metaphyseal bands, thickening of the cranial vault and sometimes growth arrest lines are observed, and in adults densitometry shows increased mineral density, especially lumbar [12]. In Kearns-Sayre syndrome, the endocrine manifestations, including hypoparathyroidism, may precede the neurological ones, so that hypoparathyroidism may be the entry point to the diagnosis of the mitochondrial cytopathy [12].

3.2 Complications of the disease and its conventional treatment

A substantial part of chronic morbidity results from the disease and another part from conventional treatment, and the two are difficult to separate in observational studies. The Second International Workshop brought together the median prevalences of complications in the studies reviewed: cataracts in 17%, nephrocalcinosis or nephrolithiasis in 15%, renal failure in 12%, infection in 11%, seizures in 11%, depression in 9% — the text of the document states 12% and the table 9%, a divergence the document itself does not resolve —, ischaemic heart disease in 7% and arrhythmias in 7% [27]. A cross-sectional study of 58 patients with chronic hypoparathyroidism, with a mean age of 52.6 ± 16.4 years and a female-to-male ratio of 3.5, who underwent physical examination, biochemistry, slit-lamp examination, cranial computed tomography and renal ultrasound, found basal ganglia calcification in 55%, cataracts in 62%, urolithiasis in 12% and renal failure in 17%, with independent association of complications with disease duration above 15 years (adjusted odds ratio 43.1; 95% confidence interval 2.63 to 703.06; p = 0.008) and with poor treatment adherence (adjusted odds ratio 8.04; 95% confidence interval 1.52 to 42.42; p = 0.014) [48]. The very wide confidence interval of the first odds ratio reflects the small number of patients and does not allow the point estimate to be taken as the true magnitude.

Median prevalences say how many patients have each complication, but not how much the disease contributes to it; that second magnitude comes from the systematic review with meta-analysis of the International Task Force, which the 2024 Parathyroid Summit consensus reproduces as adjusted risk or odds ratios in adults with chronic hypoparathyroidism of any aetiology [43]. The two sets of numbers are complementary and should be read side by side.

Ordering by magnitude of effect reverses the ordering by frequency: cataracts are the most prevalent complication and the fourth in relative risk, whereas renal failure is third in prevalence and first in relative risk. The risk ratio of 1.80 for all-cause mortality coexists with the null result of the Danish national registry of 180 patients with non-surgical hypoparathyroidism and 540 controls, discussed in section 9.1, and both observations are recorded rather than choosing one: the meta-analysis pools mainly postsurgical disease and the Danish registry measures only non-surgical disease, which is that of this article.

Two numbers from this synthesis apply directly to the genetic forms, because they explicitly discriminate surgical from non-surgical origin. The first is that renal complications affect about one third of patients with hypoparathyroidism. The second is that the risk of chronic kidney disease is about three times that of the reference population in postsurgical cases and about six times in non-surgical cases, that is, roughly double in the forms that include all the genetic ones; the proposed mechanism is the increased filtered calcium load in the absence of parathyroid hormone-mediated tubular reabsorption, aggravated by conventional therapy itself, and in autosomal dominant hypocalcaemia the hypercalciuria is even more marked than in the other forms [43]. This risk differential is the strongest quantitative argument in favour of close renal surveillance in the patients in this article, covered in section 11.2.

Intracranial calcification has, in the same synthesis, a prevalence of 25% to 78% depending on the series, is associated with longer disease duration, hyperphosphataemia and extraskeletal calcification at other sites, such as the lens with cataracts, and does not appear to correlate with neurological symptoms, which supports acting on the calcium-phosphate product and not on the imaging finding [43]. As for the skeleton, the 2024 consensus reproduces the same values from the Canadian registry and the Swedish cohort that the European guideline cites — 35% osteoporosis in postmenopausal women, with 4% meeting both the densitometric criterion and that of a previous fragility fracture, three of nine men aged 50 years or over, a risk ratio of 1.55 (1.12 to 2.14) for vertebral fracture and of 0.70 (0.50 to 0.98) for hip fracture — and adds a study of 44 women with postsurgical hypoparathyroidism in which Genant grade II and III vertebral fractures were more frequent, 11.4% or 5 of 44, compared with predominantly grade I fractures in 6.8% or 3 of 44 controls; the panel's explicit conclusion is that the relationship between bone mineral density and fracture risk in this disease remains poorly understood and requires long-term prospective data [43].

The 2025 European guideline describes the increased risk of renal stones and renal complications; basal ganglia calcification as more frequent, varying with severity, aetiology or duration of treatment, and without affected patients appearing to have more neurological or musculoskeletal symptoms; extraskeletal calcification, including cataracts and nephrocalcinosis, generally linked to high phosphate and a raised calcium-phosphate product; an increased risk of infection with unclear mechanisms; an increased risk of depression, bipolar disorder and anxiety; and an increased cardiovascular risk that appears to rise with disease duration [34]. A study of 50 patients with chronic postsurgical hypoparathyroidism and 50 age- and sex-matched controls, with coronary computed tomography angiography, found coronary atherosclerotic plaques in 68% of patients versus 42% of controls (p < 0.01), with a mean patient age of 60 years (31 to 84), 86% women and a median disease duration of 12 years (5 to 49); patients had a lower estimated glomerular filtration rate (78 versus 83 ml/min; p = 0.04) and more frequently took antihypertensives (56% versus 36%; p = 0.05) [49]. These data concern postsurgical and not hereditary disease, and serve as a reference for the natural history of conventionally treated disease, not as an estimate of risk in the genetic forms, in which exposure begins in childhood and is therefore longer.

In the skeleton, bone mineral density is typically higher than expected, because the absence of parathyroid hormone reduces remodelling, but fracture risk is mixed. Swedish registry data, published after the guideline's systematic reviews, showed risk ratios of 0.93 for major osteoporotic fractures (95% confidence interval 0.69 to 1.26, not significant), 1.55 for vertebral fractures (1.12 to 2.14), 0.70 for hip fractures (0.50 to 0.98), 1.54 for a diagnosis of osteoporosis (1.21 to 1.95) and 0.69 for anti-osteoporotic medication (0.54 to 0.88) [34]. A Canadian registry found osteoporosis in 35% of postmenopausal women and in three of nine men aged 50 years or over, that is, 33.3% [34]. The combined reading is that the overall increase in density does not protect against the specific increase in vertebral fractures.

The 2025 French protocol brings together complication data that complete the above. In the eye, registry studies diverge for postsurgical hypoparathyroidism — no excess cataract risk in a Danish registry and an excess in another population —, but agree for non-surgical hypoparathyroidism, with an excess risk in a Korean national cohort and in a Danish study, which justifies early screening in the genetic forms; because accommodation depends on muscle contraction, any decline in visual acuity should be reassessed after hypocalcaemia has been corrected [12]. In the brain, basal ganglia calcification is mainly documented in the non-surgical forms, and a 2024 Danish study described structural changes on magnetic resonance imaging, independent of calcification and related to disease duration — reduced hippocampal and thalamic volume —, associated with brain fog and poorer quality of life, also in postsurgical disease [12]. Regarding phosphate, a Danish observational study in adults associated increased risk of death with a calcium-phosphate product from 2.62 mmol²/l² and a serum phosphate above 1.28 mmol/l, and episodes of hypercalcaemia were associated with more mortality, infections and cardiovascular and renal disease [12]. In the kidney, hypoparathyroidism is in itself associated with a risk of renal failure, and prolonged treatment with activated vitamin D analogues is associated with declining renal function, which makes the minimum effective dose a goal of renal protection and not merely of comfort [12]. Regarding quality of life, the protocol describes marked asthenia, episodes of distress, anxiety-depressive disorders and phobias, reduced physical activity and the perception, reported by most patients, that professionals underestimate the symptoms [12].

3.3 Familial isolated hypoparathyroidism

The presentation of familial isolated hypoparathyroidism is usually early and the picture is isolated, with no thymic, immune, renal, auditory or developmental component, which separates it from 22q11.2 deletions, HDR syndrome, autoimmune polyendocrinopathy type 1 and the mitochondrial syndromes [37]. In type 2, due to GCM2, most patients present in the first days or weeks of life with seizures, but one patient presented at one year and another at 25 years, and serum parathyroid hormone was undetectable in four patients in a series of eight families [4]. Development may be normal if hypocalcaemia is treated with calcium and vitamin D: in the Central American family, the proband, who presented with seizures at 5 weeks of life with calcium of 5.1 mg/dl, phosphorus of 9.8 mg/dl and undetectable intact parathyroid hormone, had no further seizures after treatment with calcitriol and supplemental calcium and reached all cognitive and developmental milestones appropriately, whereas a 22-year-old uncle in the same family, who had had seizures at 2 months and was presumed hypoparathyroid, lived in a long-term care institution unable to walk, speak or attend to daily needs [4]. The contrast between the treated niece and the untreated uncle, within the same family and with the same genotype, is the most direct illustration of what is at stake in early recognition. The same pattern appears in the Moroccan family: the proband presented at 5 years with episodes of falls, generalised stiffness, pallor, upward eye deviation and loss of consciousness lasting less than a minute over three days, with bilateral Chvostek sign, hypocalcaemia and hyperphosphataemia, and normalised with calcium and calcitriol; his 8-year-old sister had presented at 10 months with cardiorespiratory arrest associated with profound hypocalcaemia and, owing to poor treatment adherence, suffered repeated episodes of severe hypocalcaemia, followed by epilepsy, progressive microcephaly and severe neurological impairment, attributed by the authors to the initial anoxic episode [4]. Ultrasound did not detect parathyroid glands in either child.

The X-linked form presents with seizures in infancy in males, and no affected male reproduced in the families described [5]. Buchs reported in 1957 three brothers with neonatal tetany, and Teebi and colleagues described in 1992 a Bedouin family with four affected male siblings, including a set of triplets, whose mother had a brother who died in early childhood of unknown causes [5].

3.4 Autosomal dominant hypocalcaemia types 1 and 2

Autosomal dominant hypocalcaemia type 1 is associated with low or normal parathyroid hormone, and the distribution of severity has been quantified: about 50% of patients have mild or asymptomatic hypocalcaemia, about 50% have paraesthesiae, carpopedal spasm and seizures, about 10% have hypercalciuria with nephrocalcinosis or renal stones and more than 35% have ectopic and basal ganglia calcification [7]. The clinical face of this entity varies extremely within the same family, as the examples cited in section 2.8 show. In one series, of the 20 affected patients from six families originally diagnosed with isolated hypoparathyroidism, 11 had carpopedal spasm or seizures in childhood, two of them with basal ganglia calcification, one with seizures continuing into adult life, and the remaining nine had asymptomatic hypocalcaemia; 16 of the 20 also had hypomagnesaemia, and urinary calcium excretion was inappropriately within the normal range or high at the time of diagnosis [7]. What happened next in that series is the most important finding for practice: of 19 patients treated with oral vitamin D, serum parathyroid hormone became low or undetectable in 16 and nine developed hypercalciuria; renal calcification developed in eight of the nine hypercalciuric patients and renal impairment in seven of them, and both calcification and renal impairment developed in seven other patients during vitamin D therapy [7]. Lumbar bone mineral density was normal in four patients from two families but increased in three patients from another.

The long-term morbidity of this entity under conventional treatment has recently been described in a series of nine adults with genetically confirmed autosomal dominant hypocalcaemia type 1 from north-east England, followed between 2005 and 2024, with five women and ages between 24 and 57 years: 89% of cases were familial, all had persistent hypocalcaemia and 66% had hypomagnesaemia; renal involvement affected 78%, with nephrocalcinosis in 56%, nephrolithiasis in 67% and chronic kidney disease, and two patients from the same family progressed to end-stage renal failure and death [50]. Extrarenal manifestations included seizures, intracranial calcification, dental anomalies and neuropsychiatric symptoms, often persistent despite conservative strategies limiting calcium supplements after diagnosis, and no clear correlation was found between mean serum calcium and disease severity, which the authors interpret as substantial phenotypic variability [50]. The conclusion they draw is that the burden of complications under conventional therapy is high enough to justify targeted treatments.

The subset with the Bartter syndrome type V phenotype has a distinct picture. Two patients, a 19-year-old man and a 26-year-old woman, presented soon after birth with tetany and hypocalcaemia and had hypomagnesaemia, hypokalaemia, metabolic alkalosis, hyperreninaemia and hyperaldosteronaemia [7]. The boy described by Vargas-Poussou and colleagues was diagnosed at 3 weeks of life with severe hypocalcaemia and hyperphosphataemia with inappropriately low parathyroid hormone and treated as neonatal hypoparathyroidism; at 7 years, during an episode of severe hypocalcaemia with seizures and electrocardiographic changes, he also had polyuria, and increasing vitamin D doses resulted in marked hypercalciuria, at which point Bartter syndrome was diagnosed; renin normalised and the plasma ionic abnormalities and polyuria improved with indometacin and magnesium, calcium and potassium supplementation [7]. The Italian monozygotic twin girls described by Hu and colleagues presented in the neonatal period with apnoea, tremors, tonic limb contractions and seizures, with severe hypocalcaemia, hyperphosphataemia and undetectable parathyroid hormone; at 20 months they had low calcium, high phosphorus and high urinary calcium excretion and, despite treatment to reduce hypercalciuria, developed nephrocalcinosis in early childhood and nephrolithiasis in the second decade, with normal renal function and no cataracts, and developed Bartter features at 22 years, with mild hypokalaemia and mild hyperreninaemia and hyperaldosteronism without alkalosis [7].

Autosomal dominant hypocalcaemia type 2, due to GNA11, ranges in severity from asymptomatic to symptomatic, with paraesthesiae, carpopedal spasm, seizures and basal ganglia calcification [8]. The Canadian family of English origin described by Hunter and colleagues in 1981 and restudied by Li and colleagues in 2014 illustrates the variability: of the eight affected members, two were asymptomatic; the proband was assessed at 6 years for "febrile seizures" and had positive Trousseau and Chvostek signs, possible laryngospasm and serum calcium of 6.3 mg/dl with phosphorus of 7.8 mg/dl and parathyroid hormone at the lower limit of normal; the affected father had carpopedal spasm and hypocalcaemia with normal phosphorus and parathyroid hormone; two paternal aunts had symptomatic hypocalcaemia and two paternal uncles asymptomatic hypocalcaemia; two male cousins had hypocalcaemia with stiffness, paraesthesiae and carpopedal spasm, and in the next generation two daughters of one of the cousins were diagnosed in infancy and the son of the other at 20 years, after an episode of severe tetany [32]. Affected members developed mild postnatal growth failure without growth hormone deficiency and were significantly shorter than unaffected relatives. In the two four-generation families described by Mannstadt and colleagues, no affected member had a history of mucocutaneous candidiasis, hearing loss or renal anomalies, and clinical examination was normal, notably without skin changes [32].

3.5 HDR syndrome (Barakat)

The GATA3 phenotype is the triad of hypoparathyroidism, sensorineural deafness and kidney disease, but the triad is often incomplete and any of the components may bring the patient to medical attention [40]. The quantification comes from the 2018 review by Barakat and colleagues, which brought together 173 published cases plus seven new ones: of patients with a known GATA3 variant, 77 had the complete triad, 34 had hypoparathyroidism and deafness, six had deafness and kidney disease, two had kidney disease only, three had hypoparathyroidism and kidney disease and one had deafness only; of the 40 patients without GATA3 testing, 30 had the triad, eight had hypoparathyroidism and deafness and two deafness and kidney disease [28]. Across all cases, hearing loss was the most common feature, affecting 96.7% of individuals, described as early-onset, sensorineural, moderate to severe and typically bilateral; hypoparathyroidism was present in 93.3%, with parathyroid hormone usually low or inappropriately normal for the degree of hypocalcaemia; kidney disease affected 72.2% and, of these, 40% had congenital anomalies of the kidney, with the remaining involvement including nephrotic syndrome, haematuria, proteinuria, renal tubular acidosis, nephrocalcinosis and chronic kidney disease [28]. Additional features in some patients were hypogonadotrophic hypogonadism, polycystic ovaries, congenital heart disease, retinitis pigmentosa, basal ganglia calcification, autism and cognitive impairment [28]. UniProt characterises the renal picture as steroid-resistant nephrosis with progressive renal failure [40].

The age at presentation spans the whole of life. One patient presented with seizures due to severe hypocalcaemia at 17 months, was found to have renal failure, hypercalciuria and nephrocalcinosis at 3 years, when bilateral sensorineural deafness was also diagnosed, presented at 4 years with nephrotic syndrome and bilateral interstitial pneumonia, developed acute pulmonary oedema and dilated cardiomyopathy in the context of a cardiac conduction defect attributed to hypocalcaemia and anaesthesia, with renal biopsy showing diffuse segmental glomerulonephritis and nephrocalcinosis, and at 15 years had persistent moderate glomerular proteinuria [28]. At the opposite extreme, a Japanese man was diagnosed with proteinuria at 18 years, with sensorineural hearing loss at 40 and with hypoparathyroidism at 47, with renal biopsy at 52 years showing 25% of glomeruli with global sclerosis and the remainder with segmental mesangial proliferation, in addition to tubulointerstitial disease; his sister and nephew had deafness and kidney disease with mild proteinuria, and his father and son had deafness [28]. Watanabe and colleagues described in 1998 a three-generation family identified through a male infant admitted for seizures beginning on the tenth day of life, with five members with hypoparathyroidism and sensorineural deafness, without renal dysplasia: renal tubular function and imaging were normal, which shows that the renal component may be entirely absent [28]. Malformations of the female genital tract have also been described: a 29-year-old Portuguese woman with severe hypoparathyroidism, mild bilateral sensorineural deafness diagnosed in childhood and agenesis of the vagina and uterus, with normal renal ultrasound and renal function, and normal uterine adnexa with a cyst in the left ovary; this was the third case of female genital tract malformation associated with HDR, after the mother and daughter described by Hernandez and colleagues in 2007, one with a non-functioning right kidney and septate uterus and the other with right renal agenesis and uterus didelphys with septate vagina [28]. A 14-year-old patient had, in addition to the triad, bilateral ptosis and horizontal nystagmus, with symmetrical pseudopapilloedema on fundoscopy and basal ganglia calcification on tomography, and other patients had recurrent cerebral infarcts in the basal ganglia, which the authors linked to GATA3 expression in the central nervous system [28].

3.6 Autoimmune polyendocrinopathy type 1

The classic triad is chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency, and the presence of two of the three has traditionally established the diagnosis [42]. In the Finnish reference series of 68 patients, the presenting manifestation was oral candidiasis in 60%, intestinal malabsorption in 9% and keratopathy in 3%; all had candidiasis at some point; hypoparathyroidism developed in 79%, with peak incidence around 5 years and possibly being the only manifestation for years, and adrenocortical failure in 72%; gonadal failure affected 60% of women aged 13 years or over and 14% of men aged 16 years or over; and half the patients had multiple endocrine deficiencies [42]. Between 4% and 29% had periodic malabsorption, gastric parietal cell atrophy, hepatitis, alopecia, vitiligo or a combination. Dental enamel hypoplasia and keratopathy were frequent and were not attributable to hypoparathyroidism — an important distinction, because the enamel anomalies in this syndrome do not improve when calcium is corrected [42]. Components accumulate over decades, typically three to five per patient, and some appear as late as the fifth decade, which makes lifelong follow-up for new components the central principle of management [42].

The phenotype is broader outside the classic European cohorts, and this is the most common reason for diagnostic delay. In a prospective American natural history cohort of 35 patients, urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis and a Sjögren-like syndrome — all uncommon in European series — each affected between 40% and 80% of patients; 80% developed a median of three manifestations outside the triad before a diagnostic dyad appeared, only 20% had their first two manifestations within the classic triad, and the classic dyad was reached at a mean of 7.38 years [42]. Urticarial eruption, intestinal dysfunction and enamel hypoplasia were prominent early features.

3.7 Hypoparathyroidism in 22q11.2 deletions and TBX1 variants

Hypoparathyroidism and the resulting hypocalcaemia are present in 17% to 60% of people with 22q11.2 deletion syndrome and are typically more severe in the neonatal period; calcium homeostasis often normalises with age, although recurrence has been described in late childhood and adulthood during intercurrent illness, puberty and pregnancy [51]. Cheung and colleagues reported that 80% of adults with the syndrome had hypocalcaemia at some point in their lives, and that hypoparathyroidism, hypothyroidism and hypomagnesaemia may contribute to it [51]. The two 2003 British series found hypocalcaemia in about 30% and about 42% of children outside the neonatal period [52]. The handbook of recognisable patterns of malformation records transient neonatal hypocalcaemia in 60% of cases, seizures in 21% usually resulting from hypocalcaemia, lifelong hypocalcaemia in rare individuals and periodic hypocalcaemia with surgical stress, puberty and pregnancy, with only 1% of patients lacking T lymphocytes and requiring referral for thymus transplantation [13]; the Brazilian handbook of genetic syndromes records hypoparathyroidism with hypocalcaemia in 60%, with tetany and seizures, and places the origin of the thymus and parathyroids in the pharyngeal arches [53]. Seizures generally accompany hypocalcaemia, but about 15% of people had unprovoked seizures [51]. The phenotype of TBX1 point variants in people without a deletion includes conotruncal heart defects, velopharyngeal or palatal anomalies, the characteristic facies, thymic hypoplasia with T-lymphocyte deficiency and hypocalcaemia due to hypoparathyroidism, with families segregating truncating variants of exon 9C showing craniofacial features and hypocalcaemia, one of them with deafness and without a heart defect [41].

3.8 FAM111A-related dysplasias and recessive TBCE syndromes

Primary hypoparathyroidism with hypocalcaemia and hyperphosphataemia is the endocrine feature shared by the two ends of the FAM111A spectrum, present in 20 of 22 individuals with Kenny-Caffey syndrome and in 6 of 6 with osteocraniostenosis, and may present with tetany, seizures or soft tissue calcification; most presented before two months of age, usually in the neonatal period, with hypocalcaemic seizures, severity is variable and most require lifelong vitamin D and calcium [17]. Hyperphosphataemia resulting from hypoparathyroidism may cause ectopic soft tissue calcification, and intracranial calcification, predominantly of the basal ganglia, is sought on brain imaging [17]. In Kenny-Caffey syndrome, in addition to proportionate short stature of postnatal onset in 19 of 20 individuals, relative macrocephaly with frontal bossing in 17 of 19, a large anterior fontanelle with delayed closure in 13 of 19 and cortical thickening of the long bones with medullary cavity stenosis in 21 of 21, ophthalmological features are prominent, with refractive errors in 15 of 18 and with microphthalmia, aniridia, cataracts, corneal and retinal calcification and pseudopapilloedema described; development and cognition are almost always normal [17]. The bone dysplasia atlas adds that patients are small at birth, that postnatal growth is insufficient and adult height ranges between 122 and 152 cm, that children may be mildly affected and the radiographic anomalies detected incidentally during investigation of short stature, that pubertal delay, hypogonadism and infertility appear frequent in males with exact incidence yet to be determined, that renal calcification may occur after prolonged vitamin D treatment and that the oldest known patients are in their fifth decade [29]. Osteocraniostenosis, by contrast, has intrauterine growth deficiency in 9 of 10, cloverleaf skull in 9 of 9 detectable antenatally, reduced cranial ossification in 10 of 10, thin ribs with thoracic hypoplasia causing pulmonary hypoplasia and respiratory failure — the cause of lethality —, perinatal fractures in some, micropenis and small testes, and splenic aplasia or hypoplasia with extramedullary haematopoiesis; most died in the first hours of life, with survival of a few to several months described [17, 47].

Sanjad-Sakati syndrome has the most robust natural history data of all the entities in this article, thanks to an international registry of 135 individuals from Gulf centres: hypoparathyroidism, developmental delay and intrauterine growth restriction were universal, with a mean birth weight of minus 3.0 standard deviations and postnatal height z-scores persistently between minus 7 and minus 8; there were hypocalcaemic seizures in 64.2%, tetany in 53.3%, nephrocalcinosis in 62.1%, recurrent respiratory infections in 63.7% and bacterial infections in 53.8%, primary hypothyroidism in 16.5% and hypoglycaemia in 27.8% [22]. The dysmorphism includes microcephaly, deep-set eyes, beaked nose, micrognathia and large floppy ears, and dental anomalies, sleep-disordered breathing and susceptibility to infection complete the picture [22]. Median survival in the cohort was 27.2 years, with 62.4% survival to 18 years, and respiratory failure caused 84% of deaths, 21 of 25 [22]. In Kenny-Caffey syndrome type 1, due to the same gene, the systematic review of 205 patients with a genetic diagnosis showed that intellectual disability is the typical feature, in 74 of 80, whereas osteosclerotic changes are uncommon, and that postnatal growth retardation, low parathyroid hormone, electrolyte disturbance, dental and ocular anomalies and seizures overlap completely between the two genetic types [22].

3.9 Mitochondrial forms and lymphoedema-hypoparathyroidism syndrome

In mitochondrial cytopathies, hypoparathyroidism is rarely the dominant manifestation but may be the first: four unrelated children with Kearns-Sayre syndrome initially presented with hypoparathyroidism and deafness [44]. The context in which it arises includes short stature, ophthalmoplegia, retinopathy and complete heart block — one of the paediatric patients presented with a seizure resulting from complete heart block and also had retinopathy and ophthalmoplegia —, diabetes mellitus, hypogonadism with amenorrhoea and delayed puberty, thyroid abnormalities, hyperaldosteronism, non-autoimmune Addison disease and hypomagnesaemia [44]. In a Korean paediatric cohort of 37 patients with primary hypoparathyroidism diagnosed before 18 years of age, one patient had Kearns-Sayre syndrome, which gives an order of magnitude of the contribution of these forms [23].

Lymphoedema-hypoparathyroidism syndrome was described by Dahlberg, Borer, Newcomer and Yutuc in 1983 in two adult brothers with congenital lymphoedema, hypoparathyroidism, nephropathy, mitral valve prolapse and brachytelephalangy: the elder brother had bilateral cataracts detected on routine examination at 19 years, limb oedema, noted soon after birth, increased after he began walking, and progressive renal failure required renal transplantation at 26 years; the other brother had similar findings, and both had a broad nasal bridge and lateral displacement of the inner canthi, with radiological suspicion of pulmonary lymphangiectasia [25]. The mode of inheritance is unclear and includes autosomal recessive and X-linked recessive possibilities, and the molecular basis has not been established.

3.10 Primary hypomagnesaemia with secondary hypocalcaemia

Primary hypomagnesaemia with secondary hypocalcaemia usually presents in the first months of life with generalised seizures or other symptoms of increased neuromuscular excitability, such as irritability, muscle spasms and tetany [36]. The biochemical profile is characteristic: very low serum magnesium, with a mean and standard deviation of 0.24 ± 0.11 mmol/l against a normal of 0.75 to 1.40, in combination with low serum calcium, 1.64 ± 0.41 mmol/l against a normal of 2.12 to 2.70; in the presence of serum hypomagnesaemia, urinary magnesium excretion is reduced and parathyroid hormone is inappropriately low, and renal magnesium wasting only becomes apparent after supplementation has been started [36]. Untreated, the disease results in permanent neurological damage or death, but magnesium supplementation corrects all clinical symptoms [36].

4. Clinical Recognition and Warning Signs

4.1 When to suspect, by age and context

In the newborn, the combination of seizures, tremor, laryngospasm or stridor with low ionised calcium requires measurement of intact parathyroid hormone in the same sample, because this is the only way to separate true hypoparathyroidism from the transient causes of neonatal hypocalcaemia. Simultaneous measurement of magnesium is equally mandatory [22]. When calcium is low with high phosphate, low or inappropriately normal parathyroid hormone and alkaline phosphatase normal for age, the biochemical diagnosis has been made and what remains is the cause. Normal alkaline phosphatase is the finding that rules out rickets and vitamin D deficiency [22]. In the presence of intrauterine growth restriction, microcephaly and characteristic dysmorphism — small deep-set eyes, depressed nasal bridge with beaked nose, long philtrum, thin upper lip, micrognathia and large floppy ear lobes —, the hypothesis is Sanjad-Sakati syndrome, and in Middle Eastern and Gulf populations targeted testing for the TBCE founder allele is the fastest route [19, 22]. In the presence of conotruncal heart disease, cleft palate or velopharyngeal anomaly and T lymphopenia, the hypothesis is 22q11.2 deletion, and in that case chromosomal microarray, FISH or MLPA precede any sequencing, because TBX1 sequencing alone does not detect the deletion [41]. In a child with a prenatal diagnosis of 22q11.2 deletion, plasma calcium is checked on the first day of life [52].

