Familial Hypocalciuric Hypercalcaemia and CASR Disorders

Disorders of the extracellular calcium-sensing axis: familial hypocalciuric hypercalcaemia types 1 to 3 (CASR, GNA11, AP2S1), neonatal severe hyperparathyroidism, transient neonatal hyperparathyroidism due to placental calcium transport deficiency (TRPV6) and, as gain-of-function allelic diseases, autosomal dominant hypocalcaemia types 1 and 2.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. One receptor, three phenotypes

The calcium-sensing receptor (CaSR) is the thermostat for extracellular calcium. In parathyroid chief cells and the renal tubule, this G protein-coupled receptor reads the ionised calcium concentration and defines the set-point at which parathyroid hormone (PTH) secretion is inhibited and urinary calcium excretion increases [5, 41]. The diseases addressed in this article result from shifts in this set-point. When the CaSR signalling pathway loses sensitivity, the body starts to “defend” a higher serum calcium concentration and retain calcium in the kidney: this is familial hypocalciuric hypercalcaemia (FHH) in its heterozygous forms, and neonatal severe hyperparathyroidism (NSHPT) when loss of function is profound. When the pathway is overactive, the set-point falls and autosomal dominant hypocalcaemia (ADH) develops, with suppressed PTH and renal calcium loss [5, 8]. The same logic applies to the three known genes: CASR, encoding the receptor itself; GNA11, encoding the Gα11 subunit, the main intracellular transducer of CaSR; and AP2S1, encoding the σ2 subunit of the AP-2 adaptor complex, responsible for receptor endocytosis and signalling [8, 9].

The clinical importance of this group lies less in the severity of the common forms, which are asymptomatic in most carriers, than in the errors caused by confusing them. FHH mistaken for primary hyperparathyroidism (PHPT) leads to parathyroidectomies that do not correct hypercalcaemia; ADH treated as ordinary hypoparathyroidism, aiming to normalise calcium, leads to hypercalciuria, nephrocalcinosis and iatrogenic renal failure; and a familial diagnosis of FHH considered “benign” conceals a reproductive risk of NSHPT when both parents are carriers [4, 5, 30].

1.2. Historical and molecular discovery milestones

The clinical observations that founded this field came from Stephen Marx's group at the US National Institutes of Health. In 1982, Marx and colleagues associated NSHPT with FHH in three families and, in 1985, proposed that the same gene was expressed mildly in heterozygotes and severely in homozygotes, an interpretation cited by Spranger and colleagues' atlas of skeletal dysplasias [10]. The molecular basis was established in 1993, when Pollak and colleagues demonstrated that missense variants in the human calcium-sensing receptor gene caused FHH and NSHPT; the mutated receptors, expressed in Xenopus oocytes, showed a markedly attenuated response to polyvalent cations, and the authors concluded that the receptor “sets” the extracellular calcium level in mammals [14]. One year later, the same group described the first gain-of-function variant, Glu128Ala (original nomenclature), in a family with autosomal dominant hypocalcaemia, demonstrating that the mutated receptor activated the inositol trisphosphate pathway at lower calcium concentrations [15].

For two decades, families with FHH or ADH without a CASR variant remained unexplained. In 2013, Nesbit and colleagues identified missense variants at AP2S1 codon Arg15 in more than 20% of families with FHH without a CASR variant, defining FHH type 3 [42]. In the same year, two groups linked GNA11 to the phenotype: Nesbit and colleagues described an in-frame deletion (Ile200del) in a family with FHH and loss-of-function variants in another patient (FHH2), as well as gain-of-function variants in two patients with ADH2, and mapped the FHH2 locus to 19p13.3 [43]; Mannstadt and colleagues independently reported germline Gα11 variants in hypoparathyroidism [44]. Acquired phenocopies were also described: Kifor and colleagues (2003) characterised hypocalciuric hypercalcaemia caused by autoantibodies against CaSR, and Suzuki and colleagues (2018) attributed a form of transient neonatal hyperparathyroidism to TRPV6 variants, encoding a calcium channel involved in placental transport [10].

1.3. Nomenclature and reclassifications

The designation “familial hypocalciuric hypercalcaemia” is now preferred to “familial benign hypercalcaemia”, but both persist as synonyms in Orphanet [1]. The word “hypocalciuric” is itself under review: a US surgical series published in 2026 calls FHH a “misnomer”, because patients with pathogenic variants may have urinary calcium excretion and calcium/creatinine clearance ratios above the classical thresholds, and an editorial in the same journal proposed rethinking diagnosis beyond hypocalciuria [45, 46]. Autosomal dominant hypocalcaemia type 1 is also termed familial hypocalcaemic hypercalciuria [4]. The ADH1 subgroup with hypokalaemic alkalosis, renal salt wasting and hyperaldosteronism was called “Bartter syndrome type 5”; that number now belongs to transient antenatal Bartter syndrome due to MAGED2, and the CASR-related form is addressed in this article, with “type 5” to be read as CASR in literature predating the reclassification [4, 5]. Some sources assign OMIM numbers inconsistently: a footnote to a GeneReviews table on MEN1 associates FHH with number 601198, which corresponds to ADH1; FHH1 has number 145980 [1, 3, 18].

1.4. Definitions of each entity

Orphanet defines FHH as a genetic disorder of calcium and phosphate metabolism, generally asymptomatic, characterised by lifelong moderate hypercalcaemia with normocalciuria or hypocalciuria and an elevated plasma PTH concentration [1]. This wording differs from the other sources regarding PTH: GeneReviews and GeneGuidance curation describe normal or only slightly elevated PTH, and the genetics group of the 5th International Workshop on PHPT refers to “inappropriately normal or slightly elevated” PTH [5, 11, 17]. The interpretation consistent with physiology is that PTH is not suppressed in the presence of hypercalcaemia, usually remaining within the reference range or slightly above it, rather than being frankly elevated as in PHPT. GeneReviews adds that, in the CASR-related form, FHH is not a pathological process, but a higher, stable baseline calcium concentration [17]. It is subdivided into FHH1 (CASR), FHH2 (GNA11) and FHH3 (AP2S1) [1].

NSHPT is defined as severe hypercalcaemia, above 3.5 mmol/L, from birth, associated with marked hyperparathyroidism [2]. Autosomal dominant hypocalcaemia is defined as a disorder of calcium homeostasis with variable degrees of hypocalcaemia, disproportionately low or normal PTH and normal or elevated renal calcium excretion; it is subdivided into ADH1 (CASR) and ADH2 (GNA11) [3]. The differential diagnosis includes transient neonatal hyperparathyroidism (NHPT), due to a maternal cause, paternal origin of a CASR variant or TRPV6 variants, and hereditary primary hyperparathyroidism, particularly multiple endocrine neoplasia type 1 (MEN1) and CDC73-related disorders [10, 17, 47]. Transient neonatal hyperparathyroidism due to TRPV6 (OMIM 618188) is a fetal and neonatal hyperparathyroidism secondary to impaired placental calcium transport, with raised PTH, normal or low plasma calcium and bone disease that regresses after birth; it was described by Suzuki and colleagues in 2018, in six children with biallelic TRPV6 variants, and, because the raised PTH is a response and not the cause, the designation “TRPV6-related intrauterine calcipenic rickets” was proposed in 2026 (sections 2.10 and 3.9) [6, 7].

2. Molecular Genetics and Pathophysiology

2.1. The calcium-sensing receptor and its functions by organ

CaSR is a dimeric class C G protein-coupled receptor, expressed in parathyroid chief cells and throughout the renal tubule, signalling through G proteins and β-arrestin [5, 41]. Besides its calciotropic functions, roles have been described in the lung, neurons, vascular tone, nutrient sensing in the digestive tract and insulin secretion [41]. The Leuven review on ADH1 summarises receptor functions by organ, explaining why the same molecular defect produces hypercalcaemia and hypocalciuria, or hypocalcaemia and hypercalciuria, depending on the direction of the change (Table 2.1) [4].

Table 2.1. Actions of CaSR activation by organ and consequences for calcium homeostasis

Source: De Coster and colleagues, 2025, Table 1 [4]. PTHrP, PTH-related protein; PMCA2, plasma membrane calcium ATPase type 2.

In the collecting duct, CaSR activation acidifies urine and reduces water reabsorption, protecting against nephrocalcinosis when urinary calcium increases [5]; in ADH1, this same pathway contributes to relative vasopressin resistance and polyuria [48].

2.2. Mechanism: shifting the set-point

In loss-of-function variants, the receptor loses sensitivity and the parathyroid “calciostat” starts operating at a higher point: PTH secretion is not suppressed at a serum calcium concentration that would normally suppress it, and the kidney inappropriately reabsorbs calcium, producing hypercalcaemia with relative hypocalciuria [5, 10]. Magnesium reabsorption is likewise increased, explaining mild hypermagnesaemia [10]. In the classical representation, the curve relating calcium to PTH is shifted to the right, and the parathyroid glands are normal or slightly hypercellular [11]. In gain-of-function variants, the opposite occurs: PTH is suppressed at normal serum calcium concentrations and the kidney loses calcium [5]. ADH1 hypercalciuria thus results from two additive mechanisms, PTH suppression and the direct renal effect of the activated receptor, such that at any serum calcium concentration urinary calcium excretion is higher than in hypoparathyroidism of another cause [4]. In variants with more intense activation, inhibition of the NKCC2 cotransporter in the thick ascending limb causes renal sodium, chloride and magnesium wasting, with hyperreninaemia, normotensive hyperaldosteronism, hypokalaemia and metabolic alkalosis: this is ADH with a Bartter-like syndrome [4].

This model has a central therapeutic consequence. In ADH, administration of calcium and active vitamin D is “perceived” by the overactive receptor as hypercalcaemia, further suppressing residual PTH and increasing urinary calcium excretion [4]. In FHH, parathyroidectomy does not correct hypercalcaemia because the defect is in calcium sensing rather than parathyroid tissue mass [5, 11]. Loss and gain of function of CASR are thus opposite mechanisms in the same gene, and the same applies to GNA11: FHH1 and FHH2 lie on one side, with hypercalcaemia and hypocalciuria, and ADH1 and ADH2 on the other, with hypocalcaemia and hypercalciuria. The gain-of-function side also belongs among the other causes of parathyroid hormone deficiency, with the differential diagnosis of ADH from the isolated forms due to GCM2 and PTH and from the syndromic forms due to GATA3, TBX1, AIRE, FAM111A and TBCE, the biochemical targets common to genetic hypoparathyroidism and the role of parathyroid hormone replacement and calcilytics.

2.3. CASR: structure of the variant spectrum

More than 150 loss-of-function variants have been catalogued, of which more than 85% are missense, and more than 70 gain-of-function variants, approximately 95% missense [5, 41]. A 2023 review reports more than 130 CASR variants in FHH1 [49], and the Leuven review counts more than 100 gain-of-function variants in ADH1 [4]. In ADH1, more than 95% of variants are heterozygous missense variants [48]. Not all variants are distributed uniformly: in the series of 51,289 exomes from the Geisinger health system (Pennsylvania, USA), 38 unrelated individuals with predicted heterozygous loss-of-function variants were identified, of which six were nonsense or frameshift and twelve missense, and two individuals with ADH1 due to missense variants whose gain of function was confirmed in functional studies [20].

In NSHPT, the genotype is usually biallelic, homozygous (frequently with consanguinity) or compound heterozygous [11]. However, NSHPT with a single heterozygous variant, de novo or inherited from the father, exists. Two non-exclusive explanations are proposed: a dominant-negative effect of the mutated protein on the receptor dimer, and superimposed secondary hyperparathyroidism in an affected fetus with a high set-point, carried by a normocalcaemic mother [10, 47]. The NM_000388.4:c.554G>A p.(Arg185Gln) variant is the best-documented example: it was described de novo in two unrelated patients with NSHPT and, inherited from the father, in neonates with a severe course [35, 47, 50].

The correlation between genotype and severity is imperfect. In the analysis by Marx and Sinaii, cited by Meira and colleagues, homozygotes for pathogenic variants had more severe neonatal hypercalcaemia and higher PTH, whereas compound heterozygotes more frequently had milder presentations and greater residual receptor activity [31]. A series of 57 cases, cited by Rosettenstein and colleagues, found serum calcium above 4.5 mmol/L only in homozygotes; the Australian neonate they described, compound heterozygous for c.190A>G p.(Asn64Asp) and c.101T>C p.(Leu34Pro), reached 5.4 mmol/L, contradicting that expectation [25]. Conversely, a woman aged approximately 40 years, born to consanguineous parents and homozygous for a frameshift insertion (c.2603_2604insTT, transcript not stated in the abstract), had FHH1 complicated by a parathyroid adenoma, without a history of NSHPT [51]. The response to cinacalcet depends on residual receptor function: in two NSHPT cases with truncating variants producing non-functional protein, the drug failed [35].

CASR loss-of-function variants have also been described, in heterozygosity or homozygosity, in adults with typical PHPT, with elevated PTH, hypercalciuric urolithiasis and osteoporosis, most with adenoma or hyperplasia and a decrease or normalisation of calcium after resection [11]. Heterozygous CASR variants were found in 14–18% of families with familial isolated primary hyperparathyroidism (FIHP) [17, 18]. No somatic CASR variants have been detected in parathyroid tumours, and common gene polymorphisms are associated, in genome-wide association studies, with serum calcium and PTH in the general population [11].

2.4. GNA11: the Gα11 subunit

Gα11 is the α subunit of a heterotrimeric G protein coupling CaSR to phospholipase C-β, producing inositol trisphosphate and diacylglycerol [8]. Germline loss-of-function variants reduce the pathway's calcium sensitivity and cause FHH2; gain-of-function variants cause ADH2 [8, 43]. In an Oxford reference service, over ten years and more than 1200 probands referred for hypercalcaemia or hypocalcaemia, 37 germline GNA11 variants were found (14 synonymous, 12 non-coding and 11 non-synonymous); nine of the non-synonymous variants had already been described as causing FHH2 or ADH2 in 13 probands (p.Thr54Met, p.Arg60His, p.Arg60Leu, p.Gly66Ser, p.Arg149His, p.Arg181Gln, p.Phe220Ser, p.Val340Met and p.Phe341Leu), and p.Ala65Thr and p.Met87Val were classified as benign, the latter based on functional studies [52]. By 2023, four probands with FHH2 and eight with ADH2 had been published [52], and an Italian family described in 2026 was presented as the eighth family with FHH2 [24].

