Pseudohypoparathyroidism and Disorders of PTH–PTHrP Signalling (iPPSD)

Pseudohypoparathyroidism types 1A, 1B and 1C, pseudopseudohypoparathyroidism, progressive osseous heteroplasia, osteoma cutis, Albright hereditary osteodystrophy and PRKAR1A- and PDE4D-related acrodysostoses: disorders of parathyroid hormone resistance and impaired cyclic adenosine monophosphate signalling, with the imprinted GNAS locus at the centre of the spectrum.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

The following table identifies each entity in this article — the forms of pseudohypoparathyroidism (PHP), Albright hereditary osteodystrophy (AHO) and acrodysostoses — by its classical designation and the 2016 classification of the European EuroPHP network, which groups these diseases under the acronym iPPSD (inactivating PTH/PTHrP signalling disorders, disorders inactivating signalling by parathyroid hormone [PTH] and parathyroid hormone-related peptide [PTHrP]) [1]. Online Mendelian Inheritance in Man (OMIM) catalogue numbers come from GeneReviews and the international consensus; Orphanet codes were confirmed in Orphadata because GeneGuidance associates pseudohypoparathyroidism type 1B with the code for type 1A and acrodysostosis type 2 with PDE4D haploinsufficiency syndrome, errors not reproduced here [2–6].

Table abbreviations: Gsα, α subunit of the stimulatory G protein; DMR, differentially methylated region; UPD(20q)pat, paternal uniparental disomy of the long arm of chromosome 20; cAMP, cyclic adenosine monophosphate; ICD-10, International Classification of Diseases, 10th revision. The Orphanet “Pseudohypoparathyroidism” group corresponds to ORPHA:97593; entries ORPHA:457059, 457062 and 280651 are obsolete [4]. Blomstrand dysplasia and Eiken dysplasia (PTH1R, iPPSD1) and hypertension with brachydactyly (PDE3A, iPPSD6) belong to the same classification, but are addressed here only as differential diagnoses [1, 9].

1. Introduction

1.1. Original description and early decades

Fuller Albright and colleagues described in 1942 patients with hypocalcaemia and hyperphosphataemia resembling hypoparathyroidism, who did not respond to parathyroid extract administration with increased urinary phosphate excretion; patients also had obesity, short stature, short metacarpals and metatarsals and neurocognitive impairment [16, 17]. The conclusion that the defect lay in the response of target tissues rather than hormone secretion gave rise to the term pseudohypoparathyroidism (PHP) and the concept of hormone resistance; the original article title presented the cases as an example of “Seabright-Bantam syndrome” [17]. Around a decade later, in 1952, the same group described a patient with the physical features and normal calcium, phosphate and phosphaturic response, pseudopseudohypoparathyroidism (PPHP); the physical phenotype common to both forms was named Albright hereditary osteodystrophy (AHO) [3, 18].

The next step was biochemical. Aurbach and colleagues showed that PTH increases cyclic adenosine monophosphate (cAMP) in renal and bone membranes and urine, and Chase and colleagues demonstrated in 1969 that exogenous PTH rapidly increases urinary cAMP in healthy individuals and surgical hypoparathyroidism, but not in PHP, whereas patients with PPHP have a normal response [16]. In 1980, Farfel and Levine, in independent studies, measured a reduction of around 50% in activity of the α subunit of the stimulatory G protein (Gsα) in erythrocyte membranes from patients with PHP and AHO, and a similar reduction in PPHP; Farfel also described patients with PTH resistance without AHO and with normal Gsα, subsequently PHP1B [16]. PHP type 2 (PHP2) was defined by a preserved rise in urinary cAMP with an absent phosphaturic response after PTH [3, 16].

1.2. Milestones in molecular discovery

Cloning of Gsα complementary DNA enabled identification of the first GNAS gene variants in 1990: Patten and colleagues described an A>G substitution in the initiation codon of exon 1 in two related patients with AHO and reduced Gsα bioactivity, and Weinstein and colleagues found, in two families, a variant at the intron 10 splicing donor site and a single-base deletion in exon 10 [19, 20]. Davies and Hughes reviewed families with AHO in two or more generations in 1993 and noted that full expression (AHO with hormone resistance) occurred with maternal transmission and partial expression (isolated AHO) with paternal transmission, pointing to genomic imprinting [21]. Progressive osseous heteroplasia (POH) was delineated by Kaplan and colleagues in 1994 and linked in 2002 to inactivating GNAS variants inherited exclusively from the father, in 13 of 18 probands; in one family, the same variant caused POH or AHO depending on parental origin [22, 23].

The mechanism of PHP1B was elucidated in 2003, when Bastepe and colleagues identified, in 12 families with the autosomal dominant form and 4 apparently sporadic patients, a heterozygous microdeletion of around 3 kb removing three exons of the STX16 gene, located around 220 kb upstream of GNAS, with loss of methylation restricted to DMR A/B [24]. In 2005, a second deletion of 4.4 kb, overlapping the first by 1286 bp, delineated the imprinting control element [25]. Acrodysostosis, described by Maroteaux and Malamut in 1968, received its first molecular basis in 2011, with a recurrent PRKAR1A variant in patients with multihormone resistance, and in 2012 exome sequencing identified PDE4D variants [26–29]. In 2015, gain-of-function PDE3A variants explained autosomal dominant hypertension with brachydactyly [9].

1.3. Nomenclature: from the classical classification to iPPSD

The classical classification distinguished PHP1A, PHP1B, PHP1C and PPHP by the presence of AHO, hormone resistance and Gsα activity in vitro, leaving out phenocopies such as acrodysostosis and POH [3]. Molecular characterisation revealed that phenotypes overlap: some patients with methylation defects have brachydactyly and TSH resistance, and some with PPHP develop mild hormone resistance. The 2018 consensus considers this classification “inadaptable and obsolete” and recommends that a new classification integrate the common pathophysiological framework and molecular genetic classification [3]. The EuroPHP network proposed the term iPPSD in 2016, with Arabic numbering by mechanism: iPPSD1 (PTH1R), iPPSD2 (Gsα loss of function), iPPSD3 (GNAS methylation alteration), iPPSD4 (PRKAR1A), iPPSD5 (PDE4D), iPPSD6 (PDE3A), iPPSDx (no identified defect) and iPPSDn+1 for future genes [1]. The classification was applied to 544 molecularly characterised patients and more than 98% of probands met the proposed criteria [30].

The new nomenclature has critics. Jüppner observed that focusing the designation on PTH/PTHrP signalling ignores resistance to other agonists and the parental allele affected, and proposed a classification focused on impaired cAMP signalling; he nevertheless acknowledged the limitations of the old nomenclature and the value of simple criteria [16]. The iPPSD proposal itself acknowledges that it does not encode parental origin, which remains essential for counselling [1]. The 2022 French National Diagnosis and Care Protocol (PNDS) adopted the iPPSD nomenclature as the sole designation, considers that the term “pseudohypoparathyroidism” should be avoided, because it neither covers all patients nor predicts the molecular diagnosis, and focuses on iPPSD2 to iPPSD5, mentioning iPPSD1 and iPPSD6 only marginally [13]. In 2020 the consensus went further than in 2018 regarding PHP1C: patients thus designated have maternal inactivating Gsα variants and should be referred to as PHP1A [15]. This article uses dual nomenclature because the classical terminology remains in databases, labels and classification codes. The most recent nosology of skeletal dysplasias also created the category “skeletal disorders of the PTH signalling cascade”, including PTH, PTHLH, PTH1R and defects in Gsα and effectors [31].

1.4. Definitions of the entities within scope

PHP1A is defined by PTH resistance, usually with resistance to TSH and other hormones acting through Gsα-coupled receptors (growth hormone-releasing hormone [GHRH], gonadotrophins, calcitonin), associated with AHO and an inactivating GNAS variant on the maternal allele [3]. PHP1C had all PHP1A features with normal Gsα activity in complementation assays that do not assess receptor-mediated activation; it is a PHP1A variant, as the 2017 GeneReviews already acknowledged [2, 15]. PHP1B was defined as isolated PTH resistance, without AHO and with normal Gsα; TSH resistance, increased intrauterine growth, early weight gain and brachydactyly in a subgroup are now recognised, and the common defect is loss of methylation of GNAS DMR A/B on the maternal allele [3, 16].

PPHP is AHO with reduced Gsα activity without PTH resistance, due to a variant on the paternal allele; intrauterine growth restriction and subcutaneous ossifications are frequent and mild PTH or TSH resistance sometimes occurs [3]. POH is progressive ectopic ossification beginning in the dermis and subcutaneous tissue and extending to muscle, tendons and ligaments, with a normal PTH response and generally without other AHO features [3, 32]. Primary osteoma cutis is ossification limited to the dermis and subcutaneous tissue, without deep progression [2]. AHO is not a separate disease but a phenotype: round face, stocky build, short adult stature, brachydactyly type E (BDE) and ectopic ossifications [3]. Acrodysostosis is a chondrodysplasia with severe brachydactyly of all phalanges, metacarpals and metatarsals, facial dysostosis with nasal hypoplasia and advanced bone age, with frequent PTH and TSH resistance in type 1 (PRKAR1A) and more frequent cognitive impairment in type 2 (PDE4D) [3, 33].

2. Molecular Genetics and Pathophysiology

2.1. The PTH/PTHrP–Gsα–cAMP–PKA pathway

PTH and PTHrP bind the same receptor, PTHR1, a seven-transmembrane-domain receptor coupled to the heterotrimeric stimulatory G protein. Activated Gsα binds guanosine triphosphate (GTP) and stimulates adenylyl cyclase, the cAMP produced binds the R1A regulatory subunits of protein kinase A (PKA), and the released catalytic subunits phosphorylate targets such as cAMP response element-binding protein (CREB) and the phosphodiesterases PDE3A and PDE4D themselves, which degrade cAMP and close the circuit [3]. Each entity in this article corresponds to a link in this chain: GNAS (PHP1A, PHP1C, PPHP, POH, PHP1B), PRKAR1A (acrodysostosis type 1), PDE4D (acrodysostosis type 2) and PDE3A (hypertension with brachydactyly); PTHLH, HDAC4 and TRPS1 cause phenocopies upstream of or outside the pathway [3]. In the proximal tubule, impaired signalling prevents the PTH-induced phosphaturic response and synthesis of 1,25-dihydroxyvitamin D; in the growth plate, ineffective PTHrP signalling accelerates chondrocyte differentiation and epiphyseal closure, explaining brachydactyly and short adult stature [18]. Gsα has two main isoforms, of 52 and 45 kDa, depending on inclusion of exon 3 [2].

Ectopic ossification is the exception to this scheme. It does not depend on serum calcium or phosphate and results from Gsα deficiency in mesenchymal stem cells, which differentiate de novo into osteoblasts in the dermis and subcutaneous fat from adipose tissue-derived progenitors; ossification is predominantly intramembranous and reticular, unlike endochondral ossification in fibrodysplasia ossificans progressiva (FOP) [3]. PHP1A obesity also depends on an imprinted tissue: in mouse models, Gsα is expressed predominantly from the maternal allele in dorsomedial hypothalamic cells expressing melanocortin receptor 4 (MC4R), and its absence reduces energy expenditure, thermogenesis and peripheral glucose metabolism [18].

2.2. The GNAS locus and imprinting

GNAS (20q13.32) is a complex transcriptional unit, with alternative first exons, alternative splicing, an antisense transcript and reciprocal imprinting [2]. Gsα is encoded by exons 1–13 and the MANE Select (Matched Annotation from NCBI and EMBL-EBI) reference transcript is NM_000516.7 (NP_000507.1) [34]. The alternative first exons (NESP55, XLαs, A/B) join exons 2–13 and produce, respectively, the 55 kDa neuroendocrine secretory protein, extra-long Gsα and an A/B transcript not translated into full-length Gsα; the antisense GNAS-AS1 transcript is non-coding [16]. The Gsα promoter at exon 1 is unmethylated, but transcription is not always biallelic [16].

Source: Jüppner 2021, table 1, and the 2018 consensus [3, 16]. The GNAS-AS1 promoter is methylated on the maternal allele and the transcript is paternal; the Oxford Desk Reference states “maternal expression” for GNAS-AS in its table of imprinting disorders, contradicting the molecular source and not reproduced here [16, 35].

The pathophysiological key is Gsα expression from the maternal allele in a few tissues. In the renal proximal tubule, thyroid, pituitary, gonads, parts of the central nervous system and brown adipose tissue, the paternal allele is silenced; in skin, renal medulla, heart, adipocytes, chondrocytes and bone, expression is biallelic [16, 18]. An inactivating variant on the maternal allele leaves the proximal tubule almost without Gsα and causes PTH resistance; the same variant on the paternal allele is compensated by the active maternal allele in the kidney and thyroid, and the phenotype is limited to tissues in which Gsα dosage is biallelic, producing AHO without hormone resistance [3, 36]. Paternal silencing develops gradually: one patient with PHP1A had a normal urinary cAMP response to PTH at 7 months and a markedly reduced response at 3.9 years, and in mice with maternal exon 1 deletion, paternal Gsα expression in the proximal tubule disappears in the first two months [16]. This latency explains why PTH resistance is generally absent at birth and appears between 0.2 and 22 years [3]. In the thick ascending limb and distal tubule, Gsα expression is biallelic, and PTH-stimulated calcium reabsorption is maintained, explaining why hypercalciuria is rare while PTH is not suppressed [18, 36].

The locus has four classical DMRs: one methylated on the paternal allele (GNAS-NESP:TSS-DMR) and three on the maternal allele (GNAS-AS1:TSS-DMR, GNAS-XL:Ex1-DMR and GNAS A/B:TSS-DMR) [3]. Recent studies use five-DMR nomenclature, adding the exon H region and dividing AS1 and AS2 [37, 38]. Maternal methylation is established during oogenesis: maternal transcripts traversing exon H and NESP are necessary to methylate the maternal DMRs, and maternal NESP transcription facilitates postzygotic remethylation of DMR A/B [16, 38].

2.3. iPPSD2: inactivating Gsα variants (PHP1A, PHP1C, PPHP, POH and osteoma cutis)

In PHP1A, inactivating variants affect GNAS exons 1–13 on the maternal allele and are point mutations or, more rarely, rearrangements; maternally inherited and de novo variants have similar frequencies [3]. Most are frameshift, nonsense or splicing variants, with no translated protein, but variants altering translation initiation also occur; exon 1 is the most frequently affected (18% of variants in GeneReviews) and only one patient is known with an exon 3 variant, truncating only the long isoform [2, 16]. GeneReviews describes a hotspot in exon 7, the 4 bp deletion historically designated c.565_568delGACT [2]. Most variants are private to each family [39].

PHP1C was associated with maternal exon 13 variants preserving the intrinsic Gsα activity measured in vitro but impairing receptor coupling; GeneReviews itself concluded that these patients have PHP1A misclassified because of limitations of the old assay, and the 2020 consensus recommends abandoning the term [2, 15]. A Korean preprint from May 2026, not yet peer-reviewed, described a de novo deletion of the GNAS promoter and 5' untranslated region in a patient with a PHP1C phenotype, with maintained messenger RNA and Gsα protein and impaired cAMP production, suggesting investigation of non-coding regions in PHP1A patients without an identified variant [40]. Smith's Recognizable Patterns states that PHP1C has no GNAS variants; that statement predates identification of exon 13 variants and is not reproduced here [2, 17].

On the paternal allele, the same class of variants causes PPHP, osteoma cutis or POH [3]. Intrauterine growth restriction in PPHP is more marked with variants in exons 2–13 than with variants in exon 1 or intron 1, pointing to paternal XLαs deficiency, since XL transcripts use exons 2–13 and are expressed only from the paternal allele; mice lacking exon XL have impaired postnatal growth and survival, and maternal UPD of 20q, without XLαs, causes prenatal and postnatal growth failure [1, 16]. POH variants are also concentrated in exons 2–13 [16]. Frequent lateralisation of POH lesions and their extension along dermomyotomal patterns suggest a second mosaic event or local variations in Gsα expression [3]. Gain-of-function exceptions have been described: a missense variant with PHP1A and testotoxicosis, and a four-amino-acid insertion at the guanosine diphosphate and triphosphate binding site in two siblings with PHP1A, transient neonatal diarrhoea and pancreatic insufficiency, inherited from an unaffected mother with germline mosaicism [2].

2.4. iPPSD3: methylation defects (PHP1B)

PHP1B results from abnormal methylation patterns at GNAS DMRs, partial or complete, at one or several DMRs; loss of methylation (LOM) at DMR A/B is present in all patients [3]. Maternal LOM at A/B makes the maternal allele unmethylated at that promoter, like the paternal allele, and silences maternal Gsα in the proximal tubule, where the paternal allele is already silenced; the functional result is the same as PHP1A in the kidney, without haploinsufficiency in biallelic tissues and therefore generally without AHO [3, 41].