In infancy and early childhood, hypocalcaemia that recurs with every infection, every physical exertion or with heat exposure points to an absent, not merely reduced, parathyroid reserve. A hypocalcaemic seizure in a previously healthy child, with undetectable parathyroid hormone, is a first episode of genetic hypoparathyroidism until proven otherwise. When hypoparathyroidism coexists with bilateral sensorineural deafness, investigation should include renal ultrasound and renal function, because the combination defines HDR syndrome; the converse is equally true and is the situation most often missed — in the investigation of deafness in early childhood, renal ultrasound is indicated when there are anomalies of the pinna, ear pits or tags, a branchial sinus, multiple congenital anomalies or low serum calcium, precisely because of HDR [54]. A child identified only through hearing loss still needs assessment of calcium and kidneys [40].

In the older child and adolescent, family history is the highest-yield clue. In a child or adolescent with non-surgical hypoparathyroidism, the three clues to hereditary disease identified in the Chinese cohort of 173 patients were family history, early age at onset — especially before 5 years — and the presence of extraparathyroid manifestations [35]. A negative family history does not, however, rule out a hereditary cause, because two of the genes in this class have both inheritance patterns documented: for PTH and GCM2, some families segregate dominantly and others recessively, so that an apparently isolated case, especially with consanguineous parents, is compatible with either and requires biochemical assessment of the parents [1, 4]. Recurrent oral candidiasis, nail dystrophy, alopecia, vitiligo, unexplained hepatitis, chronic diarrhoea, keratopathy or dental enamel hypoplasia require autoimmune polyendocrinopathy type 1 to be considered and anti-interferon omega autoantibodies to be measured without waiting for the classic triad [42]. Proportionate short stature with a large anterior fontanelle with delayed closure, frontal bossing, triangular face and significant refractive errors raise the hypothesis of FAM111A dysplasias, which can be confirmed by a skeletal survey showing cortical thickening with medullary cavity stenosis [17, 29].

In adults, the European guideline states that chronic hypoparathyroidism should be considered in the presence of persistent hypocalcaemia with low or inappropriately normal parathyroid hormone, and that postsurgical hypoparathyroidism should not be called chronic in the first 12 months after surgery [34]. Detection of hypocalcaemia in an adult without previous neck surgery should not be attributed by default to autoimmunity: the Second International Workshop recommends avoiding the label of autoimmune hypoparathyroidism in patients without autoimmune polyendocrinopathy type 1, since there are no definitive diagnostic tests for the polygenic autoimmune form [27]. The two reference documents diverge on who should be tested, and the divergence is material: the Second International Workshop, in its recommendation 3.1, restricts genetic testing to patients with non-surgical hypoparathyroidism who have a positive family history of non-surgical hypoparathyroidism, syndromic features or age below 40 years, adding, in recommendation 3.2, targeted testing of the AIRE gene when there are other manifestations of autoimmune polyendocrinopathy type 1 [27], whereas the 2025 European guideline recommends, in R.1.2 and with strong strength, genetic testing and/or family screening in every patient with non-surgical hypoparathyroidism without another evident aetiology [34]. The rationale for the broader position is explicit: family history may be negative when variants are de novo or have variable clinical expression; testing refines the clinical diagnosis, may guide targeted therapies, may help predict other medical conditions and allows assessment of the risk for relatives; and it is particularly important in younger individuals, because a genetic diagnosis allows counselling about pregnancy plans. The example the guideline gives of guiding targeted therapy is that of autosomal dominant hypocalcaemia type 1 due to activating CASR variants, in which the patient may benefit from a negative allosteric modulator of the calcium-sensing receptor; the same guideline acknowledges that access to testing varies between settings and may be limited by availability and cost [34].

The 2024 Parathyroid Summit consensus resolves this divergence in favour of the broader position, and that is the recommendation to follow. It advises genetic testing in all patients with idiopathic hypoparathyroidism, turning positive family history, syndromic features and age of 40 years or below from eligibility criteria into circumstances that strengthen the indication; the way to test is a gene panel covering all known candidate genes, and a negative result does not exclude a genetic cause because of the technical limitations of the method [43]. The same document is more demanding than the 2022 one regarding the aetiological label: in the absence of a definitive clinical test, isolated autoimmune hypoparathyroidism should be classified as idiopathic and not as autoimmune [43]. The genes to assess when a syndromic form is suspected are, in that consensus, AIRE in autoimmune polyendocrinopathy type 1, TBX1 and NEBL in DiGeorge-like phenotypes, CHD7 and SEMA3E in CHARGE syndrome, TBCE and FAM111A in Kenny-Caffey and Sanjad-Sakati syndromes and GATA3 in HDR syndrome, to which mitochondrial cytopathies are added; in the non-syndromic forms, GCM2, PTH and SOX3 in the isolated forms and CASR and GNA11 in those associated with autosomal dominant hypocalcaemia with or without Bartter phenotype [43].

The 2025 French protocol turns these clues into rules of conduct by age. In the newborn, any profound hypocalcaemia or hypocalcaemia persisting beyond the third day of life, outside physiological transient hypocalcaemia, suggests hypoparathyroidism, because severe congenital forms become apparent in the neonatal period; the second cause to consider is functional hypoparathyroidism due to suppression of the fetal parathyroids by maternal hypercalcaemia, whether due to untreated or poorly treated maternal primary hyperparathyroidism or to overtreated maternal hypoparathyroidism, and the distinction is made by measuring calcium and, ideally, parathyroid hormone in both parents, with priority to the mother [12]. In children, any first seizure, including a febrile seizure, requires calcium to be measured, because fever increases requirements and can decompensate an unrecognised hypoparathyroidism, and the same applies to recurrent epilepsy in which calcium has never been measured [12]. All hypoparathyroidism identified in a child without previous surgery is considered genetic until proven otherwise, without forgetting infiltrative and autoimmune causes, and measurement of fasting calcium, with parathyroid hormone and phosphate when possible, in first-degree relatives allows the mode of transmission to be established [12]. In an adult with an incidental finding, the history is decisive: previous neck surgery or radiotherapy is sought, previous calcium values are retrieved, other endocrinopathies are sought, especially adrenal insufficiency, together with candidiasis suggesting autoimmune polyendocrinopathy type 1, and dysmorphism or heart disease suggesting 22q11.2 deletion are looked for; hypoparathyroidism with no cause found should go through a reference or competence centre before being labelled idiopathic [12]. In syndromes already known through another route — 22q11.2 deletion diagnosed prenatally or in the neonatal period because of heart disease, HDR syndrome discovered through deafness or renal anomalies, Sanjad-Sakati or Kenny-Caffey syndrome, autoimmune disease —, hypocalcaemia is generally latent at first, and the protocol provides for regular measurement of calcium and education of the patient and family about the signs that require urgent testing [12].

4.2 Warning signs and emergencies

The immediate emergency is severe symptomatic hypocalcaemia. The emergency criteria established by the Second International Workshop are the presence of significant cardiac, respiratory or neurological symptoms, or albumin-adjusted calcium below 7.0 mg/dl (1.75 mmol/l) [27]. In the infant and young child with TBCE disease, a hypocalcaemic crisis with seizures, tetany, apnoea or laryngospasm requires urgent correction of calcium with simultaneous airway stabilisation, and both venous access and airway management are difficult in these children, with sepsis and dehydration usually precipitating the crisis [22]. Hypocalcaemic laryngospasm and bronchospasm may be mistaken for croup or asthma, and arrhythmia due to QT interval prolongation for a primary cardiac cause.

Three situations create a risk of predictable decompensation and justify anticipatory measurement of calcium. The first is the perioperative period, particularly cardiac surgery and palatal surgery in patients with 22q11.2 deletion, in which checking plasma calcium at any admission is presented as a sensible precaution [52]; recommended surveillance explicitly includes pre- and postoperative measurement [51]. The second is puberty, during which previously controlled hypocalcaemia may recur [13, 51]. The third is pregnancy and the postpartum period, covered in section 7. In the patient with autoimmune polyendocrinopathy type 1, the first presentation of adrenal insufficiency may be a crisis, and so lifelong periodic screening for new endocrine components is the life-saving measure; moreover, hypocalcaemia may be precipitated or unmasked when adrenal insufficiency is treated, so the two endocrinopathies must be managed together [42].

Two warning signs are specific to the calcium-sensing forms. The first is the detection of hypercalciuria in a patient with hypocalcaemia: when urinary calcium is inappropriately within the normal range or high in a person with untreated hypocalcaemia, suspicion of CASR or GNA11 gain of function should be raised before starting active vitamin D, because that treatment is what precipitates renal damage [7]. The second is the association of hypocalcaemia with hypokalaemic alkalosis, renal salt wasting and hyperaldosteronism, which defines the Bartter type V phenotype and indicates a strongly activating variant [30]. In the investigation of intracranial calcification for any reason, measurement of calcium, phosphate and parathyroid hormone is part of the initial panel, alongside urea and electrolytes, serology for congenital infection, cytomegalovirus polymerase chain reaction on the neonatal Guthrie card, urinary organic acids and amino acids, plasma lactate and amino acids and cerebrospinal fluid examination; neuroimaging is central and, if the pattern of calcification is not clear on magnetic resonance imaging, computed tomography should be performed [55].

Three findings outside the endocrinological setting should prompt measurement of fasting calcium, according to the 2025 French protocol: a cataract, generally subcapsular, in an adolescent or young adult; unexplained soft tissue calcification — subcutaneous tissue, muscle, heart, vessels and heart valves —; and Fahr syndrome, with basal ganglia calcification, which, when found incidentally on imaging requested for head injury or headache, bears witness to chronic hypocalcaemia [12]. As for severity, the protocol assesses it by clinical features and the electrocardiogram and not by the number: signs of severe hypocalcaemia are muscle contracture, tetany, laryngospasm, confusion, seizures, prolongation of the corrected QT interval — above 440 ms in men and 460 ms in women and children, in the adult protocol — and rhythm disturbances, and ventricular ectopy requires Holter recording to look for ventricular tachycardia [12]. The paediatric protocol of the same document uses a corrected QT threshold of 0.42 s and describes the sequence of electrocardiographic signs — QT prolongation, then flattening and inversion of T waves, which are late, and finally ventricular tachycardia and fibrillation —, and lists as clinical signs of severity in children seizures, tremor, abnormal movements, paraesthesiae, cramps and tetany, laryngospasm with stridor, apnoea or respiratory arrest, heart failure with tachycardia, malaise and anxiety [12]. The corrected QT thresholds of the 2024 Parathyroid Summit consensus, 0.45 s in men and 0.47 s in women, are slightly higher [43]. In a patient with known hypoparathyroidism and severe symptoms, treatment begins without waiting for the calcium result [12].

4.3 Newborn screening and presymptomatic detection

There is no population newborn screening for genetic hypoparathyroidism, and neither the 2025 European guideline nor the Second International Workshop guidelines provide for any such programme [27, 34]. In countries with newborn screening by quantification of T-cell receptor excision circles, the T lymphopenia of congenital athymia may be detected, which may indirectly lead to the diagnosis of a 22q11.2 deletion or a TBX1 variant and, by that route, to detection of the associated hypoparathyroidism, but this does not constitute screening for hypoparathyroidism [41].

Presymptomatic detection within the family is, by contrast, highly productive and has already changed outcomes. In the five-generation consanguineous Pakistani family with familial isolated hypoparathyroidism 2, three individuals presented in infancy with seizures, but the fourth was screened for hypocalcaemia soon after birth because of the family history, which allowed diagnosis and treatment before any episode [4]. The same principle applies to HDR syndrome, in which identification of a GATA3 variant or deletion in a proband justifies assessment of calcium, hearing and kidneys in first-degree relatives, and to autosomal dominant hypocalcaemia, in which asymptomatic relatives may have significant hypocalcaemia and, above all, hypercalciuria that determines the decision to treat.

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Formal criteria

Hypoparathyroidism is confirmed by hypocalcaemia — low albumin-adjusted calcium or ionised calcium — with undetectable, low or inappropriately normal intact parathyroid hormone, measured by a second- or third-generation assay, on two occasions at least two weeks apart [27]. Supporting findings are raised serum phosphorus, reduced 1,25-dihydroxyvitamin D and raised urinary calcium [27]; the 2024 Parathyroid Summit consensus describes the fourth supporting finding as increased fractional calcium excretion, rather than raised absolute urinary calcium, and adds reduced bone turnover markers to the first three [43]. That consensus repeats the same formal criteria with the same requirement of two occasions at least two weeks apart and of a second- or third-generation assay, and establishes, in its own right, the same temporal condition as the European guideline: postsurgical hypoparathyroidism is only confirmed as chronic 12 months or more after the operation, so that the 12-month limit is a position common to both documents and not exclusive to the European one [34, 43]. This limit does not apply to the genetic forms, which are permanent from the outset. Parathyroid hormone must be measured at the time of hypocalcaemia, because it is this simultaneity that separates true hypoparathyroidism from secondary hypocalcaemia [22].

Two pre-analytical conditions affect the validity of the result itself and should be checked before accepting a low parathyroid hormone. The first is biotin interference: an intake above 5 mg per day falsely lowers parathyroid hormone in assays using biotin-streptavidin binding and should be stopped at least three days before sampling, with alternative methods available when interference is suspected; human anti-mouse antibodies and rheumatoid factor may also interfere, though rarely [43]. The second is how calcium is obtained. Directly measured ionised calcium is preferable, and when albumin-corrected calcium is used the formulae are total calcium in mg/dl plus 0.8 times the difference between 4.0 g/dl and the patient's albumin, or total calcium in mmol/l plus 0.02 times the difference between 40 g/l and the patient's albumin in g/l; these formulae have recognised limitations in chronic kidney disease and in severe acid-base disturbances, situations in which ionised calcium is the measure to use [43]. Before starting any treatment, serum magnesium is measured and corrected if abnormal [43].

The 2025 French protocol formulates the criteria differently, and the difference is material in how calcium is measured. It defines hypocalcaemia as fasting total calcium below 2.20 mmol/l (8.8 mg/dl), at any age, always interpreted with the proteins or albumin from the same sample, and low ionised calcium as below 1.15 mmol/l; ionised calcium is the fraction regulated by parathyroid hormone, but it requires strict pre-analytical conditions — anaerobic sample, without tourniquet, transported on ice within a few minutes of collection — that make it impractical in outpatients, where in France it is not even reimbursed [12]. In the absence of hypoproteinaemia and acid-base disturbance, the protocol considers total calcium at least as reliable as albumin-corrected calcium, because the correction formulae misclassify more patients between normocalcaemia and hypocalcaemia, and recommends following uncorrected total calcium, for diagnosis, follow-up and in pregnancy [12]. This position diverges from that of the 2024 Parathyroid Summit consensus, which prefers ionised calcium and, failing that, calcium corrected by the usual formulae [43]. Parathyroid hormone must be measured in the same sample as the low calcium, preferably in EDTA plasma, and it is low or undetectable mainly in children and in complete forms, or within the laboratory range and therefore inappropriate, mainly in adults and in partial forms; reference values depend on the assay manufacturer, so the range of the laboratory that performed the measurement is always used, and there is no recommendation in favour of a second- or third-generation assay, except in the first hours after thyroidectomy, when the third-generation assay will better reflect gland function [12]. Hyperphosphataemia is a strong but not indispensable argument; fasting urinary calcium is low without treatment, but preserved or high in some patients with activating variants of CASR or its signalling pathway, with no reliable threshold [12]. Magnesium is always measured, because correction of hypomagnesaemia can cure functional hypoparathyroidism, and the protocol asks for calcium and parathyroid hormone to be repeated after prolonged correction before concluding that the hypoparathyroidism is non-functional; serum magnesium poorly reflects body content, and hypoparathyroidism itself increases urinary magnesium excretion, in which case correction does not cure the disease [12]. Outside end-stage renal failure, hypocalcaemia with raised parathyroid hormone indicates another cause, either a disorder of PTH-PTHrP signalling or secondary hyperparathyroidism [12].

The spread of parathyroid hormone reference ranges between marketed assays, reproduced in the protocol, shows why an isolated value cannot be interpreted without the laboratory's range.

5.2 Initial biochemistry and algorithm

The first-line panel is biochemical and available in any laboratory: serum calcium with albumin, or ionised calcium, phosphate, magnesium, intact parathyroid hormone, 25-hydroxyvitamin D, creatinine with estimated glomerular filtration rate and 24-hour urinary calcium and creatinine [37, 38]. Depending on the suspicion, these are complemented by an electrocardiogram for the QT interval, renal ultrasound for nephrocalcinosis, cranial computed tomography for basal ganglia calcification and slit-lamp examination for cataracts [37]. When a Bartter type V phenotype is suspected, potassium, bicarbonate, renin and aldosterone are added [30]. Alkaline phosphatase is typically normal for age and helps exclude rickets [22].

The practical algorithm unfolds in four steps. The first is to confirm hypocalcaemia with inappropriate parathyroid hormone on two occasions, excluding hypomagnesaemia and vitamin D deficiency, which are the two reversible causes of low parathyroid hormone [38]. The second is to measure urinary calcium before starting treatment, because inappropriately normal or high urinary calcium during untreated hypocalcaemia is the best biochemical clue to gain of function of the calcium-sensing receptor — and this value is irretrievably altered once active vitamin D has been started [7]. The third is to look for extraparathyroid manifestations that point to the gene: audiometry and renal ultrasound for GATA3; echocardiogram, lymphocyte subsets and palatal assessment for TBX1 and 22q11.2 deletion; skeletal survey for FAM111A and TBCE; lactate, ophthalmological examination and electrocardiogram for the mitochondrial forms; autoantibodies for AIRE. The fourth is molecular testing, targeted when there is a distinctive phenotype or a known founder allele, and by panel or exome when there is not.

Discrimination between the loss- and gain-of-function forms of the calcium-sensing receptor deserves a quantitative note, because it is probabilistic and has been treated as if it were categorical. The urinary calcium/creatinine clearance ratio, calculated from paired urine and serum calcium and creatinine and not from an isolated urinary concentration, is the classic discriminator between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: about 80% of patients with the former have a ratio below 0.01, against less than 20% of patients with the latter, and Hannan and colleagues place the overlap at about 10% of patients with primary hyperparathyroidism also having a low ratio, concluding that mutational analysis may be needed to separate them [30]. A 2026 series of 1599 patients undergoing parathyroidectomy for presumed primary hyperparathyroidism showed that conventional thresholds of 24-hour urinary calcium and clearance ratio missed the three patients with pathogenic variants associated with familial hypocalciuric hypercalcaemia — two in CASR and one in AP2S1 —, whose values were 326 mg with 1.24%, 334 mg with 1.83% and 240 mg with 1.00%, all well within the range that would normally be called primary hyperparathyroidism; the authors recommend germline genetic testing before parathyroidectomy in patients without documented previous normocalcaemia or another explanation for acquired hypercalcaemia [30]. The symmetrical conclusion for hypocalcaemia is that the urinary ratio is a sign and not a test: in a comparison of 85 patients with idiopathic hypoparathyroidism and 15 with activating CASR variants, mean serum calcium before treatment was significantly higher in the variant group, but with substantial overlap, and the urinary calcium/creatinine ratio before treatment in the variant group was almost the same as that of normocalcaemic controls and markedly higher than in idiopathic hypoparathyroidism; during treatment, however, the degree of hypercalciuria did not differ between the two disorders, and the plots of ratio against serum calcium were not separable, even over 4 to 8 years of treatment [7]. The authors concluded that an inappropriately normal ratio in untreated hypocalcaemia, generally of mild degree, is a better biochemical clue for suspecting gain of function than the development of severe hypercalciuria during treatment.

The 2025 French protocol adapts the first sampling to the clinical situation, so that investigation never delays treatment. In an asymptomatic adult, or a symptomatic one whose treatment can wait, fasting calcium, magnesium and parathyroid hormone are measured, and 25-hydroxyvitamin D, phosphate and calcium and creatinine in a 24-hour urine collection without treatment may be measured. In a symptomatic adult who must be treated immediately, calcium, phosphate, magnesium, parathyroid hormone, 25-hydroxyvitamin D and calcium and creatinine in a spot urine sample are measured without waiting for fasting, and the 24-hour collection, useful for adjusting treatment, does not delay it. In children, the same biochemistry with a spot urine sample is sufficient, and the urine collection, which is not indispensable for diagnosis, should not delay treatment. In the newborn, the assessment for an asymptomatic adult is performed in both parents, first in the mother, to separate congenital hypocalcaemia from hypocalcaemia secondary to maternal hypercalcaemia [12]. The protocol emphasises that knowing the cause does not change the nature of treatment, which is symptomatic and the same for all causes, but does change the targets, the therapeutic adjustments, surveillance of other organs and screening of relatives [12].

To interpret urinary calcium in a morning sample in children, the protocol uses simplified age-specific ranges of the calcium/creatinine ratio, which decrease with age; the higher values in infants should not be read as hypercalciuria by adult criteria.

5.3 Genetic tests, order and limits

The first-line test for non-surgical hypoparathyroidism without a guiding phenotype is a multigene panel including, as a minimum, PTH, GCM2, CASR, GNA11, GATA3, TBX1, AIRE, FAM111A and TBCE, combined with a technique that detects copy number variation. The combination has been validated in practice: in the Chinese cohort of 173 patients with childhood-onset hypoparathyroidism, next-generation sequencing targeted to 15 candidate genes combined with TBX1 dosage analysis by multiplex ligation-dependent probe amplification identified 27 pathogenic or likely pathogenic variants in five genes — TBX1, AIRE, GATA3, FAM111A and CASR —, including 13 novel ones, in 23 patients, and 12 variants of uncertain significance in five genes — GATA3, CASR, FAM111A, GCM2 and PTH — in 11 patients, while dosage analysis separately detected deletion of the whole TBX1 gene in 25 patients; in total, genetic defects were identified in 27.7% of patients with early onset [35]. The yield of the dosage component is as high as that of sequencing, which makes sequencing alone an inadequate strategy.

Five limits of the tests should appear in the report and in the conversation with the family. The first is that a negative result does not exclude the diagnosis of hypoparathyroidism, which is biochemical, nor a genetic cause: even with the panel above, about 72% of paediatric patients with early-onset hypoparathyroidism had no variant found [35]. The second is that deep intronic variants escape exome and panels: the AIRE founder variant NM_000383.4:c.1504-818G>A, which activates a cryptic splice site and includes a 109 base-pair pseudoexon, was found in 16% of a prospective cohort of 104 patients and requires genome sequencing or a targeted assay, with Puerto Rican ancestry explicitly raising the question [42]. The third is that position effects due to non-genic structural rearrangements escape any sequence-based strategy: in X-linked hypoparathyroidism, sequencing of the three genes in the critical region was normal and it was necessary to resort to single nucleotide polymorphism analysis with sequence-tagged sites, fluorescence in situ hybridisation on DNA fibres, pulsed-field gel electrophoresis, flow-sorted X chromosome-specific libraries and metaphase mapping to identify the deletion-insertion [5]. The fourth is that the copy number of a gene may be increased rather than decreased, with a similar phenotype, as in the girl with a 6.5 Mb deletion and a concomitant 1.9 Mb duplication including GATA3 [28]. The fifth is that the proportion of variants detectable by a technique is not the clinical sensitivity of the test: in FAM111A, deletion and duplication analysis has not identified causal exon or whole-gene deletions to date, so adding it does not increase the yield in that gene, unlike in TBX1 [17].

The laboratory report should name the gene, the reference transcript with version, the HGVS description at cDNA and protein level, zygosity and class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Conversion of historical nomenclature to current notation is not done by hand: the equivalences in the table in section 2.7 were all validated in VariantValidator against the MANE transcript and the GRCh38 genome, and any other conversion should follow the same route [31]. Four concrete nomenclature pitfalls in this area: version NM_022074.5 of FAM111A does not exist, although it is cited, and the MANE Select transcript of that gene is NM_001312909.2; the TBCE founder deletion appears in the literature as c.155_166del12 and as c.155-166del, the correct notation being NM_003193.5:c.155_166del, p.(Ser52_Gly55del), because the hyphen would indicate an intronic position; the dominant-negative GCM2 variant published as c.1399delC remaps, under the HGVS 3' shift rule, to NM_004752.4:c.1400del, p.(Pro467GlnfsTer64); and the isolated protein designation "F341L" for GNA11 is ambiguous, because there are two distinct variants with that consequence, c.1023C>G associated with autosomal dominant hypocalcaemia type 2 and c.1021T>C of uncertain significance, so cDNA-level notation is mandatory [31].

Variants of uncertain significance are frequent in this area — 12 in 173 patients in the Chinese cohort, thus 6.9% — and their resolution depends on three lines of evidence: family segregation, which requires samples from parents and siblings; concordance between the predicted direction of effect and the phenotype, which in the CASR, GNA11 and GCM2 genes is informative because the two directions cause opposite diseases; and functional assays, which in the case of the calcium-sensing receptor are well established — transfection in HEK293 cells with determination of the median effective concentration allows gain of function to be classified and, in highly activating variants, the Bartter phenotype to be anticipated [7, 35]. In FAM111A, by contrast, functional evidence of pathogenicity is still lacking, especially regarding the molecular targets and subcellular localisation of the variants [33].

In France, the 2025 protocol organises access to molecular diagnosis through the reference and competence centres of the rare calcium and phosphate disorders network (filière OSCAR) and recommends, in a familial form with a negative first-line molecular diagnosis, genome-wide analysis through the France Genomic Medicine Plan; it also recommends segregation analysis in relatives to interpret a variant of uncertain significance, and points out that, in a familial form, hypocalcaemia, history and the absence of another cause may suffice for diagnosis, provided the mode of transmission is compatible with the identified familial cause [12].

5.4 Tests that distinguish specific diagnostic pitfalls

Three pitfalls in this area have their own test. The first is paradoxically raised parathyroid hormone due to a bioinactive PTH variant, which leads to the wrong label of pseudohypoparathyroidism: it is resolved by a parathyroid hormone 1-34 infusion test in which an intact nephrogenous cyclic AMP response shows that the kidney responds to the hormone and that the defect lies in the patient's hormone and not in the receptor [37]. The second is acquired hypocalciuric hypercalcaemia due to autoantibodies against the calcium-sensing receptor, clinically identical to the genetic form but without a CASR variant and possibly responsive to glucocorticoids, which matters when interpreting a negative genetic test in that situation [30]. The third is autoimmune polyendocrinopathy type 1 with negative sequencing: autoantibodies against type I interferons are effectively confirmatory and are the most useful test in this article. High-titre neutralising IgG autoantibodies against most interferon alpha subtypes and especially against interferon omega were found in 60 of 60 Finnish and 16 of 16 Norwegian patients with biallelic AIRE variants, generally in the earliest samples available, preceding overt candidiasis and several of the autoimmune components and persisting for decades; they were undetectable in unaffected heterozygous relatives, in patients with autoimmune polyendocrinopathy type 2 and in isolated cases of the endocrine diseases most typical of type 1, so they are specific [42]. Lower titres against interferon beta were present in 23% and against interferon lambda-1 in a subgroup, and antibodies against interferon gamma, IL-10 and IL-12 were much rarer and non-neutralising. In the American cohort, all but one of 35 patients had anti-interferon omega autoantibodies, including four of the five patients in whom no biallelic AIRE variants were found, which means that the assay identifies patients that sequencing does not detect [42]. The practical consequence is that a clinically suspected patient with a negative genetic test has not been excluded, and autoantibodies should be measured before abandoning the diagnosis. Organ autoantibodies support and may predict the individual components: 21-hydroxylase for adrenal insufficiency, NALP5 for hypoparathyroidism, side-chain cleavage enzyme for gonadal failure, GAD65 for diabetes, thyroid peroxidase for thyroid disease, and intrinsic factor and parietal cells for pernicious anaemia [42]. The Second International Workshop formulates the criteria operationally: the diagnosis is probable in the presence of at least one of the three major manifestations — chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency — and positive anti-type 1 interferon antibodies, present in more than 95% of patients, with anti-21-hydroxylase antibodies correlating with adrenal insufficiency and anti-NALP5 with the development of hypoparathyroidism, and with molecular confirmation by AIRE gene analysis; hypoparathyroidism is present in more than 80% of patients and may be the only endocrinopathy present [27]. A separate autoimmune form, with or without this syndrome, results from activating antibodies against the calcium-sensing receptor that inhibit parathyroid hormone secretion, with recovery described as titres fall; there are no standardised diagnostic tests for these antibodies, so the entity cannot be confirmed in routine practice [27]. In patients with immune checkpoint inhibitor-induced hypoparathyroidism, antiparathyroid autoantibodies and activating autoantibodies against the same receptor are detectable [34].