The Finnish p.Phe220Ser variant, located in the hydrophobic cleft binding phospholipase C, reduces signalling; in vitro, its correction required higher cinacalcet concentrations than those effective in AP2S1 variants [53]. The Italian NM_002067.5:c.980_981del p.(His327LeufsTer150) variant shifts the reading frame in the GTPase domain and produces a protein extended by 116 amino acids [24]. In 2026, two unrelated families with complete GNA11 deletion or p.(Ser18Argfs*2), both heterozygous and loss-of-function, showed cosegregation between hypercalcaemia and dental enamel hypomineralisation; the Gna11+/− mouse reproduces the defects, and Gα11 is expressed in ameloblasts and odontoblasts [40]. In ADH2, a family with p.Arg60Leu lacked the hypercalciuria and hypomagnesaemia typical of ADH1 and had short stature [8].

Activating somatic variants at GNA11 codon Gln209 are another category. They are present in 32% of primary uveal melanomas, 57% of metastases and 7% of blue naevi, and postzygotic mosaicism causes cutis marmorata telangiectatica congenita, phakomatosis pigmentovascularis, diffuse capillary malformation with overgrowth and anastomosing haemangioma [8]. GNAQ/GNA11 mosaicism has been associated with abnormal serum calcium indices and cerebral calcification [8]. A germline FHH2 or ADH2 variant does not imply a risk of uveal melanoma, and a Gln209 variant found in a tumour provides no information on calcium disorders [8].

2.5. AP2S1: receptor endocytosis and signalling

The AP-2 complex mediates clathrin-dependent endocytosis, recognising tyrosine and dileucine motifs in proteins to be internalised; its σ2 subunit controls CaSR endocytosis and signalling through the receptor's C-terminal dileucine motif [9, 42]. FHH3 variants are heterozygous missense variants at codon Arg15 (p.Arg15Cys, p.Arg15His and p.Arg15Leu), act in a dominant-negative manner and reduce CaSR endocytosis and signalling, raising the set-point [13, 42]. In 65 probands with FHH without a variant in another gene, the Oxford team found AP2σ2 variants in 17 (five p.Arg15Cys, four p.Arg15His and eight p.Arg15Leu) [13]. The Arg15Gly, Arg15Pro and Arg15Ser substitutions, possible through a single base change, were not found; in cellular studies, these substitutions reduced the number of cells expressing CaSR, which the authors related to the observed codon bias [13]. p.Arg15Leu also weakens σ2 binding to the other AP-2 subunits and CaSR [9]. A second class of rare variants, at the interface between the σ and α subunits (p.Thr112Met, p.Met117Ile and p.Glu142Lys), was identified in exome databases and impairs receptor signalling; loss of function was corrected by cinacalcet in vitro [23].

2.6. Genotype–phenotype correlations across the three genes

FHH1 accounts for approximately 65% of FHH cases [5]. FHH3 is the most clinically marked form: in the comparison of 51 patients with FHH3 and 43 with FHH1, adjusted calcium was 2.87 ± 0.02 versus 2.76 ± 0.02 mmol/L (p<0.001), magnesium was higher and CCCR lower; more than 20% of patients with FHH3 had symptomatic hypercalcaemia, and, in 27 probands with FHH3, adjusted calcium was 3.06 ± 0.04 mmol/L with p.Arg15Leu, 2.83 ± 0.03 mmol/L with p.Arg15Cys and 2.74 ± 0.03 mmol/L with p.Arg15His (p<0.01), without differences in the other mineral metabolism indices [13]. In the same series, the AP2S1 variant detection rate in probands without a CASR or GNA11 variant exceeded 25% [13]. Probands with FHH3 also had cognitive dysfunction [13], and occasional low bone mineral density, osteomalacia and hypophosphataemia were reported [9, 11]. An 11-year-old girl with de novo p.Arg15Leu had persistent neurodevelopmental difficulties [54]. The G2P (Gene2Phenotype) register classifies “AP2S1-related developmental disorder” with moderate confidence, based on data from the DDD (Deciphering Developmental Disorders) study, and Australian PanelApp assigns strong evidence for a neurodevelopmental disorder; whether this is a distinct entity or part of the FHH3 spectrum remains unresolved [9]. FHH2 tends to be the mildest form, with adjusted calcium usually below 2.80 mmol/L [11]. In ADH, the correlation is less useful: in an English series of nine adults with ADH1, there was no clear relationship between mean calcium and complication severity, and two patients from the same family with p.Asn118Lys progressed to renal failure and death [48].

2.7. Penetrance and expressivity

Penetrance estimates depend on the method of ascertainment. In the Geisinger cohort, 21 of the 38 carriers of predicted loss-of-function variants were hypercalcaemic [20]. In UK Biobank, mean serum calcium in the 162 carriers of FHH1 variants was 10.4 ± 0.6 mg/dL, versus 9.5 ± 0.4 mg/dL in the remaining population, but the distributions overlapped from approximately 9.2–9.4 mg/dL, meaning that a proportion of carriers have serum calcium within the reference range [21]. In the Italian family with FHH2, the proband's mother had the same biochemical profile and his carrier daughter aged 15 months was normocalcaemic; the proband's serum calcium normalised after total thyroidectomy, so normalisation during follow-up does not exclude the disease [24]. In ADH, severity ranges from asymptomatic forms to severe hypocalcaemia with seizures [4, 8].

2.8. Standardised reference variants

Table 2.2 brings together the variants cited in this article, described according to Human Genome Variation Society (HGVS) nomenclature and standardised with VariantValidator for MANE Select transcripts. Numbering in some publications uses the alternative CASR transcript NM_001178065.2, encoding a longer isoform with ten additional amino acids; a variant described on that transcript as p.Ala845Asp corresponds to p.(Ala835Asp) on the MANE transcript [12, 55]. The Glu128Ala variant in the first ADH report could not be standardised because the reference base at the expected position does not match; it should be cited in its original nomenclature [12, 15].

Table 2.2. Cited variants, standardised to MANE Select transcripts (GRCh38)

Notes: the article by Höppner and colleagues writes “p.Arg185Glu”, but c.554G>A encodes glutamine (p.Arg185Gln) [12, 47]. AP2S1 genomic coordinates run in the opposite direction to the transcript because the gene is on the negative strand.

2.9. Gene–disease validity, allelic diseases and modifiers

The relationship of GNA11 with FHH2 and ADH2 is classified as strong in GenCC (Gene Curation Coalition) by several curators (Labcorp, Genomics England, PanelApp Australia), with lower classifications from Ambry (moderate for ADH2, limited for FHH2); AP2S1 has a strong classification for FHH3 from four curators; none of the three genes has ClinGen (Clinical Genome Resource) validity curation, and CASR has no ClinGen actionability assertion, meaning curation has not been performed rather than an absence of clinical action [5, 8, 9]. GeneGuidance also links CASR to hypercalciuric hypercalcaemia and susceptibility to idiopathic generalised epilepsy type 8 (OMIM 612899), and Orphanet lists it as a tested candidate gene in hereditary chronic pancreatitis [5]. Saudubray includes AP2S1 in the list of vesicular trafficking genes associated with structural bone abnormalities, without clinical description [59]. Maternal vitamin D status modifies the neonatal phenotype: NHPT was described in a child of a carrier mother with severe vitamin D deficiency, a situation in which fetal disease would not normally be expected [47].

2.10. TRPV6 and placental calcium transport

TRPV6 (7q34; OMIM gene 606680) encodes a cation channel of the vanilloid TRP (transient receptor potential) family with high selectivity for calcium, formed by four identical subunits, each with six transmembrane segments (S1–S6) and ankyrin repeats in the N-terminal domain [6, 60]. The gene has 15 exons and spans about 15.7 kb, and the channel takes part in apical calcium entry in the intestine, epididymis and placenta [6]. In the placenta, transcellular calcium transport has three steps: entry through TRPV6 in the microvillous membrane of the syncytiotrophoblast, facing the maternal blood; buffering and cytoplasmic transport by calbindin-D9k; and active exit through the basal membrane, facing the fetus, via the plasma membrane calcium ATPase [16]. The fetus accumulates 25–30 g of calcium during gestation, about 80% in the 3rd trimester, against a concentration gradient, because fetal calcium is 0.3–0.5 mmol/L higher than maternal calcium [6, 27]. In the Trpv6-null mouse, transport of radioactive calcium from mother to fetus was about 40% lower than in the wild type, with fetal hypocalcaemia and lower bone mineral weight [6, 61]. In 2026, the Japanese group that described the disease recorded, in syncytiotrophoblasts differentiated from human trophoblast stem cells, a TRPV6-dependent calcium influx at the stage of functional maturation, the first direct evidence of channel activity in human trophoblast (cell study, without clinical data) [62].

Loss of function of fetal TRPV6 reduces calcium transfer; the fetus becomes calcipenic and its parathyroids respond with secondary hyperparathyroidism that mobilises calcium from the skeleton and produces intrauterine demineralisation and fractures [6, 27]. The mechanism is the reverse of that in NSHPT: in NSHPT, the defect lies in the sensor and the hypercalcaemia is primary; in TRPV6 deficiency the sensor is intact and PTH rises to defend a serum calcium that tends to be normal or low [6, 10]. After birth, calcium arrives through the intestine, where passive paracellular absorption, independent of TRPV6, predominates, which would explain recovery with adequate enteral intake even though the intestinal channel is also affected [7, 61]. This explanation has not been demonstrated: the French authors who described the 2026 fetal case consider the mechanism of postnatal recovery still unexplained and accept compensatory paracellular absorption only as a hypothesis [28].

The MANE Select transcript is NM_018646.6, whose coding sequence has the same length and encodes the same protein (NP_061116.5) as NM_018646.5 used by most reports, so the c. numbering of published variants is unchanged [12]. The protein starts at an ACG codon, decoded as methionine, 40 codons upstream of the canonical AUG; the old version of the transcript (NM_018646.4) started at that AUG and numbers nucleotides 120 positions and amino acids 40 positions lower [12, 16]. Thus, the variant published in 2026 as NM_018646.4:c.1474C>T p.(Arg492*) corresponds to NM_018646.6:c.1594C>T p.(Arg532Ter) (GRCh37 NC_000007.13:g.142571874G>A), and the variant c.593C>G p.(Thr198Arg) from a 2020 Saudi report, published without a transcript, is consistent with the reference sequence only in the old numbering and corresponds to NM_018646.6:c.713C>G p.(Thr238Arg) [12, 27, 63]. Table 2.3 brings together the variants described in the reports consulted.

Table 2.3. TRPV6 variants described in transient neonatal hyperparathyroidism (NM_018646.6; validated in VariantValidator, GRCh38)

Inheritance is autosomal recessive in almost all cases. In the review of 14 cases published in 2026, 10 (71%) were compound heterozygous, 3 (21%) homozygous and 1 simple heterozygous; of the 19 variants, 13 were missense, 4 frameshift, 1 splicing and 1 nonsense, and the most recurrent was p.(Gly451Glu), in three patients [7]. Each of the six patients in the founding series had at least one complete loss-of-function allele, and the second allele altered splicing, membrane localisation or protein stability [6]. The heterogeneity of the variants precludes robust genotype–phenotype correlations; the combination of a null allele with c.607+5G>A gave the most severe phenotype in the founding series [6, 7]. In 2026 the first monoallelic case was described: a paternal variant, p.(Val625Glu), with no second variant on trio genome sequencing (including structural, copy-number and deep intronic variants), which in functional assays associates with the normal subunit and reduces channel activity [16]. The mother of this child had severe vitamin D deficiency (below 7 ng/mL) and secondary hyperparathyroidism, and the authors considered that maternal deficiency alone did not explain the severity [16].

Penetrance is incomplete and expressivity variable. A Japanese patient had a younger sister with the same biallelic genotype and no complications or skeletal abnormalities [64]. Vitamin D status acts as a probable modifier: in the 2026 review, 8 of the 9 newborns with vitamin D deficiency had hypocalcaemia, and none of those without deficiency had it; 1,25-dihydroxyvitamin D stimulates TRPV6 expression [7]. Maternal vitamin D deficiency is not, however, sufficient to produce the disease: in the pair of Japanese dizygotic twins, the brother without variants, exposed to the same maternal deficiency, had only a slight rise in PTH, without skeletal abnormalities [61].

TRPV6 has a second association, of a different nature. In a Japanese study, variants impairing channel function occurred in 13 of 300 patients with non-alcoholic chronic pancreatitis (4.3%) and in 1 of 1070 controls (0.1%; odds ratio 48.4; 95% CI 6.3–371.7), and in 12 of 124 patients with early onset (9.7%); in the European replication (France and Germany), in 18 patients (2.0%) and in no controls [67]. GeneReviews includes TRPV6 among the risk genes for early-onset chronic pancreatitis [19]. This is a susceptibility and not a fully penetrant Mendelian disease [37]. The variant p.(Ile223Thr), present in two patients with neonatal hyperparathyroidism, was overrepresented in Japanese patients with pancreatitis, although it did not alter function in that study's assay [6, 67]. The sources consulted do not describe pancreatitis in patients with neonatal hyperparathyroidism or in their carrier parents.

3. Clinical Spectrum and Manifestations by System

3.1. FHH1: lifelong, usually asymptomatic hypercalcaemia

FHH1 manifests as lifelong mild-to-moderate hypercalcaemia, with mild hypermagnesaemia, normal or slightly elevated PTH and inappropriately low urinary calcium excretion; most carriers are asymptomatic, and the disease is generally benign and non-progressive [5, 11]. According to the Oxford group, serum calcium in FHH generally remains up to 10% above the upper limit of normal [13]. Hypercalcaemia in the first decade of life is a distinguishing feature because it is rare in other hereditary hyperparathyroidism syndromes [11]. The Danish review by Christensen and colleagues describes normal 25-hydroxyvitamin D, slightly increased 1,25-dihydroxyvitamin D and a normal bone mineral density Z-score despite slightly increased bone turnover [68]. The genetics group of the 5th Workshop summarises the phenotype as minimal or absent symptoms, normal bone mass and no increase in nephrocalcinosis or urolithiasis, and records isolated descriptions of chondrocalcinosis, osteoporosis and nephrolithiasis, whose composition and pathogenesis are unclear [11]. GeneGuidance curation reports chondrocalcinosis becoming more frequent with age and recurrent pancreatitis in some adults [5].