The autosomal dominant form (AD-PHP1B) accounts for 15–20% of PHP1B and is maternally transmitted [3, 15]. The most frequent cause is the recurrent microdeletion of around 3 kb, flanked by direct repeats, removing three STX16 exons and a cis control element necessary to establish maternal methylation at A/B; LOM is restricted to DMR A/B (a pattern designated “category 2”) [24, 38]. STX16 is not imprinted and a paternally inherited deletion does not alter methylation [3, 41]. Other AD-PHP1B causes include the 4.4 kb STX16 deletion, a maternal 18.9 kb deletion from exon NESP to AS exon 5 (with LOM restricted to A/B), GNAS duplications, maternal deletions of AS exons 3–4 alone or with NESP (with LOM at all three maternal DMRs) and inversions [16, 25]. In July 2026, a 140 kb paracentric inversion with breakpoints in NPEPL1 and the XLαs DMR was described, the first inversion of the GNAS regulatory region associated with maternal AD-PHP1B [42]. The deletions and duplications described have no normalised genomic coordinates according to Human Genome Variation Society (HGVS) nomenclature in the sources consulted.

The sporadic form (sporPHP1B) is the most frequent; almost all patients have LOM at AS, XL and A/B with gain of methylation at NESP (“category 1” pattern), often incomplete and mosaic [16, 38]. In most, no mechanism is found; 8–10% have UPD(20q)pat, through isodisomy or heterodisomy, and there are families with a sporadic pattern in which linkage to STX16/GNAS has been excluded, indicating causes outside the locus [3, 16]. Since October 2025, two publications have explained some category 1 cases. Iwasaki and colleagues found, in a family with two affected sisters, an exon H splicing donor site variant (GRCh38 chr20:58,841,877 T>C), inherited from an unaffected mother carrying it on the paternal allele; an adjacent variant (chr20:58,841,876 G>A) had been reported in another family; both caused aberrant splicing and attenuated transcription in a minigene assay in human embryonic stem cells, and no other variants at that site were found in 108 sporadic PHP1B cases [38]. Urakawa and colleagues described in March 2026 a maternal exon H variant in a family with a broad methylation defect and showed, in induced pluripotent stem cells, that loss of the maternal exon H transcript precedes abnormal imprinting [37]. These data are genetic and experimental and are based on a few families.

PHP1B may form part of a multilocus imprinting disturbance (MLID), described at frequencies between 0 and 38% depending on the study, without evident phenotypic differences [3]. A Japanese case from 2026 combined a maternal deletion including the Gsα coding region with MLID and hypomethylation of KCNQ1OT1:TSS-DMR, the alteration in Beckwith–Wiedemann syndrome, in a child with severe obesity (body mass index [BMI] above 33 kg/m²) and PTH resistance [43].

2.5. iPPSD4: PRKAR1A and acrodysostosis type 1

PRKAR1A (17q24.2) encodes the R1α regulatory subunit of PKA [44]. Acrodysostosis type 1 variants lie in the cAMP-binding domains, reduce affinity for cAMP and prevent release of catalytic subunits, making PKA resistant to cAMP; the effect is dominant and the phenotype includes resistance to several hormones signalling through cAMP [27, 44]. The recurrent variant is NM_002734.5:c.1102C>T p.(Arg368Ter), found in 4 of 5 patients with PRKAR1A in Michot's 2012 series [28, 34]. Bone Dysplasias assigns PRKAR1A to chromosome “7q24”, a printing error; the same atlas gives 17q24.2 in another table [26, 45]. Only heterozygous point variants in PRKAR1A cause acrodysostosis; loss-of-function variants and 17q24.2–q24.3 deletions cause Carney complex through PKA hyperactivity [3, 46].

Beyond the recurrent variant, Linglart's 2012 European series of 16 unrelated patients found 14 PRKAR1A variants, all de novo: 9 with p.(Arg368Ter) and 5 novel variants, p.Gln285Arg, p.Gly289Glu, p.Ala328Val, p.Arg335Leu and p.Gln372Ter [47]. Muhn's 2013 German series found a variant in 4 of 7 patients with acrodysostosis, p.(Arg368Ter), p.Ala213Thr, p.(Tyr373Cys) and p.(Arg335Cys), and a 2012 Japanese case contributed p.(Thr239Ala), in cAMP-binding domain A, with reduced phosphorylation of the CREB factor in the patient's lymphoblastoid lines [48, 49]. The variants recorded in ClinVar are written NM_002734.5:c.715A>G p.(Thr239Ala) (pathogenic), c.854A>G p.(Gln285Arg) (conflicting classifications), c.1003C>T p.(Arg335Cys) (pathogenic or likely pathogenic) and c.1118A>G p.(Tyr373Cys) (uncertain significance); the others retain the published protein designation, with no nucleotide description available [47, 50]. Rhayem's 2015 functional study showed that all these variants reduce forskolin-induced PKA activation and the dissociation between R1α and the catalytic subunits, through a local defect in cAMP binding in the domain in which they lie; at two residues also affected in Carney complex, the Carney complex substitutions accelerated protein degradation, which explains opposite phenotypes with variants at the same codon [51]. The 2026 review by Moxom and Kimber describes a dual mechanism: mutant R1α is expressed in near-normal amounts and forms holoenzymes that respond weakly and late to cAMP (hypomorphic state) and, by retaining the catalytic subunits, limits signalling from the normal allele (dominant-negative effect) [52]. A 2025 structural study added, for the recurrent truncated mutant, accelerated PKA deactivation through faster hydrolysis of cAMP by phosphodiesterases [53]. In the mouse knock-in heterozygous for p.Arg368Ter, published in 2017, growth restriction, brachydactyly of all digits and facial dysostosis were reproduced, with delayed mineralisation in the newborn, raised plasma PTH and basal urinary cAMP, and absence of offspring from carrier females [54].

2.6. iPPSD5: PDE4D and acrodysostosis type 2

PDE4D (5q11.2–q12.1) encodes a cAMP-specific phosphodiesterase [55]. Acrodysostosis type 2 missense variants act through a dominant-negative mechanism, demonstrated by mutant transcript overexpression and knockdown in zebrafish, and result in reduced PKA activation [33, 55]; true haploinsufficiency through 5q12.1 deletion produces an opposite phenotype, with intellectual disability, low BMI and long fingers (ORPHA:439822, OMIM 615668), rather than acrodysostosis [3, 55]. Most variants arise de novo; in Lynch's 2013 series, only one of five families showed transmission, from a father with subtle features [56]. Metaphyseal acroscyphodysplasia (OMIM 250215), with distal femoral and proximal tibial epiphyses embedded in cup-shaped metaphyses, severe growth retardation and brachydactyly, was associated in 2014 with PDE4D variants (p.Thr224Ile and p.Ile333Thr) in three patients with acrodysostosis and with GNAS variants (p.Gln19Ter and p.Arg231Cys) in two patients with PHP or AHO; the 2018 series confirmed it as a phenotypic variation of PDE4D and PRKAR1A [57, 58]. Familial transmission of PDE4D shows variable expressivity: in a German family reported in 2017, a 3.5-year-old child with short stature, midface hypoplasia, severe brachydactyly, developmental delay and mild TSH resistance carried the variant p.Ser190Phe (published designation c.569C>T), shared by the mother, who had only midface hypoplasia and brachydactyly, without short stature, intellectual disability or hormone resistance; the variant affects the serine phosphorylated by PKA [59].

The direction of the enzymatic defect in acrodysostosis type 2 remains under discussion. The hyperactivation hypothesis rests on Briet's 2017 study, in which four variants located in different domains made the PDE4D3 isoform more readily activated by PKA phosphorylation, with greater cAMP hydrolysis even under basal conditions [60]. The overcompensation hypothesis rests on Kaname's 2014 study: two catalytic-domain variants reduced PDE4D activity when expressed in HEK293 cells, but a patient's cells had low cAMP through a compensatory increase in the PDE4A and PDE4B isoforms, and the Pde4d-null mouse had short metacarpals and phalanges [61]. A 2024 review considers that neither model explains the fine control of PDE4D activation and subcellular localisation, on which the intellectual disability, present in about 90% of patients, is thought to depend [62]. The effect of PDE4 inhibition depends on stimulus intensity: in cells with PTHR1, inhibition increased cAMP little in response to strong stimuli and greatly in response to weak stimuli, which may explain the near-normal renal response to PTH alongside the defect in bone development [63].

2.7. iPPSD1 and iPPSD6

Loss of function of PTH1R causes Blomstrand dysplasia (lethal, with osteosclerosis and markedly accelerated skeletal maturation) and Eiken dysplasia, and was included as iPPSD1 [1, 31]. In the 2026 Franco-Italian cohort, 3 of 117 patients had iPPSD1, with PTH resistance in 2 [14]. Gain-of-function PDE3A variants increase cAMP hydrolysis and cause severe salt-independent hypertension with brachydactyly type E; without treatment, patients frequently die from stroke before 50 years [9].

2.8. Variant spectrum and nomenclature

The 2018 consensus gives NM_001077488.1 (NG_016194.1, LRG_1051) as the reference, whose numbering differs from MANE Select NM_000516.7; conversion uses normalisation tools rather than manual calculation [3, 34]. The following variants were normalised in VariantValidator (GRCh38) from the sources of this article.

The maternal variant published as “c.568_571del” illustrates the problem of historical nomenclature: a deletion in a repetitive sequence may be described at different positions, and the HGVS 3' alignment rule places it at c.569_572del in the MANE transcript [34]. In methylation defects, the report describes the affected DMR, extent of loss or gain of methylation and method, rather than a sequence variant [3].

2.9. Genotype–phenotype correlations, penetrance and expressivity

Penetrance is complete, but expressivity is highly variable, even within a family with the same variant [2, 3]. There is no clear correlation between GNAS variant type or location and age at onset, endocrine severity, neurocognitive phenotype or number of AHO features [3]. Known exceptions concern ossifications: truncating variants are associated with more extensive ossifications than missense variants, and exon 1 variants with a higher prevalence of ossifications; short metacarpals and metatarsals were more frequent with missense variants in one series [2, 16, 66]. Parental origin determines endocrine phenotype and birth weight: in AD-PHP1B due to STX16 deletion, newborns of healthy carrier mothers have a birth weight differing by almost 4.5 standard deviations (SD) from those with PPHP or POH with paternal variants in exons 2–13 [16]. Bone Dysplasias reports twice as many affected women as men, without a denominator; the 2026 Franco-Italian cohort included 67 women and 50 men [14, 67]. Women with PHP1A, PPHP or carrying AD-PHP1B alterations preferentially transmit the altered allele, and women affected by AD-PHP1B have significantly fewer children than unaffected carriers, related to the role of Gnas exon 1 in oocyte maturation in female mice [16].

2.10. Allelic diseases

Activating GNAS variants produce the opposite phenotype. Germline activating variants are presumed embryonically lethal; postzygotic somatic variants at p.Arg201 (more than 95%) or p.Gln227 cause McCune–Albright syndrome and fibrous dysplasia, with autonomous endocrine hyperfunction, café-au-lait macules and FGF23-mediated phosphaturia [2, 68]. PRKAR1A is allelic between acrodysostosis type 1 (variants reducing the cAMP response) and Carney complex (loss of function, hyperactive PKA); patients with acrodysostosis do not develop Carney complex manifestations [44, 46]. PDE4D is allelic between acrodysostosis type 2, acroscyphodysplasia and 5q12.1 haploinsufficiency syndrome [55, 58].

3. Clinical Spectrum and Manifestations by System

3.1. Comparison of subtypes

The 2018 consensus summarised the frequency of main features by subtype. The table reproduces those values, which come from heterogeneous published series rather than a single cohort; frequencies change with the age of included patients because almost all features are progressive [3].

In the 2020 update, the frequency of ossifications in PHP1A changed to 30–70% and brachydactyly type E was reported in 70–80% of PHP1A and PPHP [15]. Differences between sources reflect the definition used: GeneReviews reports ossifications in 60–70% of patients with AHO, Salemi's series found them in 47 of 67 patients with PHP1A or PPHP (70.1%) examined by the same physician over 16 years, and the 2026 Franco-Italian cohort in 39 of 62 patients with iPPSD2 (63%), with none in the 21 with iPPSD3 [2, 14, 66].

The French PNDS summarises growth by class. Birth length is reduced on average by about 2 SD in paternal GNAS variants and by about 1 SD in maternal ones; it is normal or increased in methylation defects, including UPD(20q)pat, sometimes with macrosomia; it averages −2.4 SD in iPPSD4 and about −0.7 SD in iPPSD5, the latter value deriving from unpublished data from the French reference centre [13]. After birth, growth velocity may be insufficient, especially at puberty, and final height lies between −2 and −3.5 SD; only in iPPSD3 is final height similar to that of unaffected relatives [13]. The PNDS attributes the growth deficit to the combination of PTHrP resistance, advanced skeletal maturation, GH deficiency and gonadotrophin resistance [13].

3.2. PHP1A (and PHP1C)

Endocrine system and calcium–phosphate metabolism. PTH resistance is absent at birth and evolves with age; the first abnormalities are rising PTH and phosphate, and hypocalcaemia develops later, with an interval that may reach 4.5 years [3]. With hypocalcaemia, urinary calcium is low and calcitriol low or normal [3]. Random PTH is frequently elevated and serum calcium fluctuates; some patients remain eucalcaemic, and hypercalcaemia has been observed early in resistance, because of maintained renal production of 1,25-dihydroxyvitamin D in response to elevated PTH (a personal observation by one GeneReviews author) [2]. Symptoms of hypocalcaemia occur in 45–80% of patients and are the most important manifestation; rapid growth periods, pregnancy and calcium or vitamin D deficiency precipitate them [3, 17]. Unrecognised hypocalcaemia causes tetany, seizures and laryngospasm, and severe hypocalcaemia with a prolonged QT interval may cause heart failure [2, 69]. With chronic hypocalcaemia and hyperphosphataemia, an elevated calcium × phosphate product leads to intracranial calcifications of the basal ganglia, sometimes extending to the thalami, cortex and white matter, and posterior subcapsular cataracts; these calcifications are not described in PPHP, POH or acrodysostoses [3, 15]. Other reported ocular findings are corneal opacities, macular degeneration, nystagmus, anisocoria, papilloedema, retinal vascular tortuosity and microphthalmia [3, 17]. Bone mineral density is normal or increased [2, 3].

TSH resistance is often the first manifestation, frequently present at birth and detected on newborn screening as congenital hypothyroidism, with elevated TSH, a small thyroid, absent goitre and normal or slightly low thyroxine (T4) [3, 15]. In a compilation of published cases, mean TSH in PHP1A was 14.1 ± 10.3 mIU/L (range 1.4 to 46.0) [3]. Resistance is less severe than PTH resistance because Gsα imprinting in the thyroid is partial, and may increase with age [15, 70]. Thyroid autoantibodies are generally absent, but their presence does not exclude TSH resistance [3]. In a 2026 Turkish series, 1 patient with PHP1A and 2 with PHP1B had low free T4 with inappropriately normal TSH, which the authors interpreted as central hypothyroidism due to thyrotrophin-releasing hormone (TRH) resistance [71].

GHRH resistance causes growth hormone (GH) deficiency in 50–80% of patients with PHP1A; insulin-like growth factor 1 (IGF-1) is often normal at diagnosis [2, 3]. The French PNDS estimates GH deficiency at 70–80% of patients with maternal iPPSD2 and bases the diagnosis on an insufficient response to stimulation tests with low IGF-1 [13]. Gonadotrophin resistance is subtler: puberty begins at the usual age but Tanner stage plateaus at III–IV, the pubertal growth spurt is attenuated or absent, menstrual irregularities are common (differential diagnosis with premature ovarian insufficiency of genetic cause) and cryptorchidism is highly prevalent; luteinising hormone (LH) and follicle-stimulating hormone (FSH) are not consistently elevated [2, 15, 18]. Calcitonin is elevated in a large subgroup, without C-cell hyperplasia or medullary carcinoma, and acts as a marker of hormone resistance [3]. The PNDS also describes it in iPPSD3 and iPPSD4 and considers it a diagnostic aid, especially in young patients, noting that in adults raised calcitonin requires medullary thyroid carcinoma to be excluded; according to the same text, gonadotrophin resistance has been identified only in maternal iPPSD2 and in iPPSD4 [13]. Adrenal resistance to adrenocorticotrophic hormone has not been documented, despite older reports cited in Bone Dysplasias [3, 67].

Growth. Birth length is moderately reduced, but children are not short for most of childhood; growth may even be accelerated by obesity and bone age is advanced by more than 2 SD in 70–80% [3, 18]. From 9–13 years onwards, early epiphyseal closure and absence of a pubertal spurt lead to short adult stature in around 80% of PHP1A, with a mean deficit of −2.5 SD and means of 149 cm in women and 155 cm in men [3, 18]. Germain-Lee emphasises that short stature in childhood should not be a diagnostic criterion and that hand bone age may be mistaken for precocious puberty, leading to inadvertent initiation of gonadotrophin-releasing hormone agonists [18]. In Hanna's international cohort (242 PHP1A, 64 PPHP, 220 PHP1B), PHP1A had slightly below-average birth weight, a marked BMI increase up to the first year, absence of a pubertal spurt and short final height [18]. In the Chinese cohort of 92 patients with PHP1, men with PHP1A measured 157.0 ± 6.9 cm and those with PHP1B 171.9 ± 8.9 cm; women measured 146.8 ± 10.2 and 156.2 ± 4.9 cm [72]. Around 40% have a head circumference above the 90th percentile [2].