5.5 Prenatal and preimplantation diagnosis

Prenatal diagnosis is technically possible in all entities with an identified gene, by targeted analysis of the familial variant in chorionic villi or amniocytes, and preimplantation genetic diagnosis is applicable when the variant is known in both parents in recessive forms or in one of them in dominant forms. Two situations merit specific comment. In osteocraniostenosis, antenatal ultrasound detection is possible and characteristic — cloverleaf skull and reduced cranial ossification, in addition to short limbs and bowed radius —, and there are consensus guidelines on the prenatal assessment and delivery of patients with skeletal dysplasia that apply to this situation [17, 33]. The counselling problem here is the absence of genotype-phenotype correlation: when a FAM111A variant is found prenatally, the genotype does not predict Kenny-Caffey syndrome, compatible with adult life, rather than osteocraniostenosis, which is lethal perinatally, and this must be stated clearly [17]. In Sanjad-Sakati syndrome, intrauterine growth restriction is universal and can be detected by ultrasound, but it is non-specific.

As for the newborn of a mother with hypoparathyroidism, the European guideline states that the paediatrician or neonatologist should be informed, because maternal hypercalcaemia can suppress neonatal parathyroid hormone and cause hypocalcaemia in the newborn, whereas maternal hypocalcaemia can cause secondary hyperparathyroidism in the infant; ionised calcium is measured from day 2 of life, typically every 48 hours in the first week, ensuring routine vitamin D for the newborn [34]. The reverse situation exists and is documented historically: Buchs described in 1961 three siblings with congenital hypoparathyroidism apparently in response to maternal hyperparathyroidism, and Aceto and colleagues described in 1966 fetal and infantile hyperparathyroidism due to maternal hypoparathyroidism, with two children of an affected mother, by different fathers, having hypoparathyroidism — observations that simulated recessive inheritance and are now recognised as effects of the maternal environment and not as genetic disease in the child [1].

6. Differential Diagnosis

6.1 The differentials that matter most

The first differential to resolve is pseudohypoparathyroidism, not because it is difficult but because it is the confusion with the greatest practical consequence in two opposite directions. The usual direction is the correct one: raised parathyroid hormone with hypocalcaemia and hyperphosphataemia indicates hormone resistance and points to disorders of PTH-PTHrP signalling. The reverse direction is the pitfall: in PTH variants that produce a complete but biologically inactive hormone, measured parathyroid hormone may be high and the child labelled as having pseudohypoparathyroidism when there is a deficiency of functional hormone [37]. The test that resolves this is parathyroid hormone 1-34 infusion with measurement of nephrogenous cyclic AMP, which shows an intact renal response in the bioinactive variant and a reduced response in true resistance [37]. Physical examination helps before any test, because pseudohypoparathyroidism type 1A has the phenotype of Albright hereditary osteodystrophy: short stature and obesity in most, round face with a sometimes depressed nasal bridge, short and often asymmetrical digits due to short metacarpals, with the distal phalanx of the thumb as the most affected bone, and subcutaneous ossifications, signs that do not occur in the hormone deficiency forms in this article; radiographic signs of hyperparathyroidism, such as subperiosteal resorption and wide growth plates, may coexist, and acrodysostosis and terminal deletions of chromosome 2 overlap phenotypically with this picture [56].

The second is hypomagnesaemia, genetic or acquired — acquired causes include gastrointestinal losses, alcoholism, proton pump inhibitors, loop diuretics, aminoglycosides and platinum compounds, and are more frequent than genetic causes in adults. Hypomagnesaemic hypocalcaemia exactly reproduces the biochemical profile of true hypoparathyroidism — low calcium, inappropriately low parathyroid hormone — because severe hypomagnesaemia blocks the synthesis and release of the hormone and, in addition, prevents the peripheral response to administered parathyroid hormone [36]. The difference is reversibility: hypocalcaemia resolves rapidly with magnesium replacement, unlike the persistent hypocalcaemia of the parathyroid forms [22]. This requires magnesium to be measured in the same sample in which calcium and parathyroid hormone are measured, at any age, and makes hypomagnesaemia a condition to be excluded before a diagnosis of genetic hypoparathyroidism is given. The difficulty is that hypomagnesaemia often coexists with the genetic forms rather than replacing them: 16 of 20 patients in a series of autosomal dominant hypocalcaemia had hypomagnesaemia [7], as did 66% of adults with that condition in north-east England [50], and hypomagnesaemia is described in Kearns-Sayre syndrome and in Kenny-Caffey syndrome [29, 44]. In these cases, hypomagnesaemia aggravates rather than explains.

The third is the distinction between the gain- and loss-of-function forms of the calcium-sensing receptor, because the direction of effect determines both the disease and the direction of harm caused by wrong treatment. Treating familial hypocalciuric hypercalcaemia as primary hyperparathyroidism leads to parathyroidectomy that is neither necessary nor effective, because the defect lies in calcium sensing and not in glandular mass, and recurrence of hypercalcaemia after parathyroidectomy is itself a clue that this was the diagnosis from the outset [30]. Treating autosomal dominant hypocalcaemia as common hypoparathyroidism, seeking to normalise serum calcium, is how iatrogenic renal damage is produced, and the extreme outcome is documented in a patient treated for symptomatic hypocalcaemia in childhood who progressed to end-stage renal failure due to nephrocalcinosis and nephrolithiasis [30]. The biallelic loss-of-function form, neonatal severe hyperparathyroidism, is the emergency of this gene, with serum calcium typically between 3.5 and 5.0 mmol/l, bone demineralisation with fractures, respiratory distress, failure to thrive and death without treatment [30].

The fourth differential is skeletal, between the FAM111A dysplasias and the entities that mimic them. The GeneReviews chapter lists in the differential of Kenny-Caffey syndrome LRP5 (osteosclerosis), SOST (sclerosteosis and van Buchem disease, with tall stature, progressive skeletal overgrowth, thickened ribs, facial bone hyperplasia, skull hyperostosis, cranial nerve compression, variable syndactyly and increased serum parathyroid hormone), TBXAS1 (Ghosal haematodiaphyseal dysplasia, autosomal recessive, with wide diaphyseal medullary cavities, marrow hypocellularity and haematological anomalies), TGFB1 (Camurati-Engelmann disease, autosomal dominant, with sclerosis and cortical thickening with medullary stenosis of the long bones, macrocephaly with skull hyperostosis, mandibular enlargement, proptosis and facial palsy due to cranial nerve compression) and TBCE [17]. TBCE is the one that matters most, because biallelic variants produce a clinically similar disease — short stature, delayed fontanelle closure, frontal bossing, micrognathia, low parathyroid hormone, hypocalcaemia, medullary stenosis and thin long bones — and it is autosomal recessive, so that getting the gene wrong changes the recurrence risk from 50% to 25% and entirely changes carrier testing; it is distinguished by more severe intrauterine growth restriction, microcephaly more common than in Kenny-Caffey syndrome, recurrent infection and intellectual disability or developmental delay, very rarely described in the FAM111A form [17]. In the differential of osteocraniostenosis, none of the alternative entities has cortical thickening or medullary stenosis of the long bones: skeletal ciliopathies, including the perinatally lethal short rib-polydactyly syndromes and Jeune asphyxiating thoracic dystrophy, are not associated with hypoparathyroidism and commonly have polydactyly and multisystem manifestations; perinatally lethal osteogenesis imperfecta has blue sclerae and markedly bowed long bones, without splenic hypoplasia or cloverleaf skull; and achondrogenesis has minimal or absent ossification of the vertebral bodies and of the iliac and ischial bones [17]. The bone dysplasia atlas adds intrauterine hypomobility, in which narrow diaphyses are a non-specific sequel of prolonged immobilisation but the cortices are thin rather than thickened; diaphyseal medullary stenosis with malignant fibrous histiocytoma, which occurs in adults and is not associated with dwarfism; Marfan syndrome and homocystinuria, with thin tubular bones but tall patients; 3M syndrome and other forms of primordial dwarfism, with a different face and without cortical thickening, microcephaly or hypocalcaemia; and Hallermann-Streiff syndrome, which resembles osteocraniostenosis but without splenic a/hypoplasia and with a different facial phenotype [29, 47]. An observation that matters for the investigation of a case with tubular stenosis and hypocalcaemia is that tubular stenosis with other manifestations of Kenny-Caffey syndrome has also been described with 22q11.2 haploinsufficiency, and may be secondary to fetal or infantile hypoparathyroidism — that is, the radiological finding is not gene-specific [29].

The table above includes, in its syndromic half, entities that the 2025 European guideline itself lists in its table of genetic aetiologies of hypoparathyroidism and that are rarely remembered in this context: DiGeorge syndrome 2, due to partial monosomy of 10p14; CHARGE and Kabuki syndromes, due to CHD7 and KMT2D variants; Pearson syndrome, due to a large single mitochondrial DNA deletion; long- and medium-chain fatty acid oxidation defects, due to HADHA, HADHB and ACADM variants; and Smith-Lemli-Opitz syndrome, due to DHCR7 variants [34]. In these, hypoparathyroidism is a finding within a multisystem picture that dominates the presentation, but its existence means that hypocalcaemia with low parathyroid hormone in a patient with any of these syndromes should not be attributed by default to another cause.

The 2024 Parathyroid Summit consensus publishes its own table of genetic causes, adapted from Mannstadt and colleagues, which confirms line by line the genes, loci, inheritance patterns and OMIM numbers of the entities in section 0 and adds to the hypomagnesaemia half the entities and identifiers incorporated in the table above [43]. Its own contribution is organisational: it groups the causes into four mechanistic categories — disorders of gland formation, disorders of parathyroid hormone secretion, hypomagnesaemia syndromes and damage to the formed gland — and, within this scheme, classifies familial isolated hypoparathyroidism type 2, due to GCM2, as a disorder of formation, and type 1, due to PTH, as a disorder of secretion, which matches the known function of each gene and keeps the two entities in distinct categories despite the common name [43]. Autosomal dominant hypocalcaemia type 1 and Bartter syndrome subtype 5 appear as a single line, with the same gene and the same OMIM number, a position that coincides with that covered in section 3.4. The two entities in the table above that do not appear in either of the two earlier reference documents are hypomagnesaemia, seizures and intellectual disability type 2, due to ATP1A1, and the mitochondrial hypomagnesaemia, hypertension and hypercholesterolaemia syndrome, both relevant only as causes of magnesium-dependent hypocalcaemia and not as primary hypoparathyroidism.

The fifth differential is immunological and syndromic, between the 22q11.2 deletion and its mimics. The 10p13-p14 deletion may show overlapping features, including heart defects, immune deficiency, hypoparathyroidism, cleft palate, developmental delay, microcephaly and cryptorchidism, and the distinction is made by microarray [51]. Because the HDR critical region maps distal to the DiGeorge syndrome region at 10p13-p14, a terminal 10p deletion may produce variable combinations of the two syndromes, which explains why four of five patients with hypoparathyroidism in a series of 14 with 10p13 deletion had received a diagnosis of partial DiGeorge syndrome [28].

Finally, acquired causes should not be forgotten in a young patient, nor their relative frequency overestimated in the opposite direction: about three quarters of all chronic hypoparathyroidism is iatrogenic, mainly postsurgical, and about one quarter is genetic or metabolic [57]. In the operated patient, parathyroid hormone measured 12 to 24 hours after thyroidectomy predicts permanence, and a value above 10 pg/ml (1.05 pmol/l) makes permanent hypoparathyroidism very unlikely, whereas a lower value has less predictive value, with a probability of permanent disease below 50%, because many patients recover [27]. The magnitude of this recovery is quantified in the systematic review of the 2025 European guideline, which pooled 14 studies with 8832 patients undergoing thyroid surgery: 2981, or 33.8%, developed postoperative hypoparathyroidism, of whom 73.9% recovered at 6 months and 81.3% at 12 months, leaving 558 of 8832, or 6.3%, with chronic disease at one year; the additional recovery gain between 6 and 12 months was 7.4%, and it was this difference that led to redefining chronic postsurgical hypoparathyroidism as that persisting beyond 12 months, against 6 months in the previous guideline [34]. The risk of postoperative hypocalcaemia depends on the number of glands preserved in situ — 16% with one to two, 6% with three and 2.5% with four —, permanent hypoparathyroidism after total thyroidectomy occurs in 2% to 10% of cases, especially with lymph node dissection for carcinoma, and 60% to 70% of postoperative hypocalcaemia resolves within 4 to 6 weeks [34]. None of this applies to the genetic forms, in which the defect is permanent from the outset, but it explains why the adult with hypocalcaemia and a neck scar is not the patient of this article. Autoimmune hypoparathyroidism induced by immune checkpoint inhibitors is rare and largely irreversible, typically arising between 3 weeks and 7 months of treatment, and the European guideline notes that in some non-surgical forms, including autoimmune hypoparathyroidism, parathyroid hormone secretion may be re-established, unlike in the genetic forms of glandular agenesis or aplasia [34]. The 2024 Parathyroid Summit consensus adds that recovery of parathyroid function is possible even after many years, although rare: there are patients diagnosed with permanent postsurgical hypoparathyroidism who recovered function 8 to 16 years later, with normalisation of calcium and parathyroid hormone and reduction or discontinuation of supplements, which justifies maintaining surveillance rather than considering the diagnosis closed [43]. This possibility does not exist in the entities in this article in which the gland did not form, and it is the reason why the frequency of parathyroid hormone measurement is a matter of divergence between the documents, discussed in section 11.2.

The 2025 French protocol groups the causes into three categories — acquired, congenital and transient or functional — and adds to the differential three easily recognised situations: neonatal functional hypoparathyroidism due to suppression of the fetal parathyroids by maternal hypercalcaemia, which requires an adaptation period of a few days to a few weeks; magnesium disorders, in which hypomagnesaemia, mainly iatrogenic — proton pump inhibitors, thiazide or loop diuretics — or due to malabsorption, reduces parathyroid hormone secretion and causes peripheral resistance, and hypermagnesaemia, rarer and generally iatrogenic, inhibits hormone secretion and renal calcium reabsorption, probably through a competitive action on the calcium-sensing receptor; and acute alcohol intoxication, of poorly understood mechanism and probably linked to induced hypomagnesaemia [12]. Among acquired forms, in addition to neck surgery and radiotherapy, the protocol lists infiltration or overload of the glands — Wilson disease, haemochromatosis, amyloidosis, thalassaemia major, tuberculosis, metastases, Riedel thyroiditis — and autoimmunity due to antibodies against the calcium-sensing receptor, against NALP5 or against other parathyroid epitopes, often with other autoimmune diseases; in the French Épi-Hypo cohort, up to 14% of cases, and more in children, had no identified cause, due to causes yet to be discovered or incomplete investigation [12].

7. Treatments and Risk Management Strategies

7.1 Acute hypocalcaemia

Severe symptomatic hypocalcaemia is treated intravenously. The 2025 European guideline indicates administration of 90 to 180 mg of elemental calcium, for example one to two ampoules of calcium gluconate with 1 g per ampoule, over 10 to 20 minutes, followed by a slower infusion with about 900 mg of elemental calcium in 1 litre of 5% dextrose or normal saline at 100 ml per hour, with monitoring of calcium and the electrocardiogram and simultaneous initiation of oral calcium and active vitamin D, for example calcitriol 0.25 or 0.5 µg twice daily [34]. The Second International Workshop gives the same values for the bolus — 90 to 180 mg of elemental calcium over 10 to 20 minutes, with cardiac monitoring — and specifies the infusion as 10 ampoules, equivalent to 900 mg of elemental calcium, in 1 litre of 5% dextrose or normal saline, started at 50 ml per hour and titrated, aiming for calcium just below the normal range; concomitant oral therapy is calcitriol 0.25 to 0.5 µg twice daily or alfacalcidol [27]. The divergence between the two documents is limited to the initial rate of the maintenance infusion, 50 versus 100 ml per hour, and the reference is the more recent guideline, with the rate in any case adjusted to the measured calcium. The 2024 Parathyroid Summit consensus adopts 100 ml per hour and adds five details of execution that determine the safety of the procedure. The first is that calcium gluconate is preferred to calcium chloride despite containing less elemental calcium per ampoule — 90 mg versus 272 mg — because the risk of soft tissue necrosis in case of extravasation is lower, and that rapid infusion of intravenous calcium can cause cardiac arrest, so the bolus requires secure large-bore venous access and cardiac monitoring. The second is that bicarbonate and phosphate are never added to the solution, because they form insoluble calcium salts. The third is that the indication for intravenous calcium exists regardless of the serum calcium value when there is a prolonged corrected QT interval on the electrocardiogram — above 0.45 s in men and 0.47 s in women —, laryngospasm, bronchospasm, seizures or tetany, and also in the patient unable to take oral supplements or with a history of seizures. The fourth is the dose-effect to use as a reference: 15 mg/kg of elemental calcium intravenously over 4 to 6 hours raises serum calcium by about 0.5 to 0.75 mmol/l. The fifth is the frequency of monitoring: calcium is measured every 6 hours and then daily until stable, with the goal of restoring it to just below the lower reference limit and not within the normal range [43]. The same document states that injectable active vitamin D requires further research and that parathyroid hormone and its analogues may have value postoperatively with unstable refractory hypocalcaemia, but that none of these uses is approved by the Food and Drug Administration [43].

In the child with Sanjad-Sakati syndrome or another neonatal form, the crisis requires urgent correction of calcium with simultaneous airway stabilisation, and both venous access and airway management are difficult in these children; sepsis and dehydration usually precipitate the crisis, so treatment of the triggering cause is part of the treatment of hypocalcaemia [22]. In seizures, calcium and magnesium are corrected first, and phenytoin and phenobarbital should be avoided because they disturb calcium metabolism [22]; in 22q11.2 deletion syndrome, standard anticonvulsant treatment is reserved for seizures unrelated to hypocalcaemia [51]. Magnesium replacement is part of acute treatment when there is hypomagnesaemia: in primary hypomagnesaemia, supplementation should initially be intravenous, with concurrent parenteral calcium supplementation [36].

The 2025 French protocol contains an adult and a paediatric emergency protocol, both resulting from consensus between rare disease network specialists and emergency physicians, and recommends that every patient with chronic hypoparathyroidism carry an emergency card that identifies them and refers to the protocol [12]. Before any treatment, whenever possible, total and ionised calcium, phosphate, creatinine, magnesium, parathyroid hormone — unnecessary if chronic hypoparathyroidism is known —, 25-hydroxyvitamin D and calcium and creatinine in the first urine are collected; if tests cannot be done urgently, blood and urine tubes collected before treatment are kept for later analysis, and urine collections never delay treatment of a seizure or a conduction disturbance [12]. Minimum preparation includes an electrocardiogram, continuous monitoring and two peripheral venous lines with normal saline, and telemetry is required in haemodynamic or neurological failure, with electrocardiographic repercussions and under digitalis, which is stopped with a request for a cardiological opinion [12].

In severe hypocalcaemia in adults, the French protocol gives 10% calcium gluconate — each 10 ml ampoule contains 2.25 mmol, or about 90 mg, of elemental calcium —, two ampoules in 100 ml of 5% dextrose over 10 minutes, repeated if symptoms persist at the end of the infusion; if symptomatic hypocalcaemia persists, five ampoules are diluted in 500 ml of 5% dextrose or normal saline, to be infused over 12 hours at a controlled rate, and total calcium, with or without ionised calcium in venous blood, is measured every 4 to 6 hours to adjust the dose [12]. There is no maximum amount of infused calcium nor any need for a central line, except with prolonged calcium chloride, but it is rarely necessary to maintain the infusion for several days or to exceed 10 ampoules per day, and in that case advice is sought from a network centre; the infusion is as short as possible, with a switch to the oral route as soon as possible and attention to the fall in calcium after stopping [12]. Calcium chloride is the alternative when gluconate is unavailable, is venotoxic and is switched to a central line if the infusion continues for several days; the protocol gives the equivalence of half an ampoule of 10% calcium chloride for one ampoule of 10% gluconate, or 4.9 ml of chloride for the 2.25 mmol of one gluconate ampoule, but the ratio of elemental calcium content cited by the 2024 consensus — 272 mg versus 90 mg per ampoule — corresponds to about one third of an ampoule, so conversion is made using the elemental calcium content declared on the label of the available product [12, 43]. In metabolic acidosis, hypocalcaemia is corrected first and alkali given only afterwards, so as not to worsen it, and hypomagnesaemia is corrected; the goal is not to normalise calcium but to make severe symptoms disappear [12].

In hypocalcaemia without signs of severity, the protocol keeps the intravenous route, in the same way, in severe malabsorption — coeliac disease, intestinal resections — and when the oral route is impossible, and accepts it with calcium at or below 1.80 to 1.90 mmol/l, especially in an acute fall, acknowledging that there is no consensus value for profound hypocalcaemia [12]. In asymptomatic hypocalcaemia or hypocalcaemia with minor symptoms, if it is chronic and of known cause, as in a patient attending the emergency department for another reason, background treatment is not changed and the patient contacts their team; if the cause or duration is unknown, guiding tests are performed and the patient is referred. Oral treatment is calcium carbonate, 1 to 3 g per day in 500 mg doses away from meals, avoiding massive or prolonged intake because of the risk of positive calcium balance, with calcium citrate or acetate, after specialist advice, in achlorhydria — gastrectomy, bypass, Biermer anaemia, proton pump inhibitors —; associated hyperphosphataemia does not need correction, and every patient leaving the emergency department on 1 g per day or more of calcium must be reassessed, if possible by a specialist, in the following weeks [12]. On discharge, the protocol requests, fasting and within the next 5 days, full electrolytes with bicarbonate, creatinine with estimated filtration rate, total calcium, phosphate, magnesium, proteins, albumin, 25-hydroxyvitamin D2 and D3 and parathyroid hormone, and prescribes, if 25-hydroxyvitamin D is below 30 ng/ml, oral colecalciferol 50,000 IU per week for 1 to 2 months and then one ampoule per month for 6 months [12].

The paediatric protocol of the same document defines moderate hypocalcaemia as total calcium of 1.8 to 2.2 mmol/l or ionised calcium of 0.9 to 1.1 mmol/l, and severe hypocalcaemia as total calcium below 1.8 mmol/l, or below 2.2 mmol/l with symptoms, or ionised calcium below 0.9 mmol/l [12]. In the severe form, the child is placed under continuous monitoring and oximetry with a defibrillator nearby, an intensive care opinion is sought if there is haemodynamic instability, heart failure, tachycardia or ventricular fibrillation, and seizures are treated according to the local protocol with clonazepam, diazepam or midazolam [12]. Calcium is given as a continuous intravenous infusion of 10% calcium gluconate diluted one in ten — one 10 ml ampoule in a final 100 ml of 5% dextrose, or five in 500 ml —, at 1 l/m² per 24 hours, which corresponds to about 900 mg of elemental calcium per m² per day; in parallel, oral alfacalcidol 2 µg per day in a single dose is started, vitamin D is replaced with one oral ampoule of 80,000 to 100,000 IU, hypomagnesaemia is corrected and phosphate is not corrected; the infusion is monitored because of the risk of skin necrosis in case of extravasation, and a loading dose is decided only by the intensivist in severe rhythm disturbances [12]. Ionised calcium is measured on blood gas at the sixth hour and then calcium and magnesium every 12 hours while clinical or electrocardiographic signs persist; the infusion is stopped and the oral route used when total calcium exceeds 2 mmol/l or ionised calcium 1 mmol/l, allowing for a fall of about 0.2 mmol/l after stopping [12]. Renal function is estimated with the Schwartz formula, 36.5 times height in centimetres divided by creatinine in µmol/l [12]. In moderate hypocalcaemia — total calcium above 1.8 mmol/l and asymptomatic child —, oral calcium is given up to twice the recommended intake for age, as calcium carbonate equal to once the recommended intake if the diet is normal or twice if it is deficient, with alfacalcidol as in the severe form; the reference recommended intakes are 280 mg per day from 7 to 11 months, 450 mg from 1 to 3 years, 800 mg from 4 to 10 years and 1150 mg from 11 to 17 years [12].

7.2 Conventional maintenance therapy

First-line treatment in chronic hypoparathyroidism is conventional therapy — oral calcium salts plus an active vitamin D metabolite — and not hormone replacement. The Second International Workshop recommends it as first line with a weak recommendation and low-quality evidence, reserving parathyroid hormone for when conventional therapy is unsatisfactory [27], and the 2025 European guideline strongly recommends treatment with vitamin D, using an activated analogue — alfacalcidol or calcitriol — when available, also with strong strength although with very low-quality evidence, and with colecalciferol at supraphysiological doses only when activated analogues are unavailable or too expensive [34]. The reason for preferring the activated analogue is mechanistic and not a matter of preference: parathyroid hormone deficiency blocks renal 1-alpha-hydroxylation, so plain vitamin D does not substitute for the active metabolite [22]. Between the two activated analogues there are equivalences to know: calcitriol is about twice as potent as alfacalcidol in its calcaemic effect, so that a typical daily dose of 0.25 to 2.0 µg of calcitriol is equivalent to 0.5 to 4.0 µg/day of alfacalcidol, and an adjustment of 0.5 µg/day of alfacalcidol is equivalent to one of 0.25 µg/day of calcitriol; at initiation or in severe hypocalcaemia and hypercalcaemia, 1.0 to 2.0 µg/day of alfacalcidol or 0.5 to 1.0 µg/day of calcitriol are used, doses are not adjusted at intervals shorter than two to three days, and with colecalciferol at supraphysiological doses two to three months should elapse between adjustments, because of its long half-life [34]. Onset of action is one to two days for both activated analogues and offset of action two to three days for calcitriol and five to seven days for alfacalcidol, which explains why correction of hypercalcaemia is slower with the latter [34]. Plasma half-life is a quantity distinct from duration of effect and, in the 2024 Parathyroid Summit consensus, is 5 to 8 hours for calcitriol and 3 to 6 hours for alfacalcidol in the conventional therapy table, although the text of the same document gives 3 to 6 hours for the serum elimination half-life of calcitriol — an internal divergence that the document does not resolve and that does not change management, because the practical consequence is the same with either value: the short half-life requires divided doses through the day and reassessment of calcium 2 to 3 days after each adjustment [43]. Alfacalcidol has an onset of activity of about 6 hours, because it requires hepatic 25-hydroxylation, and the 1,25-dihydroxyvitamin D resulting from it reaches peak serum concentration at 12 hours [43]. In postsurgical hypoparathyroidism with severe hypocalcaemia, higher initial doses may be needed, of the order of 0.25 to 0.5 µg of calcitriol twice daily [43].