The association with pancreatitis and other diseases depends on study design. In the Geisinger genomic cohort, a variant-set association test found an association between loss-of-function variants and cardiovascular, neurological and other diseases [20]. In UK Biobank, with 454,787 exomes, the phenome-wide association analysis of 162 FHH1 variant carriers was dominated by calcium and parathyroid traits, and pancreatitis and diabetes lost significance after correction for multiple comparisons; serum phosphate was lower in carriers (3.3 ± 0.5 versus 3.6 ± 0.5 mg/dL) [21]. Both studies measure variant carriers in a population not selected clinically, and UK Biobank has neither urinary calcium nor PTH data, so the findings should not be interpreted as individual complication risks in diagnosed patients [21].

A more recently described manifestation is a short QT interval. In a Marseille family with the p.(Ile555Thr) variant, the 20-year-old daughter had exertional syncope at 16 years and palpitations, and her asymptomatic 19-year-old brother had atrial ectopic beats and a QT of 340 ms; their mother had a QT of 360 ms [56]. In ADH, conversely, a long QT, above 440 ms, attributed to CaSR activation has been described [56].

Two 2026 clinical series illustrate the phenotype in the clinic. In Beijing, 11 patients with confirmed FHH1 were compared with 55 patients with sporadic PHPT: 63.6% were women, 63.6% had a family history and 72.7% were diagnosed incidentally; they were younger (38.1 ± 17.4 versus 53.6 ± 14.0 years), with lower PTH (median 41.8 versus 233.9 pg/mL), higher phosphate (1.06 versus 0.77 mmol/L), lower urinary calcium and bone markers, less low bone mass and often negative parathyroid imaging, with serum calcium similar to PHPT [29]. In an endocrinology clinic in Milwaukee (USA), 25 probable FHH cases comprised 20 FHH1, one FHH2 and four FHH3; 24-hour urinary calcium was often above 100 mg and sometimes above 200 mg, and some patients, particularly with FHH3, had hypercalcaemia warranting cinacalcet [69].

3.2. FHH2: the rarest and usually mildest form

FHH2 causes generally mild lifelong hypercalcaemia, normal or low urinary calcium and normal or slightly elevated PTH; most patients are asymptomatic, and some adults have chondrocalcinosis or pancreatitis [8, 11]. The Finnish proband with p.Phe220Ser had headaches, constipation and pruritus [53]. In the 2026 Italian family, the 39-year-old proband, with multinodular goitre, had mild hypercalcaemia, normal PTH, CCCR below 0.01, normal bone mineral density and no urolithiasis [24]. Dental enamel hypomineralisation described in two families with GNA11 loss of function is a new feature leading the authors to suggest including a dentist in the team [40].

3.3. FHH3: the most expressive form

FHH3 is described as the most clinically severe variant: hypercalcaemia may be symptomatic, and hypophosphataemia, osteomalacia, low bone mineral density, cognitive dysfunction and neurodevelopmental disorders have been reported [9, 11, 13, 34]. The three probands in Howles and colleagues' series, from the United Kingdom and Ireland, illustrate the symptomatic pattern: a 34-year-old woman with 12 years of hypercalcaemia, fatigue, headaches and generalised pain that did not resolve after parathyroidectomy; a 22-year-old man with fatigue and rib pain; and a 52-year-old woman with approximately 20 years of hypercalcaemia, headaches, abdominal pain, vomiting, fatigue and musculoskeletal pain, without improvement with pamidronate or parathyroidectomy [34]. A 16-year-old Finnish adolescent with a 22q11.2 deletion and FHH3 due to de novo p.(Arg15Leu) had hypercalcaemia from childhood with inappropriately high PTH and hypocalciuria, and surgical neck exploration did not locate parathyroid tissue to remove [58]. Misleading parathyroid localisation by 18F-fluorocholine positron emission tomography has also been reported in FHH3 [9].

3.4. NSHPT: the severe neonatal form

NSHPT presents at birth or in the first weeks, with diagnosis typically in the first month and up to approximately three months [17]. Spranger and colleagues' atlas lists variable-severity respiratory distress and symptoms of hypercalcaemia as major clinical findings: growth failure, vomiting and anorexia, constipation and abdominal pain, drowsiness or irritability, polyuria and dehydration, lethargy and seizures, cardiac conduction disturbances and hypertension [10]. Major radiological findings are multiple fractures, particularly of the ribs, long-bone bowing, subperiosteal metaphyseal resorption (particularly of the proximal humerus and distal femur) with submetaphyseal fragmentation, and coarse bone trabeculation; laboratory findings include increased PTH, elevated alkaline phosphatase, marked hypercalcaemia with normal or low phosphate and normal or low urinary calcium excretion in patients with CASR variants [10]. Serum calcium is typically between 3.5 and 5.0 mmol/L (14–20 mg/dL), with demineralisation, fractures and respiratory distress, and the disease is lethal without treatment; OMIM and UniProt, cited by GeneGuidance, describe a severe neurodevelopmental disorder, sometimes lethal without parathyroidectomy, generally in the first six months [5]. The genetics group of the 5th Workshop adds hypotonia, marked enlargement and hyperplasia of all parathyroid glands and neurodevelopmental impairment in survivors not treated early [11].

The atlas illustrates radiological evolution with two neonates, without a genotype stated in the text. On fetal computed tomography at 30 weeks, the first patient already had thin, wavy ribs, narrowed long bones and metaphyseal osteopenia; at birth, there were multiple rib fractures, subperiosteal resorption in the proximal humeri and femora, bowed femora and rachitic-type metaphyseal irregularities in the distal radius and ulna; at three months mineralisation was restored, and between one year and 14 months the rib deformities and femoral bowing gradually remodelled. The second patient, with multiple rib fractures, frayed humeral metaphyses and femoral submetaphyseal fragmentation, had remodelled rib fractures with a twisted appearance and persistent mild femoral bowing at one year (Figures 15.2.1–15.2.3 of the atlas) [10]. The same text notes that some infants had a benign course, adapting to an elevated set-point with bone normalisation within a few months, and that CASR-related NSHPT, unlike other hyperparathyroidism, is not associated with nephrocalcinosis or urolithiasis [10]. This last statement should be read as a tendency: one of Fisher and colleagues' infants had stable mild nephrocalcinosis at diagnosis [35].

3.5. Transient neonatal hyperparathyroidism of paternal or de novo origin

A neonate heterozygous for a CASR loss-of-function variant, born to a normocalcaemic mother, perceives the maternal environment as hypocalcaemic; the result may be fetal and neonatal hyperparathyroidism with bone resorption and intrauterine fractures, tending to regress after birth if calcium supply is sufficient [11, 47]. Most published neonatal FHH cases are of paternal or de novo origin, but paternal origin does not always cause neonatal disease, as shown by the two siblings described by Höppner and colleagues, only one of whom had fractures (section 10) [47]. Preterm infants with paternally derived FHH have been described in pregnancies complicated by antepartum haemorrhage at 27 weeks and progressive pre-eclampsia at 34 weeks [47].

3.6. ADH1: hypocalcaemia with hypercalciuria

ADH1 is the most frequent genetic form of isolated hypoparathyroidism [4]. Biochemistry combines hypocalcaemia, inappropriately low but detectable or normal PTH, high-normal or high phosphate and normal or low magnesium; approximately half of patients have hypercalciuria [4]. Severity ranges from absence of symptoms to paraesthesiae, carpopedal spasm and seizures; more than 50% have symptomatic hypocalcaemia and more than 30% renal or intracerebral calcifications [5]. According to Roszko and colleagues' systematic review, cited in the Leuven review, 39% of patients had seizures, particularly at young ages and frequently during febrile episodes, and 32% had central nervous system calcifications, mainly in the basal ganglia but also at the grey–white matter junction, thalamus, dentate nucleus and cerebellum [4]. Chronic complications include nephrocalcinosis, urolithiasis, renal failure, cognitive dysfunction and posterior subcapsular cataract [4].

The north-east England series (Newcastle, 2005–2024) provides a picture of adults followed over time: nine patients with confirmed ADH1, aged 24–57 years, all British of European origin and 89% with a family history, had persistent hypocalcaemia (mean adjusted calcium 1.26–2.10 mmol/L), hypomagnesaemia in 66% and renal involvement in 78% (nephrocalcinosis 56%, nephrolithiasis 67%, chronic kidney disease); two patients from the family with p.Asn118Lys progressed to renal failure and death; seizures, intracranial calcifications, dental abnormalities (hypoplasia, hypodontia, caries), neuropsychiatric symptoms (depression, anxiety and, in one case, early dementia) and short stature were also recorded [48]. A patient treated in childhood for symptomatic hypocalcaemia with the aim of normalising calcium progressed to end-stage renal disease due to nephrocalcinosis and nephrolithiasis, illustrating that some renal damage is iatrogenic [5].

In the Danish national registry (1977–2012), which includes ADH among other causes of non-surgical hypoparathyroidism, 180 patients were identified and 123 were alive (prevalence 2.3/100 000); mortality was not increased, but risk was higher for renal failure (hazard ratio 6.01), cardiovascular disease (1.91), neuropsychiatric disease (2.45), infections (1.94), seizures (10.05), cataract (4.21) and upper limb fractures (1.93), and lower for neoplasms (0.44) [70]. These figures are not specific to ADH. In chronic hypoparathyroidism generally, the medians of observational studies assembled by the 2nd Workshop were 17% for cataract, 11% for infection, 15% for nephrocalcinosis or nephrolithiasis, 12% for renal failure, 11% for seizures, 12% for depression and 7% for ischaemic heart disease and arrhythmias [32].

ADH with a Bartter-like syndrome adds hypokalaemic metabolic alkalosis, renal salt wasting, hyperreninaemia and hyperaldosteronism with normal blood pressure [4, 5]. This form is also part of the classification of Bartter syndromes.

3.7. ADH2

ADH2 manifests as hypocalcaemia with low or inappropriately normal PTH, paraesthesiae, carpopedal spasm, seizures and basal ganglia calcification, with variable severity [8]. The absence of hypercalciuria and hypomagnesaemia and the short stature in a family with p.Arg60Leu suggest a renal profile differing from ADH1, but the number of families described is small [8, 52].

3.8. Comparative synthesis

Table 3.1. Clinical and biochemical comparison of the entities in this article

Sources: [4, 5, 8, 9, 11, 13, 21, 30, 40, 56].

3.9. Transient neonatal hyperparathyroidism due to TRPV6

The disease begins in utero. In the founding series of six children (Canada, USA and Japan), five had skeletal abnormalities detected in the 3rd trimester (polyhydramnios, short bell-shaped thorax, short ribs, short and bowed femora) and normal 2nd-trimester ultrasound scans, consistent with the transfer of about 80% of fetal calcium in the last trimester [6]. Onset may be earlier: narrow thorax at 19 weeks in the Malay case, bell-shaped thorax and short long bones at 20 weeks in the Dutch and British cases, and femora and humeri below the 1st centile with a bowed fibula at 23 weeks in the French fetus [16, 27, 28, 65].

At birth, the picture is that of a metabolic bone disease with hyperparathyroidism. The review of 14 cases published in 2026 gives the frequency of each finding: gestational age 32 to 40 weeks, 8 girls and 6 boys, small for gestational age in 79% (11/14), abnormalities on prenatal ultrasound in 79% (11/14), respiratory distress due to thoracic deformity in 92% (12/13), with transient or prolonged positive-pressure ventilation and tracheostomy in two, and fractures, mainly of the ribs and long bones, in 67% (8/12), often already present before birth [7]. PTH was raised in all (14/14), alkaline phosphatase in 86% (12/14), and there was hypocalcaemia in 64% (9/14), hypophosphataemia in 21% (3/14) and vitamin D deficiency in 75% (9/12) [7]. PTH values range from 75 pmol/L in cord blood, with total calcium of 2.06 mmol/L, to more than 263 pmol/L with adjusted calcium of 2.09 mmol/L, or 2700 pg/mL with calcium of 7.7 mg/dL, illustrating the hyperparathyroidism with normal or low calcium that distinguishes this form from NSHPT [7, 27, 61]. The authors of the review note that about 14% of the data were missing and that severe cases tend to be published more often [7].

Radiographs show thin, deformed and fractured ribs, a narrow thorax, metaphyseal constriction and diaphyseal tunnelling due to subperiosteal resorption, and mild bowing of the femora; they may mimic osteogenesis imperfecta, the initial diagnosis in several cases [6, 63]. In the French fetus, with termination at 26 weeks, autopsy also revealed bilateral cataracts with corneal opacity, a 5 mm atrial septal defect, right ventricular hypertrophy and a moderately hypotrophic placenta; this was the first description of ocular involvement, and the link between fetal hypocalcaemia and cataracts is not clear [28].

The course is one of recovery. In the founding series, five children had a normalised skeleton by 2 years and normal developmental milestones; the sixth, with the most severe genotype, had hydrocephalus, needed thoracic expanders at 7 months and had developmental delay, attributed to the cerebral complications, although the skeletal abnormalities also improved [6]. In the 2026 review, skeletal abnormalities resolved between 6 months and 2 years, PTH normalised between 1 and 3 months and alkaline phosphatase between 3 and 17 months, and seven of eight children with follow-up had appropriate development at 2 years [7]. The British infant, ventilator-dependent from birth, had improved bone density but died at 4 months after cardiac arrest; autopsy found no placental pathology and showed reduced diaphyseal trabeculae with already well-mineralised metaphyses, a histological sign of postnatal recovery [65]. All patients described received mineral supplementation, so there is no untreated natural history; regression with adequate enteral intake is the rule [7, 10].

4. Clinical Recognition and Warning Signs

4.1. In adults with hypercalcaemia

The most frequent scenario is hypercalcaemia found on routine tests, with non-suppressed PTH, in an adult referred for PHPT assessment. The 5th International Workshop guideline recommends suspecting FHH in younger people with CCCR below 0.01 and/or a family history of hypercalcaemia, and considering it whenever hypercalcaemia is longstanding or lifelong, age is below 30 years or relatives are affected [30]. Other clues are PTH within or slightly above the reference range, serum magnesium at the upper limit, phosphate less low than in PHPT and negative parathyroid imaging [11, 29]. A personal or family history of hypercalcaemia persisting or recurring after parathyroidectomy strongly suggests that the diagnosis was FHH [5, 11]: in the Marseille family, the mother underwent surgery for presumed PHPT, with removal of two hyperplastic glands, and hypercalcaemia persisted [56]. Coexisting multiglandular disease, hypercalcaemia in several family members or a syndromic presentation also requires consideration of hereditary PHPT forms, addressed in the differential diagnosis [30].