Obesity and metabolism. Obesity begins in the first months, often before any endocrine abnormality, and is fully expressed by the end of early childhood [3, 70]. The PNDS stresses the reconstruction of weight and BMI curves from the neonatal period, because obesity may be the first and only sign, and notes that only patients with a paternal GNAS variant are spared obesity; in the study by Long and colleagues cited in its supporting argument (40 patients with PHP1A and 13 with PPHP), 66% of patients with PHP1A were obese, compared with 30% of those with PPHP and 32% of the American reference population [13]. In the Franco-Italian cohort, 61% of patients with iPPSD2 were obese, with a median onset age of 2 years [14]. Among children with PHP1A in the Vanderbilt study, 33 of 35 (94%) were obese, and BMI in adults with PHP1A was 39.8 ± 8.7 kg/m², compared with 30.2 ± 7.4 in PPHP [73]. The main mechanism is reduced resting energy expenditure; hyperphagia occurs, begins early (interest in food at 2.0 ± 2.3 years, compared with 5.2 ± 3.2 years in obese controls) and does not progress as in Prader–Willi syndrome, and Hyperphagia Questionnaire scores did not differ from those in obese children without PHP after adjustment for age, sex and BMI [3, 73]. The Oxford Desk Reference states that AHO obesity is not associated with hyperphagia; 2025 data show moderate, non-progressive hyperphagia, reconciling the two positions [73, 74]. In adulthood obesity tends to be less marked [3]. Insulin sensitivity is reduced early, not solely because of obesity: in ten adults with PHP1A, four had type 2 diabetes, and postprandial hyperglycaemia is common in children with PHP1A and PHP1B [3, 15]. Hypertension was described in 53% of adults with PHP in a 1988 study, but subsequent Danish cohorts did not show increased cardiovascular disease, and the 2020 update revised the 2018 message accordingly [3, 15]. The 2022 French PNDS maintains that arterial hypertension is frequent in young adults with iPPSD and recommends annual measurement from the age of 2 years [13]. In a Chinese cross-sectional study of 60 patients with PHP1 compared with controls matched for BMI, age and sex, GNAS defects were independently associated with higher resistin, chemerin and monocyte chemoattractant protein 1 (MCP-1) and lower interleukin 8, exploratory data on the adipose tissue inflammatory profile [75].

Nervous system and cognition. Cognitive impairment affects 40–70% of patients with PHP1A and varies in severity; around 30% have normal cognitive development [3, 15]. In the Vanderbilt observational study, intelligence quotient (IQ) was 85.9 ± 17.2 in PHP1A, compared with 104.3 ± 8.9 in healthy siblings and 103.2 ± 11.5 in obese controls [76]. In a series of 16 children, 25% had a composite IQ below 70, with executive and adaptive deficits and a higher frequency of attention-deficit hyperactivity disorder (ADHD) [18]. Language delay is greater than motor delay, and speech apraxia, anxiety and behavioural crises are frequent [15, 18]. Older series cited in Smith's reported mean IQ around 60 and GeneReviews mentions intellectual disability in up to 79%, values obtained before molecular confirmation and standardised testing [2, 17]. Early hypothyroidism treatment does not appear to prevent cognitive delay [3]. Chiari type 1 malformation, syringomyelia, craniosynostosis, hearing loss and reduced sense of smell form part of the spectrum [3, 16, 67]. Seizures appear more frequent even without hypocalcaemia [2]. The PNDS adds autism spectrum disorders at the severe end of the behavioural abnormalities, describes a tendency to improve in late childhood and accepts a multiple mechanism (cerebral Gsα deficiency, Chiari malformation, prolonged hypocalcaemia), with no apparent role for mild hypothyroidism [13].

Skin and ectopic ossifications. Ossifications are true intramembranous bone in the dermis and subcutaneous tissue; they appear as hard nodules or plaques, sometimes initially bluish, particularly on the scalp, hands and feet and at pressure sites (heel, waist, nasal bridge under glasses), may be painful and occasionally extrude chalky material [2, 18]. The PNDS gives frequencies of 80–100% with paternal variants and 30–60% with maternal ones, describes miliary forms and plaques (osteoma cutis) that progress from the dermis into deeper tissues, with contractures, joint locking and sometimes delayed growth of a limb, and reports worsening after local trauma and surgery and a predominance at pressure sites such as the heels [13]. The same text reports that red hair is frequent in AHO and attributes it to melanocortin resistance [13]. In Salemi's series, prevalence and severity were similar in PHP1A and PPHP, more severe in males and with frameshift or nonsense variants, unrelated to hormonal status or BMI, and worsened with age [66]. Ossifications may be present at birth: 80% of affected patients in the Franco-Italian cohort already had them by 3 years, with a median appearance age of 1 year [14]. Extensive or deep ossifications are uncommon in PHP1A but do not exclude it [3]. Ossifications in the sclera, choroid and interventricular septum have been described, and visceral involvement is rare [2]. The Oxford Desk Reference describes subcutaneous deposits as “gritty” to touch, particularly on the scalp, hands and feet [77].

Musculoskeletal system. Brachydactyly type E particularly affects the 4th and 5th metacarpals and 3rd and 4th metatarsals, frequently with brachydactyly type D of the distal thumb phalanx (short, broad nail); it is progressive, often asymmetrical, and becomes evident only before puberty; AHO features may appear as late as adolescence and, in an affected man, a short proximal hallux phalanx may be the only sign [2, 3, 67]. On making a fist, knuckles are replaced by dimples, the Archibald sign [18]. The short, broad distal thumb phalanx is also called “murderer's thumb” (murderer's thumb) [13]. Craniosynostosis in iPPSD2 ranges from sagittal synostosis to pansynostosis; when fusion is late, the deformity may be minimal and only cranial CT reveals it, so the head circumference curve should be reconstructed and followed [13]. Lateral cephalometry shows reduced vertical, sagittal and transverse development of the midface and abnormalities of the skull base [13]. Carpal tunnel syndrome was reported by 67% of patients with PHP1A or PPHP, compared with 15% in the general population, and the paraesthesiae it causes may be confused with hypocalcaemia [2, 3]. Other abnormalities include Madelung deformity, spinal stenosis due to absent caudal widening of lumbar interpedicular distances, acro-osteolysis, enchondromas, short humerus, bowed radius, exostoses perpendicular to the diaphysis, craniosynostosis and calvarial hyperostosis [2, 3, 67].

Teeth. Enamel hypoplasia, short blunt roots, enlarged pulp chambers, failure of eruption (in more than 30%), molar impaction, hypodontia, malocclusion and gingivitis have been described [2, 3, 15]. The PNDS estimates dental anomalies in about 90% of patients with maternal iPPSD2, impaction being the most frequent (83%), and adds ankylosis, gingival hyperplasia and root resorption; in the study by Le Norcy and colleagues cited in the supporting argument (19 patients with PHP1A), 89% had dental anomalies, including agenesis, infraocclusion, short roots and taurodontism, with limited development of the facial skeleton [13].

Airways, sleep and ear. Sleep apnoea is frequent: the relative risk of sleep-disordered breathing was 4.4 compared with equally obese children without PHP1A and, in a prospective study, 60% of children with PHP1A had significant obstructive sleep apnoea syndrome (OSAS); central apnoea also occurs [3, 18]. GeneReviews reports sleep apnoea in 45% of patients [2]. Asthma was reported in 50–75% of patients with PHP1A and is also more frequent in PPHP and PHP1B; recurrent otitis media often leads to tympanostomy tubes and adenotonsillectomy [3, 18]. The PNDS associates asthma with an allergic background with eczema and includes partial or total hearing loss; in the German multicentre study by Koch and colleagues cited in the supporting argument, 63% of 22 patients with PHP (11–56 years) had symmetrical sensorineural hearing loss [13].

Digestive system. Constipation is a feature only recently characterised systematically: 50% of patients with iPPSD2 in the 2023 cohort and more than 60% of 36 children with iPPSD2 or iPPSD3 at the French referral centre, with treatment effective according to only 3 families; neonatal vomiting, gastro-oesophageal reflux and selective eating were reported in 40–50% [78, 79]. In the same 2023 cohort, 13.1% of children with PHP1A had cow's milk protein allergy [78].

Neonatal period. In the Franco-Italian cohort of 136 patients, 47% of newborns with PHP1A had neonatal complications, compared with 20% in PHP1B; 18.4% had transient respiratory distress and 10.5% hypoglycaemia, and around 39% of complications were severe (prolonged or intensive care admission for arrhythmias, asphyxia, seizures, cardiac arrest or septicaemia) [78]. TSH resistance before 1 year was independently associated with complications (odds ratio [OR] 4.84; 95% confidence interval [CI] 1.43–18.39) [78].

3.3. PHP1B

PTH resistance is the dominant feature and may coexist with mild TSH elevation in 30–100% of patients; mean TSH was 5.3 ± 4.7 mIU/L, varying over time [3]. Hypocalcaemia is variable, and some patients remain normocalcaemic with the same epigenetic defect [3]. As patients have fewer physical stigmata, hypocalcaemic seizures are a more frequent presentation than in PHP1A [18]. Prolonged secondary hyperparathyroidism, with calcitriol deficiency, causes bone resorption and demineralisation resembling rickets (irregular, widened metaphyses), Madelung-like deformity, slipped upper femoral epiphysis, brown tumours and tertiary hyperparathyroidism; Bone Dysplasias calls this presentation “pseudo-hypo-hyperparathyroidism” [3, 67]. Very high bone density is rare [2].

Intrauterine growth is increased: in a series of 114 patients cited in a 2022 review, birth weight had a Z score of +0.73 ± 1.2, without overgrowth in 12 patients with PHP1A [80]. Growth velocity and BMI are increased in childhood, the pubertal spurt is reduced or absent and adult height is normal; early obesity, sometimes in the first months, is an important feature [15, 18]. In the 2026 Franco-Italian cohort, 26% of patients with iPPSD3 were obese, with median onset at 0.4 years [14]. Brachydactyly occurs in 15–33%, is milder, and ossifications are very rare [3, 18]. Intellect is typically normal [2]. Median age at diagnosis was 12.2 years in the 2026 cohort and 10–12 years in symptomatic patients in an earlier French series [2, 14]. In children of STX16 deletion carriers, PTH was already elevated around 2 years and rose progressively, whereas total calcium remained normal until around 5 years, in a study with pretreatment data in 19 of 25 carriers [81].

3.4. PPHP

PPHP manifests through the physical features of AHO without PTH resistance, with restricted birth weight and length, moderate catch-up, absence of a pubertal spurt and short adult stature in 50–70% [3, 18]. Patients generally have normal weight or thinness, cognitive impairment in 0–10% and frequent ossifications, almost pathognomonic of Gsα deficiency [2, 3]. The most common presentation is a mother bringing her child with PHP1A to a consultation, in whom AHO features are noticed [18]. Some patients with PPHP develop mild hormone resistance; the 2020 update therefore considers determination of the affected allele relevant in de novo cases [15]. The reverse situation is a clinical pitfall: as PHP1A endocrine abnormalities may arise after AHO features, a child labelled PPHP may have PHP1A, and investigation of the mother helps clarify this [2]. Apparent PPHP may also evolve into POH [18].

3.5. Progressive osseous heteroplasia

POH begins in infancy, often with a maculopapular rash or band-like erythema at the future dermal ossification site, followed by membranous ossification in the dermis progressing to deep tissues, including muscle, tendons and ligaments [3, 32]. Lesions may predominate on one side of the body and follow dermomyotomal patterns; radiography shows a reticular pattern, and histology intramembranous ossification, sometimes with an endochondral component [3]. Disease causes severe ankyloses and focal growth impairment, and stabilises after adolescence; disability depends on location and extent [3, 32]. Patients are frequently born SGA, are thin and have a normal PTH response; POH-like features also occur with maternal allele variants, and POH/PHP1A overlap is very rare [3, 18]. Bone Dysplasias illustrates progression in a Korean infant with band-like erythema over the right hemithorax and left ankle, ossification at those sites at 1 year, enlargement at 3 years and a new focus at the knee at 6 years, and in patients aged 19 and 6 years with muscular ossification in the thigh and elbow [32].

3.6. Osteoma cutis

Primary osteoma cutis is generally present at birth or appears very early, more rarely in childhood or adulthood, as a single large plaque, dermal nodules or multiple facial papules; calcium and phosphate remain normal throughout life, suggesting a paternal allele variant [3]. Plate-like osteoma cutis, considered a limited POH variant, also occurs in PHP1A, as shown by the case in section 10 [64]. It should be distinguished from osteoma cutis secondary to trauma, burns, acne or skin tumours [3].

3.7. Acrodysostosis type 1 (PRKAR1A) and type 2 (PDE4D)

Acrodysostosis skeletal abnormalities may be present at birth, unlike AHO: severe brachydactyly of all phalanges, metacarpals and metatarsals (sparing thumbs and halluces), cone-shaped epiphyses, advanced bone age in all patients and, in the neonatal period, epiphyseal stippling regressing by 4 months and almost always disappearing by 8 months [3, 33]. Facial dysostosis includes a round face, maxillary and nasal hypoplasia, a small upturned nose, prognathism, epicanthus and hypertelorism [26, 33]. Mean adult stature is −3.5 SD (from −8.8 to −0.5); Bone Dysplasias describes heights ranging from normal to −7.2 SD [3, 26]. In acrodysostosis type 2, the same atlas describes frequent otitis with hearing impairment and an abnormal iris colour changing with age [26]. Older series of around 60 patients without genotypes described intellectual disability in 77% (mean IQ 61), hearing impairment in 67%, maxillary hypoplasia in 100%, loss of lumbar interpedicular widening in 75%, hypoplastic genitalia and cryptorchidism in 29% [33]. Lumbar spinal stenosis, sometimes cervical, causes weakness, hyperreflexia and asymmetrical reflexes [26].

The two types differ in endocrinology and cognition. In PRKAR1A-related acrodysostosis, almost all patients have PTH and TSH resistance, with variable gonadotrophin resistance, elevated calcitonin, markedly short stature and usually normal intelligence with behavioural problems; hypocalcaemia is not documented [3, 15, 26]. In PDE4D-related acrodysostosis, PTH resistance occurs in 29% and TSH resistance in 16%, PTH is generally normal except with calcifediol deficiency, maxillonasal hypoplasia is more severe and cognitive impairment is frequent; in Lynch's series, short stature and endocrine resistance were rare and obesity frequent [3, 33, 56]. Radiology and hormonal profile do not reliably distinguish the two types, so confirmation is molecular [55]. The estimates of the French PNDS are intermediate: PTH and TSH resistance in about 65% of patients with iPPSD4 and in about 15% of those with iPPSD5 (about 20% in another passage of the same text), and raised FSH, cryptorchidism or absent pubertal development in up to 20% of patients with iPPSD5; hypothyroidism occurs in iPPSD4 but not in iPPSD5 [13]. The same text describes craniosynostoses with signs of intracranial hypertension from presentation, lower limb deformity, atopy, rhinitis and eczema, and grade III obesity in some adults; OSAS is more frequent in iPPSD4, independently of obesity [13]. On radiographs, brachydactyly predominates in the metacarpals, with the 2nd and 5th rays particularly affected [13]. In the 2026 Franco-Italian cohort, PTH resistance was present in all 11 patients with iPPSD4 and 1 of 5 with iPPSD5, and brachydactyly in all, with a median detection age of 5 years [14]. In Michot's 2018 series, 7 of 27 patients with a clinical diagnosis of acrodysostosis had no variant, and had brachydactyly and cone-shaped epiphyses without the characteristic facial dysostosis [58].

Acrodysostosis and Albright hereditary osteodystrophy: similarities and differences

Acrodysostosis and AHO share brachydactyly, short stature, round face, obesity and, in type 1 and PHP1A, PTH and TSH resistance, which for decades led to interchanged diagnoses [82, 83]. An American child with acrodysostosis type 1, described in 2020, was at one point considered possible PHP1A because of the overlapping features and the resistance to growth hormone-releasing hormone common to both diseases [83]. The 2021 review by Elli and Mantovani proposes that PHP, acrodysostosis and POH be read as a spectrum with shared major and minor features, distinguished by the distribution of brachydactyly, the presence of ossifications and facial dysostosis [82]. The table brings together the features that separate the two pictures in clinical practice.

Sources: 2018 consensus, review by Elli and Mantovani, series by Linglart (2012), Muhn (2013) and Wang (2026), Bone Dysplasias and Smith's [3, 26, 33, 47, 48, 82, 84].