The thresholds for treatment are defined. The European guideline strongly recommends treating patients who are symptomatic and/or have albumin-adjusted calcium below 2.0 mmol/l (8.0 mg/dl), approximately ionised calcium below 1.00 mmol/l, and suggests as good clinical practice considering treatment of apparently asymptomatic patients with calcium between that threshold and the lower reference limit, to assess whether well-being improves [34]. The biochemical targets under conventional therapy are calcium in the lower part of the reference range or slightly below it, personalised around well-being and not a fixed number (good clinical practice), normal 24-hour urinary calcium (weak recommendation, very low quality), which the guideline's own table of targets quantifies as less than 7.5 mmol per 24 hours (300 mg) in men, less than 6.25 mmol per 24 hours (250 mg) in women or less than 0.1 mmol/kg per 24 hours (4 mg/kg) in both sexes, with simultaneous measurement of urinary creatinine and sodium, phosphate within the reference range, magnesium within the reference range and 25-hydroxyvitamin D of 75 nmol/l or more, equivalent to more than 30 ng/ml, all with weak recommendation and very low quality [34]. The Second International Workshop gives the 25-hydroxyvitamin D target as 75 to 125 nmol/l and defines the 24-hour urinary calcium limits numerically: below 6.25 mmol per 24 hours (250 mg) in adult women and below 7.5 mmol per 24 hours (300 mg) in adult men, noting that the risk is inferred from the general population because there are no data specific to this disease [27]. The 2025 European guideline gives the same limits and adds the alternative of 0.1 mmol/kg per 24 hours (4 mg/kg) in both sexes, with the recommendation to measure urinary creatinine and sodium in parallel [34]. One point on which the two documents differ is the calcium target under hormone replacement: the 2022 document does not distinguish the two scenarios, whereas the 2025 European guideline states that, under parathyroid hormone replacement, the target is the lower half of the normal range but not below it, it being acceptable to aim for the value the patient had before the disease, even if in the upper half, or the upper half itself when this is necessary to control symptoms or improve quality of life, avoiding hypercalcaemia and hypercalciuria [27, 34].

The reference doses of each agent are shown in the following table, with the guideline dose as the reference and the label dose as comparison.

In children, the targets are explicitly more conservative: serum calcium in the lower half of normal, about 8.0 to 8.5 mg/dl, serum phosphate of 4.5 to 5.5 mg/dl and calcium-phosphate product below 55, with biochemistry — calcium, phosphate, magnesium, alkaline phosphatase, parathyroid hormone and urinary calcium — checked about every two weeks during initial stabilisation and quarterly once stable [22]. These values come from a narrative review with expert perspectives and not from a graded guideline, and should be read as such. The 2024 Parathyroid Summit consensus adopts the same calcium-phosphate product of 55 mg²/dl², equivalent to 4.4 mmol²/l², as a target also in adults, and this is the reference threshold; the US calcitriol label uses 70 mg²/dl², a more permissive value that is included only for comparison [43, 58].

Paediatric dosing of conventional therapy is, in that consensus, explicitly age-based, and it is the only guideline paediatric dosing available in this disease, so it constitutes the reference; the labels are included for comparison. Under 4 years, calcitriol oral solution is used, 0.02 to 0.1 µg/kg/day, with calcium carbonate 40 to 60 mg/kg/day, both divided into three daily doses. Between 4 and 10 years, the oral calcitriol dose is titrated in 0.25 µg increments until calcium is in the lower half of normal, with calcium carbonate 800 to 1000 mg/day as solution or chewable tablets, both divided into three to four doses. Over 10 years, adult calcitriol doses are used with 1000 mg of calcium supplement per day, divided into three to four doses. Monitoring specific to this age group is calcium, magnesium and creatinine in a spot urine sample, instead of a 24-hour collection, and annual renal ultrasound; vitamin D deficiency and insufficiency, defined as 25-hydroxyvitamin D below 25 nmol/l and between 25 and 75 nmol/l, are corrected in parallel [43].

Three paediatric dose divergences are declared rather than resolved. The first concerns calcium: the 2024 consensus gives 40 to 60 mg/kg/day under 4 years and the paediatric review with expert perspectives gives about 50 to 75 mg/kg/day, ranges that overlap in the central band but whose extremes differ in both directions [22, 43]. The second concerns calcitriol: the consensus uses weight-based dosing under 4 years and the Food and Drug Administration label uses fixed doses by age band, 0.25 to 0.75 µg/day between 1 and 5 years, so that, for a 10 kg infant, the guideline range — 0.2 to 1.0 µg/day — exceeds the label maximum at its upper limit [43, 58]. The third concerns formulation: the consensus dosing assumes calcitriol oral solution under 4 years and liquid or chewable calcium carbonate between 4 and 10 years, whereas in Portugal the summary of product characteristics for calcium carbonate states that the product is not indicated under 12 years and that for calcitriol does not establish paediatric dosing, a situation in which the alternative with approved paediatric dosing is alfacalcidol, as discussed in section 7.15 [59–61].

A note on geographical practice, which the consensus records and which helps interpret the doses found in the literature: in Europe, higher doses of active vitamin D with lower doses of calcium supplement are usually prescribed, and in North America the reverse, so that a dose that seems excessive in the light of one practice may be standard in the other [43]. The consensus further adds that conventional therapy is particularly difficult after bariatric surgery, in any malabsorptive state and with nasogastric tube feeding, circumstances in which absorption of calcium and of the activated analogue is no longer predictable [43].

The 2025 French protocol sets the goals of conventional therapy by tolerance and not by normalisation. Calcium above 1.80 mmol/l is generally enough to avoid symptoms and allow the child to develop, and the usual target is fasting calcium in the lower part of the range, between 2.0 and 2.2 mmol/l, adjusted to each patient; at follow-up, the protocol asks for normal calcium in the growing child and low-normal or moderately low calcium, above 2 mmol/l, in adults [12]. First line is the hydroxylated vitamin D analogues, alfacalcidol (Un-Alfa® in France) or calcitriol (Rocaltrol®), with oral calcium, at the lowest dose that suppresses symptoms; initiation is with low doses, for example 1 µg/day of alfacalcidol or 0.5 µg/day of calcitriol in adults, in two doses, and 2 to 4 µg/day of alfacalcidol or 1 to 2 µg/day of calcitriol in children, with an effect on calcium after 1 to 3 days with calcitriol and 5 to 7 days with alfacalcidol; the protocol sets no maximum dose, and the maintenance ranges and reference maxima are those in the dose table above [12]. The need for high doses requires looking for poor adherence, malabsorption, a bioavailability problem or another superimposed cause of hypocalcaemia before escalating [12].

As for calcium, the protocol recalls that the growing child has the greatest metabolic need for elemental calcium, that adults need about 1 g per day, about 1.2 g in postmenopausal or pregnant women, the equivalent of three to four dairy servings per day, and that a calcium-rich diet may suffice in some patients [12]. Each dose of calcium salt should not exceed 500 mg, and doses are spread over the day and night to prevent hypercalciuria; calcium carbonate — Orocal®, Calcidose®, Caltrate® and Cacit® in France — is preferably taken away from meals to increase absorption — a position without experimental support, because carbonate absorption is equal or greater when taken with a meal [68] —, and in achlorhydria or under proton pump inhibitors calcium citrate as a compounded preparation or calcium acetate (Phosphosorb®), whose dissociation does not depend on pH, is preferred; calcium-rich mineral waters count towards intake [12]. The protocol acknowledges that taking calcium with meals limits hyperphosphataemia, but at the cost of lower calcium absorption [12]. Maintaining a normal store of native vitamin D is recommended, with a 25-hydroxyvitamin D target between 75 and 150 nmol/l, higher in patients on parathyroid hormone analogues, using colecalciferol (Uvédose® or ZymaD®) or calcifediol (Dédrogyl®) taken with a meal, because they are fat-soluble; in children, the French medicines agency recommends not using over-the-counter forms sold as food supplements, because of the risk of overdose [12].

7.3 Hyperphosphataemia and magnesium

Hyperphosphataemia is a direct consequence of parathyroid hormone deficiency, because proximal tubular phosphate reabsorption is no longer inhibited, and it has its own consequences: raised phosphate and a raised calcium-phosphate product are linked to extraskeletal calcification, including cataracts and nephrocalcinosis [34], and raised phosphorus may cause ectopic soft tissue calcification [17]. The European guideline suggests, with a weak recommendation, dietary changes and/or adjustment of calcium and vitamin D doses and, if this is not effective, parathyroid hormone replacement [34]. Paediatric practice adds dietary phosphate restriction and, if necessary, phosphate binders [22]; published experience with sevelamer in an adolescent with autosomal dominant hypocalcaemia type 1 was of inefficacy with significant abdominal pain and diarrhoea requiring discontinuation [69]. Maintaining normal serum calcium and phosphate is recommended to minimise the risk of cataracts and intracerebral calcification [17]. The 2024 Parathyroid Summit consensus specifies the dietary restriction and quantifies the target and its main obstacle. The foods to limit in adults are dairy products, legumes, meat, nuts, seeds, cereals and boxed or canned processed foods, and the diet should at the same time be enriched in calcium; the obstacle is phosphorus added as a food additive, which can raise the phosphorus content of the diet by up to 41% and is therefore explicitly avoided. The target is normal serum phosphate with a normal calcium-phosphate product, specified as 4.4 mmol²/l² or 55 mg²/dl², and phosphate binders are considered when there is a raised calcium-phosphate product or soft tissue calcification, the panel acknowledging that the evidence supporting their use in this disease is scarce and that the evidence for the efficacy of dietary restriction itself is limited. Taking calcium supplements with meals is part of the anti-phosphate strategy, because calcium simultaneously acts as a binder [43].

Magnesium is the third ion of the problem and the most often forgotten. Hypomagnesaemia impairs both parathyroid hormone secretion and the peripheral response to the hormone and makes hypocalcaemia refractory and seizures more likely even with adequate calcium and vitamin D; the threshold used differs between sources, with the 2025 European guideline considering hypomagnesaemia below 0.7 mmol/l and the paediatric review with expert perspectives using 0.65 mmol/l [22, 34]. The mechanism is twofold: magnesium activates the calcium-sensing receptor and reduces parathyroid hormone synthesis and secretion, and hypomagnesaemia also causes resistance to the hormone, because intracellular magnesium is a cofactor of adenylyl cyclase; both hypomagnesaemia and hypermagnesaemia can impair parathyroid function, and magnesium abnormalities require assessment of the cause and correction, especially in patients on parathyroid hormone therapy [27]. The relationship is bidirectional and the 2024 Parathyroid Summit consensus adds the missing half: the absence of parathyroid hormone also impairs magnesium uptake in the distal convoluted tubule, so that hypoparathyroidism itself generates hypomagnesaemia, which in turn worsens hormone resistance and the refractoriness of hypocalcaemia [43]. The same document emphasises that a low measured serum magnesium indicates a significant, not marginal, intracellular deficit and should be replaced accordingly [43]. When the question is whether there is an intracellular deficit with normal serum magnesium, the European guideline describes a retention test: 0.5 mmol of magnesium per kilogram of body weight in 500 ml of normal saline, as an intravenous infusion over six hours, avoided in severe renal failure and with a reduced dose in mild renal dysfunction; 24-hour urinary excretion of less than 50% of the amount administered indicates a probable intracellular deficit, and the infusion itself serves as treatment [34]. The distribution of body magnesium explains the limitation of the serum value: 53% is in bone, 27% in muscle, 19% in soft tissues and only 0.8% in the circulation, of which 0.3% in serum [34]. The European guideline suggests, with a weak recommendation, measures to raise magnesium in hypomagnesaemia and includes magnesium in the biochemical targets and in monitoring every 3 to 6 months [34]. In primary hypomagnesaemia due to TRPM6, the individual dose varies widely between patients, between 0.4 and 3.9 mmol/kg/day of elemental magnesium, and dividing oral supplementation into three to five doses reduces fluctuations in serum magnesium and prevents chronic diarrhoea in many patients, although not all; with this regimen serum calcium normalises, but serum magnesium generally remains slightly below normal, because renal leak becomes apparent after supplementation has been started [36].

The 2025 French protocol recommends keeping the calcium-phosphate product below the upper limit of normal for age and aiming for phosphate in the upper half of the normal range for age, which it considers the most reasonable compromise, because no intervention study has demonstrated the benefit of correcting the product and the threshold to aim for has not been established; it cites the Danish data on increased mortality from 2.62 mmol²/l² and phosphate above 1.28 mmol/l and the threshold of 4.4 mmol²/l², or 55 mg²/dl², used by other recommendations [12]. First line is dietary, with attention to phosphate additives, identified on food labels by code E339, which can double the daily phosphate load — a higher estimate than the increase of up to 41% cited by the 2024 consensus [12, 43]. Because the main mechanism of hyperphosphataemia is tubular reabsorption and not intestinal absorption, the clinical benefit of dietary restriction remains to be assessed [12]. Activated vitamin D analogues also increase intestinal phosphate absorption, so limiting high doses is part of phosphate control, and phosphate is reassessed after each dose increase [12]. Non-calcium binders — sevelamer carbonate or hydrochloride and lanthanum carbonate — are used off-label when the risk of calcification is high or phosphate remains high despite diet, only by a doctor at a reference or competence centre accustomed to their use, with the disadvantage of a large number of tablets or sachets daily and without demonstrated benefit on vascular calcification [12].

On magnesium, the protocol adds that hypoparathyroidism favours deficiency, both through the lack of parathyroid hormone and through treatment with thiazides or parathyroid hormone receptor agonists; hypomagnesaemia, defined as magnesium below the laboratory's lower limit, requires supplementation with dosing according to cause, depth and duration, and supplementation even without hypomagnesaemia may help some chronic symptoms and may be done by self-medication, without any expected rise in calcium [12]. Magnesium is available as lactate or carbonate tablets, as chloride or sulphate ampoules for oral or intravenous use and as compounded preparations, and magnesium-rich mineral waters count towards intake; serum magnesium is monitored regularly, and more closely in renal failure, because of the risk of hypermagnesaemia [12].

7.4 Hypercalciuria, nephrocalcinosis and thiazides

Nephrocalcinosis due to overtreatment is the central iatrogenic risk of this whole article, and the mechanism is inescapable: without parathyroid hormone, the distal tubule cannot reabsorb calcium, so any dose of calcium and active vitamin D that normalises serum calcium causes hypercalciuria [22]. Prevention rests on three measures: deliberately aiming for the lower half of the normal range, monitoring the urinary calcium/creatinine ratio, and performing renal ultrasound about every six months in children on treatment [22]. When hypercalciuria is present, the European guideline suggests, with a weak recommendation, reducing the doses of calcium and/or active vitamin D, reducing sodium to less than 6 g of sodium chloride or less than 2.4 g of sodium per day, and/or adding a thiazide, and, if this is not effective, parathyroid hormone replacement [34]. The hypercalciuria thresholds the guideline uses as a criterion for considering hormone replacement are more than 7.5 mmol per 24 hours (300 mg) in men, more than 6.25 mmol per 24 hours (250 mg) in women, or more than 0.1 mmol/kg per 24 hours (4 mg/kg) in both sexes [34]. If nephrocalcinosis is confirmed, the approach is to reduce calcium and active vitamin D, maintain hydration and consider a thiazide [22]. Thiazides are avoided in pregnancy and adrenal insufficiency and used with caution in autosomal dominant hypocalcaemia [27], and should be stopped before conception or as soon as pregnancy is confirmed, and may be used with caution in the second and third trimesters after risk-benefit assessment [34].

The 2024 Parathyroid Summit consensus adds four conditions of use that determine whether the thiazide works and at what cost. The first is that the hypocalciuric effect depends on a low-sodium diet, the implementation of which generally requires formal dietary advice, and that the recommended dose is 25 to 100 mg of hydrochlorothiazide per day, with a plasma half-life of 6 to 12 hours. The second is that treatment requires monitoring of serum potassium and magnesium and may require supplementation of both, in addition to causing postural hypotension. The third is that thiazide use is associated with a small increase in the incidence of non-melanoma skin cancer, which is why some of the panel's experts recommend sun protection for patients on prolonged treatment — an observation with practical consequences in a disease treated from childhood and for life. The fourth is that use is explicitly off-label in this condition [43]. The same document extends the 24-hour urine collection of the renal assessment to oxalate and citrate, in addition to calcium and creatinine, because these characterise the lithogenic risk, and notes that calcium citrate, preferable under proton pump inhibitors, also reduces urinary oxalate excretion [43].

Direct evidence of the efficacy of thiazides in the gain-of-function forms of the calcium-sensing receptor comes from two Japanese patients with activating CASR variants, one of them the variant with the Bartter phenotype: both developed generalised tonic seizures due to hypocalcaemia a few weeks after birth and, despite treatment with a standard dose of 1,25-dihydroxyvitamin D3 in one case and of 1-alpha-hydroxyvitamin D3 in the other, acceptable serum calcium close to the lower limit of normal could not be achieved and urinary calcium excretion increased inappropriately; the addition of hydrochlorothiazide at 1 mg/kg reduced urinary calcium excretion, kept serum calcium close to the lower limit of normal, allowed the doses of active vitamin D to be reduced and relieved symptoms [7].

The 2025 French protocol distinguishes two forms of hypercalciuria with different consequences. Output hypercalciuria is measured, in adults, in a 24-hour collection whose completeness is confirmed by urinary creatinine, which should lie between 0.13 and 0.17 mmol/kg/day in women and between 0.15 and 0.21 mmol/kg/day in men; it is defined as above 7.5 mmol/day (300 mg) in men and 6.25 mmol/day (250 mg) in women and, in children, above 0.15 mmol/kg/day in both sexes [12]. Concentration hypercalciuria is measured in any sample and defined as above 3.8 mmol/l, the threshold above which the crystals that give rise to stones form [12]. Hydration acts on the second and not on the first, and output depends linearly on salt and animal protein and not linearly on ingested calcium [12]. The measures are therefore quantified: a normal-sodium diet, with about 6 g of salt per day, verified by 24-hour natriuresis of 100 mmol/day or less in the same collection; a normal-protein diet, with 0.8 to 1 g/kg/day, verifiable by 24-hour urinary urea and achieved, in practice, with a single daily serving of meat, fish or egg; dietary calcium intake at least equal to that of the general population; and hydration spread through the day, of about 1 to 1.5 l/m² per day, or a urine output of 2 l or more, with hyperhydration to obtain clear urine throughout the day and night if there is active lithiasis [12]. To reduce lithogenic risk, the protocol adds increasing the urinary antilithogenic factors, magnesium and citrate, and referring every patient at risk of lithiasis or nephrocalcinosis to a nephrologist or urologist trained in stone prevention; to protect renal function, avoiding nephrotoxic drugs and renal parenchymal infections [12].

Citrate salts are indicated in patients with lithiasis or nephrocalcinosis or at high risk of them, as a compounded preparation of sodium, potassium or magnesium citrate powder dissolved in drinking water through the day, reimbursable in France when prescribed as a therapeutic compounded preparation without an equivalent proprietary product, or as potassium citrate (Lithosolv®) or potassium and magnesium citrate (Lithos®) tablets, taken with meals in two to three doses, with possible bloating or diarrhoea [12]. As for thiazides, the protocol starts with a minimal dose, for example 12.5 mg/day of hydrochlorothiazide, with monitoring of potassium and calcium, and notes that the effective dose is often 50 mg/day in adults, higher than that for hypertension and within the 25 to 100 mg/day range of the Second Workshop and the 2024 consensus, whose maximum of 100 mg/day corresponds to the 50 mg twice daily of the European guideline; unlike in the general population, the thiazide is often poorly tolerated in adults with hypoparathyroidism, with fatigue, cramps and palpitations, requires control of sodium intake, is more effective when residual parathyroid hormone secretion persists and, in the presence of lithiasis or nephrocalcinosis, requires measurement of 24-hour citraturia and citrate supplementation if necessary [12]. In children, the thiazide may cause hypokalaemia and growth delay and exposes the child to fluid and electrolyte decompensation in viral gastroenteritis, so it is reserved for the most severe forms, after advice from a specialist centre [12].

7.5 Parathyroid hormone replacement

Parathyroid hormone replacement has moved from a theoretical alternative to an established option in adults. The 2025 European guideline recommends it with strong strength and low-quality evidence when signs or symptoms persist despite optimised vitamin D and calcium, and suggests, with a weak recommendation, titrating it to a sustained target calcium without concomitant active vitamin D or calcium supplements [34]. It further suggests, also with a weak recommendation, considering replacement even with optimised conventional therapy if any one of five criteria is present: frequent calcium fluctuations or symptomatic hypocalcaemia, defined as three or more adjustments per year of the doses of active vitamin D and/or calcium to maintain the target; impaired quality of life attributable to the disease; estimated glomerular filtration rate below 60 ml/min/1.73 m²; hypercalciuria above the thresholds already cited; or hyperphosphataemia [34]. The effect of treatment is assessed at 6 to 12 months, according to the goals, as good clinical practice [34]. The Second International Workshop, which predates the approval of palopegteriparatide, already listed as indications of inadequate control symptomatic hypocalcaemia, hyperphosphataemia, renal failure, hypercalciuria and poor quality of life, and as other considerations poor adherence, malabsorption, intolerance of high doses of calcium or active vitamin D and osteoporosis requiring denosumab, setting escalation thresholds of calcium above 2 g/day or active vitamin D above 2 µg/day [27]. The 2024 Parathyroid Summit consensus confirms that replacement with palopegteriparatide has been approved and is an important therapeutic option, especially when conventional therapy is inadequate or not tolerated [43]. The goals that this consensus sets for replacement are to relieve symptoms while avoiding hypercalcaemia and symptomatic hypocalcaemia, defined as ionised calcium below 1.00 mmol/l, to normalise urinary calcium and serum phosphate and magnesium, to preserve renal function, to avoid lithiasis and nephrocalcinosis and to improve quality of life [43].

The same document publishes a daily-decision titration algorithm that is more granular than that of the label and that, being a guideline, is the reference when the two differ. It starts with 18 µg subcutaneously once daily. If albumin-corrected calcium is below the target range, palopegteriparatide is increased by 3 µg every 7 days; if the need arises before 7 days, calcium and active vitamin D are increased instead of the drug, reserving the 3 µg increment for day 7. If calcium is normal, the dose is maintained until day 7 and on that day active vitamin D is reduced and palopegteriparatide is increased by 3 µg in the same decision; if the patient is no longer on active vitamin D, calcium is reduced by 1500 mg per day and palopegteriparatide increased by 3 µg. If calcium is raised, the order of de-escalation is fixed and begins with conventional therapy: active vitamin D is stopped or reduced first, then calcium, and only last, with the patient already off active vitamin D and calcium, is palopegteriparatide reduced [43]. The material difference from the Food and Drug Administration label lies in the direction and sequencing, not in the numbers: the label sets the same initial 18 µg, the same 3 µg increments with a minimum interval of 7 days and the same table for reducing active vitamin D and calcium, but treats adjustment of conventional therapy and of the drug as separate decisions, whereas the consensus explicitly combines them on day 7 and establishes the de-escalation hierarchy [43, 63]. The upper limit continues to diverge between jurisdictions — 30 µg/day in the US label and 60 µg/day in the European and Portuguese summary —, a divergence covered in section 7.6, which the consensus does not resolve because it sets no maximum dose.

Two situations that the label covers summarily have their own procedure in the consensus, and they are the ones that cause most hypocalcaemia accidents. The first is the intercurrent sick day or the missed dose: in either case serum calcium is measured with albumin, preferably fasting or at the time of symptoms, with daily monitoring for 3 to 5 days under medical supervision. With teriparatide, a missed dose may be taken if less than 12 hours have passed since the scheduled time, then measuring calcium and giving a supplementary dose if necessary. With palopegteriparatide, the missed dose should not be taken: albumin-corrected calcium is measured and supplementary calcium carbonate or citrate is given, 600 mg two, three or four times daily as needed, under medical supervision [43]. The difference stems from the half-life of about 60 hours, which makes overlapping doses a predictable cause of hypercalcaemia. The second is the switch from replacement to conventional therapy: teriparatide is reduced gradually over several days, because abrupt cessation causes hypocalcaemia; calcium is measured daily during the transition, particularly in patients with unstable calcium; a need for conventional therapy greater than the patient had before starting replacement is anticipated, because bone remodelling has been reactivated and bone takes up calcium; and palopegteriparatide can be weaned with reintroduction and titration of conventional therapy under daily measurement of albumin-corrected calcium [43]. The point about the increased requirement due to reactivated remodelling is what the European guideline does not contain — it merely indicates reinstitution of the doses used before starting the drug and states that a comparison between abrupt discontinuation and gradual reduction is lacking —, and it is clinically decisive, because restoring exactly the previous dose predictably underestimates the requirement [34, 43].

In children, parathyroid hormone replacement has no approved product in any jurisdiction, but it has consensus dosing with more than a decade of published experience, and this is the available reference. Recombinant human parathyroid hormone 1-34, teriparatide, may be given by subcutaneous injection or by infusion pump, off-label, at doses of 0.34 to 1.4 µg/kg/day, continuously by pump or in two daily administrations by injection [43]. Three observations determine the choice between the two routes. The first is that smaller, more frequent doses avoid the fluctuations in serum and urinary calcium that occur immediately after each subcutaneous injection, preventing transient rises in calciuria and turnover markers. The second is that the pump allows a lower total daily dose for the same effect: in a direct comparison in children with familial hypoparathyroidism, the dose was 0.32 µg/kg/day by pump versus 0.85 µg/kg/day in two daily administrations. The third is that the pump is the method of choice when calciuria or turnover markers remain intermittently above normal despite two to three daily administrations, and that pump infusion simultaneously normalises blood and urinary calcium and turnover markers in adults with postsurgical disease and in children with autoimmune polyendocrinopathy type 1 or CASR gain-of-function variants [43]. Parathyroid hormone 1-34 by injection is associated with normal growth and bone mass accrual in children with hypoparathyroidism, and adults and children on this treatment have been followed for up to 19 years [43]. The indication is resistance to conventional therapy, which is frequent in paediatrics and particularly marked in autoimmune polyendocrinopathy type 1, where malabsorption makes high oral doses of calcitriol and calcium ineffective and where escalating these doses to bring calcium closer to normal produces renal calcification with loss of function [43].

Palopegteriparatide is a prodrug of PTH(1-34) with an effective half-life of about 60 hours, consisting of the active fragment transiently conjugated to a polyethylene glycol carrier by a cleavable linker: the carrier blocks binding to the parathyroid hormone receptor and reduces renal clearance and enzymatic degradation, and after subcutaneous injection exposure to physiological pH and temperature cleaves the linker and releases the fragment in a controlled manner, maintaining stable concentrations throughout the day [27, 34]. In 2025 it is the only parathyroid hormone analogue approved by the European Medicines Agency and the Food and Drug Administration for chronic hypoparathyroidism, with European authorisation in 2023 and US authorisation in 2024 [34]. The Food and Drug Administration label, in the version effective on 12 August 2026, indicates it for the treatment of hypoparathyroidism in adults, with two declared limitations of use: it has not been studied in acute postsurgical hypoparathyroidism, and its titration scheme has only been evaluated in adults who had first achieved albumin-corrected serum calcium of at least 7.8 mg/dl with calcium and active vitamin D [63]. Before starting, in the two weeks before the first dose, it is confirmed that serum 25-hydroxyvitamin D is in the normal range and that albumin-corrected calcium is 7.8 mg/dl or higher [63]; the European summary of product characteristics requires stable calcium within the normal range or slightly below, between 1.95 and 2.64 mmol/l (7.8 to 10.6 mg/dl), in at least one laboratory value in that period [64]. Adjustment of active vitamin D and calcium on the day of initiation or of a dose increase follows an explicit table: with calcium of 8.3 mg/dl or higher and calcitriol above 1 µg/day, calcitriol is reduced by at least 50% and calcium maintained; with calcium of 8.3 mg/dl or higher and calcitriol of 1 µg/day or less, calcitriol is stopped and calcium maintained; with calcium between 7.8 and less than 8.3 mg/dl and any dose of active vitamin D, calcitriol is reduced by at least 50% and calcium maintained; and with calcium of 7.8 mg/dl or higher without active vitamin D, the daily calcium dose is reduced by at least 1500 mg, or stopped if the dose is 1500 mg/day or less, and dietary calcium supplements at doses of 600 mg/day or less may be kept instead of stopping completely [63, 64]. Serum calcium is measured 7 to 10 days after the first dose and after any change in the dose of palopegteriparatide, active vitamin D or calcium, and, once the maintenance dose has been reached, at least every 4 to 6 weeks [63]. If albumin-corrected calcium is 12 mg/dl or higher, the drug is withheld for 2 to 3 days and calcium repeated [63]. Discontinuation requires its own procedure, which the European guideline describes: monitor calcium frequently, for example every two to three days, until control is re-established with conventional therapy, bearing in mind that calcium may remain stable for several days because of the long half-life and that no relevant biological activity is expected beyond 10 to 14 days, and promptly reinstitute conventional therapy at the doses used before starting the drug; there are no studies comparing abrupt discontinuation with gradual reduction of 3 µg every two to three days, so the optimal strategy has not been defined [34].