4.2. In children

Hypercalcaemia in the first decade of life is rare in hereditary PHPT syndromes and is therefore a sign favouring FHH [11]. In a child with hypercalcaemia, inappropriate PTH and neurodevelopmental difficulties or low bone mineral density, FHH3 should be considered, including the possibility of a de novo variant with normocalcaemic parents [54, 58].

4.3. In neonates and infants

Marked hypercalcaemia (above 3.5 mmol/L), respiratory distress, hypotonia, feeding refusal, weight loss and rib fractures or diffuse demineralisation in a neonate are emergency signs [2, 10, 31]. Diagnosis may be delayed when hypercalcaemia is not investigated: one of Fisher and colleagues' infants had neonatal hypercalcaemia of 11.7–12.9 mg/dL not investigated until 11 months, with motor and language delay, dysphagia requiring gastrostomy, a bell-shaped chest and periosteal reactions, and was initially diagnosed with Jeune syndrome [35]. Metaphyseal fractures at different stages of healing, wormian bones and wide sutures in a neonate with elevated PTH should prompt testing of parental serum calcium before considering another cause of fractures [47]. Parental biochemistry (calcium, PTH and fractional calcium excretion) is a rapid, informative step: in the Portuguese case, both parents had an FHH profile [25, 31]. In a newborn with demineralisation, rib fractures, narrow thorax and raised PTH, but with normal or low calcium and normocalcaemic parents, TRPV6 deficiency should be considered, especially if the 3rd-trimester ultrasound showed short long bones, a bell-shaped thorax or polyhydramnios and if maternal vitamin D deficiency does not explain the severity (section 3.9) [7, 16, 61].

4.4. In pregnancy and the perinatal period

Neonatal hypocalcaemia with tetany or seizures in a child of a mother with undiagnosed hypercalcaemia may be the first manifestation of maternal FHH or maternal PHPT, owing to fetal parathyroid suppression [49, 71]. More than 90% of gestational hypercalcaemia is due to PHPT, and FHH is the other PTH-dependent cause; only FHH is usually associated with low urinary calcium [71].

4.5. In hypocalcaemia

ADH should be considered in any non-surgical hypoparathyroidism, particularly before 40 years, with a family history or hypercalciuria disproportionate to serum calcium; the 2nd International Workshop on hypoparathyroidism recommends genetic testing in these scenarios [32]. In a US and Canadian genetic testing programme with 327 people with non-surgical hypoparathyroidism, ADH1 accounted for 18.4% of all those tested [26]. Warning signs are seizures, particularly during febrile episodes, basal ganglia calcifications, nephrocalcinosis developing or progressing on calcium and active vitamin D therapy, and association with hypokalaemia, metabolic alkalosis and hyperaldosteronism (ADH with a Bartter-like syndrome) [4, 5]. Severe acute hypocalcaemia, with significant neurological, cardiac or respiratory symptoms, or calcium below 1.75 mmol/L, is an emergency [4].

4.6. Newborn screening

The sources consulted do not describe newborn screening programmes for these diseases. Neonatal recognition depends on clinical suspicion and prior knowledge of FHH in one or both parents [11, 47].

Table 4.1. Warning signs by context

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Biochemical assessment and preanalytical conditions

Assessment includes albumin-corrected total calcium or, preferably, ionised calcium, magnesium, phosphate, intact PTH, 25-hydroxyvitamin D and creatinine, and, as a discriminating test, the calcium/creatinine clearance ratio (CCCR), calculated from simultaneously collected urinary and serum calcium and creatinine, rather than an isolated urinary concentration [5, 30]. The formula is CCCR = (urinary calcium × serum creatinine) ÷ (serum calcium × urinary creatinine), with all quantities in the same units; this is the same expression used for fractional calcium excretion [25]. Hypercalcaemic PHPT is defined by elevated adjusted calcium with elevated or inappropriately normal intact PTH, measured by a second- or third-generation assay, on two occasions at least two weeks apart [30]. Calcium correction adds 0.8 mg/dL for every g/dL of albumin below 4 g/dL, and ionised calcium is preferred when available [30]. Biotin may falsely lower PTH in some immunoassays and should be discontinued at least 48 hours before sampling [30].

Urinary calcium loses reliability in several circumstances that should be excluded before interpreting a low CCCR: lithium or thiazide treatment, vitamin D deficiency, chronic kidney disease and pregnancy [13, 30, 49]. In pregnancy, physiological absorptive hypercalciuria makes CCCR poorly interpretable, and prepregnancy values, family investigation and genetic testing should be used [49]. A patient with PHPT and vitamin D deficiency may have low urinary calcium [49]. In the 2024 survey of 266 UK endocrinologists and surgeons, 71.4% considered 25-hydroxyvitamin D of at least 50 nmol/L adequate for measuring urinary calcium [72].

5.2. CCCR performance and limitations

CCCR is a probabilistic discriminator, not a confirmatory test. The 5th Workshop guideline summarises that a ratio below 0.01 favours FHH and is present in 70–80% of patients with FHH, that up to 20% of patients with PHPT have a ratio below 0.01, that up to 10% of patients with FHH have a ratio above 0.02 and that approximately 40% of patients with either disease fall between 0.01 and 0.02 [30]. Table 5.1 summarises the main studies.

Table 5.1. Studies of urinary calcium excretion indices for distinguishing FHH from PHPT

The heterogeneity of these results reflects different populations, different FHH proportions in the sample and the dependence of predictive values on prevalence. Christensen and colleagues proposed a two-step procedure, screening with CCCR below 0.020 and testing CASR in everyone below this value, with 98% diagnostic sensitivity [68, 73]. Taylor and colleagues' series shows the opposite limitation: with conventional thresholds, none of the three patients with a pathogenic variant would have been identified, and the authors recommend germline testing before parathyroidectomy in patients without documented previous normocalcaemia or another explanation for acquired hypercalcaemia [45]. In UK practice, according to the 2024 survey, the preferred index for distinguishing PHPT from FHH is CCCR in 24-hour urine (43.6%), followed by CCCR in a spot sample (24.8%); among CCCR users, 55.6% consider a value above 0.01 to exclude FHH and 26.7% use 0.02, and 70.3% calculate it using albumin-adjusted calcium [72]. NICE guideline NG132, according to the same survey, recommends 24-hour urinary calcium, CCCR or a spot calcium/creatinine ratio without defining thresholds [72]. A low CCCR supports FHH and should halt the surgical pathway until a genetic result is available; a normal or high CCCR does not exclude the disease [5, 45].

5.3. Index for distinguishing FHH3 from FHH1

Hannan and colleagues proposed the CMCR index, combining calcium, magnesium and CCCR, all in mmol/L, written in the article as “sCa × sMg/100 × CCCR” [13]. The interpretation arithmetically consistent with the published threshold is calcium × magnesium ÷ (100 × CCCR): with calcium of 2.87 mmol/L, magnesium of 0.9 mmol/L and CCCR of 0.005, the result is approximately 5.2. A value at or above 5.0 identified FHH3 among patients with FHH with 83% sensitivity and 86% specificity [9, 13]. The index guides the order of genetic investigation, but confirmation requires the variant, in practice almost always at codon Arg15 [9].

5.4. Criteria and diagnostic algorithm in hypercalcaemia

There are no formal FHH-specific criteria issued by a society. The algorithm proposed by the Oxford group considers the combination of hypercalcaemia, normal or elevated PTH and CCCR below 0.01 compatible with FHH, provided thiazide use, vitamin D deficiency and renal failure are excluded [13]. The 5th Workshop guideline considers genetic testing indicated whenever FHH is a possibility and recommends considering genetic assessment in patients under 30 years, multiglandular disease by history or imaging, a family history of hypercalcaemia or syndromic disease, and also with atypical adenoma or parathyroid carcinoma; PHPT diagnosis itself does not require genetic testing, and more than 10% of patients with PHPT have a variant in one of ten genes [30]. When testing reveals FHH, surgery is contraindicated in most cases [30].

Table 5.2. Practical algorithm in hypercalcaemia with non-suppressed PTH

5.5. Diagnosis of NSHPT and neonatal hyperparathyroidism

NSHPT is diagnosed by the combination of severe hypercalcaemia with very elevated PTH, high alkaline phosphatase, demineralisation and fractures, with low or normal urinary calcium excretion [10, 11]. In the Portuguese case, serum calcium at 32 days was 6.15 mmol/L (24.6 mg/dL), with phosphate 0.73 mmol/L, PTH 89.26 pmol/L (842 ng/L), fractional calcium excretion 0.9% and tubular phosphate reabsorption 10% [31]. Parental biochemistry guides diagnosis before the genetic result, and trio genome sequencing can provide an answer within days: in the Australian case, it confirmed compound heterozygosity seven days after admission [25]. Enlarged parathyroid glands may be visible on neck ultrasound, but sestamibi scintigraphy and four-dimensional computed tomography may fail to identify them [25].

5.6. Diagnosis of ADH

The initial assessment proposed by the Leuven review includes calcium, albumin, phosphate, magnesium, potassium, sodium, PTH, creatinine and 25-hydroxyvitamin D; 24-hour urine with calcium, sodium and creatinine; renal ultrasound, cerebral computed tomography and ophthalmological examination at diagnosis [4]. If a Bartter-like form is suspected, potassium, bicarbonate, renin and aldosterone are added [5]. Hypercalciuria is defined as excretion above 6.25 mmol/24 h in women and 7.5 mmol/24 h in men or, without reliable collection, a urinary calcium/creatinine ratio above 0.6 mmol/mmol; there is no ADH1-specific definition [4]. The 2nd Workshop recommends genetic testing in non-surgical hypoparathyroidism with a family history, syndromic features or age below 40 years, and advises against the “autoimmune” label outside autoimmune polyendocrinopathy type 1 (APECED), because there is no definitive test and anti-CaSR antibodies have no standardised assay [32]. In the US and Canadian testing programme, 46% of the 327 individuals had a pathogenic, likely pathogenic or uncertain-significance variant in a 26-gene panel; CASR was the most frequent gene (35% of positives), followed by AIRE (17%), GATA3 (10%), TBX1 (7%) and GNA11 (3%) [26]. This programme was sponsored by a company with a commercial interest in ADH1, which should be considered when interpreting it [26].

5.7. Genetic testing: what to request and how to interpret the result

The confirmatory test is analysis of CASR, GNA11 and AP2S1, ideally in a hereditary hyperparathyroidism or hypoparathyroidism panel including the differentials (MEN1, CDC73, CDKN1B, GCM2, RET in hypercalcaemia; AIRE, GATA3, TBX1 and others in hypocalcaemia) [5, 17, 26]. The yield of each gene is unequal: AP2S1 explains more than 20–25% of FHH without a CASR variant in the Oxford series [13, 42], and GNA11 accounted for less than 1% of the more than 1200 probands tested at the same centre [8, 52]. The sources consulted do not provide the overall clinical sensitivity of the panel, that is, the proportion of clinical FHH without an identified variant; the proportion of variants detectable by sequencing does not equate to that sensitivity.

A negative result in the proband does not exclude genetic disease. If the phenotype is highly suggestive, the 5th Workshop group recommends considering another sequencing platform, maintaining surveillance and, with a variant of uncertain significance (VUS), undertaking careful phenotyping and familial segregation analysis [11]. The complete GNA11 deletion described in a family with FHH2 shows that the panel should include copy-number analysis [40]. The report should state the gene, versioned transcript (CASR NM_000388.4, GNA11 NM_002067.5, AP2S1 NM_004069.6), cDNA and protein HGVS nomenclature, zygosity and class according to ACMG/AMP criteria (American College of Medical Genetics and Genomics / Association for Molecular Pathology) [12]. Variants described on the alternative CASR transcript have shifted numbering and should be converted (Table 2.2) [12, 55]. Since the same gene causes diseases in opposite directions, interpretation of a missense CASR or GNA11 variant should be consistent with the patient's biochemistry: loss of function in hypocalciuric hypercalcaemia, gain of function in hypercalciuric hypocalcaemia [5, 8]. In a phase 3 ADH1 trial, activating variants of uncertain significance were accepted as an inclusion criterion provided there was biochemistry of hypoparathyroidism and compatible symptoms or signs [78], illustrating the weight of phenotyping in interpreting these variants.

5.8. Anti-CaSR autoantibodies

Acquired hypocalciuric hypercalcaemia due to autoantibodies against CaSR is clinically identical to FHH, has no germline variant, is usually non-familial and accompanies other autoimmune diseases; it may respond to glucocorticoids [5, 11]. It should be considered in hypocalciuric hypercalcaemia without an identified variant, particularly with personal or familial autoimmunity [11]. Assays for these antibodies are not standardised [32].

5.9. Prenatal and preimplantation diagnosis

DNA testing enables prenatal and preimplantation diagnosis after the familial variant has been identified, and the 5th Workshop group lists prevention through these routes among the uses of genetic testing in hereditary hyperparathyroidism [11]. Its indication is particularly meaningful when both parents have FHH1 and there is a risk of NSHPT (section 8) [11, 31].

5.10. Diagnosis of neonatal hyperparathyroidism due to TRPV6

There are no formal criteria. Diagnosis rests on the combination of raised PTH with normal or low calcium, high alkaline phosphatase and normal or low phosphate in a newborn with demineralisation and fractures, supplemented by maternal biochemistry (calcium, PTH and 25-hydroxyvitamin D) and by the absence of hypercalcaemia in the parents, which rules out parental FHH [6, 7, 37]. No biochemical test confirms the disease; confirmation is molecular [37]. Normal lysosomal enzyme activity rules out mucolipidosis II, a cause of secondary neonatal hyperparathyroidism with an overlapping radiological picture [6, 64].

TRPV6 is not part of every panel. In the British case, testing of CASR, GNA11 and AP2S1 and a 336-gene skeletal dysplasia panel were negative, and the diagnosis came from trio exome sequencing [33]. In the French fetus, trio exome sequencing was inconclusive and trio genome sequencing identified both variants, mainly because the maternal variant was reclassified from uncertain significance to likely pathogenic [28]. In the Malay case, a hyperparathyroidism panel including TRPV6 found a single variant, and trio genome sequencing excluded a second deep intronic, structural or copy-number variant [16]. Several variants have been reported as of uncertain significance, which reflects the scarcity of functional and population data for the gene and not a lack of clinical correlation; functional assays (patch-clamp currents, membrane biotinylation, radioactive calcium uptake) are available only in research laboratories [6, 7, 27]. An isolated heterozygous variant cannot be dismissed without further study, given the existence of a dominant-negative mechanism, but it may also correspond merely to carrier status for a recessive disease [16, 37].