Genotyped series confirm this separation with small numbers. In Linglart's 2012 series, the 14 patients with PRKAR1A had PTH and TSH resistance and neither of the 2 with PDE4D had it; intellectual disability was concentrated in patients with PDE4D, two patients with novel PRKAR1A variants had a distinct brachydactyly pattern, and pigmented skin lesions were described for the first time in both genotypes [47]. In Muhn's German series, the most common findings with PRKAR1A were radiological hand abnormalities, raised TSH and PTH and short stature; the characteristic facial dysmorphism, sensorineural hearing loss and mild intellectual disability were less frequent; in a cohort of 44 patients with brachydactyly type E, only one PRKAR1A variant was found, p.Asp227Asn, of uncertain effect, so the gene has no relevant role in isolated brachydactyly type E [48]. In a Japanese series of 15 patients classified by the iPPSD nomenclature, the 2 siblings with PDE4D had the most severe skeletal and developmental delay and no hormone resistance, the 6 patients in the group with hormone resistance without hypocalcaemia all had short metacarpals with cone-shaped epiphyses, but only 2 had an identified PRKAR1A variant, and the 7 with PHP1A were also heterogeneous [85]. In a Chinese series of 6 children diagnosed by exome sequencing between 2023 and 2026, with a median age at diagnosis of 6.3 years, 5 had PRKAR1A (p.Arg368Ter in 3) and 1 PDE4D; the 4 patients with PRKAR1A tested had PTH resistance and 3 TSH resistance, the child with PDE4D had mild intellectual delay without hormone resistance, and bone age was advanced in 3 and delayed in 1 [84].

Spinal canal stenosis is the most serious neurological complication of acrodysostosis. A 19-year-old woman with acrodysostosis, described in 2022, developed progressive paraparesis of the lower limbs, sensory loss and urinary retention, with spinal cord signal change at T2–T3 and cord oedema between T6 and T8; six months after laminectomies at T2–T3 and T6–T7 her symptoms had improved, but she still needed a wheelchair, and the authors recommend regular surveillance for spinal cord compression to allow early decompression [86].

3.8. Natural history in recent cohorts

European cohorts with genetic diagnoses show that the full presentation develops over years. In the Milan and Paris cohort published in 2026 (117 patients, 67 children and 50 adults), median age at diagnosis was 5.9 years, the first major criterion appeared at a median of 4.2 years, 64% had no major criterion at 2 years and 20% still had none at 10 years; only 6 patients (5%) were diagnosed after a hypocalcaemic seizure [14].

IQR, interquartile range. The cohort also included 3 patients with iPPSD1 and 15 with iPPSDx [14]. Patients with inherited disease were diagnosed earlier than de novo patients (median 2.55 versus 7.8 years), mainly because of earlier TSH and PTH resistance. Before 2 years, the most frequent features were obesity or overweight (36.1%), TSH resistance (34.5%), ossifications (22.2%), neurocognitive impairment (22%) and PTH resistance (16.7%); 71% had at least one minor criterion [14]. In the 2023 cohort, only 28% had a major criterion before 12 months and most children with PHP1A had hypocalcaemia at 7–8 years [78]. Kayemba-Kay's and colleagues described a bimodal PHP1A presentation: before 2 years, moon face, subclinical hypothyroidism, ossifications and rapid weight gain; after 2 years, intellectual disability, brachydactyly, hypocalcaemic seizures, short stature and overt TSH resistance [14]. The French PNDS gives mean ages at diagnosis of about 6.5 years in maternal iPPSD2 and about 13 years in iPPSD3, with diagnoses frequently made after the age of 20 years in the latter, and cognitive impairment in about 70% of patients with maternal iPPSD2; in the retrospective study by Usardi and colleagues cited in the supporting argument (20 patients with maternal iPPSD2, mean age at diagnosis 3.9 years), PTH resistance and hypocalcaemia developed progressively [13].

Outside Europe, a multicentre Chinese paediatric series of 87 patients found variants in GNAS exons 1–13 in 31 and imprinting defects in 39, 11 of whom had a clinical PHP1A phenotype, reinforcing overlap between iPPSD2 and iPPSD3; ossifications occurred only in iPPSD2 [87]. The 2026 Turkish series recorded clinical gonadal dysfunction in 4 of 6 girls with PHP1A and intellectual disability in half of patients with PHP1A [71].

3.9. Untreated and treated disease

Complications described in older series (seizures, cataracts, cerebral calcifications, hyperparathyroid bone disease) largely reflect untreated or late-diagnosed hypocalcaemia and hyperparathyroidism [2, 3]. In cohorts with early diagnosis, hypocalcaemic seizures as the presentation are rare (5%) [14]. In a Turkish series of 23 children with hypoparathyroidism or iPPSD, treatment with oral calcium and calcitriol normalised calcium, phosphate and PTH after 1 year in the iPPSD group, without renal complications during a median follow-up of 6.6 years [88]. Features depending on tissues with biallelic expression or hypothalamic imprinting (brachydactyly, short adult stature, ossifications, obesity, cognitive impairment) are not modified by conventional endocrine treatment [3].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

In newborns and infants, features are non-specific: fetal growth restriction (PPHP, POH, acrodysostosis), macrosomia (PHP1B), congenital hypothyroidism with moderately elevated TSH and a small thyroid, rapid weight gain, hard skin nodules or plaques and neonatal respiratory complications or hypoglycaemia [15, 78]. Without a family history or ossifications, diagnosis may be delayed for years [15]. The combination of positive newborn screening for hypothyroidism and cutaneous ossifications should prompt immediate investigation for PHP1A, as should a child with hypothyroidism well controlled with levothyroxine who continues to gain excessive weight [18]. The 2023 cohort recommends investigating PHP1A in infants with unexplained elevated TSH and screening for a maternal GNAS variant with ossifications, TSH resistance, early obesity or family history, even without PTH resistance [78].

In children, signs are growth deceleration, brachydactyly, obesity and hypocalcaemia with neuromuscular symptoms or seizures [15]. In older children, adolescents and adults, the most common PHP1B presentation is symptomatic hypocalcaemia or a seizure, and PPHP presentation is detection in a mother with an affected child [18]. Hypocalcaemia may become apparent during periods of increased calcium requirements, such as adolescence and pregnancy [17]. Severe childhood obesity may be the only manifestation of a GNAS variant: in the British Genetics of Obesity study, 22 of 2548 children with severe obesity (around 0.9%) had GNAS variants, almost all impairing MC4R signalling, and only 1 of 10 reaching final height had short stature; variants impairing TSH receptor signalling were associated with developmental delay and higher TSH (8.4 ± 4.7 versus 3.9 ± 2.6 mIU/L in 340 children with severe obesity without a variant) [89]. AHO therefore belongs in the differential diagnosis of short stature and syndromic obesity, alongside Prader–Willi and Smith–Magenis syndromes [39, 90]. Isolated cutaneous ossifications, even without PTH resistance, justify GNAS investigation [18].

4.2. Warning and emergency signs

Signs that should suggest PHP or a related disease are: elevated PTH with elevated phosphate and normal calcifediol, even without hypocalcaemia; cutaneous or subcutaneous ossifications, particularly in the first year; brachydactyly with shortening of the 4th and 5th metacarpals or dimples replacing knuckles; obesity before 2 years associated with elevated TSH; congenital hypothyroidism without goitre or autoimmunity; basal ganglia calcifications or cataracts in a child or young adult [3, 18]. Suspected FOP changes the approach: with deep ossifications and malformed halluces, biopsy is contraindicated [3].

Emergency signs are tetany, laryngospasm, seizures, QT interval prolongation and heart failure due to severe hypocalcaemia [2, 69]. In children with PHP1A and OSAS, snoring and daytime sleepiness warrant polysomnography before starting GH [18]. In acrodysostoses, lower limb weakness, hyperreflexia or asymmetrical reflexes suggest spinal stenosis with compression [26]. AHO physical features, except ossifications, are non-specific and diagnosis tends to be overassigned when based on these alone [74]. The PNDS asks that patients and families know the stress situations, such as infections and surgery, that can precipitate hypocalcaemia in an already precarious balance, and that they be able to recognise the signs and seek emergency care [13].

4.3. Newborn screening

There is no targeted newborn screening for PHP. Congenital hypothyroidism screening using TSH, performed systematically in France and Italy, detects some patients with PHP1A because TSH resistance is often present at birth [3, 14]. In the 2023 cohort, 34.2% of children with iPPSD2 had TSH resistance before 1 year [78]. A positive result with a small thyroid and no other cause justifies examination of the skin and hands and measurement of calcium, phosphate and PTH during follow-up [18]. Children of women with identified GNAS variants or STX16 deletions should be assessed from birth (TSH, calcium, phosphate and examination for ossifications) [15, 81].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. International consensus criteria (2018, retained in 2020)

Diagnosis is clinical and biochemical and should be confirmed by molecular investigation, which characterises the subtype [3]. The 2020 update retained the major criteria [15].

Strengths follow the consensus method: A to D for level of agreement and evidence, and +, ++ and +++ for 26–49%, 50–69% and at least 70% of votes [3].

5.2. iPPSD criteria (EuroPHP, 2016)

The 2016 proposal uses three major criteria — proximal tubular PTH resistance, ectopic ossifications and BDE — and six minor criteria: TSH resistance; other resistance (GHRH, calcitonin, gonadotrophins); motor and cognitive delay; intrauterine and postnatal growth retardation; obesity or overweight; flat nasal bridge, maxillary hypoplasia or round face [1]. Clinical iPPSD diagnosis requires PTH resistance or ectopic ossifications, with or without minor criteria, or BDE with at least two minor criteria; BDE with isolated obesity or isolated cognitive impairment is insufficient, to reduce overdiagnosis [1]. In validation involving 459 probands and 85 relatives, more than 98% met the criteria, 85% had a combination of signs and family history proved a useful additional criterion [30]. The 2022 French PNDS adopts these criteria with three additional minor criteria — craniosynostosis, dental anomalies (ankylosis, oligodontia) and family history — and lists atypical signs (hearing loss, Chiari malformation, cataract, obstructive sleep apnoea, otitis, asthma); a single major criterion suffices to establish the diagnosis, with the proviso that BDE counts only if accompanied by two minor criteria, and the molecular diagnosis confirms the type but is not required for the initial diagnosis [13]. The PNDS cites the same European validation, with at least one major criterion in 98% of 459 genetically confirmed probands [13, 30].

5.3. Proposed criteria for children under 2 years

The study by Del Sindaco and colleagues published in October 2026 showed that existing criteria fail in infants: 64% of children had no major criterion at 2 years, and the most frequent features at that age were minor criteria [14]. The authors propose their own flowchart: TSH resistance associated with rapid weight gain before 2 years, or ectopic ossifications, justify genetic testing with an iPPSD-targeted next-generation sequencing (NGS) panel; isolated elevated TSH or isolated weight gain requires other suggestive features (other resistance, BDE, elevated PTH, neurocognitive impairment) [14]. The combination of obesity or overweight with TSH resistance was present in 20% of patients before 2 years [14]. This is a retrospective proposal from two centres with small subgroups, rather than a consensus recommendation [14].

5.4. Biochemical assessment

Initial assessment includes total or ionised calcium, phosphate, magnesium, PTH, 25-hydroxyvitamin D (calcifediol), creatinine, urinary calcium and phosphate (or tubular phosphate reabsorption), TSH, free T4, thyroid autoantibodies and, according to age, IGF-1, with or without a GH stimulation test [1, 2]. Severe vitamin D deficiency and hypomagnesaemia reduce the PTH response or cause secondary hyperparathyroidism and mimic PTH resistance, so should be excluded and corrected before interpretation [2, 3]. Phosphate has age-dependent reference ranges; the 2026 cohort used 1.3–2.2 mmol/L from 0 to 4 years, 1.2–1.7 from 4 to 10, 1.1–1.8 from 10 to 18 and 0.8–1.5 mmol/L in adults, and defined hypocalcaemia as calcium at or below 2.20 mmol/L [14]. Markedly elevated PTH with normal or low calcium and normal or elevated phosphate, with high TSH and normal or low triiodothyronine (T3) and T4, is the typical PHP1A pattern [39]. Elevated calcitonin supports diagnosis, but routine measurement or screening for other resistance is not recommended except for diagnostic purposes [15]. With hypocalcaemia and elevated PTH, the consensus recommends using different assays to confirm PTH elevation when a PTH gene variant is considered [3].

Historical functional tests have lost their role. The exogenous PTH infusion test (modified Ellsworth–Howard), measuring urinary cAMP and phosphate, and measurement of Gsα bioactivity in erythrocyte membranes are not necessary for diagnosis and are reserved for research [3]. The comparative table in Bone Dysplasias, summarising these tests (serum calcium, cAMP after stimulation and erythrocyte Gsα by subtype), contains errors: it writes “POH” where AHO is intended, shifts a column in the PHP1B row and lists acrodysostosis with normal calcium without mentioning frequent PTH resistance in type 1; it should be read only as a historical outline [67].

The 2022 French PNDS defines hypocalcaemia and hyperphosphataemia relative to laboratory and age-specific reference ranges, and requires hyperphosphataemia of renal origin to be demonstrated by an elevated tubular reabsorption of phosphate (TRP) or, better, an elevated renal phosphate threshold (TmP/GFR) [13]. TRP is calculated as (1 − [urinary phosphate × serum creatinine] / [serum phosphate × urinary creatinine]) × 100, with all concentrations in the same molar units; when TRP is not clearly abnormal, TmP/GFR is calculated [13]. PTH is measured by a 2nd- or 3rd-generation assay, and secondary hyperparathyroidism from other causes is excluded with 25-hydroxyvitamin D, creatinine with estimated GFR, magnesium and urinary calcium; because resistance may be absent or mild, investigations are repeated [13]. Unlike the consensus, which reserves the Ellsworth–Howard test for research, the PNDS accepts it in ambiguous situations, in highly specialised centres [3, 13]. In iPPSD2 TSH is almost always raised, but as a rule below 50 mIU/L, with low-normal or slightly low free T3 and T4; in iPPSD3 it is at the upper limit of normal or slightly raised [13]. Total serum calcium includes calcium bound to proteins and anions; in case of doubt, ionised calcium is measured in hospital, under strict pre-analytical conditions [13]. Phosphate has a circadian rhythm (in adults, about 0.3 mmol/L higher in the afternoon than in the morning, with a nocturnal peak around 2–3 a.m. and a nadir between 8 and 10 a.m.), and reference values were established in the fasting state, in the morning [13].

Source: 2022 PNDS, appendix 1, based on a French handbook of paediatric calcium–phosphate metabolism; the 2–4-year band does not appear in the original table, and PTH values vary widely between commercial assays, so the ranges of the laboratory performing the measurement take precedence [13].

5.5. Imaging

Radiographs of the hands and feet identify BDE: most frequent shortening of the distal thumb phalanx and 4th, 5th and 3rd metacarpals, cone-shaped epiphyses, periarticular soft-tissue calcification in around half of patients and occasional exostoses perpendicular to the diaphysis [67]. The metacarpal sign is positive when the line tangential to the heads of the 4th and 5th metacarpals intersects the 3rd [67]. The metacarpophalangeal profile differs between AHO and acrodysostosis: in the latter, metacarpals 2–5 are more affected than the phalanges, thumbs and halluces are spared and lumbar interpedicular distance is reduced [33]. Bone age is useful, but dysostosis reduces the reliability of height prediction and hand bone age is ahead of knee bone age [3, 18]. Brain computed tomography (CT) is justified only with neurological manifestations; ophthalmological examination looks for cataracts [3]. Ossifications are imaged only if painful, impairing function or if surgery is planned [3]. The French PNDS proposes a radiological survey targeted at the areas usually affected in constitutional bone diseases — anteroposterior and lateral lumbar spine, anteroposterior pelvis, left hand and wrist and anteroposterior left knee —, preferably with a low-dose system (EOS) and repeated if necessary, because the abnormalities are subtle in young children [13]. In iPPSD2, radiological signs appear around puberty: brachymetacarpia always affecting the 4th ray, predominating in the 4th, 5th and 1st rays, brachytelephalangia of the 1st ray, narrow lumbar canal due to absent widening of the interpedicular distance from L1 to L4, short femoral necks, cone-shaped epiphyses, small exostoses and demineralisation due to hyperparathyroidism; in adults, calcification of the vertebral ligaments and constitutional canal stenosis may compress the spinal cord, and axial ossifications may mimic diffuse idiopathic skeletal hyperostosis [13]. Unlike the consensus, which reserves brain CT for neurological manifestations, the PNDS considers it frequently indicated to look for craniosynostosis and calcifications, supplemented by brain and spinal MRI if Chiari malformation or canal stenosis is suspected [3, 13].

5.6. Genetic tests and algorithm

The consensus recommends that molecular diagnosis include sequence, methylation and copy-number variation (CNV) at the GNAS locus, and proposes an algorithm centred on the presence of AHO [3].

Source: 2018 consensus, figure 2 and recommendations 2.1–2.10 [3]. When clinical features point to a gene, sequencing that gene is sufficient; without clear direction, a PTH/PTHrP pathway panel is used [3]. MS-MLPA simultaneously assesses methylation and deletions of STX16, NESP/AS and the entire GNAS; alternative methylation methods (COBRA, pyrosequencing, MS-SNuPE, EpiTYPER) do not distinguish primary epigenetic defects from those caused by deletions [3, 15]. Whole-locus deletions may mimic the global methylation defect of sporadic PHP1B, so a global defect requires CNV investigation [2]. With UPD(20q)pat or large deletions, karyotyping of the proband and father is recommended because a translocation increases recurrence risk [3].