An administration point with clinical consequences: the Food and Drug Administration label specifies that only one injection be used to achieve the recommended daily dose, because two injections increase the variability of the total dose administered and may cause unintended changes in serum calcium, including hypocalcaemia and hypercalcaemia — and this is why the maximum dose in the US label is 30 µg/day, the maximum value a single pen delivers [63]. The European summary of product characteristics allows a range of 6 to 60 µg/day, and patients on the maximum dose of 60 µg/day with continued hypocalcaemia may require co-administration of therapeutic calcium and/or active vitamin D [64]. The European guideline explicitly notes that doses above 30 µg/day would be given as two simultaneous injections [34]. The divergence between jurisdictions is therefore material and not formal, and a European patient may receive twice the maximum dose permitted in the United States.

In France, according to the 2025 protocol, teriparatide — Forsteo®, Terrosa®, Movymia® and generic versions — has neither European nor French authorisation in hypoparathyroidism and is prescribed off-label after advice from a reference or competence centre; the protocol notes that some European countries, such as Italy, formally frame this use [12]. It has been used for almost 30 years in this indication, studied mainly in children, allows in most cases the calcium target to be reached while reducing or stopping conventional therapy and lowering calciuria, and numerous studies have shown no increase in the risk of bone tumours with prolonged use; it is used subcutaneously with a 20 µg pen, in one to two injections per day, and treatment may last many years, with more than 10 years reported in children [12]. Continuous pump infusion, which reduces the total dose and improves biochemical control, is reserved for specialist centres in forms refractory to the intermittent regimen, because it adds off-label use of the pump and consumables to off-label use of the drug, but the protocol considers it indispensable in certain situations, especially in paediatrics and in malabsorption [12]. Palopegteriparatide (Yorvipath®) has been available in France since 15 October 2024 under post-authorisation early access, with initial hospital prescription and dispensing by hospital pharmacies throughout the country, and the protocol anticipates a move to the standard regime within one to two years; parathyroid hormone 1-84 has never been available in France [12].

7.6 Regulatory table

7.7 Clinical trials and what they allow us to conclude

The 2025 European guideline adds to this table three sets of data brought together by the panel's systematic review, which should be cited with their nature. For conventional therapy there are only two observational studies and two randomised trials, with 170 patients in total and very low-quality evidence, with no data on optimal regimens — that is, first-line treatment of this disease rests on weaker evidence than second-line treatment [34]. For parathyroid hormone replacement there are 19 studies with 2069 patients, 79% women, of which 11 with parathyroid hormone 1-84, seven with parathyroid hormone 1-34 — four with teriparatide, two with palopegteriparatide and one with oral parathyroid hormone — and one with eneboparatide, including six randomised trials, with very low-quality evidence except moderate for the reduction in pill burden [34]. Regarding renal and cardiovascular outcomes, a five-year observational study comparing parathyroid hormone 1-84 with conventional therapy gave adjusted risk ratios of 0.47 (95% confidence interval 0.25 to 0.87) for incident chronic kidney disease, 0.35 (0.13 to 0.89) for decline in estimated glomerular filtration rate and 0.25 (0.08 to 0.81) for a cardiovascular event; with palopegteriparatide, at 26 weeks, mean estimated glomerular filtration rate rose by 7.9 ± 10.4 ml/min/1.73 m² versus 1.9 ± 8.6 with placebo (p < 0.001), and at 52 weeks, in patients with a baseline rate below 60 ml/min/1.73 m², the mean increase was 11.5, with a standard deviation of 11.3 [34].

The REPLACE trial, phase 3, blinded and placebo-controlled, included 134 patients, with 53% of those treated with parathyroid hormone 1-84 achieving the primary outcome versus 2% with placebo, with reductions in calciuria in both arms without a statistically significant difference, and with hypercalcaemia in 18% [27]. In the palopegteriparatide studies preceding the pivotal trial, the four-week phase 2 with a 26-week open-label extension, in 59 adults, allowed active vitamin D to be stopped with calcium supplements reduced to 500 mg/day or less in 91% of participants, and the phase 3 with 84 patients allowed active vitamin D to be stopped in 93% at 26 weeks while maintaining normal serum calcium [27]. The 2024 Parathyroid Summit consensus gives, for the same outcome of independence from conventional therapy at 26 weeks in PaTHway, 93% or 57 of 61 participants, and for the primary composite outcome 79% or 48 of 61 versus 5% or 1 of 21 with placebo, with p below 0.0001 — values that correspond, rounded, to those of the European summary of product characteristics and not to those of the US label, whose more restrictive definition gives 68.9%; treatment-related adverse events were injection-site reactions in 31.1%, hypercalcaemia in 9.8% and headache in 9.8%, with no withdrawals for reasons attributed to the drug [43]. More than 90% of participants in phases 2 and 3 achieved independence from conventional therapy at 24 weeks, with reduced calciuria and serum phosphate relative to placebo [43]. The renal finding from PaTHway with the greatest clinical consequence is a post-hoc analysis of one-year data that showed a statistically significant mean increase in estimated glomerular filtration rate of 9.3 ml/min/1.73 m² from baseline, suggesting improved renal function on the drug; the mechanism is unclear and may reflect both the effect of palopegteriparatide and the cessation of conventional therapy, and the post-hoc nature of the analysis prevents the result from being treated as a demonstration of renal benefit [43]. The 3-year results of PaTH Forward, up to week 162, showed 91% of participants meeting the primary outcome and 24-hour calciuria maintained within the normal range, with the N-terminal propeptide of type 1 procollagen peaking at 26 weeks and the C-terminal telopeptide at 12 weeks, then falling over the three years, and with bone mineral density falling but remaining within the normal range, stabilising after 26 weeks and with Z values approaching age- and sex-specific norms without falling below zero; declines were greater in participants with higher baseline density [43]. For eneboparatide, the open-label phase 2 study allowed the activated vitamin D analogue to be discontinued in 92% and calcium supplements in 88% of patients [34]. For parathyroid allotransplantation, three studies brought together 141 allotransplants in 109 patients: in one study with 10 patients, 70% of grafts were functioning at one year with discontinuation of conventional therapy; in another, with 14 patients, there was a reduction but not discontinuation of therapy; and in the largest, with 85 patients, 57% of grafts were functioning immediately after transplantation, with mean cell survival of 6.3 ± 13.1 months — the basis on which the guideline concludes that allotransplantation has no role in the treatment of chronic hypoparathyroidism [34].

Four limits condition the reading of this table. The first is that the trials are not comparable with one another: the populations differ in the proportion of postsurgical and genetic causes, the composite outcomes are not the same and the definitions of independence from conventional therapy vary, so the difference between 68.9% in PaTHway and 31.1% in CALYPSO does not measure a difference in efficacy between the two drugs. The second is that relative reductions must be read with absolute rates: in PaTHway, the difference of 64.2 percentage points results from a placebo response rate of 4.8%, that is, a single patient out of 21, and the confidence interval of the normal calcium component, from 9.2 to 56.3 percentage points, is wide enough for the true magnitude of that component to be uncertain. The third is the loss of effect over time when the outcome is kept strict: the proportion meeting the composite outcome in PaTHway fell to 39.3% at weeks 52 and 78, and only by allowing dose increases did 64% to 66% remain normocalcaemic and independent, which means that a substantial proportion of patients need upward titration over time [63]. A fifth limit concerns reading rather than design: the same trial produces two different numbers depending on the jurisdiction, because the composite outcome is not defined in the same way. At 26 weeks, the Food and Drug Administration label gives 68.9% (42 of 61) and the European summary of product characteristics gives 78.7% (48 of 61), with the same 4.8% placebo rate, because the US definition adds to the components the absence of missing calcium and vitamin D data from week 22 and a dose of 30 µg/day or less throughout the 26 weeks [63, 64]. Any number cited must state which label is the source. It should also be noted that the PaTHway cohort of 82 patients included five patients with genetic forms — one with autosomal dominant hypocalcaemia type 1 due to a CASR variant, one with DiGeorge syndrome, one with HDR syndrome due to a GATA3 variant and two with autoimmune polyendocrinopathy type 1 —, which is the only randomised trial data available for the entities in this article and is insufficient for any subgroup analysis [63].

The fourth is the hierarchy of evidence: the CALYPSO results are available as a company press release, of 18 March 2025, and as a presentation at the European Congress of Endocrinology, in Prague, on 12 May 2026, without peer-reviewed publication, and the number of participants disclosed in the press release — 202 — differs from that registered on ClinicalTrials.gov — 165 —, a divergence that only publication can resolve [74, 84, 95]; the proof-of-concept study of encaleret in postsurgical hypoparathyroidism is available only as a preprint without completed peer review [80]; and the encaleret data in autosomal dominant hypocalcaemia type 1 with more than 24 weeks of follow-up come from conference abstracts. There are no head-to-head trials between conventional therapy and parathyroid hormone replacement with long-term renal or fracture outcomes, and the European guideline itself states that long-term safety and outcome data for palopegteriparatide on fractures and cardiovascular and renal events are lacking [34]. The ClinicalTrials.gov search for Kenny-Caffey syndrome, Sanjad-Sakati syndrome and the genes GCM2, PTH, GNA11, GATA3, TBCE, FAM111A and mitochondrial DNA as an indexed condition returned no trials, and the search did not cover negative trials, suspensions or withdrawals, nor the European and Brazilian clinical trial registries; a search without findings is not proof of non-existence. No negative trials, suspensions or withdrawals were found in these indications; it should be noted, however, that the calcilytic class had already failed in a different indication, with ronacaleret and JTT-305/MK-5442 not being effective in trials in postmenopausal osteoporosis, before being redirected to autosomal dominant hypocalcaemia [30].

7.8 Treatment particularities by entity

In autosomal dominant hypocalcaemia, the therapeutic principle is reversed relative to the rest of the article. Active vitamin D metabolites with adequate dietary calcium or calcium supplements are used only in symptomatic patients, and the crucial caveat is that this treatment predisposes to marked hypercalciuria, nephrocalcinosis, nephrolithiasis and renal impairment, because the kidney in this condition is already wasting calcium [30]. The European guideline recommends close monitoring of these patients on calcium or active vitamin D, because they may be at greater risk of hypercalciuria and renal complications, states that asymptomatic patients should generally not be treated unless calcium is very low and there is no hypercalciuria, and notes that the target calcium may be lower than in other forms of hypoparathyroidism [34]. Treating autosomal dominant hypocalcaemia as if it were common hypoparathyroidism, seeking to normalise serum calcium, is the mechanism by which iatrogenic renal damage is produced [30]. In autosomal dominant hypocalcaemia type 2 there is no disease-specific guideline, and the recommendations for type 1 — which warn of this risk and cover thiazide diuretics and monitoring — apply by analogy [8, 96].

In autoimmune polyendocrinopathy type 1, adrenal insufficiency is the emergency and dominates the therapeutic hierarchy. Glucocorticoid replacement uses hydrocortisone: the label for hydrocortisone sodium succinate, with an effective date of 5 September 2025, indicates it in primary or secondary adrenocortical insufficiency when oral therapy is not feasible and states that hydrocortisone or cortisone is the drug of choice, with synthetic analogues used together with mineralocorticoids where applicable; mineralocorticoid replacement uses fludrocortisone acetate 0.1 mg tablets, indicated as partial replacement therapy in primary and secondary adrenocortical insufficiency in Addison disease, with a label effective on 8 January 2026 [42]. All patients with adrenal insufficiency need stress-dose rules for sick days, an emergency parenteral hydrocortisone kit with training of the patient and family, and medical alert identification [42]. The caveat specific to this syndrome is that hypocalcaemia may be precipitated or unmasked when adrenal insufficiency is treated, so the two endocrinopathies must be managed together [42]. Chronic mucocutaneous candidiasis is treated with azole antifungals — fluconazole is indicated in oropharyngeal and oesophageal candidiasis, with a label effective on 2 April 2026 —, but treatment should be intermittent and culture-guided when possible, because prolonged continuous azole exposure in this population selects azole-resistant Candida; aggressive control of oral candidiasis is not cosmetic, it is cancer prevention [42]. Non-endocrine autoimmune manifestations, such as autoimmune hepatitis, pneumonitis and enteropathy, are treated with immunosuppression, but no agent has an indication for this syndrome and all such use is off-label [42]. A series of four patients with hypoparathyroidism associated with this syndrome who started palopegteriparatide and were followed for 4 to 15 months observed a robust calcaemic response with wide fluctuations in serum calcium during titration and the possibility of stopping oral calcium and active vitamin D supplements; the authors emphasise that in this syndrome conventional therapy is often complicated by malabsorption and by oesophageal diseases, prevalent in these patients, and that supplementation without correction of the parathyroid hormone deficit can cause renal and other soft tissue calcification, and raise the question of aetiology-specific differences in response that influence dose requirements and calcaemic stability [97].

In the recessive TBCE syndromes, hypocalcaemia is the treatable and potentially fatal problem and is managed lifelong, but respiratory failure caused 84% of deaths in the registry cohort, so the airway, sleep-disordered breathing and infection prevention deserve the same attention as calcium [22]. In the FAM111A dysplasias, survivors with osteocraniostenosis need aggressive respiratory support and management of restrictive lung disease with a respiratory specialist; all affected individuals receive supplemental calcium and activated forms of vitamin D under endocrinology; refractive errors and cataracts are managed by ophthalmology, dental manifestations by a dental specialist or oral surgeon, short stature with environmental and occupational modifications, scoliosis conservatively or surgically, development with individualised support and psychosocial distress with referral to psychology [17]. In HDR syndrome, treatment is directed at hypoparathyroidism, which is the treatable component: the GeneReviews overview of genetic hearing loss lists the syndrome among diseases with specific medical therapy and gives that therapy as oral calcium and calcitriol, with parathyroid hormone injection; hearing loss and kidney disease are managed by the respective specialty and there is no gene-directed therapy [40]. In 22q11.2 deletion, calcium supplementation is given conventionally, with referral to endocrinology and nephrology because of the increased risk of renal stones when long-term supplementation is needed [51]. In the mitochondrial forms, hypocalcaemic tetany was well controlled with low doses of 1,25-dihydroxycolecalciferol in the four children with Kearns-Sayre syndrome who presented with hypoparathyroidism and deafness, and two of three patients had hypomagnesaemia to be corrected in parallel [44]. In the congenital athymia of the syndromic forms, processed allogeneic thymus tissue is approved by the Food and Drug Administration for immune reconstitution in paediatric patients with congenital athymia of any cause, and is not indicated in severe combined immunodeficiency [41].

In neonatal severe hyperparathyroidism, which is the allelic entity of biallelic CASR loss of function and enters here through the differential diagnosis, hypercalcaemia is refractory to glucocorticoids and other attempts at conservative treatment and total or subtotal parathyroidectomies have been performed; some infants, however, had a very benign course, with the body adjusting to a high calcium set point and normalisation of bone structure within a few months, so it seems prudent to observe and not to rush into surgery unless the situation is life-threatening [98]. The hypercalcaemia of some infants responds to cinacalcet, but long-term control usually requires parathyroidectomy [30]. In familial hypocalciuric hypercalcaemia type 1, no intervention is indicated in the great majority and the clinical task is to recognise it and not operate, because parathyroidectomy does not correct the hypercalcaemia — the defect lies in calcium sensing and not in parathyroid mass — and recurrence of hypercalcaemia after parathyroidectomy is a recognised indicator of this diagnosis [30]. When hypercalcaemia is genuinely symptomatic, case report-level evidence supports cinacalcet, including a symptomatic proband with the type 2 form in whom the drug normalised serum ionised calcium; this use is off-label, because the current cinacalcet label does not cover familial hypocalciuric hypercalcaemia [8].

Two paediatric situations common to all entities have their own management in the 2025 French protocol. With fever, requirements rise and treatment is increased temporarily, for example by 30% of the usual dose of the activated vitamin D analogue, with a written action plan given to the family; in an intercurrent illness with complete gastrointestinal intolerance, the referring doctor is contacted urgently to switch to the parenteral route if necessary [12]. In malabsorption, 1-hydroxylated vitamin D analogues are not absorbed and become ineffective, and the patient is referred to a reference or competence centre, where intermittent subcutaneous or pump parathyroid hormone may be used [12]. The same logic applies to adults with coeliac disease, Crohn disease or other inflammatory bowel disease, pancreatic insufficiency, chronic infections, parasitic infections or bariatric surgery: the mechanism and the intestinal segment affected determine the dose, form and route of calcium, magnesium and vitamin D supplementation, in collaboration with dietitians and the specialty of the affected organ [12]. In autoimmune polyendocrinopathy type 1, in which malabsorption is frequent, this approach has direct application.

7.9 Agents and circumstances to avoid

Phenytoin and phenobarbital should be avoided for seizures in these patients because they disturb calcium metabolism [22]. In infants with lymphocyte abnormalities in the syndromic forms with thymic hypoplasia, live vaccines are contraindicated, for example oral poliovirus vaccine and measles, mumps and rubella vaccine, and irradiated blood products are recommended until normalisation of the immune system is confirmed [51]. Carbonated drinks and alcohol consumption may worsen hypocalcaemia, and caffeine may contribute to anxiety [51]. In patients taking palopegteriparatide, concomitant digoxin may predispose to digitalis toxicity if hypercalcaemia arises, so serum calcium and digoxin levels are measured frequently and signs of toxicity monitored [63]. Palopegteriparatide is not recommended in patients at increased risk of osteosarcoma [63]. In autoimmune polyendocrinopathy type 1, prolonged continuous azole exposure should be avoided because it selects resistant Candida, and smoking avoidance should be addressed explicitly, since four of the six Finnish cases of oral or oesophageal carcinoma were long-term smokers [42]. Thiazides are avoided in pregnancy and adrenal insufficiency and used with caution in autosomal dominant hypocalcaemia [27]. Antiresorptives are used with caution when osteoporosis makes them necessary, because they carry a risk of hypocalcaemia in a patient without the capacity for a parathyroid hormone response, and the dose of active vitamin D may need to be increased to avoid it [43]. In patients taking palopegteriparatide, a missed dose should not be made up, for the reasons and with the management described in section 7.5 [43]. Abrupt discontinuation of palopegteriparatide is the circumstance with the highest risk of severe hypocalcaemia and should be avoided [63]; a 2026 report describes discontinuation without rebound hypocalcaemia in chronic hypoparathyroidism, but it is an isolated observation that does not contradict the label warning [99].

The 2025 French protocol is more restrictive than the 2024 consensus regarding antiresorptives: it declares bisphosphonates, denosumab and cinacalcet contraindicated in the patient with hypocalcaemia, because they increase the risk of hypocalcaemia, whereas the consensus allows antiresorptives with caution when osteoporosis makes them necessary, with a possible increase in the dose of active vitamin D [12, 43]. The same protocol recalls that corticosteroids and non-steroidal anti-inflammatory drugs may reduce intestinal calcium absorption, that loop diuretics are not enough to explain hypocalcaemia and that thiazides lower calciuria and not calcaemia [12]. To avoid iatrogenic hypercalcaemia, it recommends regular monitoring of calcium, teaching the patient to recognise the signs of hypercalcaemia — polyuria with polydipsia in a treated patient should suggest it —, reassessing calcium after each dose change, not combining several hypercalcaemic treatments and avoiding acute dehydration [12]. As for unconventional practices, sought by many patients and without demonstrated efficacy, the protocol recommends assessing them with the patient without driving them away from conventional care, because of the risk of loss to follow-up [12].

7.10 Pregnancy, lactation and the neonatal period

The European guideline recommends using active vitamin D and calcium supplements in pregnancy as in non-pregnant women, and notes that case series and registry data show higher rates of induction of labour, preterm delivery, lower birth weight, blood transfusions and congenital anomalies, robust cohort or trial data being lacking [34]. Parathyroid hormone replacement is not currently recommended in pregnancy outside clinical studies, although it may be considered in individually poorly controlled patients; the Second International Workshop is more categorical and states that parathyroid hormone is not recommended in pregnancy [27, 34]. The European summary of product characteristics for palopegteriparatide records that there are no or limited data on use in pregnant women, that animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity but that a risk to the pregnant woman or fetus cannot be excluded, and that the decision to start or stop should weigh risks and benefits, with close monitoring of maternal serum calcium; as for breastfeeding, it is unknown whether palopegteriparatide is excreted in human milk [64]. These two gaps are being directly investigated: a study of drug transfer into human milk in lactating women has been recruiting since 19 March 2026, with 10 planned participants, and a global pregnancy registry to assess maternal, fetal and infant outcomes after exposure to the product has been recruiting since 18 February 2026, with 50 planned participants and expected completion in January 2036 [100, 101].

Thiazides should be stopped before conception or as soon as pregnancy is confirmed, and may be used with caution in the second and third trimesters after risk-benefit assessment [34]. The recommended monitoring is strong: measure ionised and/or albumin-adjusted calcium every 3 to 4 weeks throughout pregnancy and lactation, and weekly in the 4 weeks before and after delivery, aiming for the lower limit of the normal range [34]; the Second International Workshop indicates calcium every 3 to 4 weeks and repeat calcium 2 to 3 days after any change in calcitriol dose [27]. During lactation, the rise in parathyroid hormone-related protein may cause hypercalcaemia, so active vitamin D and calcium are generally reduced immediately after delivery, although some women instead become hypocalcaemic in the early postpartum period [34].

The 2024 Parathyroid Summit consensus explains the physiological reason why the dose required in pregnancy is not predictable and adds the moment of risk that the European guideline does not single out. Parathyroid hormone-related protein, produced by the placenta and the breast, rises between 3 and 13 weeks of gestation and increases the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which raises maternal intestinal absorption of calcium and phosphate; in some women this endogenous rise is enough to cover the needs of the fetal skeleton and the dose of conventional therapy may have to decrease, whereas in others it is insufficient and the dose has to increase, and it is not possible to predict which of the two scenarios will occur in a given patient [43]. During lactation, oestrogen withdrawal increases bone resorption and the breast produces large amounts of parathyroid hormone-related protein, which raise serum calcium and endogenous 1,25-dihydroxyvitamin D. The critical moment is weaning: the abrupt fall in parathyroid hormone-related protein markedly increases the need for calcium and active vitamin D, and this rise in requirement should be anticipated by the endocrinologist rather than discovered through hypocalcaemia, so the patient must inform the team of the weaning plan before starting it [43]. The direction of change is therefore opposite to that of the immediate postpartum period, and the two should be considered separately.

The frequency of monitoring is the only point on which the two documents diverge, and both are recorded: the European guideline strongly recommends measuring ionised or albumin-adjusted calcium every 3 to 4 weeks throughout pregnancy and lactation, and the 2024 consensus indicates every 2 to 4 weeks, with joint monitoring of calcium, magnesium, phosphate and creatinine; the text of the consensus itself states 3 to 4 weeks in the physiology section and 2 to 4 weeks in the recommendation, an internal divergence that the document does not resolve [34, 43]. After any change in the dose of calcium or active vitamin D, the consensus repeats albumin-corrected calcium in 4 to 7 days, an interval somewhat wider than the 2 to 3 days of the Second International Workshop [27, 43]. Because the intravascular volume expansion of pregnancy dilutes albumin, total calcium underestimates true calcium and measurement must be of directly measured ionised calcium or albumin-corrected calcium [43].

The complications to monitor are listed explicitly and should be included in the information given to the patient before conception. On the maternal side: pre-eclampsia, premature rupture of membranes, seizures, arrhythmias, hypercalciuria with renal stones, diabetes mellitus, chronic kidney disease and preterm labour; the studies describing them are retrospective and causal attribution to hypoparathyroidism has not been established in the absence of randomised trials, so the association is presented as such [43]. On the fetal and neonatal side, the direction of the maternal error determines the consequence: low maternal calcium during pregnancy causes hyperparathyroidism in the newborn, high maternal calcium causes neonatal hypoparathyroidism, and neonatal seizures and lower birth weight have also been described [43]. This is why the target is the lower part of the reference range or just below it, with phosphate, magnesium, 25-hydroxyvitamin D and 24-hour urinary calcium kept normal, and why neonatal surveillance with measurement of serum calcium in the first days of life is mandatory, with heightened attention if the newborn is lethargic, irritable or gaining weight poorly [43]. Preconception preparation is when most of the work is done: optimise control and stabilise calcium before conception, switch parathyroid hormone replacement to conventional therapy because there are no pregnancy safety data for parathyroid hormone or its analogues, stop thiazides, educate the patient about the signs of hypo- and hypercalcaemia and what to do about them, discuss the risk of transmission when the cause is genetic with planning of the infant's follow-up, and consider preimplantation genetic testing of the embryo when the molecular aetiology is known; care is provided by a team, with endocrinology, obstetrics and neonatology [43]. In women with 22q11.2 deletion, pregnancy surveillance must take into account pre-existing conditions, including congenital heart disease, scoliosis and reactive airway disease, and should include measurement of calcium, thyroid function and platelets; calcium should be measured regularly during pregnancy [51].

The 2025 French protocol describes the two pregnancy scenarios — a lower need for conventional therapy, due to placental synthesis of 1,25-dihydroxyvitamin D, especially in the first trimester, and to parathyroid hormone-related protein produced by several tissues, with a risk of maternal hypercalcaemia; or a greater need, especially in the third trimester, with a risk of hypocalcaemia, which is associated with miscarriage, preterm delivery, stillbirth, skeletal anomalies and fetal parathyroid hyperplasia — and recommends measuring calcium every 3 weeks during pregnancy, weekly in the last month, and during breastfeeding, with a low-normal target, which may be transiently higher [12]. Haemodilution makes total calcium less reliable, but corrected calcium is no better than total calcium, and ionised calcium is used if necessary; during breastfeeding, active vitamin D and calcium may need to be reduced rapidly, because of mammary synthesis of parathyroid hormone-related protein [12]. The 3-week frequency lies between the 3 to 4 weeks of the European guideline and the 2 to 4 weeks of the 2024 consensus, and the French protocol concentrates weekly surveillance in the last month of pregnancy, whereas the European guideline extends it to the 4 weeks before and after delivery [12, 34, 43]. The newborn of a mother with hypoparathyroidism or primary hyperparathyroidism is at high risk of transient hypercalcaemia, due to parathyroid hyperplasia, or transient hypocalcaemia, due to parathyroid hypoplasia, so the protocol recommends delivery in a level III maternity unit, or a level II unit able to treat neonatal dyscalcaemia early, specific biochemical surveillance and a paediatric endocrinology consultation from the prenatal period to plan immediate postnatal surveillance; the paediatrician or neonatologist should be informed of the maternal diagnosis [12].

7.11 Perioperative care and transition

The perioperative period is a time of predictable risk. In 22q11.2 deletion, recommended surveillance explicitly includes measurement of ionised calcium before and after any surgical procedure [51], and checking plasma calcium at any admission, particularly for cardiac or palatal surgery, is presented as a sensible precaution [52]. A published case of HDR syndrome in which the patient developed acute pulmonary oedema and dilated cardiomyopathy in the context of a cardiac conduction defect attributed to hypocalcaemia and anaesthesia shows the consequence of entering a procedure with uncorrected hypocalcaemia [28]. Transition from paediatric to adult care coincides, in these diseases, with the time when calcium and vitamin D requirements change with the end of growth and when adherence tends to deteriorate; poor adherence was a factor independently associated with long-term complications, with an adjusted odds ratio of 8.04 (95% confidence interval 1.52 to 42.42; p = 0.014) [48]. In Kenny-Caffey syndrome, pubertal delay, hypogonadism and infertility appear frequent in males, with exact incidence yet to be determined, which adds a specific endocrinological reason to the transition clinic [29].