Prenatal diagnosis is possible: in two cases, trio exome sequencing on chorionic villi or during pregnancy identified the variants before birth [7, 63]. The French authors recommend including calcium and phosphate metabolism genes in the investigation of any unexplained fetal skeletal dysplasia [28]. The report should state the NM_018646.6 transcript, the current HGVS numbering (converting old descriptions on NM_018646.4) and the phase of the variants, confirmed by parental testing.

6. Differential Diagnosis

6.1. Comparative table

Table 6.1. Differential diagnosis of the entities in this article

HPT-JT, hyperparathyroidism–jaw tumour syndrome; CNV, copy-number variation; FISH, fluorescence in situ hybridisation.

6.2. FHH and primary hyperparathyroidism

The most frequent differential with the greatest consequences is PHPT. Biochemical overlap is extensive: both conditions cause hypercalcaemia with non-suppressed PTH, and CCCR distinguishes the groups only probabilistically (section 5.2) [17, 30]. FHH tends to present at younger ages, with longstanding hypercalcaemia, a family history, lower PTH, higher phosphate, normal bone markers and bone mineral density and negative parathyroid imaging [11, 29, 68]. The importance of the distinction is evident when surgical criteria for asymptomatic PHPT are applied: a patient with FHH and calcium more than 1 mg/dL (0.25 mmol/L) above the upper limit, or aged under 50 years, would meet parathyroidectomy criteria if FHH were not considered [30]. The two diagnoses are not mutually exclusive: CASR loss-of-function variants have been described in adults with typical PHPT and hypercalciuria who benefited from resection, and a patient homozygous for a CASR variant had FHH1 complicated by a parathyroid adenoma [11, 51]. The 5th Workshop includes this question (whether CASR variants in PHPT and FHH are similar or different) among research gaps [30].

6.3. Hereditary primary hyperparathyroidism

MEN1 is the most common hereditary cause of PHPT, present in 2–4% of patients, and approximately 10% of operated PHPT patients according to the Oxford Desk Reference; PHPT is the first manifestation in most carriers, with typical onset between 25 and 35 years, and parathyroid hyperplasia occurs in 95% of MEN1 patients and 20–30% of MEN2A patients [17, 79]. MEN1 screening is recommended with two spectrum tumours, one tumour before 30 years or an affected first-degree relative [79]. MEN1 variants are present in approximately 20% of FIHP families [17]. The 2017 Oxford Desk Reference estimate that approximately one-third of clinical MEN1 cases without a MEN1 variant would have MEN4 is disputed by other sources, which suggest less than 5% [79]. The same book draws attention to phenocopies: patients with a clinical MEN1 presentation without a MEN1 variant may, on broader investigation, have CDC73 or CASR variants [79]. FIHP is defined by parathyroid adenoma or hyperplasia in at least two members of the same family without other MEN1 endocrinopathies; CASR, MEN1 or CDC73 variants explain approximately 30% of cases, and GCM2 is a candidate gene [11, 18].

CDC73-related disorders (formerly HRPT2, encoding parafibromin) deserve particular attention because they are the opposite of FHH in terms of risk [17]. In HPT-JT, PHPT occurs in up to 95% of carriers, with onset in late adolescence or young adulthood (the youngest patient was 7 years old) and median age at diagnosis between 23 and 38 years; in a Dutch cohort, PHPT penetrance was 8%, 53% and 75% at 25, 50 and 70 years [17]. Disease is uniglandular in 95% of cases, frequently with a cystic or atypical adenoma, but parathyroid carcinoma occurs in at least 10–15% (31% and 23.5% in recent series), with the earliest case at 8 years; metachronous recurrence reaches 23.5–25% after 5–27 years [17]. Ossifying fibromas of the mandible and maxilla occur in 11–40%, renal lesions (cysts, hamartomas, Wilms tumour) in 15–20%, and benign uterine tumours are frequent (38% of 32 women) [17, 79]. Germline CDC73 variants are present in 18–29% of parathyroid carcinomas without a family history, 7–26% of FIHP families and approximately 1–2% of patients with PHPT before 45 years without a family history; high-impact variants (large indels, splicing, frameshift, nonsense, C-terminal) are more strongly associated with carcinoma and jaw tumours [17]. Carcinoma should be suspected with calcium above 12 mg/dL, intact PTH above three times the upper limit, a neck mass, urolithiasis or hoarseness [17]. In people of Roma ethnicity from Portugal, the founder variant NM_024529.5:c.766_767del p.(Val256LysfsTer10), historically designated 255/256delTG, may be tested first [17].

CDC73 management differs radically from FHH management: parathyroidectomy is preferred, without preoperative fine-needle aspiration because of dissemination risk, en bloc resection with the ipsilateral thyroid lobe if carcinoma is suspected, and annual surveillance of calcium, PTH and 25-hydroxyvitamin D from 10 years, with six-monthly dental examination, panoramic dental radiography and renal ultrasound at least every five years, and gynaecological assessment [17]. ClinGen classifies CDC73 actionability as moderate in adults [82]. Familial hypercalcaemia should therefore not be labelled FHH without genetic confirmation, and a panel including CDC73 avoids the two symmetrical errors: operating on FHH and surveillance without surgery in a CDC73 carrier [17, 30].

6.4. Neonatal differential diagnosis

In a neonate with hyperparathyroidism, NSHPT is distinguished from transient neonatal hyperparathyroidism by severity and persistence. Transient forms include paternal or de novo origin of a heterozygous CASR variant with a normocalcaemic mother [47], that secondary to maternal hypocalcaemia (hypoparathyroidism, ADH) in an unaffected fetus, causing demineralisation, intrauterine fractures and low weight [49, 83], and the form due to biallelic TRPV6 variants, a calcium-permeable channel whose loss of function impairs placental transport; in this form, plasma calcium is normal or low and bone changes regress spontaneously within six months to one year [10]. Spranger's atlas also lists mucolipidosis II, with facial dysmorphism and stippled tarsal and lumbosacral epiphyses, and hereditary self-limiting neonatal primary hyperparathyroidism (MIM 239199), with hypercalciuria, nephrocalcinosis and renal tubular acidosis [10]. In older children, primary hyperparathyroidism occurs in FHH, MEN syndromes, familial hyperparathyroidism and HPT-JT, and McCune–Albright syndrome may also be associated with hyperparathyroidism [10]. Williams–Beuren syndrome enters the differential of infantile hypercalcaemia, although hypercalcaemia is infrequent in this syndrome [80]. In TRPV6 deficiency, the main differential diagnosis is osteogenesis imperfecta, the initial diagnosis in several cases, followed by hypophosphatasia, non-accidental fractures, mucolipidosis II, metabolic bone disease of prematurity and hyperparathyroidism secondary to maternal vitamin D deficiency; raised PTH with normal or low calcium, high alkaline phosphatase, normal lysosomal activity and recovery in the first months guide the distinction, and the dizygotic twin without variants, exposed to the same maternal deficiency, shows that this deficiency alone does not reproduce the picture [37, 61, 63, 64, 84].

6.5. Differential diagnosis of ADH

In hypocalcaemia with low or inappropriately normal PTH, 22q11.2 deletion is a frequent cause in children: 30–60% of patients have hypocalcaemia at some point, particularly neonatally, and hypocalcaemia outside the neonatal period was found in approximately 30% and 42% of children in two series [81]. Other genetic causes include AIRE, GATA3, TBX1, GCM2, PTH itself and other genes of the congenital and hereditary hypoparathyroidism panel [26], mitochondrial respiratory chain disorders, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein deficiencies, and Kenny–Caffey syndrome, which Saudubray mentions among metabolic causes of hypoparathyroidism [85]. The feature most suggestive of ADH is hypercalciuria disproportionate to low serum calcium, worsening with treatment [4]. ADH hypercalciuria and nephrocalcinosis in turn enter the differential of familial hypercalciuria–hypomagnesaemia–nephrocalcinosis and Bartter syndromes [4, 85].

7. Treatments and Risk Management Strategies

There is no society guideline dedicated to FHH or NSHPT. Recommendations in this article derive from the 5th International Workshop guideline on PHPT (2022) and its genetics group document, the 2nd International Workshop on hypoparathyroidism (2022), recommendations from a Leuven centre for ADH1 (2025), medicine labels and case series and reports [4, 11, 30, 32]. The evidence level is therefore mainly observational, and all cinacalcet use in FHH and NSHPT, and PTH use in ADH, is off-label.

7.1. FHH: treatment consists of avoiding surgery

In the vast majority of patients with FHH, no intervention is indicated; the clinical task is to recognise the disease and avoid parathyroidectomy [5, 8]. The 5th Workshop guideline considers surgery contraindicated in most patients whose genetic test reveals FHH [30]. Subtotal parathyroidectomy leaves persistent hypercalcaemia and total parathyroidectomy produces permanent hypoparathyroidism, without correcting the calcium-sensing defect [11]. The exception is rare individuals or families with a CASR variant and a typical PHPT phenotype with hypercalciuria, who may benefit from surgery [11]. In FHH3, genetic diagnosis avoids unnecessary interventions: two of the three probands in Howles and colleagues' series had undergone surgery without symptom improvement [9, 34]. Patients and families should know the diagnosis and communicate it to any doctor assessing hypercalcaemia, to avoid further investigations and surgery.

7.2. Cinacalcet in symptomatic FHH (off-label)

Cinacalcet is a calcimimetic that increases CaSR sensitivity to extracellular calcium, suppressing PTH and increasing renal calcium excretion [5, 25]. No label includes FHH: in the USA, according to the Food and Drug Administration (FDA), Sensipar® is indicated in secondary hyperparathyroidism in adults with chronic kidney disease on dialysis, hypercalcaemia of adult parathyroid carcinoma and adult PHPT hypercalcaemia when parathyroidectomy would be indicated by serum calcium but is not possible [86]. Evidence in FHH is limited to case series and reports, without a controlled trial, and doses used come from these reports (Table 7.1).

Table 7.1. Cinacalcet in symptomatic FHH: evidence by genotype

The PHPT label is the closest dosing reference, without validated extrapolation to FHH: initial dose 30 mg twice daily, titrated every 2–4 weeks through 30 mg 2×/day, 60 mg 2×/day, 90 mg 2×/day and 90 mg 3 to 4 times daily, as needed to normalise calcium; calcium is measured in the first week after initiation or adjustment and then every two months according to the US label, or every 2–3 months according to the European Union (EU) label approved by the European Medicines Agency (EMA); tablets (30, 60 and 90 mg) are taken whole and with food [86, 88]. The drug should not be started with calcium below the lower limit of normal [86]. The most frequent adverse effects are nausea and vomiting (≥25%); warnings include hypocalcaemia, with fatal events described, including in children, QT prolongation and ventricular arrhythmia, seizures (1.4% versus 0.7% with placebo in trials), upper gastrointestinal bleeding, hypotension and worsening heart failure [86]. Strong CYP3A4 inhibitors (ketoconazole, itraconazole) increase cinacalcet exposure, and cinacalcet is a strong CYP2D6 inhibitor, requiring adjustment of drugs such as desipramine, metoprolol, carvedilol, flecainide and tricyclic antidepressants [86]. In mild FHH, benefit should be weighed against these effects and cost, and the decision should be individual and ideally made at a multidisciplinary meeting; Cuny and colleagues propose an acute 30 mg test with hourly calcium, phosphate, PTH and electrocardiogram measurements for 8 hours to select patients [56].

7.3. NSHPT: stabilisation, cinacalcet and parathyroidectomy

NSHPT is an emergency. Initial measures described in reports are intravenous hyperhydration with normal saline, furosemide, intravenous bisphosphonates (pamidronate 0.5–1 mg/kg), calcitonin, glucocorticoids and low-calcium formula [25, 31, 35]. NSHPT hypercalcaemia is usually refractory to glucocorticoids and other conservative measures, and the response to bisphosphonates is transient [10, 35, 57]. The 5th Workshop genetics group considers that NSHPT generally requires urgent total parathyroidectomy [11], whereas Spranger's atlas advises observing infants and avoiding precipitous surgery except in a potentially fatal situation, because cases with spontaneous adaptation exist [10]. The two positions reflect NSHPT heterogeneity: heterozygous and compound heterozygous forms with residual receptor function may respond to medical treatment, and homozygotes for severe variants rarely respond [31, 35].

Cinacalcet came into use off-label as a bridge or monotherapy in variants with residual function (Table 7.2). Long-term control, according to GeneGuidance, generally still requires parathyroidectomy [5].

Table 7.2. Cinacalcet in neonatal hyperparathyroidism (published reports, all off-label)

Fisher and colleagues justified a calcium target below 12 mg/dL rather than normocalcaemia because patients with FHH tolerate similar serum calcium, and proposed monitoring calcium, phosphate, PTH and alkaline phosphatase, with intermittent assessment of renal function, urinary calcium and renal ultrasound [35]. Cinacalcet failure in two cases with truncating variants indicates that the choice of medical treatment should consider variant type [35], but the Australian case shows that missense compound heterozygotes may also be refractory [25].

Total parathyroidectomy is preferred to subtotal by most surgeons because of recurrence [31]. Identifying all glands may be difficult: in the Portuguese case, one specimen was thymus, and recurrence on postoperative day 17 was resolved only three months later by right hemithyroidectomy, removing a parathyroid gland at the upper pole of the thyroid lobe [31]. Parathyroid tissue autotransplantation carries risks of graft-dependent hypercalcaemia (approximately 33%) and graft failure (approximately 6%), according to data cited by Meira and colleagues [31]. Prolonged hungry bone syndrome may occur postoperatively: the Australian infant required up to 360 mg/kg/day calcium and 720 ng/kg/day calcitriol, as well as phosphate, for approximately 70 days, and at 3 years was receiving 28 ng/kg/day calcitriol, with normal growth and development [25]. Because renal calcium excretion remains low after parathyroidectomy, ordinary hypoparathyroidism calcium targets (lower half of the reference range) may not apply: the two reports suggest accepting values within the normal range and titrating cautiously because excessive supplementation readily causes hypercalcaemia [25, 31].