Source: GeneReviews, table 1 [2]. GNAS screening (exons and splicing sites) detected variants in around 75% of a cohort with confirmed reduced Gsα bioactivity [39]. In the Italian cohort used by the consensus, maternal loss-of-function variants accounted for 35.9% of patients, paternal variants for 5.9%, deletions or inversions for 2%, broad sporadic methylation defects for 38%, UPD(20q)pat for 2.7% and isolated A/B LOM with STX16 deletion for 13.5% [3]. Overall, a molecular cause is identified in around 80–90% of patients, and in the 2026 Franco-Italian cohort 12.8% remained iPPSDx [14, 15]. These proportions describe each method's yield in published series and are not measures of clinical sensitivity.

The French PNDS follows a different pathway: with at least one major criterion, the first test is an NGS panel of the pathway genes (receptor, Gsα, PRKAR1A, PDE4D), with methylation analysis of the GNAS DMRs when the clinical picture suggests iPPSD3, interpretation of the results at a multidisciplinary consultation meeting and, if there is no variant or methylation abnormality (about 30% of patients, according to the PNDS), genome sequencing within the France Genomic Medicine Plan 2025 [13]. In LOM restricted to the A/B DMR, the recurrent 3 kb STX16 deletion is sought; in broad LOM, UPD(20q)pat [13]. The 30% proportion without a diagnosis is higher than the 10–20% inferred from the 2020 update and the 12.8% iPPSDx in the Franco-Italian cohort, a difference that depends on the population tested, the methods and the period [13–15]. The PNDS lists three French laboratories with a dedicated panel (Hôpital Bicêtre, Hôpital Cochin and CHU de Caen), two of which offer GNAS methylation analysis [13].

5.7. Test limitations

A negative result does not exclude diagnosis. GNAS exon 1 is very GC-rich and NGS coverage may be incomplete, justifying complementary Sanger sequencing [3]. Multigene panels and exome or genome sequencing do not detect imprinting defects, so a negative panel does not exclude PHP1B [2, 36]. Loss of methylation identifies the defect but not the cause; PHP1A may have partial methylation defects of uncertain significance, and mosaic alterations in sporPHP1B may be incomplete [2, 16]. Deep intronic variants, regulatory variants (such as those in exon H or the GNAS promoter) and inversions escape routine tests; they were identified by genome or long-read sequencing [37, 38, 40, 42]. Older microarray platforms could fail to detect the recurrent STX16 deletion [2]. Somatic mosaicism (for example in unilateral POH) may render blood testing negative; the consensus recommends testing another tissue (saliva, buccal swab) or deep sequencing when suspicion is high, and including technical limitations in the report [3].

5.8. Reporting, variants of uncertain significance and segregation

A sequence variant report gives the gene, transcript with version (NM_000516.7 for GNAS, NM_002734.5 for PRKAR1A), complementary DNA and protein HGVS description, zygosity and ACMG/AMP class [3, 34]. In methylation defects, it describes the affected DMRs and method. Parental investigation is recommended whenever an alteration is detected because parental origin has implications for the expected phenotype and recurrence risk; with a de novo variant, determining the parental allele affected may be necessary [3, 15]. With a de novo variant or variant of uncertain significance (VUS), parental germline mosaicism should be considered [3]. When the mechanism has not been identified, GeneReviews suggests storing proband DNA [2].

5.9. Prenatal and preimplantation diagnosis

Very few cases have had antenatal diagnosis because fetal manifestations are non-specific; acrodysostosis dysplasia may begin prenatally, particularly with PRKAR1A [3]. Once the mechanism is identified, prenatal diagnosis and preimplantation genetic diagnosis (PGD) are possible, but the consensus recommends considering ethical and legal issues with counselling (A++) and does not recommend methylation analysis for prenatal diagnosis (A++) [2, 3]. The predicted phenotype depends on the transmitting parent's sex rather than severity in that parent [3].

6. Differential Diagnosis

6.1. Comparative table

The differential diagnosis is organised by the sign prompting consultation: hypocalcaemia with elevated PTH, brachydactyly, ossifications, early obesity, early hypothyroidism or hypertension [3].

AD, autosomal dominant; AR, autosomal recessive; FISH, fluorescence in situ hybridisation; stroke, cerebrovascular accident; FGF23, fibroblast growth factor 23. Sources: 2018 consensus (table 2), 2022 French PNDS (table 3), GeneReviews, Bone Dysplasias, Smith's and Oxford Desk Reference [2, 3, 9, 13, 32, 45, 46, 67, 68, 93].

6.2. Main differential diagnoses

PHP is distinguished from hypoparathyroidism by PTH: in hypoparathyroidism, low calcium and high phosphate accompany low PTH; in PHP, PTH is elevated [2]. This distinction has therapeutic consequences because PTH replacement therapy, recommended in refractory hypoparathyroidism, has no role in PHP [3, 94]. The other side of this boundary is parathyroid hormone deficiency, in the isolated forms due to GCM2 and PTH, in autosomal dominant hypocalcaemia due to gain of function of CASR and GNA11, in the syndromic forms due to GATA3, TBX1, AIRE, FAM111A and TBCE, and in those of mitochondrial cause, with a diagnostic algorithm starting from hypocalcaemia with low or inappropriately normal parathyroid hormone, the biochemical targets of conventional therapy, the indications for parathyroid hormone replacement and renal surveillance; it also includes the reverse pitfall, that of PTH variants producing an immunoreactive but biologically inactive hormone, in which measured parathyroid hormone is high and the picture is mistaken for resistance. Vitamin D deficiency and hypomagnesaemia must be corrected before concluding PTH resistance; normocalcaemic hyperparathyroidism and chronic kidney disease also belong in the biochemical differential diagnosis [1, 3].

Isolated brachydactyly is the domain of phenocopies. Hands in isolated BDE and AHO may be indistinguishable, but BDE has no ossifications, cognitive impairment or hormone resistance, and Gsα bioactivity is normal [67]. The 2q37 deletion syndrome is the closest phenocopy: the AHO-like phenotype occurs in distal deletions including HDAC4 and in 50–60% of subtelomeric 2q microdeletions, with intellectual disability and normal endocrine function; 5% of cases result from a parental balanced translocation, so parental FISH studies are proposed [45, 93]. Acrodysostosis is distinguished from AHO by early, generalised brachydactyly, facial dysostosis with nasal hypoplasia, spinal stenosis (not described in PPHP) and absence of ossifications [3, 67]. Desbuquois dysplasia and dyschondrosteosis also belong in the radiological differential diagnosis [67].

Acrodysostosis is distinguished from AHO by radiographs of the hands and feet, by the face and by the absence of ossifications: in acrodysostosis, brachydactyly affects all rays, cone-shaped epiphyses and advanced bone age are present from early on and there is facial dysostosis, whereas in AHO brachydactyly follows the type E pattern and subcutaneous ossifications are frequent [3, 82]. PTH and TSH resistance does not separate acrodysostosis type 1 from PHP1A, and confirmation is always molecular; with an acrodysostosis phenotype and negative PRKAR1A and PDE4D sequencing, GNAS should be studied, because GNAS variants also produce acroscyphodysplasia [57, 85].

With ossifications, the decisive differential diagnosis is FOP. In POH, ossification begins in the dermis, is intramembranous, is not preceded by muscular swelling and the halluces are normal; in FOP, ossification is endochondral, affects muscles and fasciae, is triggered by trauma, injections and surgery and the halluces are malformed [3, 32]. The consensus therefore contraindicates biopsy whenever FOP is possible, and surgery and invasive dental treatment are also avoided in FOP because they trigger ossification [3, 77]. Unlike FOP, there is no formal evidence that trauma, viral infections or vaccines trigger ossifications in GNAS disorders [3]. GNAS-associated forms have ossification rather than calcification alone, and plate-like osteoma cutis is localised and non-progressive [32].

McCune–Albright syndrome is the molecular mirror of PHP: postzygotic somatic activating GNAS variants cause fibrous dysplasia, irregular-bordered café-au-lait macules and autonomous endocrine hyperfunction (precocious puberty, thyrotoxicosis, GH excess, Cushing syndrome), with FGF23-mediated phosphaturia, whereas PHP has hyperphosphataemia [17, 68]. It is not hereditary and diagnosis is generally clinical because molecular detection in leukocytes depends on the degree of mosaicism [68].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no mechanism-directed treatment or drug approved specifically for GNAS inactivation disorders or acrodysostoses [36, 55]. By 2018 no prospective trial on PHP management or outcomes had been published, and consensus recommendations rest on case series, retrospective studies and expert opinion [3]. The consensus recommends a coordinated multidisciplinary team from childhood to adulthood, preferably at referral centres, with timely transition to adult care (A++) [3, 15]. Recommendations apply to all patients with a clinical diagnosis, with or without molecular confirmation [3]. The consensus gives no numerical doses of active vitamin D or calcium [3]; the 2022 French PNDS is the specific guideline consulted that does so, and its doses serve as the reference, with the labels and the hypoparathyroidism guideline as comparison [13]. The PNDS sets as goals improving quality of life, preventing acute and chronic complications and promoting social and occupational integration, with coordination by a specialist (usually the paediatric and then the adult endocrinologist) in liaison with the reference or competence centre [13].

7.2. PTH resistance: when to treat and with which targets

The consensus recommends measuring PTH, calcium, phosphate and calcifediol at diagnosis and before treatment (A+++) [3]. Active vitamin D should be considered with substantial progressive PTH increases and hyperphosphataemia, even without hypocalcaemia (A++), and also when PTH exceeds 2 times the upper limit of normal (ULN), regardless of calcium (B+) [3]. The 2026 Franco-Italian cohort generally initiated treatment with PTH above 2 times the ULN [14]. Treatment is based on calcitriol or alfacalcidol, with or without oral calcium, aiming to maintain calcium and phosphate within the normal range without hypercalciuria and reduce PTH as far as serum and urinary calcium permit (A++) [3].

The PTH target has been formulated differently over time, and the difference has clinical significance: suppressed PTH favours hypercalciuria and renal calcification because distal calcium reabsorption is no longer stimulated; excessively high PTH impairs skeletal mineralisation and the growth plate and may progress to tertiary hyperparathyroidism [3, 15]. The serum calcium target is higher than in PTH-deficient hypoparathyroidism, where low-normal is sought [3, 94].

This article adopts the more recent 2020 target and intervals, reporting the others as divergences. Monitoring should be more frequent with symptoms, rapid growth, intercurrent illness, pregnancy, breastfeeding or after a dose change [3, 15]. Calcifediol should be normalised and maintained in all patients (A+++) [3]. Patients and families should learn to recognise signs of hypocalcaemia and hypercalcaemia (A++) [3]. The French PNDS starts treatment with hypocalcaemia or, before it, when PTH reaches about 2 times the ULN [13]. In children, the goal is clinical (absence of symptoms) and biochemical: normal calcium and phosphate and PTH as low as possible, ideally below 2 times the ULN, without hypercalcaemia or hypercalciuria; doses often rise in early childhood, at puberty and in stress situations [13]. In adults, the PNDS aims for normal calcium and PTH at the upper limit of normal, because slightly raised PTH stimulates distal calcium reabsorption, but below 2 times the ULN to protect bone mineralisation; raised bone turnover markers indicate excessive bone stimulation by PTH, and normalising PTH may be difficult, perhaps because of associated resistance of the calcium-sensing receptor [13].

Hypercalciuria and nephrocalcinosis are rare, but consensus experts observed nephrolithiasis in PHP1A and PHP1B, particularly after completion of pubertal growth, when calcium and active vitamin D requirements fall; monitoring urinary calcium, age-appropriate renal imaging with persistent hypercalciuria (B++) and renal imaging at transition to adult care (B+) are therefore recommended [3, 15]. Increased urinary excretion of uric acid and phosphate may add to stone risk [3]. With calcium stones or nephrocalcinosis, the PNDS asks that all risk factors be assessed and corrected: urine volume, urinary calcium, natriuresis, urea excretion, oxaluria, citraturia, urinary pH and early-morning urine osmolality, which reflects the distribution of fluid intake [13].

7.3. Active vitamin D, native vitamin D and calcium

Calcitriol (Rocaltrol® and generics). This is the active vitamin D metabolite and does not depend on renal 1α-hydroxylation, impaired by PTH resistance. In the United States of America (USA), the Food and Drug Administration (FDA)-approved oral calcitriol label expressly includes treatment of hypocalcaemia and its manifestations in postsurgical hypoparathyroidism, idiopathic hypoparathyroidism and PHP; capsules were approved in 1978 and the 1 mcg/mL oral solution in 1998 [95]. The recommended starting dose is 0.25 mcg/day in the morning, increased at 2–4-week intervals if response is unsatisfactory; during titration, serum calcium should be measured at least twice weekly, and the drug discontinued immediately with hypercalcaemia until normocalcaemia [95]. Most adults and children aged 6 or older respond to 0.5–2 mcg/day, with no maximum dose defined in the label; in hypoparathyroidism between 1 and 5 years, 0.25–0.75 mcg/day has been used, but the label states that the number of treated PHP patients under 6 years is too small to recommend a dose and that there is no dosing guidance below 1 year in hypoparathyroidism [95]. The label requires calcium intake of at least 600 mg/day, periodic measurement of calcium, phosphate and 24-hour urinary calcium, monthly serum calcium once the dose is established, a calcium × phosphate product not exceeding 70 mg²/dL² and discontinuation of other pharmacological vitamin D forms [95]. Germain-Lee divides the daily dose into two administrations and prefers oral solution for precise titration or when children cannot swallow capsules [18]. In the United Kingdom, the summary of product characteristics (SmPC) for 0.25 microgram calcitriol capsules lists only renal osteodystrophy and postmenopausal osteoporosis and states that safety and efficacy in children are insufficiently studied; PHP use is therefore off-label in that setting [96]. In the European Union (EU), calcitriol is authorised through national procedures, and the Portuguese SmPC was not among the sources consulted [96].

Alfacalcidol (One-Alpha®). This is a 1α-hydroxylated analogue converted to calcitriol in the liver. The British SmPC for oral drops (2 micrograms/mL; 1 drop = 0.1 microgram), authorised in 2000, includes hypoparathyroidism among indications without naming PHP; the consensus lists it as an alternative to calcitriol [3, 97]. The starting dose is 1 microgram/day in adults and children over 20 kg, 0.5 microgram/day in older people, 0.05 microgram/kg/day in children under 20 kg and 0.05–0.1 microgram/kg/day in newborns and premature infants [97]. Dose is adjusted to response, with initially weekly measurements and increases of 0.25–0.5 microgram; most adults respond to 1–3 micrograms/day and maintenance lies at 0.25–1 microgram/day; with hypercalcaemia, treatment is stopped until calcium normalises (around one week) and restarted at half the dose [97]. In hypoparathyroidism, severe hypocalcaemia is corrected faster with higher doses (3–5 micrograms) combined with calcium [97]. The most frequent adverse effects are hypercalcaemia, hyperphosphataemia, pruritus, rash and gastrointestinal discomfort, and renal failure has been reported [97].

Native vitamin D. The consensus requires normal calcifediol in all patients but gives no dose [3]. The 2025 European Society of Endocrinology (ESE) guideline for adult hypoparathyroidism, applicable by analogy, recommends 800–2000 IU (20–50 µg) daily of native vitamin D to maintain 25-hydroxyvitamin D at or above 75 nmol/L (30 ng/mL) [94]. Bone Dysplasias mentions vitamin D3 as chronic treatment; this reference does not replace active vitamin D in treating PTH resistance [3, 67].

Calcium. In PHP, calcium is adjusted to dietary intake and serum calcium, and can often be reduced from initial doses; Germain-Lee prefers calcium carbonate, taken with meals also to reduce phosphate absorption [2, 3, 18]. The 2017 GeneReviews gives 1–2 g/day or 25–50 mg/kg/day of elemental calcium [2]. ESE 2025 recommends, in non-pregnant adults with hypoparathyroidism, dietary intake of around 800–1000 mg/day of elemental calcium and divided supplements when exceeding 500 mg/day [94]. In the Italian series of pregnant women with PHP, mean calcium carbonate dose was 875 ± 530 mg/day in the first and second trimesters and 1125 ± 177 mg/day in the third [65].

Phosphate. If phosphate remains elevated, dietary phosphate is restricted (dairy products, meat) [2, 18]. Non-calcium phosphate binders are rarely indicated, only in persistent severe hyperphosphataemia (B++) [3]. Thiazides are rarely used, for hypercalciuria [2].