The 2025 French protocol associates three measures with transition. Treatment is adapted to life events — puberty, pregnancy, surgery and menopause —; in adolescence and in any plan for parenthood, a dedicated genetic counselling consultation confirms that the patient knows the mode of transmission and the possibilities of prenatal diagnosis or early presymptomatic diagnosis; and therapeutic education, which in children includes the parents, progressively transfers management of decompensations to the adolescent [12]. Before any neck surgery, the same protocol asks for a fasting calcium, so as not to overlook pre-existing hypoparathyroidism or hypercalcaemia due to primary hyperparathyroidism [12].

7.12 Developments in the last twelve months, with level of evidence

Between November 2025 and November 2026 there were five developments to record, with distinct levels of evidence that should not be mixed. The first, at the level of official regulatory authorisation and decision, is the withdrawal of the European marketing authorisation for Natpar on 1 July 2026, by the European Commission at the holder's request, because of unresolved product-specific supply problems, which definitively removes parathyroid hormone 1-84 from the therapeutic arsenal in any jurisdiction [67]; and, at the same level, the registration of palopegteriparatide in Brazil by the National Health Surveillance Agency, granted by Resolution-RE no. 3,645 of 17 September 2026, published in the Diário Oficial da União on 21 September 2026 [73], and the amendment of the Food and Drug Administration label in August 2026 to add the warning about hypersensitivity reactions, including anaphylaxis, angioedema and urticaria described in the post-marketing phase [63]. The second, at the level of published guideline, is the revised European Society of Endocrinology guideline, published on 30 October 2025, which for the first time strongly recommends parathyroid hormone replacement in patients with persistent symptoms despite optimised conventional therapy, and the good practice recommendations of the 2024 Parathyroid Summit, published in October 2025 [34, 43] — a document whose methodological nature determines the weight to give it and should be declared: it was launched by the Canadian Society of Endocrinology and Metabolism with an international panel divided into nine thematic teams, updated by narrative review, and not by a new systematic review, the period from May 2022 to March 2025 in three bibliographic databases, on the explicit basis that no major new studies had been published in the previous two years, was approved at a consensus meeting on 31 May 2024 and in six rounds of circulation without formal voting, with agreement reached by iterative discussion, and is endorsed by more than twenty scientific societies with the participation of two representatives of the patient association; its own declared limitations are reliance on expert consensus in domains of scarce evidence, the possibility of selection bias inherent to narrative review and variability of application between health systems and regulatory regimes [43]; for the parathyroid component of 22q11.2 deletions, the reference document remains the updated clinical practice recommendations for the management of children with that syndrome, published in 2023 [102]. The third, at the level of published trial result, is the 3.5-year PaTHway data, published on 27 October 2026, and the 3-year skeletal data from PaTH Forward [76, 77]. The fourth, at the level of press release and conference presentation, is the CALYPSO results with eneboparatide [74, 84]. The fifth, at the preclinical level, is the body of work on new agents: the characterisation of quinazolinone-derived calcilytics for autosomal dominant hypocalcaemia type 1 and the description of a chemoreactive calcilytic, both without human data [103, 104]; the demonstration that a long-acting parathyroid hormone receptor agonist corrects hypocalcaemia in mice with autosomal dominant hypocalcaemia type 1 [105]; and the characterisation of canvuparatide, a parathyroid hormone prodrug evaluated in phase 1 trials with a half-life of 184 to 213 hours, which would justify weekly administration, generally well tolerated, with injection-site reactions as the most common emergent adverse event and mild, transient hypercalcaemia as a predictable on-target effect, with doses for later studies determined [57]. An oral small-molecule parathyroid hormone receptor agonist is also under evaluation [57].

Four off-label paediatric uses were described in the same period and constitute initial clinical experience and not a recommendation. Palopegteriparatide was used in a 16-year-old boy with autosomal dominant hypocalcaemia type 1, described in section 10 [69], and as a rescue strategy in a 14-year-old boy with Graves disease and profound hypocalcaemia after total thyroidectomy, with serum calcium of 5.9 mg/dl, ionised calcium of 0.83 mmol/l and undetectable parathyroid hormone, in whom biochemical control remained poor after 16 days of high-dose intravenous and oral calcium with calcitriol: serum calcium improved within 48 hours, intravenous calcium was stopped after 5 days and calcitriol, sevelamer and calcium acetate were stopped within 11 days, with good tolerance, leading the authors to suggest that early parathyroid hormone replacement may be a useful rescue strategy in selected children with severe, refractory post-thyroidectomy hypocalcaemia [106]. Use in autoimmune polyendocrinopathy type 1 has also been described [97]. The first phase 3 trial aimed at adolescents began recruiting in April 2026, with only 12 planned participants [85].

7.13 Therapies aiming to restore gland function

Three approaches seek to replace the tissue rather than the hormone, and none is in routine clinical practice for this indication. Parathyroid transplantation is the oldest: autotransplantation is considered the most effective alternative to replacement therapy and significantly reduces the risk of permanent hypoparathyroidism, and allotransplantation is the alternative when autotransplantation is not possible, with the limitations of rejection and the need for systemic immunosuppression. In practice, immediately after excision the parathyroid tissue is cooled in 0.9% normal saline at 4 °C for about 30 minutes, divided into fragments about 1 mm thick and implanted into a selected skeletal muscle; alternatively, a suspension of fragmented tissue in buffered saline may be given, most often into the sternocleidomastoid muscle [57]. The 2025 European guideline does not recommend parathyroid allotransplantation [34], and the case described in section 10 — a parathyroid cell allotransplant performed at 2 years of age, without achieving graft function — illustrates why [69]. Microencapsulation, which encloses cells in semipermeable biomaterial shells, has not entered routine clinical practice because data are lacking on the optimal number of microcapsules, the number of cells needed for a therapeutic effect and the most favourable anatomical site [57]. Cell therapy with stem cells is the most distant: previous results indicate that mesenchymal stem cells may be a potential therapeutic strategy, and in the future it may be possible to obtain functional parathyroid cells by reprogramming the patient's own fibroblasts or peripheral blood cells and differentiating them into parathyroid cells, but none of these approaches has completed the various phases of clinical trials and ethical questions remain about obtaining and modifying human embryonic stem cells [57]. Advances in parathyroid regenerative biology with pluripotent cells are creating platforms for future curative therapies, and research directions include new forms of microcapsules, gene therapy and regenerative medicine [57, 107]. There is no gene therapy in clinical trials for any of the entities in this article. In autoimmune polyendocrinopathy type 1, the approach closest to a mechanism-directed therapy is an antisense oligonucleotide that reversed pseudoexon inclusion and restored the normal AIRE transcript in lymphoblastoid lines from patients with the deep intronic founder variant, work done in cell culture without in vivo or human data; Janus kinase inhibition with ruxolitinib, tested in five patients after normalising the interferon gamma response in Aire-deficient mice, produced remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren-like syndrome, urticaria and thyroiditis without identified serious adverse effects, but five patients in an open series are a promising signal and not an evidence base; and an anti-CD45RC antibody prevented and treated the experimental disease only in an animal model [42]. None of these approaches corrects established hypoparathyroidism, because the destroyed gland does not regenerate.

7.14 Divergences between documents

Eight divergences between sources affect concrete decisions and should be known. The first is the strength assigned to parathyroid hormone replacement: the 2022 Second International Workshop recommends conventional therapy as first line with a weak recommendation and reserves parathyroid hormone for when conventional therapy is unsatisfactory, whereas the 2025 European guideline strongly recommends replacement when signs or symptoms persist despite optimised vitamin D and calcium [27, 34]; the difference reflects the approval of palopegteriparatide and the trial data published in the meantime, and the reference is the more recent document. The second is the maximum dose of palopegteriparatide, 30 µg/day in the US label and 60 µg/day in the European and Portuguese label, with the US restriction justified by the variability of the dose delivered when two injections are used [63, 64]. The third is the maintenance infusion rate in acute hypocalcaemia, 50 ml/hour in the 2022 document and 100 ml/hour in the 2025 one, with the same composition [27, 34]. The fourth is the frequency of routine monitoring: the European guideline strongly recommends biochemistry every 3 to 6 months and, after any therapeutic change, every 1 to 2 weeks, whereas the 2022 document gives intervals of 3 to 12 months in the survey and 6 to 12 months in the narrative text, an internal divergence the document itself does not resolve [27, 34]. The fifth was introduced by the 2024 Parathyroid Summit consensus and is the frequency of parathyroid hormone measurement: the European guideline measures it annually to detect recovery of secretion, and the consensus limits it to the initial assessment and, in postsurgical disease, to the first year, only to establish chronicity [34, 43]. In the entities in this article in which the gland did not form, the restrictive position is the one that matches the biology, and annual measurement is only justified in forms in which recovery is conceivable, such as the autoimmune form. The sixth is the frequency of monitoring in pregnancy and lactation, 3 to 4 weeks in the European guideline and 2 to 4 weeks in the 2024 consensus, which in its own text gives the two intervals in different sections [34, 43]. The seventh is the paediatric calcium dose, 40 to 60 mg/kg/day under 4 years in the 2024 consensus and about 50 to 75 mg/kg/day in the paediatric review with expert perspectives [22, 43]. The eighth is the plasma half-life of calcitriol within the 2024 consensus, 5 to 8 hours in the conventional therapy table and 3 to 6 hours in the text, with no consequence for management, which is the same with either value [43]. As for divergences between the guideline and the labels, the reference is the guideline dose, and the label dose is cited alongside for comparison; where the guideline gives no dose for the condition, the reference becomes the most recent consensus document that does — for the paediatric age group, which the European guideline does not cover, the 2024 Parathyroid Summit consensus, which has age-band dosing for calcitriol and calcium and weight-based dosing for parathyroid hormone 1-34, and, failing that, the 2022 document — and, last, the label, with the extrapolation declared.

The 2025 French protocol adds its own divergences from the guidelines already cited, all with practical consequences. The first is calcium measurement: the protocol recommends uncorrected total calcium, for diagnosis and follow-up, and the 2024 consensus prefers ionised calcium and, failing that, albumin-corrected calcium [12, 43]. The second is the maintenance infusion in adults: five ampoules of gluconate, about 450 mg of elemental calcium, in 500 ml over 12 hours, or about 37 mg/h, against 900 mg in 1 l at 100 ml/h in the European guideline, or 90 mg/h, and at 50 ml/h in the 2022 document, or 45 mg/h; the French protocol is the most conservative and, like the others, adjusts the rate to the measured calcium [12, 27, 34]. The third is the threshold for corrected QT prolongation: 440 ms in men and 460 ms in women and children in the adult protocol, 0.42 s in the paediatric protocol, and 0.45 s and 0.47 s in the 2024 consensus [12, 43]. The fourth is how calcium carbonate is taken: away from meals in the French protocol, to maximise absorption, and with meals in the European guideline and the 2024 consensus, because carbonate requires an acid medium and calcium acts as a phosphate binder; the French protocol acknowledges the anti-phosphate effect of taking doses with meals, but the absorption argument has no experimental support: fasting, the fraction of calcium absorbed from carbonate was similar to that from citrate in normal individuals (0.225 versus 0.243) and much lower in achlorhydria (0.042 versus 0.452), and normalised when carbonate was given with breakfast; taking carbonate with meals, which does not lose absorption and adds the phosphate-binding effect, is therefore kept as the reference, with citrate in achlorhydria [12, 34, 43, 68]. The fifth concerns antiresorptives and cinacalcet, contraindicated in the French protocol and allowed with caution by the consensus [12, 43]. The sixth is the initiation dose of activated analogues in children: 2 to 4 µg/day of alfacalcidol or 1 to 2 µg/day of calcitriol in the French protocol, fixed values higher than those for adults, against 0.02 to 0.1 µg/kg/day of calcitriol under 4 years in the consensus and 0.04 to 0.08 µg/kg/day of alfacalcidol under 20 kg in the Portuguese summary of product characteristics; for a 10 kg infant, the French alfacalcidol dose is several times higher than the label dose, and the paediatric weight-based reference remains that of the consensus [12, 43, 60]. The seventh is time to effect: the French protocol gives 1 to 3 days for calcitriol and 5 to 7 days for alfacalcidol, whereas the European guideline gives 1 to 2 days onset of action for both and reserves the 5 to 7 days for the offset of action of alfacalcidol [12, 34]. The eighth is the ceiling for 25-hydroxyvitamin D, 150 nmol/l in the French protocol against 125 nmol/l in the Second Workshop and the consensus [12, 27, 43]. The ninth is the paediatric hypercalciuria threshold, 0.15 mmol/kg/day in the French protocol against 0.1 mmol/kg/day (4 mg/kg/day) in the European guideline and the Second Workshop, so that a child with 0.12 mmol/kg/day is hypercalciuric by the latter and not by the former [12, 27, 34]. The tenth is the frequency of calciuria measurement, every 6 months when the situation is stable in the French protocol, against 1 to 2 years in the European guideline and 6 to 24 months in the consensus [12, 34, 43]. The eleventh is the initial thiazide dose, 12.5 mg/day of hydrochlorothiazide in the French protocol against 25 mg/day at the lower limit of the Second Workshop and the consensus [12, 27, 43]. The twelfth is the calcium threshold for the intravenous route without signs of severity, 1.80 to 1.90 mmol/l in the French protocol, against the emergency criterion of 1.75 mmol/l of the Second Workshop [12, 27]. There is also an internal divergence in the protocol: the text does not recommend routine brain imaging at diagnosis, whereas the attached follow-up schedule lists it at diagnosis in the three paediatric age bands; in adults, both reserve it for selected patients [12].

7.15 What is approved, what is off-label and what is accessible

The distance between what the guidelines recommend, what the labels approve and what is actually available is, in this disease, large enough to condition practice, and should be stated plainly. Of conventional therapy, which all guidelines place first line, only part has an approved indication. Calcitriol has the indication of postsurgical hypoparathyroidism, idiopathic hypoparathyroidism and pseudohypoparathyroidism in both the US label and the Portuguese summary of product characteristics [58, 59], and alfacalcidol has the indication of hypoparathyroidism and pseudohypoparathyroidism in the Portuguese summary [60]; calcium carbonate has, in Portugal, the explicit indication of adjuvant supplement in acute and chronic hypoparathyroidism [61], but in the United States oral calcium carbonate and citrate circulate as dietary supplements or over-the-counter antacids, without a medicinal product label for this condition, so the use of therapeutic doses of elemental calcium in hypoparathyroidism is, in that jurisdiction, off-label, despite being the basis of conventional therapy in all guidelines [58, 62]. Colecalciferol at supraphysiological doses, which the European guideline allows when activated analogues are unavailable, is off-label, because the labels refer to vitamin D deficiency [34]. Magnesium is the extreme case: no guideline consulted specifies the salt, dose, route or maximum, and no magnesium label consulted has an indication for hypoparathyroidism, so all use is off-label and the paediatric doses cited in section 7.3 come from a narrative review with expert perspectives and from a series of patients with primary hypomagnesaemia, not from a label [22, 36, 66].

Three divergences between jurisdictions directly affect the choice of drug in children, which is the population where this article plays out. The first concerns calcitriol: the US label gives explicit paediatric doses for hypoparathyroidism — 0.25 to 0.75 µg/day between 1 and 5 years and 0.5 to 2 µg/day from 6 years onwards —, whereas the Portuguese summary of product characteristics states that the safety and efficacy of the capsules in children have not been sufficiently studied to allow dose recommendations, even though the indication of hypoparathyroidism appears without age restriction [58, 59]. The second concerns alfacalcidol, which is the mirror image of the first: the Portuguese summary has approved weight-based paediatric dosing — 1 µg/day in adults and children over 20 kg and 0.04 to 0.08 µg/kg/day below that weight —, and the drug is not approved in the United States, where no alfacalcidol product exists [60]. The practical consequence is that, for an infant or young child with congenital hypoparathyroidism, the option with approved dosing in Portugal is alfacalcidol and in the United States is calcitriol, and the choice is determined by the jurisdiction and not by pharmacology. The third concerns calcium carbonate, which in Portugal is not indicated in children under 12 years, above which age the summary leaves the dose to medical judgement [61].

The most awkward tension is that of the thiazide. The guidelines propose adding a thiazide diuretic with a low-sodium diet to reduce urinary calcium excretion [27, 34], but the US calcitriol label lists thiazides as an interaction, noting that there are reports that concomitant administration of thiazides with calcitriol causes hypercalcaemia and that caution should be exercised when co-administration is necessary — that is, the label warns precisely against the combination that the guideline recommends [58]. Use is therefore off-label and with a declared interaction, and the practice rests on the guideline recommendation and on two published paediatric cases with activating calcium-sensing receptor variants in which hydrochlorothiazide at 1 mg/kg reduced urinary calcium excretion and allowed the doses of active vitamin D to be reduced [7]. This practice is also, for the first time, being formally tested: a phase 4 trial is comparing prolonged-release indapamide 1.5 mg with placebo in patients with postsurgical hypoparathyroidism and is recruiting [91]. In Portugal, it was not possible to confirm the existence or absence of a single-component hydrochlorothiazide presentation, because Infomed searches mainly returned fixed antihypertensive combinations, but it is confirmed that single-component indapamide is authorised [66].

As for access, the situation in Portugal and Brazil deserves to be stated rather than omitted. Palopegteriparatide is authorised in Portugal for the three presentations but without marketed presentations recorded in Infomed, so access depends on an exceptional use authorisation or a holder programme [64, 66]; in Brazil it has been registered since 21 September 2026, with indication and dosing published by the agency itself, but without a published professional package insert — the Electronic Package Insert Database returns no record for the product or the active substance and the corresponding field on the registration record is empty —, so the contraindications and warnings citable in Brazil are those of the US label or the European summary, by declared extrapolation, and not positions published by the Brazilian agency; marketing further depends on the price set by the Medicines Market Regulation Chamber and access in the Unified Health System on the National Commission for the Incorporation of Technologies [71–73]. The Brazilian professional package insert does not yet exist, which is different from being inaccessible: the National Health Surveillance Agency's Electronic Package Insert Database returns no record for the product, the active substance or the registration number, the package insert field on the product record is empty and the holder's website does not list the medicine [72]. What exists officially is the registration record, the resolution published in the Diário Oficial da União and the agency's own page on new medicines, and these sources provide the essential information. The registration has number 122140142, process 25351.128566/2025-11, was granted on 21 September 2026 with validity until September 2036, is active, is in the "new" category with prioritisation for rare disease, has ATC code H05AA and belongs to ADIUM S.A.; the publication is Resolution-RE no. 3,645 of 17 September 2026, in the Diário Oficial da União of 21 September 2026 [72, 73]. The three registered presentations are 0.3 mg/ml solutions for subcutaneous injection, in a carton with a glass cartridge of 0.56 ml, 0.98 ml and 1.4 ml accompanied by two applicator pens, corresponding to the 168, 294 and 420 microgram PTH(1-34) pens of the European label; storage is between 2 °C and 8 °C, protected from light, sale is on medical prescription with a red stripe and use is restricted to adults, with no approved paediatric population [72]. The approved indication is parathyroid hormone replacement therapy for the treatment of adults with chronic hypoparathyroidism, without distinguishing surgical and non-surgical subgroups and without requiring failure of conventional therapy in the text of the indication [72]. The approved dosing is subcutaneous, once daily, initiated and monitored by professionals experienced in the disease, individualised by albumin-adjusted serum calcium with the lowest effective dose and ideally without active vitamin D or therapeutic calcium supplementation, with nutritional supplementation of up to 600 mg/day allowed: starting dose of 18 micrograms per day, increments of 3 micrograms at minimum intervals of seven days and a dose range of 6 to 60 micrograms per day, with laboratory monitoring 7 to 14 days after initiation and after each adjustment [72]. The risks highlighted by the agency are injection-site reactions, headache, paraesthesia, fatigue and nausea, generally of mild to moderate intensity, with a single case of grade 3 hypercalcaemia considered related to treatment, and hypercalcaemia predominantly at initiation and during titration, transient and manageable with temporary interruption; the same page notes that long-term safety data are limited, particularly regarding bone, renal function, immunogenicity and prolonged exposure to polyethylene glycol, aspects being monitored in the extension studies [72]. There are, to date, no contraindications, formal warnings, interactions or pen instructions for use published in Brazilian text, so this information has to be taken from the Food and Drug Administration label or the European summary of product characteristics, with the extrapolation declared [63, 64, 72]. Actual marketing further depends on approval of the maximum price by the Medicines Market Regulation Chamber, and availability in the Unified Health System depends on assessment and recommendation by the National Commission for the Incorporation of Technologies, so as of 1 November 2026 there is no confirmation of marketing or incorporation [72]. Parathyroid hormone 1-84 has ceased to exist in any jurisdiction, with three distinct dates to record: manufacture ceased in December 2024, the US special use programme ended on 31 December 2025, with the manufacturer stating that the Food and Drug Administration had supported the programme because of the absence of an approved parathyroid hormone alternative and that this situation had changed with the availability of a new option, and the European authorisation was withdrawn on 1 July 2026; in Portugal, the status recorded in Infomed is "Revoked" and in Brazil there was never a registration [62, 66, 67, 108]. The consequence is that, at present, the only parathyroid hormone replacement actually marketed in Portugal and Brazil is teriparatide, whose label does not contain the word hypoparathyroidism and which is approved only for osteoporosis, all use in this condition being off-label [62, 65, 66]. The European guideline describes replacement with short-acting parathyroid hormone 1-34 as currently off-label and explains the pharmacological reason why it does not reproduce physiology: the plasma half-life is about one hour for parathyroid hormone 1-34 and about three hours for 1-84, so once-daily injections do not produce sustained activity, and studies with twice-daily administration are scarce [34]. Regarding teriparatide in children there is a further tension: the label instructs that it be avoided in patients with open epiphyses because of the risk of osteosarcoma and states that it is not approved in the paediatric age group, while the reference literature on paediatric hypoparathyroidism has used parathyroid hormone 1-34 in children, including by continuous subcutaneous infusion, with better metabolic control and lower doses than with injections [27, 65].

In France, the 2025 protocol mentions that some of the pharmacological and non-pharmacological measures of chronic treatment may not be reimbursed, notably dietary supplements, which is relevant for magnesium, mineral waters and some compounded preparations [12].

7.16 Non-pharmacological measures and therapeutic education

The 2025 French protocol considers diet a key element of treatment, ideally guided by a dietitian familiar with the disease, with six rules: adapted calcium intake, which may suffice to control calcium without pharmacological calcium, as shown by a randomised trial in patients not adherent to treatment; increased fluid intake to keep urinary calcium concentration below 3.8 mmol/l throughout the day and night; control of salt and animal protein in patients with hypercalciuria, lithiasis or nephrocalcinosis; limitation of phosphate in hyperphosphataemia; and increased magnesium in hypomagnesaemia, hypomagnesiuria and lithiasis [12]. Mineral waters serve as a supplement: in France, calcium-rich ones, such as Contrex®, Hépar® or Courmayeur®, and magnesium-rich ones, such as Hépar® or Rozana® [12].

Therapeutic education is, in the protocol, a right of every patient with chronic hypoparathyroidism, child or adult, with the participation of the parents and relatives who support the patient: it addresses mechanisms, symptoms, follow-up, treatment, diet and physical activity, teaches how to avoid acute dyscalcaemias and manage them without recourse to a professional, seeks the compromise between absence of symptoms and absence of iatrogenic complications and prevents relatives, through failing to understand invisible symptoms, from causing the patient to feel misunderstood or guilty; in France there are several face-to-face and remote programmes, one of which is co-run by the patient association [12]. Quality of life is a goal in itself, and the protocol also asks that professionals — surgeons, family doctors, specialists — be trained to recognise the symptoms that degrade it [12]. Adapted physical activity may reduce muscle pain and improve mood [12]. Psychological support, in hospital or in private practice, helps integrate the diagnosis of a rare chronic disease with invisible symptoms, and in France the health insurance psychological support scheme gives access, from 3 years of age, to 12 partially reimbursed consultations; in disabling cognitive disorders, neuropsychological rehabilitation may be indicated [12].

8. Reproductive Options and Family Counselling

8.1 Recurrence risks by inheritance pattern

The recurrence risk depends on the gene and, for two genes in this article, on the specific variant. In autosomal dominant forms with an affected parent — autosomal dominant hypocalcaemia types 1 and 2, HDR syndrome, Kenny-Caffey syndrome type 2 and the dominant forms of familial isolated hypoparathyroidism 1 and 2 — the risk is 50% for each pregnancy, regardless of the child's sex. In autosomal recessive forms — autoimmune polyendocrinopathy type 1, TBCE syndromes, recessive forms of familial isolated hypoparathyroidism 1 and 2, primary hypomagnesaemia due to TRPM6 — the risk is 25% for each pregnancy when both parents are carriers, with a 50% probability that the child is an unaffected carrier. In the X-linked form, a carrier woman has a 50% probability of transmitting the allele to each child, with affected sons and carrier daughters; no offspring of affected males are known in the families described, which prevents their fertility from being estimated [5].

Two genes have two documented patterns and require counselling to be based on the variant and not on the gene. For PTH, signal peptide variants causing endoplasmic reticulum retention with an apoptotic effect segregate dominantly, whereas splice site variants and some signal peptide variants in the homozygous state in consanguineous families segregate recessively [1]. For GCM2, most families are recessive, but last-exon frameshift alleles act as dominant negatives and produce dominant transmission; OMIM lists the phenotype as dominant and recessive, whereas UniProt and most GenCC submitters record it only as recessive, a divergence that should be declared when interpreting a report [4, 38]. Determining the pattern requires, in these cases, biochemical assessment of the parents and, when possible, of other relatives, and not merely reading the gene name.

The distinction between FAM111A and TBCE is the clearest example of how getting the gene wrong alters counselling: FAM111A disease is dominant, with a recurrence risk of 50% when a parent is affected, and TBCE disease is recessive, with a risk of 25%, so swapping the genes changes the risk from 50% to 25% and entirely changes the logic of carrier testing [17]. In Kenny-Caffey syndrome type 2, most cases are sporadic, and in the few cases of dominant transmission the affected parent was always the mother and never the father, probably owing to infertility in affected males [29]. Osteocraniostenosis is sporadic, due to de novo variants, so the recurrence risk for the couple is low but not zero, and the risk for the offspring of a survivor would be 50% [47]. In the mitochondrial forms, counselling follows the rule of mitochondrial inheritance: a large single mitochondrial DNA deletion is generally sporadic and the recurrence risk is low, whereas a point variant such as m.3243A>G has maternal inheritance with variable heteroplasmy and a transmission risk that is difficult to quantify — in the published case of MELAS with hypoparathyroidism, the variant was present in the proband and the mother and absent in the two siblings [109]. In lymphoedema-hypoparathyroidism syndrome, the mode of inheritance has not been resolved and allows autosomal recessive and X-linked recessive possibilities, so counselling must present both [25].

8.2 Germline mosaicism and de novo variants

Mosaicism is not a theoretical rarity in this area and has a direct consequence for the stated risk. Hendy and colleagues described two siblings with hypocalcaemia due to a missense variant in exon 7 of CASR in whom both parents and a third sibling were genotypically normal on direct sequencing, but the mother was mosaic for the variant, as demonstrated by analysis of multiple subclones and by denaturing high-performance liquid chromatography of the amplification product from leucocytes; this was the first report of mosaicism for an activating CASR variant and the authors concluded that caution is needed when counselling about recurrence risks in a situation where a de novo variant seems likely [7]. In HDR syndrome, Sun and colleagues described a Han Chinese brother and sister with hypoparathyroidism and sensorineural hearing loss due to the GATA3 nonsense variant p.(Arg367Ter), absent in both unaffected parents, and concluded that one of them must have germline mosaicism [28]. The practical consequence is that, when a dominant variant appears to be de novo in a child, the recurrence risk is not zero, and offering prenatal or preimplantation diagnosis in a subsequent pregnancy is reasonable.