7.4. Neonatal hyperparathyroidism of paternal origin

In paternally derived NHPT, the course tends to be favourable with adequate calcium and vitamin D supply, but forms with fractures have been treated with cinacalcet [47]. In sibling 2 described by Höppner and colleagues, supplemental calcium was discontinued, cinacalcet was started on day 26 and stopped at 6 months, with vitamin D3 500 IU/day; the authors acknowledge that improvement could have been spontaneous [47].

7.5. Severe hypercalcaemia: general measures

For severe or symptomatic hypercalcaemia of parathyroid origin, the CDC73 GeneReviews describes intravenous fluids and bisphosphonates, cinacalcet for long-term control when parathyroidectomy is not possible and denosumab in bisphosphonate-refractory hypercalcaemia [17]. In FHH, these measures are rarely necessary because serum calcium is stable and well tolerated.

7.6. ADH: principles and algorithm

The rule in ADH is to treat the patient rather than the number. Conventional calcium and active vitamin D therapy, effective in postsurgical hypoparathyroidism, is perceived by the overactive receptor as hypercalcaemia, suppresses residual PTH and worsens hypercalciuria, with a risk of nephrocalcinosis, urolithiasis and renal failure [4, 5]. GeneGuidance curation therefore limits calcium and active vitamin D to symptomatic patients [5], and the Leuven review proposes an algorithm with serum calcium targets of 1.8–2.1 mmol/L, below the reference range (Table 7.3) [4]. In Roszko and colleagues' cohort of 57 ADH1 patients, cited in that review, 59% received active vitamin D alone, 2% calcium alone and 39% both, 14% received magnesium and 21% a thiazide in combination [4]. ADH2 has no specific recommendations; symptomatic hypocalcaemia is treated with calcium and active vitamin D, and ADH1 recommendations apply to it only by analogy [8].

Table 7.3. ADH1 treatment algorithm proposed by the Leuven review (2025)

Source: De Coster and colleagues, 2025, Figure 3 and text [4]. Recommendations come from one centre, are based on small series and do not cover pregnancy, intensive care or end-stage chronic kidney disease. SGLT2, sodium–glucose cotransporter type 2.

7.7. ADH: conventional drugs and divergence between sources

Conventional treatment doses differ between sources (Table 7.4). The 2nd International Workshop, addressing hypoparathyroidism generally, recommends calcium and active vitamin D as first-line treatment (weak recommendation, low-quality evidence), targeting calcium in the lower half of the reference range or slightly below, 24-hour urinary calcium below 6.25 mmol (250 mg) in women and 7.5 mmol (300 mg) in men, prevention of hyperphosphataemia, magnesium normalisation and 25-hydroxyvitamin D between 75 and 125 nmol/L [32]. The same document recommends a thiazide with a low-sodium diet for hypercalciuria, monitoring blood pressure, magnesium, potassium and renal function, but warns that thiazides should be used cautiously in ADH because they worsen urinary magnesium losses [32]. The Leuven review suggests lower targets (1.8–2.1 mmol/L), 1000 mg elemental calcium instead of the 800–2000 mg in the 2015 European guideline, and 25-hydroxyvitamin D of 20 ng/mL (approximately 50 nmol/L), and recommends not treating asymptomatic patients without hypercalciuria [4]. The 2015 European Society of Endocrinology (ESE) guideline is known in this source collection only through citations in the two reviews.

Table 7.4. Conventional therapy in ADH: doses according to the sources

Sources: [4, 32].

The 2nd Workshop recommends considering PTH when control is inadequate (symptomatic hypocalcaemia, hyperphosphataemia, renal failure, hypercalciuria or poor quality of life) or when high doses are required (calcium above 2 g/day or active vitamin D above 2 µg/day) [32].

7.8. ADH: PTH and analogues

PTH studies in hypoparathyroidism included few patients with ADH1 (Table 7.5). PTH1-34 (teriparatide) is authorised only for osteoporosis, so its use in ADH1 is off-label; the Leuven review considers that it may have a role in seizure prevention, but the evidence does not justify first-line use [4].

Table 7.5. Studies of PTH and analogues including patients with ADH1

Source: De Coster and colleagues, 2025, Table 2 and text [4]; PaTHway data also from the US label [83].

Palopegteriparatide (Yorvipath®) is a PTH1-34 prodrug transiently linked to a polyethylene glycol carrier, prolonging its half-life to approximately 60 hours [4]. It is approved for adult hypoparathyroidism, without a specific ADH indication, and doses differ between jurisdictions: in the USA, start at 18 µg once daily, with 3 µg adjustments and a maximum of 30 µg daily in a single injection; in the EU, start at 18 µg once daily, with 3 µg adjustments every 7 days and a range of 6 to 60 µg daily [83, 89]. Before initiation, the US label requires normal 25-hydroxyvitamin D and corrected calcium of at least 7.8 mg/dL in the preceding two weeks, and the European label calcium between 1.95 and 2.64 mmol/L; at initiation, active vitamin D is stopped if calcium is at least 2.07 mmol/L and reduced by 50% or more if lower [83, 89]. Calcium is measured 7–10 days after each adjustment and then at least every 4–6 weeks [83]. Safety and efficacy below 18 years are not established [83, 89]. In a congress abstract, a 16-year-old Polish boy with ADH1 due to p.(Ala835Asp), with nephrocalcinosis, cataracts, basal ganglia calcifications, hypercalciuria and hyperphosphataemia of 8–11 mg/dL on alfacalcidol 1.25 µg/day, calcium 600 mg/day, hydrochlorothiazide, magnesium and potassium chloride, received palopegteriparatide 9 µg/day, off-label because of age; at 4 months, calcium was 8.68 mg/dL and phosphate 5.46 mg/dL, the dose was reduced to 6 µg/day with alfacalcidol 0.25 µg and no calcium, without tetany, but phosphate did not normalise [55]. This is an isolated case, reported by an investigator in a trial of the drug [55].

Recombinant PTH 1-84 (Natpar®) received conditional authorisation in the EU on 24 April 2017 as an adjunct in chronic hypoparathyroidism; the European Commission withdrew authorisation on 1 July 2026, at the holder's request, because of permanent discontinuation due to supply problems [90]. According to the Leuven review, rhPTH1-84 was to be withdrawn from the global market at the end of 2024 because of manufacturing problems [4].

7.9. Calcilytics: therapy targeting the mechanism

Calcilytics are negative allosteric CaSR modulators that reduce receptor sensitivity and thus correct the molecular defect in ADH [4, 5]. In preclinical models, NPS-2143 corrects increased signalling of gain-of-function receptors in vitro and raises calcium and PTH in mice with ADH1 and ADH2, although with limited efficacy in severe Bartter-like variants, in which quinazolinone-derived calcilytics were superior [5, 8]. Oral JTT-305/MK-5442, in ADH1 knock-in mice, increased calcium, magnesium and 1,25-dihydroxyvitamin D, reduced phosphate and urinary calcium and, unlike PTH1-34, did not cause renal calcifications [4]. Ronacaleret and JTT-305/MK-5442 had failed in postmenopausal osteoporosis and were repurposed for ADH [5].

The first human study, with intravenous NPSP795 (5–30 mg) in five adults with four different variants, increased PTH dose-dependently, but with a variable response (two patients with the same variant responded differently) and without a significant calcium increase or reduction in fractional calcium excretion [4, 91]. Oral encaleret (CLTX-305) was studied in an open-label phase 2b trial (NCT04581629) in 13 adults with ADH1 and nine distinct CASR variants, all of non-Hispanic European origin: after one or two 5-day admissions for adjustment and 24 weeks as outpatients, with calcitriol and calcium discontinued, it corrected hypocalcaemia and reduced hypercalciuria, increased intact PTH, magnesium and 1,25-dihydroxyvitamin D and reduced phosphate and tubular phosphate reabsorption; required doses ranged from 5 to 190 mg twice daily, but were stable in each patient; there were no serious adverse events or discontinuations, and related adverse effects were mild, transient and asymptomatic hypophosphataemia or hypercalcaemia [91]. In extension follow-up with 42 months of continuous treatment, presented as a congress abstract, predose PTH rose from 6.3 ± 7.8 pg/mL to 23.7 ± 16.8 pg/mL, corrected calcium from 7.1 ± 0.4 to 9.0 ± 0.3 mg/dL and urinary calcium from 395 ± 216 to 162 ± 103 mg/day; bone turnover markers, initially low, increased, and the bone mineral density Z-score fell until 24 months of extension and stabilised at 36 months (spine 2.6 → 2.2; total hip 2.2 → 1.7) [92].

The phase 3 CALIBRATE trial (NCT05680818) randomised 67 adults and adolescents aged 16 years or older with closed growth plates, in a 2:1 ratio, to encaleret or conventional therapy, open-label; the primary outcome combined corrected calcium and 24-hour urinary calcium within target at week 24 [78, 93]. According to the preliminary results press release of 29 October 2025, 76% (34/45) of patients achieved the primary outcome with encaleret, versus 4% (2/45) of the same participants during conventional therapy at week 4 (p<0.0001), and 91% had intact PTH above the lower limit, versus 7% [93]. In the presentation at the 2026 European endocrinology congress, the between-arm comparison at week 24 was 76% with encaleret versus 19% with conventional therapy (p<0.0001), with restoration of endogenous PTH in 91.1% versus 0%; there were no discontinuations in the encaleret arm, and serious adverse events had a similar frequency between arms [94]. Results have not been published in a peer-reviewed journal, confidence intervals have not been disclosed and the dose used in the phase 3 trial is not included in the sources consulted.

7.10. Comparative regulatory status

Table 7.6. Regulatory status of relevant drugs (USA and EU), as of 10 October 2026

Sources: [4, 36, 83, 86, 88–90, 93–95]. The cinacalcet PHPT indication is included in the current US label; its correspondence with the 2011 supplement derives from the FDA record chronology. The sources consulted do not describe national access to these drugs in Portugal or Brazil.

7.11. Trials and intervention studies

Table 7.7. Clinical trials and intervention studies in CaSR disorders

These data have limitations affecting interpretation. CALIBRATE compares encaleret with conventional therapy known to be unfavourable for urinary calcium in ADH1, and the 76% versus 4% comparison uses the same participants at an earlier trial phase rather than the control arm; the between-arm comparison (76% versus 19%) is more informative, but confidence intervals and the distribution of adverse events are unpublished [93, 94]. Outcomes are biochemical; there are no data on seizures, long-term renal function or cerebral calcifications. The initial fall in bone mineral density Z-score in the phase 2 extension warrants follow-up [92]. The NPSP795 study, negative for calcium, shows that the response to calcilytics varies even among carriers of the same variant [4]. PTH studies included few ADH1 patients, and indirect comparison between encaleret and palopegteriparatide from trials with different populations and outcomes is not legitimate. There is no controlled trial in FHH or NSHPT.

7.12. Developments in the last twelve months

Between October 2025 and October 2026, the developments with the greatest impact were regulatory and epidemiological. Preliminary CALIBRATE results were announced by press release in October 2025, the encaleret application was submitted to the FDA in May 2026 and accepted in July, with a decision expected on 8 May 2027 and no advisory committee planned; in the EU, submission was only announced (company press releases; no authorisation) [36, 93, 94]. The European Commission withdrew the authorisations for Mimpara® (December 2025) and Natpar® (July 2026) (regulatory decisions) [90, 95]. A genotype-first UK Biobank study estimated the FHH1 carrier frequency at 33.0/100 000 and did not confirm an association with pancreatitis or diabetes (published observational study) [21]. A surgical series of 1599 patients showed that classical urinary thresholds miss patients with pathogenic variants, leading to a recommendation for germline testing before surgery in selected patients (published observational study, with an editorial) [45, 46]. Also published were a series of 25 FHH patients in a US clinic [69], a Chinese FHH1 cohort [29], the association between GNA11 loss of function and enamel hypomineralisation (human series and mouse model) [40], a new Italian FHH2 family [24], a paediatric FHH3 case treated with cinacalcet [54], nine-year follow-up of NSHPT on cinacalcet monotherapy [57], 25-year follow-up of homozygous NSHPT in Portugal [31], an English series of renal and systemic ADH1 complications [48] and a correction, published in September 2026, to the article on reversal of short QT with cinacalcet, whose content was not detailed in the sources consulted [97].

7.13. Pregnancy and lactation

In pregnancy, total calcium falls because of plasma volume expansion and reduced albumin, while ionised and adjusted calcium remain stable; the latter should be used [30, 49]. In a pregnant woman with FHH, mild hypercalcaemia does not require treatment, and the main issue is the neonate (section 8.3) [47, 49]. Cinacalcet is not considered suitable in pregnancy but may be used as a last resort in severe hypercalcaemia (for example, adjusted calcium above 3.0 mmol/L) without a surgical option; it crosses the placenta in animals and, since the placenta expresses CaSR, may suppress fetal PTH, with transient neonatal hypocalcaemia described [49]. The US label reports insufficient human data and pup loss with maternal hypocalcaemia in rats exposed to 2–3 times the maximum human dose; the European label reserves use for cases in which benefit justifies risk [86, 88]. Bisphosphonates and denosumab are justified only in severe (above 3.5 mmol/L), uncontrollable hypercalcaemia [49]. The 5th Workshop recommendation for PHPT in pregnancy (hydration and calcium monitoring; surgery in the 2nd trimester if calcium exceeds 11.0 mg/dL; surveillance for neonatal hypocalcaemia if surgery is deferred) applies to PHPT rather than FHH, in which surgery is not indicated [30]. Cinacalcet passes into rat milk with a high milk/plasma ratio; there are no human data, and the European label requires a decision between stopping breastfeeding or the drug [86, 88].

In a pregnant woman with ADH or other hypoparathyroidism, calcium and active vitamin D are maintained, being safe, with calcium in the lower half to middle of the normal range and normal phosphate, magnesium and 25-hydroxyvitamin D; thiazides and PTH or its analogues should be avoided in pregnancy [32, 49]. Calcium is measured every 3–4 weeks, 1–2 weeks after each change and weekly in the last month, with coordination between obstetrics and paediatrics regarding transient neonatal hypo- or hypercalcaemia [32, 49]. Postpartum and during lactation, requirements fall and there is a risk of hypercalcaemia, requiring weekly calcium in the first month and then every 4 weeks; abrupt weaning may cause hypocalcaemia [49]. Neonatal calcium should be measured on alternate days in the first week [49]. In a Swedish registry of 97 women with hypoparathyroidism, labour induction was more frequent (odds ratio 1.87; 95% CI 1.13–2.94) and birth weight was 188 g lower (95% CI −312 to −64), without an increase in small-for-gestational-age neonates, malformations or perinatal death [49]. Poorly controlled maternal hypocalcaemia is associated with miscarriage, premature or dysfunctional labour and possibly pre-eclampsia, and with fetal and neonatal hyperparathyroidism with demineralisation, subperiosteal resorption, osteitis fibrosa cystica and neonatal seizures [83]. Palopegteriparatide has insufficient pregnancy data, and the European label does not exclude risk [83, 89]. The sources consulted do not specifically describe pregnancy in which both mother and fetus have ADH.