Doses in the French PNDS. In children, maintenance combines alfacalcidol 1–3 µg/day as a single dose or calcitriol 0.5–1.5 µg/day in two doses, native vitamin D (colecalciferol or ergocalciferol) to keep 25-hydroxyvitamin D near 30 ng/mL (between 20 and 60 ng/mL) and, if necessary, calcium according to dietary intake and age [13]. In adults, the mean dose is 0.5–1 µg/day of calcitriol or 1–2 µg/day of alfacalcidol, with 500–1000 mg/day of oral calcium and sufficient dietary intake, and 25-hydroxyvitamin D is kept between 20 and 60 ng/mL [13]. With hyperphosphataemia, dietary phosphorus is limited to 100% of recommended daily intakes [13]. The PNDS paediatric doses are not expressed by weight or age, unlike the British alfacalcidol SmPC (0.05 microgram/kg/day below 20 kg), and the children's calcitriol range (0.5–1.5 µg/day) overlaps that of the American label from 6 years (0.5–2 mcg/day); below 6 years, an age at which the American label sets no dose in PHP, the PNDS is the only specific dose source consulted [13, 95, 97]. Because it is not scaled, the PNDS paediatric range cannot be transposed as it stands to infants and young children: 1 µg/day of alfacalcidol in an 8 kg infant corresponds to about 0.13 microgram/kg/day, more than twice the initial SmPC dose below 20 kg; at these ages, treatment starts with the SmPC weight-based dose, titrated by serum calcium, urinary calcium and PTH up to the PNDS range, if necessary [13, 97]. The PNDS 25-hydroxyvitamin D target (20–60 ng/mL, optimum 30–60 ng/mL) is more permissive at the lower limit than that of the 2025 ESE guideline for adult hypoparathyroidism (30 ng/mL or higher) [13, 94].

7.4. Acute hypocalcaemia

Severe symptomatic hypocalcaemia requires immediate correction, possibly with intravenous calcium, according to acute hypocalcaemia guidelines for hypoparathyroidism, with concomitant initiation of active vitamin D (A+++) [3]. Intravenous calcium gluconate is the usual treatment [67]. For adults, ESE 2025 describes: 90–180 mg elemental calcium, preferably 1–2 calcium gluconate ampoules (1 g calcium gluconate per ampoule), over 10–20 minutes, followed by a slower infusion, for example 10 ampoules (around 900 mg elemental calcium) in 1 litre of 5% dextrose or normal saline at 100 mL/h, with calcium and electrocardiogram monitoring and initiation of oral calcium and active vitamin D (for example calcitriol 0.25 or 0.5 µg twice daily) [94]. The French PNDS defines severe hypocalcaemia in adults as total calcium below 1.8 mmol/L (ionised below 0.9 mmol/L), clinical symptoms or electrocardiographic abnormalities, and refers intravenous calcium, in children and adults, to each centre's protocols [13]. In asymptomatic hypocalcaemia, with calcium below normal but above 1.8 mmol/L, the PNDS accepts oral treatment: in children, alfacalcidol 1–4 µg/day, oral calcium 40–60 mg/kg/day and native vitamin D; in adults, alfacalcidol usually 1–3 µg/day and oral calcium 1–2 g/day in divided doses [13]. Neither the PNDS nor the consensus gives the paediatric intravenous calcium dose; as a comparison, extrapolated from the general indication of acute symptomatic hypocalcaemia, the American label for calcium gluconate injection (100 mg/mL, with 9.3 mg elemental calcium per mL) recommends, between 1 month and 17 years, boluses of 29–60 mg/kg of calcium gluconate, repeatable every 6 hours, or a continuous infusion started at 8–13 mg/kg/hour; in newborns, boluses of 100–200 mg/kg or an infusion started at 17–33 mg/kg/hour; in adults, 1000–2000 mg [98]. The bolus is diluted and must not exceed 100 mg/minute in children and 200 mg/minute in adults, through a secure intravenous line, with electrocardiogram and serum calcium every 4–6 hours for intermittent administration and every 1–4 hours during infusion; label doses are expressed as calcium gluconate and not as elemental calcium, and the final decision follows the institution's paediatric protocol, as the PNDS requires [13, 98]. In a Turkish series, 34.8% of symptomatic children with hypoparathyroidism or iPPSD required intravenous calcium at diagnosis [88].

7.5. Recombinant PTH and analogues

The consensus recommends not treating PHP with PTH or PTH analogues (A++), because patients are resistant to the hormone [2, 3]. The recommendation covers teriparatide, PTH(1-84) and palopegteriparatide, whose indication is hypoparathyroidism [3]. ESE 2025 recommends PTH replacement in refractory hypoparathyroidism, but that recommendation does not apply to PHP [94].

7.6. Thyroid

Thyroid function, with autoantibodies in adolescents and adults, should be assessed at diagnosis in all patients; thereafter TSH is measured every 6 months below 5 years and annually in older children and adults (A++) [3]. The indication, levothyroxine dose and targets are those for any hypothyroidism or subclinical hypothyroidism (A++); PHP sources give no specific doses [3]. Germain-Lee treats for normal TSH and free T4 and monitors thyroid function around every 3 months in growing children, a shorter interval than the consensus [18]. As some patients have TRH resistance with central hypothyroidism, free T4 should be measured with TSH [71]. Levothyroxine requirements increase in early pregnancy [2]. The PNDS adds screening for autoimmune thyroid disease during follow-up, given its prevalence, and, in pregnant women with TSH resistance, monthly free T4 and TSH, with levothyroxine adjusted to keep free T4 in the upper half of the reference range [13].

7.7. Growth and growth hormone

Height should be measured at every consultation, at least every 6 months, until final height (A+++) [3]. Skeletal maturation is assessed radiographically in all children except PHP1B, and the GH–IGF-1 axis is assessed clinically and biochemically in all, typically between 3 and 6 years, repeating if necessary (B++) [3, 15]. Germain-Lee recommends testing all patients with PHP1A from 3 years, even if not short, because short stature develops only near adolescence [18]. The PNDS recommends growth surveillance about every 6 months until adult height, somatotrophic assessment (IGF-1 and stimulation test) from 3–6 years and an annual radiograph of skeletal maturation; because bone age is not readable with brachydactyly, maturation is assessed mainly by comparison with the previous examination [13].

Confirmed GH deficiency should be treated with somatropin (A++), and children with PHP born SGA without catch-up growth may qualify for treatment, with caution regarding ectopic ossifications (B++) [3]. In adults with GH deficiency, benefit has not been demonstrated and treatment follows national rules (B++) [3]. The PNDS accepts GH in GH deficiency and in intrauterine growth restriction without catch-up, with the dose adjusted to clinical efficacy because of the chondrodysplasia, and refers other situations to a decision by the reference centre network at a multidisciplinary meeting; in adults, the decision follows national regulations [13]. Efficacy evidence comes from small studies. In 8 prepubertal children with PHP1A and GH deficiency (7 girls and 1 boy, 5.8–12 years), height standard deviation score (SDS) increased from −2.4 ± 0.58 to −1.8 ± 0.47 at 12 months and −1.15 ± 0.6 in the third year, and growth velocity from 3.5 ± 0.6 to 7.0 ± 0.9 cm/year, with a response similar to 9 controls with idiopathic deficiency [99]. GeneReviews reported that GH increased growth velocity without improving final height in small series, attributing failure to partial PTHrP resistance in the growth plate [2]. Germain-Lee reports preliminary results from study NCT00209235 with increased final adult height relative to untreated adults with PHP1A and GH deficiency, presented at a conference and unpublished [18]. A 2025 Chinese series described improved height and growth velocity in 3 treated children with PHP1A [87]. In acrodysostosis, a multicentre retrospective cohort of 20 patients with iPPSD4 and 17 with iPPSD5 found median final height of −2.8 SDS in 5 treated patients with iPPSD4 and −3.9 SDS in 4 untreated patients; GH initiation was relatively late and the sample does not permit firm conclusions [100].

The dose used by Germain-Lee in PHP1A with GH deficiency is 0.3 mg/kg/week, divided into daily doses, with glucose, free T4 and IGF-1 monitoring, and growth and IGF-1 every 3–4 months; SGA or very small children typically receive higher doses, with no maximum dose defined in the source; the maxima are those of the approved indications (section 7.13) [18]. Consensus experts suggest, in prenatal growth restriction, higher doses than in idiopathic deficiency, such as SGA doses, in an unpublished opinion [3]. Label doses are in the regulatory table (section 7.13): PHP is not a labelled somatropin indication, and it is used within approved indications (GH deficiency, SGA, idiopathic short stature in the USA) [101, 102]. Before starting GH, children with moderate or severe obesity or who snore should undergo otorhinolaryngological assessment and polysomnography because of the risk of worsening OSAS through adenotonsillar hypertrophy [18]. Sources differ on ossifications: GeneReviews states that they may increase with GH, Germain-Lee did not observe this effect and the consensus states that there are no data, recommending documentation of plaque progression during GH [2, 3, 18].

Puberty blockers have been proposed to delay epiphyseal closure. The 2018 consensus cited a girl treated with a GnRH analogue who had a growth advantage relative to her sister, but the 2020 update concludes that evidence is insufficient regarding efficacy and safety for increasing final height [3, 15].

7.8. Puberty, gonads and fertility

Tanner stage should be assessed at regular intervals (A+++), testicular descent checked from infancy and cryptorchidism corrected according to usual recommendations (A++) [3]. Routine gonadal biochemical assessment is not recommended except with delayed puberty, oligomenorrhoea or amenorrhoea, or hypogonadism symptoms in men; hypogonadism is treated with sex hormones according to usual criteria and doses (B++ to B+++) [3]. Germain-Lee observed that oestrogens are often necessary in women with PHP1A and draws attention to deep vein thrombosis risk (personal observation) [18]. Infertility is referred for medically assisted reproduction according to national guidelines (A+) [3].

7.9. Obesity, metabolism and sleep

Obesity is the most difficult problem to treat [2]. The consensus recommends early monitoring of BMI and eating behaviour and offering educational programmes and psychological support, even with normal BMI, as prevention, and dietary counselling accounting for reduced resting energy expenditure (A++) [3, 15]. Tamaroff and Shoemaker propose fixed mealtimes and controlled portions from diagnosis, since hyperphagia begins early but does not lead to disruptive food-seeking behaviours [73]. Diet and exercise help but are difficult to maintain, and exercise should follow a sustainable pace [18]. Pharmacological or surgical treatments are described only in isolated cases: a PHP1C patient treated with a cannabinoid CB1 receptor antagonist and a PHP1A patient undergoing gastric bypass [3]. GLP-1 receptor agonists and setmelanotide are described in section 7.15. The French PNDS insists on prevention: with an early diagnosis, especially in iPPSD2, feeding should be structured from the first months, with a dietitian and a physician experienced in syndromic obesities, regular quantification of intake, control of access to food and advice that takes reduced resting energy expenditure into account; intervention begins as soon as BMI acceleration is observed and, with established obesity, relies on a network (dietitian, psychologist, physician, physical educator) and on support for the whole family [13]. The PNDS does not consider iPPSD2 obesity a good indication for bariatric surgery, because malabsorptive techniques may unbalance calcium–phosphate metabolism; the supporting argument draws on series of hypocalcaemia after bariatric surgery (3.6% of 999 patients) and after thyroidectomy in patients with previous bariatric surgery (40% of 48, 60% after bypass) [13]. Gastro-oesophageal reflux in the first months, favoured by obesity, is treated by the usual means with dietary measures, and constipation may require prolonged oral laxatives [13].

Glucose and lipids should be measured regularly (B++), as should blood pressure, at least once yearly from 2 years with an appropriately sized cuff, treating hypertension (B++) [3, 15]. Restless sleep, snoring, inattention and daytime sleepiness should be assessed regularly and, if present, justify polysomnography (B++) [3]. Asthma and bronchial hyperreactivity warrant assessment [18]. The PNDS recommends early screening for OSAS by respiratory polygraphy in children and offering non-invasive ventilation if present; in adults, it asks at every consultation about unrefreshing sleep, snoring, daytime sleepiness and attention deficit, with polysomnography if necessary, and screens regularly for type 2 diabetes and hypertension, because insulin sensitivity is reduced in iPPSD2 independently of BMI [13].

7.10. Ectopic ossifications and progressive osseous heteroplasia

There is no effective treatment preventing or reversing ossifications [3]. The consensus recommends examining skin plaques at every consultation in all patients with a GNAS alteration, particularly paternal, teaching self-examination and documenting location, size, joint involvement, movement restriction, relationship to weight-bearing areas, triggering events, puberty and GH treatment (A++) [3]. Regular imaging is not indicated; CT or magnetic resonance imaging (MRI) is reserved for painful, symptomatic lesions impairing joint or organ function, or before surgery (A++) [3]. Biopsy may be performed when diagnosis is doubtful and FOP has been excluded (B++) [3].

Physiotherapy and meticulous skin care are the most important measures (B+) [3]. Surgical excision by an experienced surgeon is reserved for well-demarcated superficial lesions causing pain or limitation; it gives good results in osteoma cutis and superficial PPHP and PHP1A lesions, but POH lesions are rarely demarcated and recurrence and complications are frequent [2, 3]. Germain-Lee advises against removal except with joint limitation, severe pain or interference with daily activities, because regrowth may be worse [18]. Plaster immobilisation near joints should be avoided because of ankylosis risk (B+) [3]. In severe POH, functional repositioning of a joint and amputations for severe growth impairment, ankylosis or recurrent ulcer infection have been described [3, 32].

There is no evidence supporting non-steroidal anti-inflammatory drugs (NSAIDs), bisphosphonates or corticosteroids in primary or perioperative treatment of asymptomatic ossifications (B+) [3]. Bisphosphonate data are limited to reports: pamidronate in one patient with POH, apparently delaying new bone formation, etidronate with apparent benefit in a patient with a POH-like phenotype and without improvement in another, and a conference abstract on bisphosphonates in PHP [3]. Germain-Lee has not observed long-term success with NSAIDs or bisphosphonates [18]. Topical sodium thiosulfate was used in a 2026 paediatric case (section 7.15). Hedgehog pathway inhibitors and retinoic acid receptor γ agonists, such as palovarotene approved for FOP, are candidates only in preclinical research for POH; no registered clinical trial with these drugs in POH was found [3, 76]. The French PNDS restricts surgery to localised ossifications with functional impact, such as a well-circumscribed ossification of the heel, discussed case by case because of the risk of complications and local recurrence, and reports that topical sodium thiosulfate sometimes has a favourable effect on superficial ossifications, with no studies quantifying the benefit [13]. The French trial NCT03582800 (phase 2, sponsor CHU de Limoges, recruiting since January 2020, 40 patients estimated, estimated completion June 2029) is testing local subcutaneous sodium thiosulfate in iPPSD2 ossifications with significant morbidity, from 2 years of age, by infusion with a portable pump for 6 months after 6 months of observation, with the primary outcome being the change in lesion volume on CT; it has no published results [13, 76].

7.11. Skeleton, teeth, ear and neurodevelopment

Severe brachydactyly impairs fine motor skills and writing; the consensus recommends formal fine motor assessment, early occupational therapy and orthopaedic devices, such as special footwear and insoles (A++) [3]. Additional radiology is justified only with suspected orthopaedic malformation or functional impairment, particularly with neurological signs (A++) [3]. Spinal stenosis, bilateral slipped upper femoral epiphyses, temporomandibular ankylosis, early scoliosis, Chiari type 1 malformation and craniosynostosis require multidisciplinary assessment (A++) [3]. In acrodysostosis, lumbar or cervical decompressive laminectomy may be necessary [26, 33]. Carpal tunnel syndrome is treated as in the general population [18]. The PNDS includes head circumference, fundoscopy and, depending on the clinical picture, brain MRI or 3D cranial CT for craniosynostosis in follow-up; symptomatic craniocerebral disproportion is treated surgically [13]. Cases of papilloedema with diplopia, blurred vision and headache have been described, requiring imaging investigation and, depending on the cause, medical treatment with acetazolamide or craniocerebral decompression [13].

Dental reviews occur every 6–12 months in childhood and according to clinical findings in adults (A++); Germain-Lee proposes six-monthly consultations and notes a frequent need for orthodontics [3, 18]. Recurrent otitis and adenotonsillar hypertrophy often lead to tympanostomy tubes and otorhinolaryngological surgery [3, 18]. Ophthalmological examination for cataracts should be systematic and regular, and brain CT reserved for patients with neurological manifestations (A++) [3, 15]. The PNDS adds an orthodontic examination at 6 years, because of the risk of skeletal base disharmony and eruption disorders, and asks for an audiogram whenever hearing loss is suspected and before insertion of tympanostomy tubes, with referral for hearing aids when indicated [13].

Neuropsychological assessment should occur at diagnosis or preschool age, particularly in PHP1A and PDE4D-related acrodysostosis (A++); most patients with PHP1A will need specialist educational support and occupational, physical and speech therapies [3, 15, 18]. ADHD and anxiety are treated through usual approaches [18]. At school age a classroom assistant and educational support may be needed, and attention or psychiatric disorders are followed by paediatric neurology or child psychiatry; in adults, neuropsychological assessment and psychological support remain useful [13].

7.12. Particular features of acrodysostoses and paternal forms

In acrodysostosis, treatment is symptomatic (otitis, speech delay, intellectual disability, spinal stenosis), hormone resistance should be sought and treated, and GH appears to have a favourable growth impact, with the limitations described [26, 33, 100]. No PDE4 inhibitor (roflumilast, apremilast, crisaborole) has an acrodysostosis indication, and their labels do not mention it [55]. In forms due to a paternal GNAS variant (PPHP, POH) and PDE4D-related acrodysostosis, PTH, calcium and phosphate need measurement only at diagnosis because these patients generally do not develop PTH resistance [3]; the 2020 update nevertheless notes that some patients with PPHP develop mild hormone resistance [15]. In PPHP and POH with short stature and SGA birth, GH may be used if approved indication criteria are met [18].