8.3 Cascade testing and carrier detection

Cascade testing is particularly productive in dominant forms with variable expressivity, because it identifies relatives with unrecognised biochemical disease. The 2025 European guideline strongly recommends offering genetic testing and/or family screening in non-surgical hypoparathyroidism without another evident cause [34]. In families with autosomal dominant hypocalcaemia, half of those affected may be asymptomatic, and a relative with mild hypocalcaemia and hypercalciuria is exactly the patient in whom starting active vitamin D would cause harm without benefit [7]. In HDR syndrome, a relative identified only through deafness still needs assessment of calcium and kidneys [40]. In the Pakistani family with familial isolated hypoparathyroidism 2, the fourth affected individual was screened soon after birth because of the family history, which allowed diagnosis and treatment before any seizure [4].

Carrier detection in founder populations is organised in one case. The TBCE founder allele, the 12 base-pair in-frame deletion, represents practically 100% of pathogenic alleles of that gene in the Negev Bedouin population, where the carrier frequency is 1 in 49, and is included in the Israeli national carrier screening programme [22]. No birth prevalence was derived from this frequency because the consanguinity of the population violates the assumption of panmixia that a Hardy-Weinberg calculation would require, so any figure obtained in this way would underestimate the true rate by an unknown margin [22]. The same allele was found in a patient of Moroccan origin, which is consistent with Arab migration to North Africa in the seventh century and means that targeted testing for it is not limited to Gulf populations [19]. In autoimmune polyendocrinopathy type 1, there are founder alleles in Finland, Sardinia and Puerto Rico, and the PHD1 alleles causing the dominant form have been found at a frequency above 0.0008 in mixed populations on exome arrays, which implies that the dominant form is more common than the classic disease and substantially under-recognised [42].

One counselling scenario deserves highlighting because it reverses intuition. In the parents of an infant with neonatal severe hyperparathyroidism, typically heterozygous for familial hypocalciuric hypercalcaemia, a family diagnosis considered benign carries a reproductive risk that must be stated, because the biallelic form is potentially lethal without treatment [30]. Symmetrically, a family with familial hypocalciuric hypercalcaemia type 1 or type 2 has no increased risk of uveal melanoma or of the other diseases associated with somatic variants of the same gene, and this separation should be stated explicitly when the laboratory report mentions both contexts [8].

The 2025 French protocol recommends offering genetic analysis to every patient without neck surgery or radiotherapy, especially with a family history of mineral metabolism disease or with an unknown cause, accompanied by family enquiry into first-degree ancestors, collaterals and descendants; in a form such as autosomal dominant hypocalcaemia, measurement of fasting calcium may suffice as the first family screen [12]. Once the cause has been identified, genetic counselling and testing of relatives according to the mode of transmission are offered, and a carrier relative without hypocalcaemia continues an adapted follow-up, which includes calcium [12].

8.4 Prenatal and preimplantation diagnosis

In all entities with an identified gene, prenatal diagnosis is possible by targeted analysis of the familial variant in chorionic villi or amniocytes, and preimplantation genetic diagnosis is applicable when the variant is known in the parents. The decision depends on the expected severity, and this is where the absence of genotype-phenotype correlation becomes a practical problem: in the FAM111A spectrum, the genotype does not predict whether the child will have Kenny-Caffey syndrome, compatible with adult life and with normal cognition, or osteocraniostenosis, lethal perinatally, and this must be stated clearly when the variant is found prenatally [17]. Osteocraniostenosis is, by contrast, detectable by ultrasound, with cloverleaf skull and reduced cranial ossification, in addition to short limbs and bowed radius, and there are consensus guidelines on the prenatal assessment and delivery of patients with skeletal dysplasia applicable to this situation [17, 33]. In Sanjad-Sakati syndrome, intrauterine growth restriction is universal but non-specific, so ultrasound alone neither establishes nor excludes the diagnosis.

8.5 Pregnancy in an affected woman and counselling of minors

A woman with genetic hypoparathyroidism who becomes pregnant has two questions to resolve in parallel: the risk of transmission, covered above, and management of her own treatment, covered in section 7. The two converge in the neonatal period, because maternal hypercalcaemia can suppress the newborn's parathyroid hormone and cause neonatal hypocalcaemia, whereas maternal hypocalcaemia can cause secondary hyperparathyroidism in the infant, so the newborn's ionised calcium is measured from day 2 of life, typically every 48 hours in the first week, regardless of the result of the genetic test [34]. Historical observations illustrate the effect of the maternal environment to the point of simulating inheritance: Buchs described in 1961 three siblings with congenital hypoparathyroidism apparently in response to maternal hyperparathyroidism, and Aceto and colleagues described in 1966 fetal and infantile hyperparathyroidism due to maternal hypoparathyroidism, with two children of an affected mother, by different fathers, having hypoparathyroidism [1].

The 2024 Parathyroid Summit consensus treats this conversation as a matter of preconception counselling and not of obstetric management, and sets six mandatory contents for it: inform the patient that she can carry a pregnancy to term and of the risks of hyper- and hypocalcaemia and the close monitoring they require; adjust treatment before conception to stabilise calcium in the lower part of the reference range or just below; replace parathyroid hormone therapy with conventional therapy, because there are no safety data for parathyroid hormone or its analogues in pregnancy, a decision that should be discussed before pregnancy is planned and not after it is confirmed; stop thiazides; discuss the risk of transmission to offspring when the cause is genetic, with planning of the infant's follow-up; and include in the discussion the role of preimplantation genetic testing [43]. The sequence matters because three of these decisions — switching from palopegteriparatide to conventional therapy, stopping the thiazide and stabilising calcium on the new regimen — take weeks to consolidate and cannot be carried out at the same time as a first trimester already under way; this is why the counselling consultation precedes pregnancy planning in a woman on hormone replacement. Details of dose and monitoring are given in section 7.10.

Counselling of minors follows the principle that testing is justified when it changes management in childhood, which in these diseases is the rule rather than the exception: identifying a child at risk of genetic hypoparathyroidism allows calcium to be measured before the first seizure, and the contrast between the proband treated from five weeks of life, with normal development, and the untreated uncle, institutionalised and without autonomy, within the same family and with the same genotype, is the most direct argument in favour of early testing [4]. In the syndromic forms, identification of the gene also alters surveillance of other organs — hearing and kidney for GATA3, endocrine components and oral mucosa for AIRE, skeleton and eye for FAM111A, airway and kidney for TBCE —, which strengthens the indication. By contrast, in allelic entities without hypoparathyroidism, such as progressive encephalopathy due to a hypomorphic TBCE allele, testing an asymptomatic relative does not have the same management justification and should be discussed in the usual terms of predictive testing [22].

The 2025 French protocol limits genetic testing in children to cases in which it brings immediate benefit to the child — a condition that, for the reasons above, is met in most of the forms in this article — and places the dedicated genetic counselling consultation, carried out by a geneticist, genetic counsellor or physician experienced in the disease, in adolescence and at the time of any plan for parenthood, to ensure that the patient knows the mode of transmission and the possibilities of prenatal diagnosis or early presymptomatic diagnosis [12].

9. Special Considerations: Population Diversity and Epidemiology

9.1 The relative weight of the genetic forms

Hypoparathyroidism is, overall, a predominantly iatrogenic disease: about three quarters of chronic cases are postsurgical or of another acquired cause, and about one quarter is genetic or metabolic [57]. The 2025 European guideline gives, for the disease as a whole, a prevalence of 6.4 to 38 per 100,000 and an annual incidence of 0.8 to about 7 per 100,000 inhabitants, varying by region and reflecting the completeness of registries, and confirms that at least 75% of cases result from neck surgery [34]. A 2026 review gives an almost identical range, of 6.4 to 37 per 100,000, but describes it as incidence; the order of magnitude and comparison with the guideline show that it is prevalence, so the range serves as a framework and the term used by that source is not adopted [57]. Hypoparathyroidism was designated an orphan disease by the European Commission in January 2014, with number EU/3/13/1210 [34]. As for overall mortality, a recent synthesis describes an 80% increase in all-cause mortality, with a risk ratio of 1.8 and a 95% confidence interval of 1.49 to 2.17, although individual studies are discordant — and a Danish national registry with 180 patients with non-surgical hypoparathyroidism and 540 controls found no increased mortality [27, 34].

The two most useful population estimates for separating the weight of the non-surgical forms come from Japan and measure different things. A national postal survey of 3501 departments selected by stratified sampling from a total of 13,156, with a response rate of 52.0%, estimated for 2017 a number of 2304 patients with non-surgical hypoparathyroidism, with a 95% confidence interval of 1189 to 3419, and 1484 patients with pseudohypoparathyroidism, with an interval of 1143 to 1825, corresponding to prevalences of 1.8 and 1.2 per 100,000 inhabitants [110]. Sampling and partial response require extrapolation, hence the wide intervals, and patients followed outside the surveyed departments escape the count; it is nonetheless the best available estimate of the weight of the non-surgical forms, which include all the genetic ones. An analysis of a health insurance claims database in the same country, with a denominator of 2,241,717 individuals observed between 2015 and 2018, identified 509 patients with chronic hypoparathyroidism of any cause, with a mean age of 49 years, and gave a standardised prevalence of 38.3 per 100,000 in 2018, with a 95% confidence interval of 33.4 to 43.6 [111]. The two values are not comparable: the second includes the postsurgical forms, which are the majority, and its operational definition — prescription of conventional therapy plus a record of surgery, radiotherapy or relevant disease — excludes untreated patients.

In absolute terms, the most frequent genetic cause of congenital hypoparathyroidism is 22q11.2 deletion, whose birth prevalence is estimated at 1 in 4000 to 1 in 6000 births, equivalent to about 17 to 25 per 100,000, probably underdiagnosed particularly in non-Caucasian populations [13]. Because the fraction of patients with hypoparathyroidism or hypocalcaemia in this syndrome varies between 17% and 60% depending on the series and the time of assessment, its absolute contribution is still greater than that of any monogenic entity in this article [51].

The 2025 French protocol places the frequency of permanent hypoparathyroidism after thyroidectomy between 0.5% and 9%, confirms that in adults more than two thirds of cases are postsurgical and that in children the cause is more often genetic than acquired, and designates autosomal dominant hypocalcaemia type 1 as the most frequent cause of the isolated genetic forms; for 22q11.2 deletion it gives 1 in 4000 live births, a value consistent with the range above [12].

9.2 Autosomal dominant hypocalcaemia: two national values that differ by a factor of twenty-four

Autosomal dominant hypocalcaemia has two validated point estimates, obtained by methods that measure different phenomena. Clinical ascertainment in a Danish national registry gave a point prevalence of 0.161 per 100,000, which measures clinically recognised disease and leaves out mild or asymptomatic forms [6]. Genomic ascertainment in a biobank cohort from a single health system in the United States, with 51,289 sequenced individuals, identified two hypocalcaemic individuals with a CASR gain-of-function missense variant, with functional validation, and gave a prevalence of 3.9 per 100,000 for type 1; the same study identified 18 loss-of-function variants in 38 individuals, 21 of them hypercalcaemic, and gave 74.1 per 100,000 for familial hypocalciuric hypercalcaemia type 1, concluding that this is a common cause of hypercalcaemia, with a prevalence similar to that of primary hyperparathyroidism, and that autosomal dominant hypocalcaemia type 1 is an important cause of non-surgical hypoparathyroidism [7]. The estimate of 3.9 per 100,000 rests on two cases and is therefore very imprecise, and comes from the population of one health system and not from a national sample; the roughly twenty-four-fold difference between Denmark and the United States mainly measures the difference between clinical and genomic ascertainment, and not a biological difference between populations. Orphanet records the worldwide class as unknown, and this is the honest statement, rather than extrapolating one of the two national values [6].

For autosomal dominant hypocalcaemia type 2 there is no estimate: Orphadata has no prevalence line for familial hypocalciuric hypercalcaemia type 2 nor a specific estimate for the hypocalcaemic form, and the only number available is a reference proportion — probably causal GNA11 variants were found in less than 1% of more than 1200 probands tested for hyper- or hypocalcaemia —, which has no population denominator [8]. As a reference for the mirror disease of the same mechanism, a study in the west of Scotland gave an estimated minimum prevalence of 1 in 78,000, that is, 1.28 per 100,000, for familial hypocalciuric hypercalcaemia of all genetic types, the CASR form accounting for about 65% of the total [30].

9.3 Entities for which only case counts exist

For most of the monogenic entities in this article, what exists are cumulative counts of published cases and Orphanet prevalence classes, and neither converts into a rate per 100,000, because the count has no denominator and the class is an upper limit and not a point estimate. HDR syndrome has 180 published cases and a worldwide class below 1 per 1,000,000, with onset at all ages [10]. Familial isolated hypoparathyroidism has 10 families described in the same class, with two subgroups recorded separately — two families in the parathyroid agenesis subgroup and no epidemiological data in the impaired parathyroid hormone secretion subgroup [2, 112, 113]. The X-linked form has been described in two lineages from eastern Missouri, shown to be related by mitochondrial D-loop analysis, plus isolated families in Switzerland and a Bedouin family with four affected male siblings, including triplets [5]. Osteocraniostenosis has 30 published cases, with antenatal or neonatal onset and ascertainment bias through autopsy and prenatal ultrasound, given the perinatal lethality [16]. Lymphoedema-hypoparathyroidism syndrome has two published cases, two adult brothers described in 1983, and with two cases no epidemiology is possible [24, 25]. Primary hypomagnesaemia with secondary hypocalcaemia has 100 published cases and about 40 TRPM6 variants identified, with no population prevalence [26, 36]. The FAM111A-related dysplasias have a prevalence declared unknown by the authoritative source, with 35 individuals described up to the GeneReviews chapter — 22 with Kenny-Caffey syndrome and 13 with osteocraniostenosis —, from about twenty publications between 2013 and 2023 [17, 33].

9.4 Founder populations and the effect of consanguinity

Three entities in this article have founder alleles with practical consequences. The first is TBCE disease: the 12 base-pair founder allele is carried by 1 in 49 individuals in the Negev Bedouin population, in Israel, where it represents practically 100% of pathogenic alleles of the gene, and is included in the Israeli national carrier screening programme; it was the homozygous genotype in all 68 genetically tested individuals in the Gulf registry cohort [22]. No birth prevalence is derived from this frequency because consanguinity violates the panmixia assumption of a Hardy-Weinberg calculation, and any figure so obtained would underestimate the true rate by an unknown margin [22]. The largest series of the entity is the multicentre cohort of 135 individuals from Gulf centres, whose natural history data are given in section 3; it is a cohort from referral centres, biased towards more severe and diagnosed cases, and does not provide prevalence [22]. The earlier founder series are from Saudi Arabia, with 12 infants seen over three years, from Kuwait, with eight consanguineous families used in mapping, and from Arab families in Israel [19].

The second is autoimmune polyendocrinopathy type 1, where variation within Europe spans an order of magnitude and should be presented as such and not summarised in a single value. The validated Orphanet entries give 4 per 100,000 in Finland, corresponding to about 1 in 25,000, and 0.5 per 100,000 in France, about 1 in 200,000, the latter being the best available value for a non-founder, unselected European population; the aggregated European entry is rounded to zero and marked as not validated, so it is not used [11]. The disease belongs to the "Finnish disease heritage" and is even more frequent in some subpopulations of that country, which prevents any extrapolation [114]. Other European and regional estimates obtained by heterogeneous methods give about 1 in 14,000 in Sardinia — derived from a carrier frequency of the p.(Arg139Ter) variant of 1.7%, which corresponds to about 7 per 100,000 —, 1 in 43,000 in Slovenia, 1 in 80,000 to 1 in 90,000 in Norway and 1 in 129,000 in Poland [42, 114]. Among Jews of Iranian origin, 19 families with 23 affected individuals gave a calculated prevalence of 1 in 6500 to 1 in 9000, about 11 to 15 per 100,000, reflecting high consanguinity; in this population, hypoparathyroidism was present in 96% of those affected and 91% were diagnosed by 20 years of age, with rare candidiasis and absent keratopathy — that is, the founder phenotype differs from the Finnish one and extrapolation of the clinical picture is as problematic as that of frequency [42, 114]. A founder allele is also documented in the Puerto Rican population, the deep intronic variant present in 17 of 104 prospectively studied patients from 14 families, 15 of them of that ancestry, for which there is no published prevalence figure; because the variant is not covered by exome or current panels, its true frequency is underestimated [42].

The third population observation concerns the recurrent FAM111A variant. A 2023 literature review brought together 23 patients with Kenny-Caffey syndrome type 2, of whom 16 of 23, that is, 69.6%, had the recurrent variant p.(Arg569His), more frequent in females, 11 of 16, and only four women were followed beyond 18 years; the geographical distribution included Switzerland, India, Germany, Italy, Japan, Canada, the United States, Australia, China, Turkey and two cases from Brazil [115].

The 2025 French protocol gives a frequency of 1 in 80,000 for autoimmune polyendocrinopathy type 1, without stating the population or the method, and a frequency of hypoparathyroidism of 80% to 95% of patients, in whom it is the most frequent component; the value lies between the validated Orphanet entry for France, 1 in 200,000, and that for Finland, 1 in 25,000, and, without a reference population, does not replace either [11, 12].

9.5 Genetic aetiology in paediatric cohorts

Two paediatric cohorts allow the genetic causes to be ranked by relative frequency, although neither is a prevalence estimate. In the Chinese cohort of 173 patients with childhood-onset hypoparathyroidism, studied with a 15-gene panel combined with TBX1 dosage analysis, a genetic defect was identified in 27.7% of patients: 26 cases, 15.0%, of DiGeorge syndrome or 22q11.2 deletion; 9, 5.2%, of autoimmune polyendocrinopathy type 1; 8, 4.6%, of autosomal dominant hypocalcaemia type 1; 4, 2.3%, of HDR syndrome; and 1, 0.6%, of Kenny-Caffey syndrome type 2, in addition to 12 variants of uncertain significance in 11 patients [35]. This is the yield of a referred cohort and not of a population, and the 15-gene panel does not cover all causes — notably the Xq27.1 region and the deep intronic AIRE variant. The finding of greatest practical value is that 16 of the 26 cases of 22q11.2 deletion, that is, 61.5%, had gone undiagnosed before testing, for lack of obvious clinical clues [35]. In the Korean cohort of 37 patients with primary hypoparathyroidism diagnosed before 18 years, with a median age at presentation of 1.7 months, range one day to 17 years, and mean follow-up of 7.0 ± 5.3 years, the aetiologies were 22 cases, 59.5%, of 22q11.2 microdeletion syndrome; 5, 13.5%, of HDR syndrome; one case each of autoimmune polyendocrinopathy type 1, Kearns-Sayre syndrome and Kenny-Caffey syndrome; and 7, 18.9%, classified as idiopathic [23]. The two cohorts agree on the hierarchy — 22q11.2 deletion dominates, followed by HDR syndrome and autosomal dominant hypocalcaemia or autoimmune polyendocrinopathy — and differ in the proportions, which is expected for series from centres with different populations and panels. The proportion of "idiopathic" cases in the Korean series reflects the limits of the testing available at the time and not the absence of a cause.

The proportion of cases without a cause is the complement of these yields: in the French Épi-Hypo cohort, up to 14% of all cases of hypoparathyroidism, and a larger proportion in children, had no identified aetiology, which the French protocol attributes both to causes yet to be discovered and to aetiological investigations not carried through to completion [12].

9.6 Complications documented mainly in non-surgical hypoparathyroidism

The comorbidity table of the 2025 European guideline makes a distinction of direct interest to the genetic forms: it separates statistically significant associations in the disease as a whole from those documented only in non-surgical hypoparathyroidism [34]. With a statistically significant association overall are renal stones, reduced renal function, renal calcification, infections, seizures, depression, impaired quality of life and cataracts. Documented only in non-surgical hypoparathyroidism — that is, in the group that includes all the genetic forms — are intracerebral calcification, ischaemic heart disease, arrhythmias, stroke and proximal humerus fractures [34].

The numbers supporting this distinction come mainly from Danish registries. In a national registry with 180 patients with non-surgical hypoparathyroidism and 540 controls, the risk ratio was 1.91 for cardiovascular disease (95% confidence interval 1.29 to 2.81; p = 0.01), 2.01 for ischaemic heart disease (1.31 to 3.09; p = 0.01), 1.78 for cardiac arrhythmias (0.96 to 3.30; p = 0.03) and 1.84 for stroke (0.95 to 3.54; p = 0.03), without increased mortality, and the risk was associated with lower time-weighted serum ionised calcium, a greater number of hypercalcaemic episodes and longer disease duration [27]. In the kidney, the prevalence of chronic kidney disease in this disease varies between 2.5% and 41% depending on the definition used, and a Danish population study associated the risk with longer disease duration, a median calcium-phosphate product above 2.80 mmol²/l² and a greater frequency of hypercalcaemic episodes, with non-surgical patients having an increased risk of stage 4 and 5 chronic kidney disease compared with matched controls [27]. For infections, the incidence was higher for all types in a Danish national cohort, especially urinary and respiratory, with longer disease duration, hyperphosphataemia and more hypercalcaemic episodes as risk factors, and with a risk ratio of 1.87 (1.20 to 2.92) favouring greater prevalence in the non-surgical than in the postsurgical forms; the immune cell profile in chronic postsurgical hypoparathyroidism shows decreased monocytes and regulatory, naive and total CD4+ T lymphocytes, correlated with total calcium, ionised calcium and parathyroid hormone [27]. In the skeleton, bone mineral density is above the mean of controls matched for age, sex and body mass index, with abnormal microstructure in the cortical and trabecular compartments, increased cortical thickness and trabecular bone volume on transiliac biopsies and greatly reduced remodelling with a positive balance in each cycle; the bone material strength index measured by microindentation is lower than in controls and improved with parathyroid hormone 1-84, and the absence of parathyroid hormone is associated with density increased by up to about 30%, without a consistent increase in overall fracture risk having been observed [27, 34]. The validated disease-specific tool for measuring quality of life in this disease is the hypoparathyroidism patient experience scale, in its symptom version, and quality of life is reduced in both surgical and non-surgical forms [27].

9.7 Special populations

Children are the population in which these diseases present and, at the same time, the one lacking graded guidelines and authorisations: the 2025 European guideline covers only adults and no parathyroid hormone replacement product is approved below 18 years. The document with the most complete paediatric dosing is the 2024 Parathyroid Summit consensus, which devotes a section of recommendations to children with age-band doses of calcitriol and calcium and weight-based doses of parathyroid hormone 1-34, but which is a good practice consensus without formal grading of strength and quality of evidence; the 2022 Second International Workshop remains the only document with graded paediatric recommendations, and the other doses and targets cited here come from a narrative review with expert perspectives and from labels used with declared extrapolation [22, 27, 34, 43]. Women of childbearing age face the absence of data in pregnancy and lactation, which is being addressed for the first time by a study of drug transfer into human milk and by a global pregnancy registry, both recruiting [100, 101]. Patients with syndromic forms have, by definition, multidisciplinary needs that isolated endocrinological follow-up does not cover, and the transition from paediatric to adult care coincides with the period of greatest deterioration in treatment adherence [48].

9.8 Portugal and Brazil

In the sources consulted, no prevalence data for genetic hypoparathyroidism were found for Portugal or Brazil, and this absence does not demonstrate an absence of published data. Individual data were found, which are cases and not estimates. From Portugal, a 29-year-old woman with severe hypoparathyroidism, mild bilateral sensorineural deafness diagnosed in childhood and agenesis of the vagina and uterus, with normal kidneys and renal function, carrying the GATA3 missense variant NM_001002295.2:c.1025G>A, p.(Cys342Tyr) — the third described case of female genital tract malformation associated with HDR syndrome [28, 31]. From Brazil, two patients with Kenny-Caffey syndrome type 2 and the recurrent de novo variant p.(Arg569His), a man followed until 18 years and a girl followed until 10 years, included in the review of 23 published cases of the entity [115].

By contrast, the access framework in both jurisdictions is documented and has practical epidemiological consequences. Palopegteriparatide is authorised in Portugal for the three presentations but without recorded marketed presentations, so access depends on an exceptional use authorisation or a holder programme, and the only parathyroid hormone replacement actually marketed in Portugal and Brazil is teriparatide, off-label [64–66]. In Brazil, palopegteriparatide has been registered with the National Health Surveillance Agency since 21 September 2026, with use restricted to adults, but there is no professional package insert published in the Electronic Package Insert Database, and marketing depends on approval of the maximum price by the Medicines Market Regulation Chamber, while availability in the Unified Health System depends on assessment by the National Commission for the Incorporation of Technologies, so registration does not equate to access [72, 73]. Among the authors of the 2025 European guideline is a clinician from Coimbra and Porto, which indicates Portuguese participation in the preparation of the reference document [34].

9.9 Reference networks and patient organisations

The relevant European reference network is Endo-ERN, which brings together more than 100 reference centres in 27 European Union Member States and Norway and whose main thematic group MTG2 covers disorders of calcium and phosphate homeostasis, with its own page and with the European patient advocacy groups listed on the network's website [3]. For the syndromic forms, there are in addition ERN ITHACA, for congenital malformations and intellectual disabilities of genetic origin, ERN RITA, for rare immunological diseases, relevant in autoimmune polyendocrinopathy type 1 and in forms with thymic hypoplasia, and ERN BOND, for rare bone diseases, in the FAM111A- and TBCE-related dysplasias.

Among patient organisations, the HypoPARAthyroidism Association, based in the United States, is a non-profit association working to improve the lives of people affected by hypoparathyroidism, with education, support, research and patient advocacy, support and resource sections, patient-recommended physicians, patient stories and disability information, and free community membership [116]. In the United Kingdom and Ireland, Parathyroid UK is the only organisation dedicated to rare parathyroid diseases, with practical and emotional support, awareness and treatment improvement campaigns, education of family doctors and endocrinologists, information to members about treatments and clinical trials and private support groups [117]. The 2025 European guideline itself provides two patient-oriented resources, prepared with the collaboration of patient representatives from the United Kingdom, France, Germany and Norway: a patient information leaflet on the treatment of chronic hypoparathyroidism in adults and a standardised European emergency card for adult patients with hypoparathyroidism, both published in several languages [34]. The emergency card has direct practical utility in the genetic forms, because a hypocalcaemic crisis is the presenting form of many of them and because patients with absent parathyroid hormone do not recover spontaneously.

For the syndromic entities, the reference organisations are those of the respective syndromes, and the ongoing patient registries — including a German national registry, an Italian one, a French one, a British one that includes autosomal dominant hypocalcaemia and one from the US National Institutes of Health — are the most likely route to obtaining, in the medium term, prevalence estimates that do not exist today [88].

In France, the organisation of care is described in the 2025 protocol. The coordinating reference centre for rare disorders of calcium and phosphate metabolism in children and adults is at Bicêtre Hospital (Le Kremlin-Bicêtre, Assistance Publique–Hôpitaux de Paris), with competence centres in several regions, and is part of the OSCAR rare disease network, which disseminates and updates information on the disease and organises online multidisciplinary meetings, open to any doctor, for children, for adults and for the prevention of postsurgical hypoparathyroidism [12]. Each patient has a referring doctor — family doctor, paediatrician, endocrinologist, nephrologist or rheumatologist — who coordinates the other professionals involved, with dietitians, psychologists and social workers integrated early, and receives a prescription that allows calcium to be measured urgently in the event of symptoms [12]. The patient association Hypoparathyroïdisme France (hypopara.fr) represents French-speaking patients, runs mutual support groups, virtual cafés and webinars, organises a national hypoparathyroidism day, co-runs the remote therapeutic education programme and took part in drafting and reviewing the protocol [12].