7.14. Perioperative care, agents to avoid and transition

In FHH, the perioperative rule is not to perform parathyroidectomy for hypercalcaemia without confirming that the patient does not have FHH [30, 45]. Patients with FHH should know cinacalcet interactions if taking it, and avoid biotin before PTH assays [30, 86]. In ADH, drugs increasing urinary calcium (loop diuretics, glucocorticoids, carbonic anhydrase inhibitors and SGLT2 inhibitors), thiazides in the Bartter-like form and hypomagnesaemia, calcium phosphate and non-calcium phosphate binders should be avoided whenever possible [4]. Thiazides should be stopped at least 14 days before starting a calcilytic in a clinical trial [78]. After NSHPT parathyroidectomy, permanent hypoparathyroidism requires adjustments over decades, and transfer from paediatric to adult medicine should convey these patients' particular physiology, with low calcium excretion and poor tolerance of excessive supplementation [31]. The sources consulted do not describe a specific transition protocol for these disorders.

7.15. Guidelines and divergences

Table 7.8. Recommendations from guidance sources and divergences

Sources: [4, 10, 11, 30–32, 35, 45, 72, 73]. CT, computed tomography.

7.16. Neonatal hyperparathyroidism due to TRPV6: supportive care and mineral supplementation

There is no targeted therapy, clinical trial or guideline; the treatment described in the reports is supportive, and the disease regresses with enteral calcium intake [10, 37]. Measures include respiratory support (continuous positive airway pressure, ventilation, tracheostomy in prolonged cases), careful handling of fragile bones, analgesia and immobilisation of fractures (in one case, with a hip spica), calcium, phosphate and vitamin D supplementation and correction of maternal vitamin D deficiency [7, 16, 37, 63]. Raised PTH is an adaptive response to calcium shortage; none of the patients described underwent surgery or received calcimimetics, unlike in NSHPT [7, 10].

Because no doses have been published for this disease other than those used in isolated reports, Table 7.9 presents them alongside the doses for an analogous condition treated with the same products, metabolic bone disease of prematurity, which also results from deficient intrauterine mineral accretion and has secondary hyperparathyroidism in its calcipenic forms, according to the 2025 practical recommendations of a group of North American paediatric endocrinologists, which take up the 2013 recommendations of the American Academy of Pediatrics (AAP) [84]. The transposition is an extrapolation: the reference doses were defined for very low birth weight preterm infants and have not been studied in TRPV6 deficiency.

Table 7.9. Mineral supplementation and vitamin D in neonatal hyperparathyroidism due to TRPV6 (reports) and in metabolic bone disease of prematurity (analogous condition)

Duration depends on normalisation of PTH and alkaline phosphatase, and supplements were withdrawn gradually over months; in the Hong Kong case, PTH normalised at 2 months and alkaline phosphatase at 4 months [7]. In the mother, vitamin D deficiency should be corrected, as in the Malay case, in which maternal calcium and vitamin D were started after delivery [16]. The 2026 review proposes strengthening maternal vitamin D supplementation in pregnancy to attenuate severity, based on the association observed between vitamin D deficiency and neonatal hypocalcaemia; this is a hypothesis, without an intervention study [7].

There are no gene therapies or TRPV6-targeted drugs in clinical development in the sources consulted. The authors of the founding series suggested, as possibilities, pharmacological chaperones capable of correcting the folding of variants that do not reach the membrane, as is done in cystic fibrosis, and intra-amniotic calcium injection to prevent fetal bone disease; neither has been tested in animal models or in humans [6]. In the last twelve months, new evidence consisted of case reports (the first monoallelic dominant-negative case, a homozygous case with densitometric follow-up and a fetal case with cataracts), a case review and a cell study in human trophoblast, without clinical trials or regulatory procedures [7, 16, 27, 28, 62]. The products used (calcium and phosphate salts, colecalciferol, calcitriol and alfacalcidol) are general-use medicines or supplements, with no specific approved indication for this disease.

8. Reproductive Options and Family Counselling

8.1. Inheritance patterns and recurrence risks

FHH1, FHH2, FHH3, ADH1 and ADH2 have autosomal dominant inheritance: each child of a carrier has a 50% probability of inheriting the variant [1, 3]. De novo cases are described, particularly FHH3 due to p.(Arg15Leu) [13, 54, 58] and NSHPT due to p.(Arg185Gln) [35]. The sources consulted do not quantify germline mosaicism risk after a de novo case, so sibling recurrence risk, although low, cannot be considered zero.

NSHPT adds a recessive scenario. When both parents have FHH1, each child has a 25% probability of inheriting two variants and developing NSHPT, 50% of being heterozygous like the parents and 25% of inheriting neither variant [11]. Parents of children with NSHPT are typically heterozygotes with often undiagnosed FHH, and a familial diagnosis considered benign thus carries a reproductive risk that should be made explicit [5]. In the Portuguese and Australian cases, both parents' biochemistry revealed FHH only after the affected child's birth [25, 31]. Consanguinity increases the probability of homozygosity [11].

8.2. Perinatal risk according to genotype combination

Neonatal expression of a CASR variant depends not only on fetal genotype but also on the maternal calcium environment, making counselling more complex than simple Mendelian calculation (Table 8.1).

Table 8.1. Fetal and neonatal risk according to maternal and fetal genotype

The severity of paternally derived neonatal hyperparathyroidism is variable, and maternal vitamin D status modifies risk: neonatal hyperparathyroidism was described in a child of a carrier mother with severe vitamin D deficiency [47]. Placental calcium transfer rises from approximately 60 mg/day at 24 weeks to 300–350 mg/day in the last six weeks, and 80% of fetal mineral is deposited in the 3rd trimester, explaining the skeletal vulnerability of a fetus with a high set-point [47]. Höppner and colleagues estimated that, with a prevalence of 74/100 000, approximately 580 affected neonates would be born in Germany each year, half with paternal inheritance, a number contrasting with the rarity of reported neonatal cases and suggesting that most progress without recognised disease [47]. The same authors cite the recommendation to offer genetic counselling to all pregnant women with confirmed FHH or a partner with FHH; there is no intrauterine treatment beyond ensuring adequate maternal vitamin D and calcium [47].

8.3. Perinatal plan

When one parent has FHH, the perinatal plan should include informing the paediatrician, measuring neonatal calcium and PTH, testing for the familial variant and, if the father is the carrier, surveillance for signs of hyperparathyroidism and fractures [47]. When the mother is the carrier and the neonate has not inherited the variant, surveillance targets neonatal hypocalcaemia [49]. When the mother has ADH or other hypoparathyroidism, neonatal calcium should be measured on alternate days in the first week [49].

8.4. Cascade testing, carriers and minors

After genetic confirmation in the proband, cascade testing of first-degree relatives enables identification of asymptomatic carriers, avoidance of unnecessary investigations and surgery, and exclusion of phenocopies [11, 77]. In FHH, identifying a carrier has immediate practical consequences, including in childhood, because it prevents hypercalcaemia found later from being interpreted as PHPT; in couples of reproductive age, it identifies NSHPT risk [5, 11]. Testing a neonate of a carrier parent is justified by neonatal disease risk [47]. The Italian FHH2 family shows that a carrier child may be normocalcaemic in the first months, so biochemistry alone does not replace genetic testing [24].

8.5. Prenatal and preimplantation diagnosis

Once the familial variant is known, prenatal diagnosis and preimplantation genetic testing are technically possible, and the 5th Workshop genetics group includes prevention through these routes among the uses of genetic testing [11]. These options are most relevant for a couple in which both partners carry FHH1, with a 25% NSHPT risk [11]. In heterozygous FHH or ADH, the indication is debatable given variability and, in FHH, its usually benign nature; the decision belongs to the couple after counselling [5, 11].

8.6. Counselling content

Counselling should explain the set-point mechanism and why surgery is not indicated in FHH; autosomal dominant inheritance and the 50% risk; NSHPT risk when both partners are carriers; the perinatal scenarios in Table 8.1; the need to communicate the diagnosis to future doctors; and, in ADH, renal treatment risks and the existence of clinical trials [4, 5, 30, 47]. A three-generation pedigree, with targeted questions about hypercalcaemia, urolithiasis, parathyroid surgery, seizures and endocrine tumours, helps distinguish FHH from hereditary hyperparathyroidism [79].

8.7. Counselling in TRPV6 deficiency

In the biallelic form, the parents are heterozygous carriers without known disease and the recurrence risk is 25% in each pregnancy, higher in consanguineous couples, such as the Pakistani and Moroccan families described [6, 27]. Recurrence is documented: in the Saudi family, a previous pregnancy ended with the death of a newborn at 6 days, with skeletal deformities, narrow thorax, short long bones, pulmonary hypoplasia and polyhydramnios, then interpreted as osteogenesis imperfecta, with a negative panel for that disease [63]. Genotypic risk is not equivalent to disease risk, because a sibling with the same biallelic genotype may have no manifestations [64]. In the only monoallelic case, the variant was inherited from a father considered unaffected, which implies a 50% transmission risk with unknown penetrance [16].

Once the familial variants are known, prenatal and preimplantation diagnosis are possible, and prenatal trio exome sequencing has already been used on chorionic villi [7, 63]. The 2nd-trimester ultrasound may be normal, but cases with onset at 19–23 weeks show that ultrasound surveillance should cover the 2nd and 3rd trimesters [6, 16, 28]. The perinatal plan includes delivery in a centre with neonatal intensive care and respiratory support, biochemistry of the newborn soon after birth and maternal vitamin D status [7, 27]. In counselling on prognosis, most live-born infants recovered, but early fetal onset, the newly described complications (cataracts) and the small number of cases justify caution; in the French fetus, the parents opted for termination of pregnancy at 26 weeks [28]. The chronic pancreatitis risk of heterozygous carriers has not been assessed in the sources consulted, even though TRPV6 loss-of-function variants increase the risk of early-onset pancreatitis (section 2.10) [19, 67].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each number measures

FHH prevalence estimates vary more than fiftyfold, explained mainly by what each study measures (Table 9.1). Clinical estimates count diagnosed patients and are inherently minimum estimates in a usually asymptomatic disease; genomic estimates count carriers of variants classified as pathogenic in sequenced cohorts, without knowing whether all have the phenotype, and depend on classification criteria [20–22].

Table 9.1. Prevalence estimates and their meaning

The 5th Workshop genetics group and Geisinger cohort authors concluded that FHH1 would be a common cause of hypercalcaemia, with prevalence similar to PHPT [11, 20]. The UK Biobank study suggests a lower value, and both contrast with the rarity of diagnosed FHH [21, 22]. The 7.8/100 000 FHH3 estimate is not arithmetically compatible with the total clinical prevalence of approximately 1.3/100 000 or the observation that FHH3 represents less than 10% of FHH, reflecting different populations and methods and not to be interpreted as true prevalence [9]. Press releases from the company developing encaleret report more than 2100 people diagnosed with ADH in the USA since October 2023, based on billing data; this is a commercial estimate rather than an epidemiological measure [36].

9.2. Geography, ancestry and founder populations

Available data come mainly from the USA and Europe (Denmark, United Kingdom, Ireland, Finland, France, Germany, Italy, Austria, Poland), with a recent Chinese cohort [13, 24, 29, 47, 53, 56, 57, 73, 76]. The sources consulted do not describe founder variants in CASR, GNA11 or AP2S1. In gnomAD, estimated FHH1 frequency is higher in Amerindian/Latino ancestry and lower in Ashkenazi Jews, but standard errors are wide [21]. Participants in the phase 2 encaleret trial and the English ADH1 series were all of European origin, limiting generalisation [48, 91]. In Portugal, 25-year follow-up of a female patient with homozygous NSHPT followed at the São João Local Health Unit in Porto has been published in the Brazilian journal Archives of Endocrinology and Metabolism [31]. In the differential diagnosis, the CDC73 founder variant NM_024529.5:c.766_767del in Roma families from Portugal has national relevance [17]. The sources consulted include no Brazilian epidemiological data on these diseases. Cases of neonatal hyperparathyroidism due to TRPV6 have been described in Japan, which accounts for the largest number, in North America (families of Pakistani and African ancestry), in the United Kingdom, Saudi Arabia, Hong Kong, Singapore (Malay ancestry), the Netherlands (Moroccan ancestry) and France; there are no prevalence estimates or described founder variants, and the recurrent variant p.(Gly451Glu) has occurred only in Japanese patients [6, 7, 16, 27, 28, 33, 63, 64].

9.3. Special populations

In children, FHH3 and NSHPT concentrate severe manifestations, and cinacalcet does not have established paediatric safety and efficacy outside secondary hyperparathyroidism on dialysis in the EU [86, 88]. In pregnancy, urinary calcium interpretation and therapeutic decisions change (section 7.13), and neonatal risk depends on the genotype combination (section 8.2) [47, 49]. In patients with 22q11.2 deletion, coexistence with FHH3 has been described, with opposite effects on calcium that may mask both conditions [58, 81].

9.4. Reference networks and patient associations

In Europe, the relevant reference network is Endo-ERN (European Reference Network on Rare Endocrine Conditions), whose thematic group 2, for calcium and phosphate homeostasis disorders, has subgroups for PTH-dependent disorders, including complex hyperparathyroid hypercalcaemia not treatable by simple parathyroidectomy and genetic hyperparathyroidism syndromes, and for hypocalcaemia, including ADH [38]. ERKNet (European Rare Kidney Disease Reference Network) is relevant to nephrocalcinosis and the Bartter-like form [39], and ERN BOND, for rare bone diseases, incorporating the French OSCAR network, is cited in the study of enamel abnormalities in FHH2 [40]. No FHH-specific patient association was identified; for ADH and hypoparathyroidism, there are the HypoPARAthyroidism Association in the USA and Hypopara UK in the United Kingdom [99, 100].