Individual reports on growth hormone show benefits and risks. An 8-year-old child with acrodysostosis type 1, height −3.46 SD and IGF-1 at the lower limit of normal started somatropin at 0.35 mg/kg/week, with increased growth velocity, but after 7 months right knee pain and Legg-Calvé-Perthes disease of the right hip appeared; GH was discontinued, the femoral head collapsed over the following 6 weeks and stabilised after 8 months of conservative treatment, and adult height was 128 cm [83]. The authors suggest that this risk be included in counselling before GH in acrodysostosis type 1, because it has not been described in GH-treated PHP1A [83]. In a Greek boy aged 3 years and 9 months with acrodysostosis type 1, height −2.92 SD, growth velocity 3 cm/year, GH peaks of 8 and 5.5 ng/mL in two stimulation tests and mild hypoplasia of the anterior pituitary, somatropin raised height from −2.92 to −1.52 SD in 18 months, with 11 cm in the first year, IGF-1 within the reference range and bone age advancing from 2 years and 8 months to 4 years and 6 months, without adverse effects [103]. These reports do not replace the consensus criterion: GH is used in the approved indications (GH deficiency or SGA birth without catch-up), at the dose for the indication [3, 100]. Suspected spinal cord compression (weakness, gait changes, sensory loss, sphincter disturbances) requires magnetic resonance imaging and neurosurgical assessment, because late decompression leaves sequelae [86].

Mechanism-directed approaches are at the preclinical stage. In the p.Arg368Ter knock-in mouse, an adeno-associated viral vector of serotype 9 carrying human PRKAR1A, given intravenously at 4 weeks of age, restored the architecture of growth plate chondrocytes, improved body length, tail length and weight, with no effect on limb bone length, and almost completely normalised urinary cAMP [104]. In acrodysostosis type 2, the PDE4D hyperactivation hypothesis suggests the selection of specific PDE4 inhibitors, with no studies in patients up to the date of the review; the 2026 review on type 1 proposes strategies that restore the local dynamics of cAMP–PKA signalling rather than amplifying the pathway globally [52, 60].

7.13. Comparative regulatory status

The search performed for this article found no authorisation, authorisation application or opinion from the FDA or European Medicines Agency (EMA) specific to PHP or iPPSD up to 10 October 2026; absence of results does not prove that no processes are ongoing. National access in Portugal (INFARMED) and Brazil (ANVISA) was not documented in the sources consulted.

7.14. Clinical trials and interventional studies

The design of the theophylline trials, presented in 2023, planned 34 patients with PHP1A and obesity from 2 years, enrolment in age blocks with review by a safety monitoring committee, 2:1 randomisation and a target serum theophylline level of 10–19 mcg/mL, with simulated doses in the placebo group; by June 2023, 24 patients had been enrolled (4–55 years, 92% women), 3 adults withdrew (headache, nausea or difficulty swallowing, relocation) and the most common adverse event was transient nausea or vomiting [107]. By 10 October 2026 no efficacy results had been published; absence of publication does not equate to a negative result.

These studies have limitations precluding comparisons. They are small, GH studies lack a randomised control group, final height depends on initiation timing and the indication used, and comparison between treated and untreated patients is subject to indication bias [99, 100]. The only controlled theophylline study published in the registry (NCT02463409) was negative or inconclusive, with 6 patients and 24-hour exposure [76]. Indirect comparison of GH results in PHP1A with acrodysostosis is not legitimate because populations, doses and initiation ages differ.

7.15. Developments in the last twelve months and research

Therapeutic developments between October 2025 and October 2026 have a low level of evidence and none has changed recommendations. Diagnostically, the most relevant publication is the proposed criteria for children under 2 years (a retrospective two-centre study, October 2026), described in section 5.3 [14]. ESE published the revised guideline for chronic adult hypoparathyroidism in November 2025, replacing the 2015 guideline cited by the PHP consensus; it applies to PHP only by analogy, for acute hypocalcaemia, native vitamin D and pregnancy [94].

At the molecular level (genetic and experimental studies), exon H variants and the 140 kb inversion explained families with AD-PHP1B without an STX16 deletion, and a preprint proposed GNAS promoter region deletions in PHP1C [37, 38, 40, 42].

Therapeutically, there are three fronts. The first is the melanocortin pathway, identified as a rational target by animal models and the Mendes de Oliveira study [3, 89]. Trial NCT07496463, started in July 2026, tests setmelanotide in a single patient with PHP1A and obesity (human study, no results); the protocol dose is absent from the registry consulted [76]. An abstract presented at the 2025 joint European endocrinology congress described two patients treated with GLP-1 receptor agonists (case series, doses not reported): a patient with PHP1B and BMI of 47.6 kg/m² at 21 years, without a prior metformin response, lost 14 kg (around 11%) over 23 months with liraglutide and then semaglutide; a 13-year-old patient with PHP1A, obesity since 4 months and BMI of 32 kg/m² reduced BMI to 29.6 over 8 months with liraglutide, with improved satiety, and regained weight after self-discontinuation; adverse effects were initial nausea and reduced appetite [105]. The second front is the theophylline trials, without efficacy results (section 7.14). The third is topical sodium thiosulfate: in a 3-year-old boy with PHP1A, a compounded 25% cream applied once daily to atrophic macules considered precursors of osteoma cutis was well tolerated and there was no progression at 6 months; application was diffuse, without comparator lesions, and follow-up is short for progression that may take up to around a year (case report, experimental off-label use) [106]. The 91.7% response cited by the authors refers to paediatric ectopic calcifications, which are not ossification [106].

Multicentre registries are active in France (RaDiCo-IDMet, imprinting disorders, 2017–2028) and Italy (F.I.R.M.O. hypoparathyroidism and PHP database, 2024–2034), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) maintains a natural history study of parathyroid disorders; there are also hypoparathyroidism registries in Germany and Tunisia and a completed study in Lyon on circulating autotaxin in GNAS and PTH disorders [76]. The consensus identified research priorities as optimal calcium, phosphate and PTH levels, GH and puberty blocker indications and timing, obesity mechanisms, trials of postsurgical bisphosphonates and candidates such as Hedgehog pathway inhibitors and palovarotene, and quality of life [3].

7.16. Agents and practices to avoid

PTH and its analogues should not be used [3]. During calcitriol treatment, other pharmacological vitamin D forms are discontinued, and the calcium × phosphate product should not exceed 70 mg²/dL² [95]. PTH suppression through excessive active vitamin D and calcium favours hypercalciuria and nephrocalcinosis [3]. Plaster immobilisation near joints with ossifications and excision of poorly demarcated lesions should be avoided [3]. Biopsy of deep ossifications is contraindicated until FOP is excluded [3]. Gonadotrophin-releasing hormone agonists should not be initiated because advanced hand bone age is interpreted as precocious puberty, without appropriate assessment [18]. Dietary phosphate restriction applies only when phosphate remains elevated [2].

7.17. Pregnancy and lactation

Uncomplicated spontaneous and assisted pregnancies have been described in PHP1A and AD-PHP1B, and are more frequent in women with PPHP, who give birth to children with PHP1A; men with PHP1A have also fathered children [3, 15]. Pregnancy is monitored like any other, but active vitamin D and levothyroxine doses may need adjustment (A+) [3]. The consensus refers management of hypocalcaemia and hypothyroidism during pregnancy to the respective guidelines (B++) [3]. In 2018, vaginal delivery “may be limited” by a small pelvis and reduced hip mobility due to ossifications; in 2020 this became “may be contraindicated” [3, 15].

Calcium metabolism during pregnancy is unpredictable in PHP. GeneReviews states that thyroid hormone requirements increase in early pregnancy and active vitamin D requirements may decrease in the third trimester [2]. In a Beijing series of 5 women and 6 pregnancies, the course was stable in one, improved in another (with dose reduction) and worsened in two pregnancies in the same patient, with falling calcium and increasing doses despite 1200 mg/day elemental calcium; PTH remained low in the first two trimesters in stable pregnancies and rose in those worsening, suggesting it may predict the course [80]. The review of published cases in that series associated improvement with calcium supplementation above 1 g/day, low PTH and serum calcitriol 2–4 times prepregnancy levels through placental production, and worsening with calcium below 0.5 g/day [80]. All women in the series had caesarean sections, one at 41 weeks because of reduced hip mobility [80]. In the Italian series, the 3 pregnant women with PHP maintained corrected calcium between 9.1 and 9.3 mg/dL, with increasing calcium carbonate doses, all delivered at term, and 2 of the 3 had previous miscarriages [65].

ESE 2025, applied by analogy, recommends measuring ionised or albumin-adjusted calcium every 3–4 weeks during pregnancy and lactation and weekly in the 4 weeks before and after delivery, informing the paediatrician and reducing active vitamin D and calcium immediately after delivery because late-pregnancy and lactation PTHrP may cause hypercalcaemia; that guideline's calcium target (lower limit of normal) is for hypoparathyroidism rather than PHP [3, 94]. The newborn should be assessed for cutaneous ossifications, TSH, calcium and phosphate [15]. In the Italian series, one newborn of a mother with PHP had transient hypocalcaemia and another, with the maternal variant, respiratory distress with pulmonary hypertension [65].

The French PNDS asks for surveillance by a multidisciplinary team, in addition to the usual care, because of the hormone resistances, the pelvis, the ossifications and the risk of transmission, and notes that maternal hypocalcaemia is associated with miscarriage, preterm birth, perinatal mortality and fetal and neonatal hyperparathyroidism, whereas hypercalcaemia may arise in the third trimester, when the fetus mineralises 25–30 g of calcium and 1,25-dihydroxyvitamin D rises through placental synthesis, under the effect of placental and mammary PTHrP and prolactin [13]. In a mother with PTH resistance, albumin-corrected total calcium or ionised calcium is measured monthly, with active vitamin D and calcium adjusted to avoid both hypocalcaemia and hypercalcaemia; the 2025 ESE guideline, by analogy, asks for shorter intervals (3–4 weeks and weekly around delivery) [13, 94]. When the fetus may have inherited a paternal GNAS variant or a PRKAR1A or PDE4D variant, intrauterine growth restriction is frequent, so ultrasound surveillance is adapted to the clinical picture and fundal height and a growth scan is added at 28 weeks; scanopelvimetry helps decide the mode of delivery according to maternal skeletal involvement, and with severe growth restriction the timing and mode of delivery are decided case by case [13]. At birth, because of the risk of iPPSD2 transmission, calcium and thyroid function are measured in cord blood and the newborn is monitored in the postnatal period; newborn screening for hypothyroidism may be positive [13].

Regarding drugs, the American calcitriol label states teratogenicity in rabbits, absence of adequate studies in pregnant women and use only if benefit justifies risk [95]. The British alfacalcidol SmPC does not recommend it in pregnancy or women of childbearing age without contraception because of limited data, creating tension with the clinical needs of pregnant women with PHP [97]. Sources differ on breastfeeding: the American calcitriol label states that the mother should not breastfeed; the British calcitriol SmPC allows breastfeeding with maternal and infant calcium monitoring; the PHP consensus considers lactation not contraindicated, with close monitoring of the baby, particularly weight [3, 95, 96]. This article follows the consensus and British SmPC, with infant monitoring, and records the American label divergence. Lactation alters requirements variably: GeneReviews and ESE report reduced active vitamin D requirements, whereas in the Beijing series two breastfeeding women had falling calcium or rising PTH and two non-breastfeeding women improved (in one, calcitriol fell from 1 µg/day to 0.25 µg/day at 3 months postpartum) [2, 80, 94]. Requirements should be reassessed during lactation and after weaning [2].

7.18. Perioperative context and anaesthesia

The sources consulted include no specific anaesthetic recommendations for PHP or acrodysostoses. Identifiable risks derive from the manifestations described: hypocalcaemia with QT prolongation and laryngospasm, OSAS in 60% of children with PHP1A, obesity, hypothyroidism, bronchial hyperreactivity, midface hypoplasia and, in acrodysostoses, cervical and lumbar spinal stenosis [2, 18, 26]. In the case in section 10, the child had apnoea and desaturation episodes attributed to laryngospasm from upper airway obstruction [64]. Serum calcium, thyroid function and assessment for OSAS should be evaluated before any elective surgery, and calcium monitored postoperatively and during intercurrent illnesses, which increase monitoring requirements [15]. Ossification surgery should be performed by an experienced surgeon, without prophylactic NSAIDs, bisphosphonates or corticosteroids, and avoiding casts near joints [3].

7.19. Transition to adulthood

The consensus recommends timely transition from paediatric to adult care, preferably at referral centres, with renal imaging for nephrocalcinosis at that stage (B+) [3, 15]. Germain-Lee emphasises continuity with a specialist familiar with the disease and describes the difficulties many adults with PHP1A have with independent living and maintaining employment, requiring support with disability and insurance [18]. After pubertal growth, calcium and active vitamin D requirements may decrease, necessitating adjustment to avoid hypercalciuria and stones [3]. In adulthood, surveillance of calcium–phosphate and thyroid metabolism, renal function, fertility and sexual function, metabolism and blood pressure continues [15].

7.20. Divergences between sources and guidelines

Sources differ on seven points with practical consequences. The PTH target changed from “upper limit of normal or slightly above” (GeneReviews 2017) and “upper portion of the range” (2018 consensus) to “between the midpoint of normal and 2 times the ULN” (2020) [2, 3, 15]. The biochemical monitoring interval in children changed from 6 months (2018) to 3–6 months (2020), and Germain-Lee proposes 3 months in early childhood [3, 15, 18]. Breastfeeding is contraindicated in the American calcitriol label and permitted by the consensus and British SmPC [3, 95, 96]. Calcitriol has a labelled PHP indication in the USA but not in the British SmPC [95, 96]. The effect of GH on ossifications is described as worsening by GeneReviews, neutral by Germain-Lee and unknown by the consensus [2, 3, 18]. ESE recommends PTH in refractory hypoparathyroidism and a low-normal calcium target, which does not apply to PHP [3, 94]. The 2018 message on hypertension was attenuated in 2020 [15].

The 2022 French PNDS adds further divergences. It proposes the NGS panel as the first test with any major criterion, instead of the consensus algorithm centred on AHO, and estimates the proportion of patients without a molecular diagnosis at about 30%, compared with 10–20% in the 2020 update [3, 13, 15]. It considers calcitonin a diagnostic aid and the Ellsworth–Howard test useful in ambiguous cases, whereas the consensus does not recommend routine calcitonin and reserves the test for research [3, 13, 15]. It considers brain CT frequently indicated and recommends annual renal ultrasound and an annual radiograph of skeletal maturation, whereas the consensus limits CT to neurological manifestations and renal imaging to persistent hypercalciuria and transition [3, 13]. In children, it aims for PTH as low as possible below 2 times the ULN, without the lower limit at the midpoint of the range set in 2020, and gives active vitamin D doses not scaled by weight, unlike the British alfacalcidol SmPC [13, 15, 97]. It accepts 25-hydroxyvitamin D from 20 ng/mL, below the 30 ng/mL of the ESE, and measures calcium monthly in pregnancy, a longer interval than that of the ESE applied by analogy [13, 94]. It maintains that hypertension is frequent in young adults, whereas the 2020 update toned down that message [13, 15]. It reports worsening of ossifications through local trauma and surgery, which the consensus considers to lack formal evidence, and advises against bariatric surgery, which the consensus mentions only in an isolated case [3, 13]. It gives PTH resistance in about 65% of iPPSD4 and 15–20% of iPPSD5, compared with 100% and 29% in the consensus table and 11 of 11 and 1 of 5 in the 2026 cohort [3, 13, 14]. For doses, the French guideline is the reference and the labels are the comparison; the PNDS paediatric calcitriol range and that of the American label overlap from 6 years [13, 95].

8. Reproductive Options and Family Counselling

8.1. GNAS variants (iPPSD2)

Inheritance is autosomal dominant and the phenotype depends on the parental origin of the altered allele [2]. Each child of a carrier has a 50% probability of inheriting the variant; if inherited from the mother, the child will have PHP1A (or the phenotype formerly designated PHP1C), and if inherited from the father, PPHP, osteoma cutis or POH [3, 15]. Parental severity does not predict severity in the child because intra- and interfamilial variability with the same variant is considerable and imprinting changes the phenotype in each generation [3]. The same family may include patients with PHP1A and PPHP; Smith's states that the two forms never coexist in the same sibship, following the imprinting model (all affected children of a carrier mother will have the maternal phenotype), but Bone Dysplasias illustrates a sibship with children labelled PHP and PPHP, where the “PPHP” child may have PHP1A with resistance not yet manifest [2, 17, 67]. The French PNDS aligns with Smith's (the two forms coexist in the family, never in the same sibship) and reports an excess of maternal transmission of GNAS variants [13]. In a series cited by GeneReviews, 38% of patients had an affected parent, 38% a de novo variant and around 25% an unknown cause [2].