At the medico-social level, the protocol considers the disease disabling even when the disability is not visible and justifies its recognition as a long-term condition exempt from co-payment: in the hereditary forms, under list no. 17, of hereditary metabolic diseases requiring prolonged specialised treatment; in postsurgical forms after thyroid or ENT cancer, often under list no. 30, of malignant tumours; and in other disabling forms with costly treatment, such as a parathyroid hormone analogue, by the "off-list" route no. 31 [12]. In adults whose professional activity is compromised, recognition as a worker with a disability, workplace adaptation, retraining, invalidity or the disabled adult allowance may be requested, with the support of social workers; in children, an individualised reception plan drawn up by the referring doctor accompanies schooling, and parents may request the daily parental presence allowance, with the support of the centres' social worker and the association in applications to the departmental centre for people with disabilities [12].

10. Illustrative Clinical Case

The case described by Zygmunt and colleagues in 2026 goes through all the phases of autosomal dominant hypocalcaemia type 1 — from neonatal diagnosis to organ damage under conventional therapy, via an attempted transplant and ending in parathyroid hormone replacement — and is therefore used here as the main case [69].

The patient is a boy followed at the Department of Endocrinology and Metabolic Diseases of the Polish Mother's Memorial Hospital Research Institute, in Łódź, since 2020. Hypoparathyroidism was diagnosed at 6 weeks of life, during an admission for urinary tract infection: total calcium was 5.5 mg/dl on two measurements, for a reference range of 7.8 to 11.3; phosphorus 11.2 mg/dl, for 4.8 to 8.2; magnesium 1.44 mg/dl, for 1.6 to 2.7; and parathyroid hormone below 3 pg/ml, without the child showing clinical signs of hypocalcaemia. Calcium supplementation was started with 115 mg of calcium twice daily. About a month later, on readmission to the paediatric endocrinology department, serum calcium was 7.4 mg/dl, for a range of 8.4 to 11, parathyroid hormone was well below the reference range and 25-hydroxyvitamin D was undetectable.

In the first years he had recurrent urinary tract infections, with furazidin prophylaxis until two years of age. He was treated with variable doses of alfacalcidol or calcitriol with calcium and magnesium supplements, and a low-phosphate diet was recommended because of persistently raised serum phosphate, between 6.6 and 9.7 mg/dl for a range of 4.5 to 6.5; he received sevelamer periodically, without efficacy and with significant abdominal pain and diarrhoea that required discontinuation. Over the years he had tingling, numbness, painful muscle cramps and seizures once or twice a year, requiring admission, and the symptoms of neuromuscular excitability worsened with infections, after physical exertion and with heat exposure. The course was complicated by persistent hypercalciuria, with urinary calcium excretion between 4.6 and 5.6 mg/kg/day for a normal limit below 4.0, and renal ultrasound at one and a half years revealed bilateral nephrocalcinosis and nephrolithiasis; hydrochlorothiazide reduced urinary calcium excretion without normalising it. Imaging also showed basal ganglia calcification and an early-stage cataract was diagnosed. In March 2010, at almost two years of age, an allogeneic parathyroid cell transplant was performed, without graft function being achieved. Molecular study in April 2015, at 7 years, identified the pathogenic variant. In December 2018, at 10 years, recurrent nocturnal paroxysmal episodes appeared with altered consciousness, focal motor phenomena and post-ictal drowsiness, without fever or acute tetany and outside episodes of acute hypocalcaemia, with serum calcium around 7.0 mg/dl, which were diagnosed as focal epilepsy by paediatric neurology and treated with oxcarbazepine. The parents and the brother three years older are healthy; isolated measurements showed slightly reduced total calcium in the mother, 8.9 mg/dl, and the father, 8.5 mg/dl, and normal calcium in the brother, 9.4 mg/dl, for a range of 9.0 to 10.2, and genetic testing excluded the disease in all three.

Molecular analysis was performed by Sanger sequencing of the coding regions and exon-intron boundaries of the CASR and GNA11 genes, at Oxford University Hospitals NHS Foundation Trust, and identified the heterozygous pathogenic variant NM_000388.4:c.2504C>A, NP_000379.3:p.(Ala835Asp), de novo. Figure 1 of the article documents this result in four panels with the Sanger traces — the reference sequence, the patient with the heterozygous base highlighted, the mother and the father —, with the consensus sequence and numerical positions indicated below the traces, and is the demonstration that the variant is not present in either parent; it is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC13318765/figure/F1/ [69].

Immediately before starting palopegteriparatide, the patient was receiving alfacalcidol 1.25 µg/day, calcium carbonate 200 mg three times daily, hydrochlorothiazide 12.5 mg in the morning and 6.25 mg in the early afternoon, magnesium sulphate with 260 mg of magnesium per day and potassium chloride with 782 mg of potassium per day. Despite persistently low total calcium, between 6.5 and 7.5 mg/dl for a range of 8.8 to 10.8, he remained relatively asymptomatic, with only sporadic tetany during viral infections or after significant physical activity. He had phosphate retention, with a tubular maximum for phosphate reabsorption per glomerular filtration rate above 4.0 mmol/l, hyperphosphataemia between 8.1 and 10.8 mg/dl for a range of 2.9 to 5.1 and a calcium-phosphate product between 55 and 65 mg²/dl², in addition to fractional calcium excretion above 2.0%, hypercalciuria of 393 mg in 24 hours, nephrocalcinosis, cataracts and basal ganglia calcification.

In September 2024, at 16 years and 5 months, 61 kg and 175 cm, he started palopegteriparatide at 9 µg/day, half the recommended starting dose in adults, off-label, with informed consent from the parents and the patient and approval from the institution's ethics committee. The dose was adjusted to prevent symptoms of neuromuscular excitability and at the same time achieve the lowest possible calcium-phosphate product. The course of the parameters before treatment and at 3, 6 and 12 months was as follows: total calcium 6.52, 7.80, 7.52 and 7.56 mg/dl; ionised calcium 0.82, 0.97, 0.98 and 0.96 mmol/l; phosphate 8.71, 6.40, 6.67 and 6.94 mg/dl; calcium-phosphate product 56.8, 49.9, 50.2 and 52.5 mg²/dl²; parathyroid hormone 2.9, 3.0, 2.9 and below 5.5 pg/ml; fibroblast growth factor 23 of 75.0, 59.1 and 46.8 pg/ml; 1,25-dihydroxyvitamin D 23.9, 40.4 and 37.6 pg/ml; fractional calcium excretion 2.18, 0.52, 1.22 and 0.7%; tubular maximum for phosphate reabsorption per glomerular filtration rate 4.08, 2.97, 2.91 and 2.23 mmol/l; and magnesium 1.59, 1.8 and 1.8 mg/dl. The 24-hour urinary calcium fell from 393 mg to 266 mg at 4 months, 173 mg at 6 months and 85 mg at 16 months. The dose was finally reduced to 7.5 µg/day, alfacalcidol and calcium supplements were stopped and hydrochlorothiazide was reduced to 6.25 mg/day, with magnesium kept at 260 mg/day and potassium at 391 mg/day. The patient reported complete resolution of tetany, with greater biochemical stability, lower phosphate and a lower calcium-phosphate product. Bone mineral density of the L1-L4 lumbar spine went from 1.392 to 1.423 and then 1.410 g/cm², and that of the total hip from 1.347 to 1.275 and then 1.262 g/cm².

Three practices in this report diverge from current recommendations and are not presented as routine. The use of palopegteriparatide in the paediatric age group is off-label, with safety and efficacy under 18 years declared as not established and with no data available in the European summary of product characteristics [64]; the starting dose of 9 µg/day is half that recommended in the US and European labels, and was chosen by the team because of age and the goal of not raising the calcium-phosphate product [63, 64]; and the parathyroid cell allotransplant performed at two years of age, without graft function being achieved, is an intervention that the 2025 European guideline does not recommend [34]. The favourable outcome of a single patient does not establish efficacy, and the comparison of values before and after is intra-individual and without a control group; what the case documents solidly is the trajectory of organ damage under conventional therapy in a disease in which the kidney already wastes calcium before any treatment, and the plausibility that parathyroid hormone replacement simultaneously reduces hypercalciuria and hyperphosphataemia, which is what the adult trials show [76].

Three other published cases, of different entities, complete the clinical picture of the class. In autoimmune polyendocrinopathy type 1, Akers and colleagues described a 48-year-old woman referred for osteoporosis, with hypoparathyroidism and basal parathyroid hormone below 4 pg/ml, adrenal insufficiency on chronic corticosteroid therapy, insulin-dependent diabetes, premature ovarian insufficiency and chronic mucocutaneous candidiasis complicated by oesophageal stricture with malnutrition, body mass index of 14.98 kg/m², in addition to stage 3A chronic kidney disease, abdominal and thoracic aortic calcification, lower limb vascular calcification with digital ischaemia, basal ganglia calcification, T12 and L3 compression fractures and traumatic fractures of the pelvic ring, right hip and right ulna; undecalcified bone biopsy with double tetracycline labelling showed a mixed pattern of increased resorption with suppressed formation, with relative bone volume of 19.9% for a reference of 20.7 to 22.2, trabecular thickness of 85 µm for 129 to 143, osteoblast surface of 0.07% for 4.45 to 6.09, eroded surface of 17.91% for 2.98 to 3.51, mineralising surface of 0.6% for 6.9 to 9.8, mineral apposition rate of 0.15 µm/day for 0.55 to 0.66 and mineralisation lag time of 127 days for 9.56 to 11.72 — a pattern of uncoupled remodelling that no densitometry would reveal. On calcitriol 0.75 µg/day with 1.5 to 3 g of calcium per day, serum calcium fluctuated between 6.0 and 9.0 mg/dl; after a period on abaloparatide 80 µg twice daily, with brief, unsustained normocalcaemia, she started palopegteriparatide at 18 µg/day in December 2024, stopped calcium and calcitriol and, after several episodes of hypercalcaemia requiring adjustments, stabilised on 12 µg/day with normal serum calcium [97].

In Kenny-Caffey syndrome type 2, Yuan and colleagues described an 18-year-old woman admitted for a three-day change in behaviour, with food refusal and fixed gaze. She had been born at 33 weeks by caesarean section, weighing 3.8 kg (+1 standard deviation, value as published by the authors) and measuring 48 cm; the anterior fontanelle did not close until 5 years; she had always been shorter than children of her age, with muscle tetany and occasional numbness of the limbs and slightly below-average school performance; menarche occurred at 13 years, with irregular cycles. On examination she was 132 cm, about five standard deviations below the mean, 40 kg, head circumference 48 cm, with malar freckles, high hairline, sparse hair, prominent forehead, depressed nasal bridge, low-set ears, partially absent dentition, micrognathia, short limbs, small hands and feet and bilateral short fourth toes. Biochemistry showed corrected calcium of 1.06 to 1.12 mmol/l for a range of 2.11 to 2.52, phosphorus of 1.86 mmol/l for 0.85 to 1.51, magnesium of 0.45 to 0.69 mmol/l for 0.75 to 1.02, potassium of 2.56 to 2.57 mmol/l for 3.5 to 5.3, parathyroid hormone of 10 pg/ml for 15 to 65, 25-hydroxyvitamin D of 17.61 ng/ml and 24-hour urinary calcium of 3.66 mmol for a limit below 6.75, with very high aldosterone, renin and angiotensin II in the sitting position and normal cortisol and corticotrophin. Ophthalmological examination revealed hypermetropia without cataract or papilloedema and audiometry was normal. Cranial tomography showed symmetrical calcification of the cerebellar hemisphere, frontotemporoparietal lobes, basal ganglia and thalamus, and radiographs showed a smaller right ilium, shallow acetabular fossae, short fourth and fifth metatarsals and cortical thickening with medullary narrowing of the tubular bones. Exome sequencing, confirmed by Sanger, identified the heterozygous de novo FAM111A variant corresponding, on the MANE transcript, to NM_001312909.2:c.1706G>A, NP_001299838.1:p.(Arg569His), absent in both parents and with no TBCE variants; the authors used transcript NM_001142519 and classified the variant as of uncertain significance under the American College of Medical Genetics and Genomics criteria, which reflects the application of those criteria to an isolated case and not the state of the evidence, since this is the established recurrent variant of the entity, present in 16 of 23 published cases [17, 31, 115]. She was treated with calcium carbonate with vitamin D3 and calcitriol 0.25 µg/day and, after intravenous correction of hypomagnesaemia, switched to potassium magnesium aspartate, with calcium of 2.10 mmol/l and urinary calcium of 1.69 mmol in 24 hours at two months, without numbness or fasciculations [115].

In the mitochondrial form, Wang and colleagues described a Chinese boy aged 5 years and 8 months with normal developmental milestones, seen a year earlier at a local hospital for poor appetite and vomiting, with lactic acidosis and multiple intracranial calcifications, who returned with two days of vomiting and a seizure. He had a low hairline, mild left facial asymmetry, bilateral ptosis, height of 104.5 cm, a positive left Babinski sign and pain on facial nerve percussion. The initial blood gas showed pH 7.195, partial pressure of carbon dioxide 61.2 mmHg, ionised calcium 0.97 mmol/l for a range of 1.15 to 1.33 and lactate 6.0 mmol/l for 1.0 to 1.8; phosphorus was 1.47 mmol/l, 25-hydroxyvitamin D 7.8 ng/ml, parathyroid hormone between 6.62 and less than 3 pg/ml for a range of 10 to 69, 24-hour urinary calcium 0.15 mmol for 2.5 to 7.5 and urinary phosphorus 7.34 mmol in 24 hours for 22 to 48. Tomography showed extensive basal ganglia calcification, mainly of the striatum and globus pallidus, worsening over the year, and magnetic resonance showed right parieto-occipital hyperintensity with mild cerebellar atrophy. Given the extensive calcification, the picture was initially interpreted as Fahr syndrome, and it was the presence of lactic acidosis and cortical lesions that led to further investigation, up to the m.3243A>G variant of the MT-TL1 gene in heteroplasmy, present in the proband and the mother and absent in the two siblings. Oral calcium and vitamin D had limited effect and intravenous calcium gluconate with oral calcitriol was required, with normalisation of urinary calcium three days later; the patient was readmitted one month after discharge with lactate of 6.6 mmol/l, and parathyroid hormone remained below the detection limit [109]. Two points from this case apply to the whole article: symmetrical basal ganglia calcification with hypoparathyroidism is not a diagnosis, because the historical designation of Fahr disease describes a pattern and not an entity [55]; and the very low urinary calcium before treatment documents the physiological difference from autosomal dominant hypocalcaemia, in which urinary calcium is inappropriately normal or high in the same situation [7].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis by entity

Prognosis falls into three groups. In the first, prognosis is determined almost entirely by the adequacy of treatment of hypocalcaemia, and the available data show that the difference between early treatment and no treatment is the difference between normal development and permanent neurological damage. In familial isolated hypoparathyroidism 2, the proband treated with calcitriol and calcium from five weeks of life had no further seizures and reached all cognitive and developmental milestones appropriately, whereas an uncle in the same family with the same genotype, who had had seizures at two months and was not treated, lived in a long-term care institution unable to walk, speak or attend to daily needs [4]. In the same entity, the sister of a Moroccan proband had cardiorespiratory arrest with profound hypocalcaemia at 10 months and, owing to subsequent poor adherence, had repeated episodes of severe hypocalcaemia followed by epilepsy, progressive microcephaly and severe neurological impairment, attributed by the authors to the initial anoxic episode [4]. In primary hypomagnesaemia with secondary hypocalcaemia, prognosis is good if diagnosis is early — with treatment, growth and development are normal —, whereas untreated disease results in permanent neurological damage or death, and patients with frequent seizures induced by hypomagnesaemia and hypocalcaemia, before or after diagnosis, are at risk of psychomotor delay [36].

In the second group, prognosis is dominated by an extraparathyroid component that calcium treatment does not alter. In HDR syndrome, kidney disease is progressive in a substantial proportion of patients and includes steroid-resistant nephrosis progressing to renal failure; the two brothers in the original description died at 5 and 8 years of renal failure, and deafness is permanent and non-progressive in most families studied [28, 40]. In the recessive TBCE syndromes, median survival in the Gulf cohort of 135 patients was 27.2 years, with 62.4% survival to 18 years, and respiratory failure caused 84% of deaths, 21 of 25 — which means that the airway and infection prevention determine prognosis more than calcium control [22]. In osteocraniostenosis, respiratory failure due to pulmonary hypoplasia is what makes the condition lethal, with most affected individuals dying in the first hours of life and survival of a few to several months described [17, 47]. In Kenny-Caffey syndrome type 2, prognosis is favourable, with the oldest known patients in their fifth decade and adult height between 122 and 152 cm, development and cognition being almost always normal [17, 29]. In autoimmune polyendocrinopathy type 1, mortality is high and quantified: in the Finnish cohort followed from 1971 to 2018, with 91 patients and 29 deaths, the overall standardised mortality ratio was 11, with a 95% confidence interval of 7.2 to 16, with the highest values for endocrine and metabolic disease, 570, with an interval of 270 to 1000, and for oral and oesophageal neoplasia, 170, with an interval of 68 to 360, and with an absolute excess risk of about 10 per 10,000 person-years similar across all age groups; among the 33 deaths up to 2019, the most common primary causes were infection, 24%, circulatory disease, 18%, and oral or oesophageal neoplasia, 15%, with a median age at death of 36.7 years and median survival after diagnosis of neoplasia of 1.5 years, and adrenal crisis was an independent cause of death in two patients and a complicating factor in a fatal infection in four others [42]. The authors attribute the deaths from carcinoma and adrenal crisis to failures in overall care and, in particular, in endocrine care — that is, mortality is partly preventable.

In the third group, prognosis is determined by the treatment itself. In autosomal dominant hypocalcaemia, in which the kidney wastes calcium before any intervention, treatment with active vitamin D that normalises serum calcium causes hypercalciuria, nephrocalcinosis, nephrolithiasis and loss of renal function. The series of six families originally diagnosed with isolated hypoparathyroidism documents this clearly: of 19 patients treated with oral vitamin D, parathyroid hormone became low or undetectable in 16 and nine developed hypercalciuria; renal calcification developed in eight of the nine hypercalciuric patients and renal impairment in seven of them, and both calcification and renal impairment developed in seven other patients during vitamin D therapy [7]. In the series of nine genetically confirmed adults from north-east England, renal involvement affected 78%, with nephrocalcinosis in 56%, nephrolithiasis in 67% and chronic kidney disease, and two patients from the same family progressed to end-stage renal failure and death, despite conservative strategies limiting calcium supplements adopted after diagnosis; no clear correlation was found between mean serum calcium and disease severity [50]. The iatrogenic extreme is documented in a patient treated for symptomatic hypocalcaemia in childhood who progressed to end-stage renal failure due to nephrocalcinosis and nephrolithiasis [30].

For conventionally treated disease as a whole, the median prevalences of complications in the studies reviewed by the Second International Workshop were 17% for cataracts, 15% for nephrocalcinosis or nephrolithiasis, 12% for renal failure, 11% for infection, 11% for seizures, 9% for depression — with the text of the document stating 12% and the table 9%, a divergence the document itself does not resolve —, 7% for ischaemic heart disease and 7% for arrhythmias [27]. In a cross-sectional study with systematic imaging screening in 58 patients with long-standing disease, prevalences were substantially higher: basal ganglia calcification in 55%, cataracts in 62%, urolithiasis in 12% and renal failure in 17%, which illustrates that active screening raises prevalences relative to series that record only symptomatic complications; duration above 15 years and poor adherence were independently associated with complications, the former with an adjusted odds ratio of 43.1 and a 95% confidence interval of 2.63 to 703.06, whose width prevents the effect from being quantified [48]. In the skeleton, bone mineral density is typically above normative values and fracture risk is mixed, with risk ratios of 1.55 for vertebral fractures, interval 1.12 to 2.14, 0.70 for hip fractures, interval 0.50 to 0.98, and 0.93, not significant, for major osteoporotic fractures [34]. The practical implication is that a densitometry value within normal limits does not exclude vertebral risk, and the decision to treat follows general population criteria [34].

11.2 Surveillance table

The following table brings together the tests, intervals, action thresholds and source of each recommendation. The values coincide with those used in sections 0, 3, 7 and 9.

The 2025 French protocol publishes a follow-up schedule by age group, the result of OSCAR network consensus and adaptable to each patient, which adds paediatric stratification and some shorter intervals to the previous table [12].

On renal imaging, the French protocol adds a fourth position to the three in the previous table: renal imaging in all patients at diagnosis — ultrasound in children, ultrasound or low-dose non-contrast tomography in adults —, with creatinine and estimated filtration rate, because lithiasis and chronic kidney disease are frequent in the general population and their presence must be known before attributing them to the disease; thereafter, annual imaging in patients with a history of lithiasis or nephrocalcinosis or with persistent hypercalciuria and every 2 years in the others [12]. The French position is close to that of the Second Workshop at the initial time point and departs from the European guideline, which advises against routine imaging. As for the skeleton, it recommends a first densitometry in all adults at diagnosis, because the disease mainly affects women who need general population osteoporosis screening, and does not repeat it during follow-up except on parathyroid hormone analogues or with risk factors [12]. The protocol also asks for a written order allowing the patient to have calcium measured urgently in the event of symptoms, and recalls that any therapeutic change should be followed by a short-term calcium check [12].

11.3 Surveillance specific to the syndromic forms

Regarding the divergence on renal imaging, which the table presents in its three positions, it is important to state where it comes from and not to resolve it silently. The 2022 Second International Workshop recommends, in its recommendation 5.2, a baseline assessment with renal imaging in all patients, and the 2025 European guideline explicitly recommends against routine imaging in its R.4.5 [27, 34]. The recommendation not to perform routine imaging is aimed at chronic hypoparathyroidism in general, dominated by postsurgical disease in adults, and the guideline that formulates it allows imaging to be considered when there are additional risk factors, naming among them the type of hypoparathyroidism and giving autosomal dominant hypocalcaemia type 1 as an example [34]. The recommendations for annual or six-monthly ultrasound are aimed at syndromes with their own renal risk — the FAM111A dysplasias and the paediatric forms of glandular agenesis — and, in these, the entity-specific recommendation prevails over the general one [17, 22]. In either case, the renal surveillance shared by both guidelines is laboratory-based and annual: estimated glomerular filtration rate and albuminuria at least once a year, with a change in rate above 20% or a doubling of the urinary albumin/creatinine ratio exceeding expected variability and justifying assessment [34].

12. Summary and Final Considerations

Congenital and hereditary hypoparathyroidism is a group of entities that share a biochemical profile — hypocalcaemia with hyperphosphataemia and low or inappropriately normal parathyroid hormone, with normal renal function — and diverge in everything that determines management. The axis that organises them is mechanism: the gland may never have formed, owing to failure of the developmental transcription factors of the pharyngeal pouches, as with GCM2, GATA3, TBX1 and the 22q11.2 region, TBCE, FAM111A and the Xq27.1 rearrangement with a position effect on SOX3; the hormone may be synthesised defectively, misfolded or biologically inactive, as with PTH variants; the calcium sensor may be calibrated downwards, so that the hormone is suppressed at concentrations that should stimulate it, as in gain of function of CASR and GNA11; the formed gland may be destroyed by autoimmunity, through failure of AIRE-dependent central tolerance; or the secretory cell may fail for bioenergetic or metabolic reasons, in mitochondrial cytopathies and in severe hypomagnesaemia.

This division by mechanism has three direct clinical consequences. The first concerns diagnosis: the biochemical profile establishes the endocrine state but never the cause, and it is molecular testing — a panel including the genes of the class, combined with a technique that detects copy number variation — that identifies the aetiology, with a yield of about 28% in paediatric cohorts and with the particularity that dosage analysis yields as much as sequencing, because of 22q11.2 deletions. The time to measure urinary calcium is before starting treatment, because an inappropriately normal or high value during untreated hypocalcaemia is the best clue to gain of function of the calcium-sensing receptor, and this value is irretrievably altered after the first dose of active vitamin D. Magnesium is measured in the same sample as calcium and parathyroid hormone at any age, because severe hypomagnesaemia reproduces the biochemical profile of hypoparathyroidism but resolves with replacement. The molecular result does not, finally, remove the need to determine the inheritance pattern case by case: for PTH and GCM2, dominant and recessive transmission coexist, depending on the variant and not on the gene, so recurrence risk and screening of relatives are defined after assessing the parents' biochemistry, and not from the name of the entity [1, 4, 38].

The second consequence concerns treatment. Conventional therapy — oral calcium with calcitriol or alfacalcidol, with correction of vitamin D and magnesium — remains first line in all entities, with the target deliberately in the lower half of the reference range, but its risk is intrinsic and not accidental: without parathyroid hormone, the distal tubule does not reabsorb calcium, and any dose that normalises serum calcium causes hypercalciuria and, over time, nephrocalcinosis and loss of renal function. In the gain-of-function forms of the calcium-sensing receptor, this risk is greatest, because the kidney already wastes calcium before any intervention, and treating the entity as if it were common hypoparathyroidism is the documented route to iatrogenic renal failure. Parathyroid hormone replacement has changed status in the last two years: palopegteriparatide is approved in adults in the United States, the European Union and Brazil, with a maximum dose that differs between jurisdictions, and the 2025 European guideline now strongly recommends it in patients with persistent symptoms despite optimised conventional therapy, with efficacy and safety data up to 3.5 years, early normalisation of urinary calcium and gains in glomerular filtration rate. No parathyroid hormone product is approved below 18 years, and no PTH(1-84) has existed in any jurisdiction since the withdrawal of the European authorisation on 1 July 2026. In Portugal, palopegteriparatide is authorised without marketed presentations, and the only parathyroid hormone replacement actually marketed in Portugal and Brazil is teriparatide, off-label.

The third consequence concerns surveillance, which is not an appendix to treatment but the mechanism by which treatment is prevented from causing long-term disease. Monitoring calcium, phosphate, magnesium, creatinine and urinary calcium at the indicated intervals, and screening for cataracts, intracranial calcification and nephrocalcinosis, is what separates a patient with normal development from a patient with chronic kidney disease, cataracts and calcification at forty years of age. In the syndromic forms, calcium surveillance is only one part: in HDR syndrome, hearing and the kidney determine prognosis; in the TBCE syndromes, respiratory failure causes most deaths; in autoimmune polyendocrinopathy type 1, adrenal crisis and oral and oesophageal carcinoma are partly preventable causes of death, and it is lifelong periodic screening for new components and regular examination of the oral mucosa that prevent them.

What remains unresolved is what matters most for children, who are the population in which these diseases present. There is no guideline dedicated to paediatric genetic hypoparathyroidism, the 2025 European guideline covers only adults, the only document with graded paediatric recommendations is that of the 2022 Second International Workshop, the most detailed paediatric dosing comes from a good practice consensus without formal grading of evidence — that of the 2024 Parathyroid Summit —, current targets come from a narrative review with expert perspectives, and access to the active vitamin D metabolites in the paediatric age group depends on the jurisdiction — calcitriol has approved paediatric dosing in the United States and not in Portugal, and alfacalcidol has it in Portugal and does not exist in the United States. The developments most likely to change this picture are the first phase 3 trial of parathyroid hormone replacement in adolescents and the first paediatric trial of a calcilytic in autosomal dominant hypocalcaemia type 1, both started in 2026 and still recruiting, to which are added the study of palopegteriparatide transfer into human milk and a global pregnancy registry, which respond directly to two gaps declared in the labels. The calcilytic is, of all the approaches in development, the only one directed at the mechanism of one of these diseases rather than its consequence, and the fact that the class has already failed in a different indication is reason to await the results of the phase 3 trials before counting on it.

In France, the 2025 national diagnosis and care protocol adds to these recommendations an emergency protocol for adults and children, a follow-up schedule by age group and the organisation of care around the reference centre and the OSCAR network, and diverges from the other guidelines on points with bedside consequences — the use of uncorrected total calcium, the slower maintenance infusion, taking carbonate away from meals, the contraindication of antiresorptives and a higher paediatric hypercalciuria threshold —, divergences that should be known by those treating patients followed at French centres [12].

13. References

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