10. Illustrative Clinical Case

10.1. Two siblings with neonatal hyperparathyroidism of paternal origin (Germany)

Höppner and colleagues described two siblings, born to non-consanguineous parents, who inherited from their asymptomatic father the CASR NM_000388.4:c.554G>A p.(Arg185Gln) variant, classified as pathogenic (class V); the article writes “p.Arg185Glu”, a typographical error because c.554G>A encodes glutamine [12, 47]. The mother was normocalcaemic (postpartum calcium 2.36 mmol/L, PTH 18.4 pg/mL and 25-hydroxyvitamin D 22 ng/mL) [47].

Sibling 1 was born in 2017 by caesarean section at 25 weeks after premature membrane rupture. At birth, calcium was 3.04 mmol/L and ionised calcium 1.41 mmol/L; on day 23, PTH was 85.9 pg/mL, alkaline phosphatase 518 U/L and urinary calcium low. He received vitamin D3 500 IU/day from day 42 and calcium 128 mg/kg/day between day 48 and 3 months as preterm supplementation, and calcium stabilised at approximately 3.42 mmol/L. At 24 months corrected age, Bayley-II assessment was normal (mental development index 112, psychomotor 96), and at 4 years he was healthy, with calcium approximately 3.6 mmol/L and no nephrocalcinosis [47].

Sibling 2 was born at term, with thrombocytopenia of 15,000/µL requiring two transfusions, and hyperbilirubinaemia. Calcium was 2.69 mmol/L, ionised calcium 1.54 mmol/L, PTH 196.5 pg/mL and, on day 21, urinary calcium was undetectable, with hypotonia and growth failure. Radiographs at 3 weeks showed multiple metaphyseal fractures at different stages of healing, indicating intrauterine onset, generalised demineralisation, wide sutures and wormian bones. Figure 2 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC8518617/figure/f2/) shows, according to the legend, the skull with blurred corticomedullary boundaries, wide sutures and occipital intrasutural bones, poor skeletal mineralisation, metaphyseal fractures of both upper limbs with radial and ulnar malalignment and distal fractures of the right tibia and fibula, with advanced healing on the left. Supplemental calcium was discontinued and cinacalcet was started on day 26 at 20 mg/m²/day (5 mg/day, in two doses of 2.5 mg), increased to 6 mg/day on day 137 because of weight gain and increased serum calcium. PTH fell, urinary calcium became detectable and clinical status improved; cinacalcet was stopped at 6 months, and with vitamin D3 500 IU/day calcium was 3.20 mmol/L, PTH 26.7 pg/mL and there was no nephrocalcinosis. Figure 1 (https://pmc.ncbi.nlm.nih.gov/articles/PMC8518617/figure/f1/) depicts calcium, PTH and alkaline phosphatase evolution and treatments over the first 150 days (sibling 1) and 240 days (sibling 2) [47].

The case teaches three points. First, the same paternally derived genotype produced a mild course in one sibling and intrauterine fractures in the other, showing that paternal inheritance is necessary but not sufficient for severe neonatal disease [47]. Second, sibling 2's phenotype (fractures at different stages of healing) could have been confused with other causes of fractures, and diagnosis rested on elevated PTH with undetectable urinary calcium and family history [47]. Third, cinacalcet was used off-label and the authors themselves admit that improvement could have been spontaneous; the report does not establish cinacalcet as routine treatment for transient neonatal hyperparathyroidism [47].

10.2. Twenty-five years of follow-up of homozygous NSHPT (Porto, Portugal)

Meira and colleagues, from the São João Local Health Unit in Porto, described a 25-year-old woman followed since the neonatal period [31]. At 32 days of life she presented with severe hypotonia, prostration, feeding refusal and weight loss, with calcium 6.15 mmol/L (24.6 mg/dL), phosphate 0.73 mmol/L, PTH 89.26 pmol/L (842 ng/L), fractional calcium excretion 0.9% and tubular phosphate reabsorption 10%. Intravenous fluids, furosemide (3 mg/kg/day) and intramuscular calcitonin (dose reported in the article as 8 mg/kg/day, an atypical unit for this drug) produced only partial improvement. She underwent total parathyroidectomy with autotransplantation of one gland into the left deltoid; histology identified two parathyroid glands, and the right superior specimen was thymus. On postoperative day 17, calcium returned to 3.16 mmol/L (12.5 mg/dL) and PTH to 246 pg/mL; computed tomography located an additional gland at the upper pole of the right thyroid lobe, and right hemithyroidectomy three months later achieved remission. The parents, aged 27 and 26 years, had FHH biochemistry (father: calcium 10.4 mg/dL, PTH 46.8 pg/mL, fractional calcium excretion 0.4%; mother: 10.0 mg/dL, 33.7 pg/mL and 0.5%), and genetic testing identified the homozygous CASR NM_000388.4:c.2039G>A p.(Arg680His) variant in the patient, likely pathogenic, with both parents heterozygous [12, 31].

Autograft failure left permanent hypoparathyroidism, treated with calcium and calcitriol. Over the last decade, requirements progressively decreased and recurrent hypercalcaemia developed despite undetectable PTH; in one episode, with calcium 12.6 mg/dL, urinary calcium was 256 mg/24 h, with fractional excretion approximately 1.4%, inappropriately low. With calcium carbonate 1500 mg/day (600 mg elemental calcium), calcium stabilised at 2.4 mmol/L (9.6 mg/dL). When calcium was discontinued to meet the hypoparathyroidism guideline target (lower half of the reference range), maintaining low-dose calcitriol alone, paraesthesiae developed and calcium carbonate had to be reintroduced. Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC13354032/figure/f1/) depicts, according to the legend, calcium, phosphate and PTH evolution in recent years and corresponding treatment, with the normal calcium range and hypoparathyroidism guideline therapeutic target indicated [31].

The authors interpret the course as a consequence of renal CaSR inactivation, limiting calciuresis and allowing balance to be maintained with minimal supplementation, but also facilitating hypercalcaemia when supplementation is excessive; they propose that low targets in hypoparathyroidism guidelines, derived from populations with acquired hypoparathyroidism, may not apply to these patients [31]. This position differs from the general 2nd International Workshop recommendation and is based on a single case and small series [31, 32]. The surgical management described (autotransplantation) is not the recommended rule, and the authors themselves cite the risks of graft-dependent hypercalcaemia and graft failure [31].

10.3. Dizygotic twins discordant for TRPV6 deficiency (Japan)

Yamashita and colleagues described a girl born at 37 weeks, by caesarean section, from a dizygotic twin pregnancy of a healthy 29-year-old Japanese woman, with a weight of 2140 g (−1.6 SD), length of 45.0 cm (−1.3 SD) and Apgar scores of 4 and 8 [61]. She was admitted to neonatal intensive care for respiratory distress, with tachypnoea and subcostal recession. Radiographs showed generalised osteopenia, thin wavy ribs, a narrow bell-shaped thorax, thin demineralised cortex, subperiosteal resorption, coarse trabeculation, slightly bowed femora and metaphyseal constriction due to fracture (Figure 1A–B of the article) [61]. On day 0, intact PTH was 2700 pg/mL (reference 14–72), calcium 7.7 mg/dL, phosphate 5.6 mg/dL, alkaline phosphatase 998 U/L and 25-hydroxyvitamin D 9 ng/mL; the twin brother, with an uneventful perinatal course and a weight of 2345 g, had PTH of 176 pg/mL and 25-hydroxyvitamin D of 5 ng/mL, without skeletal abnormalities, and the mother had 25-hydroxyvitamin D of 6 ng/mL with PTH of 56 pg/mL on postpartum day 5 [61].

The initial diagnosis was hyperparathyroidism secondary to maternal vitamin D deficiency, and the child received alfacalcidol and calcium lactate [61]. PTH fell to 1257 pg/mL at 2 weeks, 99 pg/mL at 4 weeks and 13 pg/mL at 3 months, with calcium of 9.3 mg/dL at 2 weeks and normal thereafter, and alkaline phosphatase reached 2639 U/L at 2 weeks before falling to 1110 U/L at 15 months; at 6 months, the skeletal lesions had almost completely resolved (Figure 1C–D of the article) [61]. TRPV6 sequencing revealed compound heterozygosity for c.668T>C p.(Ile223Thr), of paternal origin, and c.1282G>A p.(Gly428Arg), of maternal origin, two variants already described in the founding series; the twin brother had neither of them [6, 61].

The case shows that maternal vitamin D deficiency, shared by both twins, did not explain the disease in only one of them, and that the discordance was resolved only by the fetal genotype [61]. It also shows that low serum calcium at birth, associated with very high PTH, corresponds to secondary hyperparathyroidism, and not primary as in NSHPT, and that recovery occurs with calcium and vitamin D supplementation without surgery. The figures were described from the article's legends.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In the vast majority of patients, FHH is a benign, non-progressive condition, with stable lifelong serum calcium and no increase in nephrocalcinosis or urolithiasis [5, 11]. Described complications (chondrocalcinosis, pancreatitis, osteoporosis, urolithiasis) occur in small series, and the genotype-first UK Biobank study did not confirm an association with pancreatitis or diabetes, although it did not assess urinary calcium or PTH [5, 21]. The main risk for a patient with FHH is iatrogenic: unnecessary parathyroidectomy, with persistent hypercalcaemia or permanent hypoparathyroidism [11, 30]. FHH3 has a poorer functional prognosis because of symptomatic hypercalcaemia, bone changes and neurodevelopmental disorders [13, 54]. Short QT in FHH1 is a recent observation in one family, with unknown population prognostic significance [56].

Untreated NSHPT is potentially fatal, particularly in the first six months, and survivors not treated early may have neurodevelopmental impairment [5, 11]. With treatment, reports describe normal growth and development: the Australian infant operated on day 16 was well at 3 years, the Polish child on cinacalcet monotherapy had normal growth and cognition at 9 years, and the Portuguese patient reached 25 years with permanent hypoparathyroidism controlled with low doses [25, 31, 57]. These outcomes come from isolated reports and may reflect publication bias. Bone changes of neonatal hyperparathyroidism may remodel within months [10].

In ADH1, prognosis is dominated by the kidneys and nervous system. In the English series, 78% of patients had renal involvement and two died after renal failure [48]. The Danish non-surgical hypoparathyroidism registry showed no increase in mortality but a greatly increased risk of seizures (hazard ratio 10.05) and renal failure (6.01) [70]. Some of this damage is iatrogenic and preventable with lower calcium targets [4, 5]. ADH2 has insufficient follow-up data [52].

In neonatal hyperparathyroidism due to TRPV6, the prognosis of live-born infants is generally favourable: in the review of 14 cases, skeletal abnormalities resolved between 6 months and 2 years, no new fractures appeared after supplementation began and seven of eight children with follow-up had appropriate development at 2 years [7]. The exceptions are the child in the founding series with cerebral complications and developmental delay and the British infant who died at 4 months, ventilator-dependent from birth [6, 65]. In the Dutch infant, whole-body bone mineral density by dual-energy X-ray absorptiometry (DXA) rose from 0.279 g/cm² at 4 months to 0.388 g/cm² at 10 months and 0.437 g/cm² at 17 months (local reference mean at 6 months: 0.356 g/cm²), with mild gross motor delay, a bell-shaped thorax still visible but attenuated and no new fractures [27]. The height of the Hong Kong infant at 24 months was below the 0.4th centile, with appropriate development [7]. Follow-up data beyond early childhood are lacking.

11.2. Surveillance

There is no validated FHH surveillance protocol. In asymptomatic FHH1 and FHH2, the sources define no intervals; the surveillance recommended below applies to symptomatic forms, NSHPT, cinacalcet treatment and ADH (Table 11.1).

Table 11.1. Long-term surveillance

eGFR, estimated glomerular filtration rate. The Leuven review notes that there are no studies to guide ADH1 surveillance and bases its proposals on expert surveys and hypoparathyroidism guidelines [4].

12. Summary and Final Considerations

Disorders of the CaSR–Gα11–AP2σ2 axis result from a shift in the extracellular calcium set-point. Heterozygous loss of function in CASR, GNA11 or AP2S1 causes FHH, with lifelong hypercalcaemia, non-suppressed PTH and low urinary calcium; biallelic CASR loss of function, or heterozygous loss of function in a fetus with a normocalcaemic mother, causes severe or transient neonatal hyperparathyroidism; CASR or GNA11 gain of function causes ADH, with hypocalcaemia and hypercalciuria [5, 8, 9, 47].

In FHH, the central clinical decision is to avoid surgery. CCCR below 0.01 favours diagnosis, but overlap with PHPT is extensive and patients with pathogenic variants may have normal urinary calcium; genetic testing is therefore indicated whenever FHH is a possibility, particularly before parathyroidectomy in young patients, with a family history or without documented previous normocalcaemia [30, 45]. FHH3 is the most expressive form, with sometimes symptomatic hypercalcaemia, bone and neurodevelopmental changes, and has most frequently warranted off-label cinacalcet [13, 34]. Genomic estimates suggest that FHH1 variant carriers are much more frequent than diagnosed patients, without allowing clinical prevalence to be inferred [20, 21].

NSHPT is a neonatal emergency. Medical stabilisation and cinacalcet may suffice in forms with residual receptor function, but severe forms require total parathyroidectomy, followed by hypoparathyroidism with lower and more variable calcium requirements than in other causes [11, 31, 35]. NSHPT risk when both parents have FHH and neonatal hyperparathyroidism risk when the father is a carrier justify genetic counselling for couples and a perinatal plan [11, 47]. Neonatal hyperparathyroidism due to TRPV6 has a different mechanism, impaired placental calcium transport: the raised PTH is secondary, calcium is normal or low, the parents are normocalcaemic, inheritance is recessive in almost all cases and the bone disease regresses with calcium, phosphate and vitamin D supplementation, without surgery; osteogenesis imperfecta is the main diagnosis to distinguish, and TRPV6 should be part of the genetic investigation of unexplained fetal skeletal dysplasias [6, 7, 28].

In ADH, conventional therapy aiming to normalise calcium worsens hypercalciuria and renal damage; targets should be low and treatment reserved for symptomatic patients or those with marked hypocalcaemia [4, 32]. Encaleret, a calcilytic acting on the disease mechanism, normalised calcium and urinary calcium in a phase 2 trial and, according to press releases, in an as-yet unpublished phase 3 trial, and awaits an FDA decision in May 2027; in the EU, submission has only been announced [36, 91, 93]. Meanwhile, European withdrawal of Mimpara® and Natpar® has not changed access to cinacalcet, available as generics, but has eliminated one PTH replacement option [90, 95].

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