Source: GeneReviews, tables 3 and 4 [2]. Maternal germline mosaicism is documented: a four-amino-acid insertion was transmitted to two siblings by an unaffected mother, and a 30 kb deletion was inherited from a mosaic mother [2]. Two or more affected children of unaffected parents indicate germline mosaicism [17]. A parent with somatic mosaicism may have minimal features, and family history may appear negative because features are unrecognised [2]. In apparently de novo cases, GeneReviews notes non-medical explanations, such as paternity or maternity differing from that stated or undisclosed adoption [2].

8.2. Methylation defects (iPPSD3)

Counselling in PHP1B depends on the mechanism [3].

Source: 2018 consensus, table 3, with percentages from Elli and colleagues' Italian and European cohort [3]. A woman who inherited an STX16 deletion from her father is healthy, but each child inheriting it from her will have the deletion on the maternal allele and be affected; this is how a child with PHP1B inherited the deletion from an asymptomatic mother [2, 3]. Transmission from carrier mothers is more frequent than expected: in a study cited by GeneGuidance, 63.2% of 212 children of STX16 deletion carriers inherited the altered allele [41]. Without a genetic alteration underlying the methylation defect, recurrence risk is similar to population risk [3, 15]. According to the PNDS, about 20% of sporadic broad methylation defects result from UPD(20q)pat, with a very low recurrence risk; in the consensus reference cohort, UPD(20q)pat accounted for 2.7% of all patients, close to 7% of broad methylation defects, a difference that reflects different cohorts and methods [3, 13].

8.3. Acrodysostoses (iPPSD4 and iPPSD5)

Most PRKAR1A and PDE4D variants arise de novo, and recurrence risk for siblings is close to population risk, with the caveat of parental mosaicism; an affected patient transmits the variant to 50% of children, regardless of sex, and there is no parent-of-origin effect [3, 15]. Familial transmissions have been described, such as a two-generation family in Bone Dysplasias and a father with subtle features in Lynch's series [26, 56]. The consensus grades these recommendations as A++ and those for GNAS as B++ [3].

8.4. Cascade testing and carrier follow-up

The consensus recommends testing parents whenever an alteration is identified (A++) and allows predictive testing in relatives, excluding or mentioning parental mosaicism [3]. Apparently asymptomatic first-degree relatives should undergo molecular testing if the mechanism is known; if not, physical examination and regular PTH, calcium and phosphate measurements [2]. Children of women with STX16 deletions can be identified at birth and followed, initiating calcium and calcitriol when PTH rises, before hypocalcaemia; in Kiuchi's study, the deletion was identified in 25 of 44 children of affected or carrier women [81]. In France, the PNDS frames the information of at-risk relatives within the order (arrêté) of 27 May 2013 on good practice in the examination of genetic characteristics: information is given by the patient or by a physician, and the study of relatives includes clinical examination, calcium–phosphate and thyroid assessment and genetic analysis, which guide management and the branch of the family to be studied [13].

8.5. Prenatal and preimplantation diagnosis and reproductive options

When the mechanism is identified, prenatal diagnosis and PGD are possible [2]. The consensus asks that ethical and legal issues be discussed because the phenotype of a fetus carrying a GNAS variant depends on the transmitting parent's sex and its severity is unpredictable, and advises against prenatal diagnosis by methylation analysis [3]. Options for a couple include conception without testing, prenatal diagnosis and PGD, discussed with genetic counselling before pregnancy; GeneReviews recommends offering this counselling to affected young adults or those at risk [2]. In affected women, pregnancy adds maternal hypocalcaemia risk and possible limitation of vaginal delivery (section 7.17) [15]. The PNDS accepts discussion of PGD in the most severe forms, after consultation between the calcium and phosphate reference centre and an assisted reproduction centre, and requires genetic counselling adapted to the molecular diagnosis for any pregnancy plan [13].

8.6. Counselling minors

Molecular diagnosis of a symptomatic child is part of clinical care. Testing asymptomatic children at risk is justified when it changes surveillance: in PHP1A and AD-PHP1B, early detection enables monitoring of TSH, calcium and PTH and treatment before symptomatic hypocalcaemia [14, 81]. Counselling on reproductive risk and the parent-of-origin effect should be offered to affected young adults or those at risk [2].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

GeneReviews cited 0.79/100 000 for PHP and AHO, according to Orphanet in 2008 [2]. These figures measure different things: Japanese hospital surveys count patients known to services, Polish data count diagnostic codes, and published POH and acrodysostosis cases are not prevalences. The Japanese increase between 2000 and 2017 cannot be read as increasing incidence because the surveys differ in method [10]. The American 1/20 000 estimate has no published basis and should not be used as prevalence [18]. PPHP prevalence is even harder to estimate because of overlap with PHP1A and underdiagnosis [3, 18]. For PHP1A, PHP1B, PHP1C and PPHP subtypes, Orphanet records unknown prevalence [5, 108–110]. The 2022 French PNDS adopts the range of 0.34 to 1.1/100 000 from the Japanese and Danish studies [13]. The relative distribution of subtypes in a European series of 407 patients from the EuroPHP network (France, Italy and Spain), cited in the PNDS supporting argument, was 48% PHP1A, 46% PHP1B, 4% PPHP and 2% POH; these are patients tested in reference laboratories and not a population sample [13].

9.2. Sex, ancestry and populations studied

No founder effect is described in the sources consulted, and most GNAS variants are private [39]. The 3 kb STX16 deletion is recurrent, but occurs in unrelated families through a mechanism mediated by direct repeats rather than common ancestry [24]. The excess of affected women, reported by Bone Dysplasias without a denominator, appears in cohorts as 67 women to 50 men (Milan and Paris) and 92% women in the theophylline trial, whereas ossifications are more severe in men [14, 66, 67, 107]. The Beijing Chinese cohort had more men (58 to 34) [72]. In the acrodysostoses, genotyped series are small and come from Europe (16 patients from France, Germany, Spain, Italy, Belgium and Greece in Linglart's series; 7 in Muhn's German series), Japan (15 iPPSD patients, 8 with acrodysostosis) and China (6 children), with no founder variant described; the PRKAR1A variant p.(Arg368Ter) is recurrent across all origins [47, 48, 84, 85]. Growth and clinical course data come from cohorts in Italy and France, the USA, China, Turkey, Japan and Korea, and patients in the American theophylline trial were all of European ancestry, limiting generalisation [10, 14, 64, 71–73, 107]. The Beijing cohort constructed growth curves specific to Chinese PHP1 [72].

9.3. Portugal and Brazil

The main sources consulted contain no prevalence data, cohorts or series from Portugal or Brazil. This absence in the sources read does not demonstrate that publications from these countries do not exist.

9.4. Special populations

In children under 2 years, usual diagnostic criteria have low sensitivity, and surveillance should be based on TSH, weight and skin (section 5.3) [14]. In pregnant women, calcium physiology is unpredictable and requires more frequent monitoring (section 7.17) [80]. In adults, osteoporosis prevalence is unknown; untreated hypogonadism, prolonged PTH excess, GH deficiency and menopause are risk factors, but there is no evidence of reduced bone mineral density or more fractures, and routine densitometry (DXA) is not indicated (B++); investigation is warranted with low-impact fracture or skeletal unloading due to ankyloses, correcting secondary causes first [3, 15]. There are no data on menopause [3]. In patients with cognitive impairment, independent living and employment require social support [18].

9.5. European reference networks and patient associations

The consensus was supported by Endo-ERN, the European Reference Network for rare endocrine diseases (https://endo-ern.eu/), and ERN BOND, for rare bone diseases (https://ernbond.eu/), and promoted by the EuroPHP network [3, 15]. In France, the national referral centre for rare calcium and phosphate metabolism disorders at Hôpital Bicêtre follows one of the largest cohorts [14, 79]. Among patient associations participating in the consensus, K20 in France, dedicated to chromosome 20 disorders (https://www.associationk20.com/), and the Asociación Española de PHP (AEPHP, https://asociacionespanolaphp.blogspot.com/) maintained active pages in October 2026; the addresses of the Italian POH association (IPOHA) and acrodysostosis group cited in 2018 were inaccessible at that date [3]. GeneReviews also lists Metabolic Support UK and the International Skeletal Dysplasia Registry at the University of California, Los Angeles [2].

In France, the 2022 PNDS was drawn up by the rare disease reference centres of the OSCAR health network (filière) (https://www.filiere-oscar.fr/), coordinated by Peter Kamenický and Agnès Linglart, of the reference centre for calcium and phosphate metabolism at Hôpital Bicêtre (AP-HP, Paris-Saclay), with the participation of the K20 association [13]. Management is coordinated by a specialist from the reference or competence centre and involves paediatrics, endocrinology, nephrology, general and emergency medicine, orthopaedic surgery, neurosurgery, otorhinolaryngology, ophthalmology, dermatology, dentistry, radiology, laboratory medicine, genetics, psychology and neuropsychology, nutrition, physiotherapy, psychomotor therapy and occupational therapy, and, in pregnancy, obstetrics and neonatology [13]. On the social side, iPPSD with PTH resistance may be recognised as a long-term condition (ALD no. 17, metabolic diseases), outside the list of 30 ALDs, through review of the file under articles L. 322-3 and D. 322-1 of the Social Security Code, including dental anomalies; schooling is adapted through an individualised reception plan (PAI), from nursery to secondary school; and the departmental centres for disabled people (MDPH) assess entitlements and the compensation plan [13].

10. Illustrative Clinical Case

Kim and colleagues, from Seoul National University Bundang Hospital, published in 2023 the case of a 19-month-old Korean boy seen in dermatology for hard erythematous plaques on the trunk and upper limbs that had appeared spontaneously after birth, without trauma, and were increasing in number and size [64]. The child had a history of recurrent apnoea and desaturation, attributed to laryngospasm due to upper airway obstruction [64]. On examination, he weighed 17.5 kg (above the 97th percentile), had a round (“moon”) face and mild brachydactyly of the fifth fingers, confirmed radiographically; the abdomen had slightly depressed erythematous macules and scaly patches that had suggested atopic dermatitis, and the wrist had calcified nodules (figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC10727873/figure/F1/) [64].

Laboratory tests showed PTH of 113 pg/mL (reference 8–76), phosphate of 7.9 mg/dL (2.5–4.5), calcium of 10.2 mg/dL (8.8–10.5), at the upper limit, and TSH of 4.72 mU/L (0.3–4.0), indicating subclinical hypothyroidism [64]. Skin biopsy showed well-differentiated ossified plaques in the superficial dermis, with adipocytes and vessels between trabeculae, resembling bone marrow, and osteocytes within lacunae [64]. After multidisciplinary discussion, GNAS sequencing in leukocyte DNA identified the heterozygous variant NM_000516.7:c.348del, p.(Val117TrpfsTer16), a loss-of-function variant classified as pathogenic, and the diagnosis was AHO with PHP1A [34, 64]. The letter does not describe parental studies, treatment instituted or follow-up [64].

The case brings together several points of this article. It shows that, at 19 months, the child already had the initial biochemical PTH resistance pattern (elevated PTH and phosphate with normal calcium), before any hypocalcaemia, as described by the consensus and cohorts [3, 14]. It combines three typical signs of the first and second years — cutaneous ossifications, early obesity and elevated TSH — and meets the proposed flowchart for children under 2 years [14]. The authors emphasise that plate-like osteoma cutis, usually considered a limited POH variant, may occur in PHP1A, and early lesions may be mistaken for atopic dermatitis [64]. Biopsy diagnosed ossification, but the consensus considers it unnecessary when the presentation is evident and contraindicates it if FOP is possible; here, dermal location and absence of hallux malformation made FOP unlikely [3]. Apnoea and laryngospasm episodes recall the frequency of sleep-disordered breathing and airway risk in these children [18].

A second report, from 2026, illustrates the skin course: a boy with congenital hypothyroidism and PHP1A had atrophic abdominal lesions at 5 months, initially interpreted as anetoderma, and scalp nodules that, excised at 13 months, were osteoma cutis; at 3 years, atrophic macules on the abdomen, chest, legs and back, some indurated, were interpreted as osteoma cutis precursors and treated experimentally with topical sodium thiosulfate (figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC12996817/figure/fig1/) [106]. Sodium thiosulfate management is not part of recommendations and was evaluated in a single patient for 6 months [106].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Life expectancy is not documented in the sources consulted. The Danish registry study, with 60 patients, found increased risk of neuropsychiatric disorders, infections, seizures and cataracts, and renal, cardiovascular, neoplastic and fracture risk similar to the population, with the same results in the genetically confirmed subgroup [3]. Three isolated tumours have been described (pilocytic astrocytoma in PHP1A, osteosarcoma in PHP1B and medulloblastoma in POH), insufficient to establish an association; there are no data justifying specific cancer screening (A+++) [3]. PHP1B with MLID raised a hypothesis of tumour risk by analogy with Beckwith–Wiedemann syndrome, without tumours observed in the few patients studied [3].

Functional prognosis depends on subtype. In PHP1A, dominant limitations are cognitive impairment, obesity, short adult stature (around −2.5 SD) and, with extensive ossifications, pain and joint limitation [15]. In PHP1B, with appropriate treatment, intellect and adult height are normal, and hyperparathyroid bone complications are prevented through PTH control [3, 18]. In POH, disability depends on lesion location and extent, stabilising after adolescence [32]. In acrodysostosis, most patients progress relatively well apart from intellectual disability and joint complaints, with progressively restricted movement of the hands, elbows and spine [33]. Adult obesity tends to be less severe than in childhood, but insulin resistance and type 2 diabetes are frequent in adult PHP1A [3, 15]. Recently described constipation rarely responds to treatment according to families [79].

11.2. Surveillance

The table combines the age-based action table from the 2020 update with intervals from numbered consensus recommendations and other sources, given in each row.

Intervals do not differ between sections 7 and 11: calcium–phosphate surveillance every 3–6 months in children, TSH every 6 months until 5 years and height at least every 6 months follow the 2020 update and 2018 consensus [3, 15]. Calcitonin and other hormone resistance are not part of routine surveillance, nor is regular imaging of ossifications [3, 15]. The French PNDS adds annual renal ultrasound, an annual radiograph of skeletal maturation and annual alkaline phosphatase, which are not part of the consensus recommendations [3, 13, 15].

11.3. Surveillance of particular groups

Children of STX16 deletion carriers should have PTH, calcium and phosphate measured from birth or the early years, because PTH rises around 2 years and calcium remains normal until around 5 years, enabling treatment before hypocalcaemia [81]. In POH, follow-up concentrates on ossifications, joint function and physiotherapy; calcium–phosphate surveillance only at diagnosis [3]. In acrodysostosis, neurological and radiological surveillance of spinal stenosis and hearing assessment are added because of hearing loss and frequent otitis [3, 26]. In GH-treated acrodysostosis type 1, hip or knee pain and limping justify a hip radiograph, given the published case of Legg-Calvé-Perthes disease [83]. In women with PHP, surveillance intensifies during pregnancy, postpartum and lactation [3, 94]. In pregnant women with PHP, the PNDS asks for monthly corrected or ionised calcium and, with TSH resistance, monthly free T4 and TSH, and a fetal growth scan at 28 weeks when the fetus is at risk of a paternal GNAS variant or acrodysostosis; in the newborn of a parent with iPPSD2, calcium and thyroid function in cord blood [13].

12. Summary and Final Considerations

Pseudohypoparathyroidism and related disorders form a spectrum of PTH resistance and impaired cAMP signalling, grouped by mechanism in the iPPSD classification: inactivating GNAS variants (iPPSD2), GNAS methylation defects (iPPSD3), PRKAR1A (iPPSD4), PDE4D (iPPSD5) and, as differential diagnoses within the same pathway, PTH1R and PDE3A. Maternal Gsα expression in the proximal tubule, thyroid, pituitary, gonads and hypothalamus explains why the same GNAS variant causes PHP1A with hormone resistance, obesity and cognitive impairment when maternally inherited, and PPHP, osteoma cutis or POH when paternally inherited. In PHP1B, maternal loss of methylation at DMR A/B, due to STX16 deletions, NESP/AS deletions, inversions, exon H variants, UPD(20q)pat or unknown cause, reproduces renal resistance without haploinsufficiency in biallelic tissues.

The presentation develops over years. TSH resistance, ossifications and obesity arise in the first 2 years; PTH resistance, initially without hypocalcaemia, appears at a median near 6 years; brachydactyly and short stature become evident near puberty. Consensus criteria therefore fail in infants, and the 2026 proposal for children under 2 years emphasises the combination of elevated TSH with rapid weight gain or the presence of ossifications. Molecular diagnosis follows an AHO-centred algorithm: GNAS sequencing and CNVs with AHO, MS-MLPA methylation without AHO, and PRKAR1A and PDE4D when GNAS is normal; a negative panel or exome does not exclude an imprinting defect.

Treatment is not specific. Active vitamin D with calcium aims to maintain normal calcium and phosphate with PTH between the midpoint of the reference range and 2 times the upper limit, without suppressing PTH, and PTH or analogues are never used. The 2022 French PNDS is the specific guideline that gives doses: in children, alfacalcidol 1–3 µg/day or calcitriol 0.5–1.5 µg/day; in adults, calcitriol 0.5–1 µg/day or alfacalcidol 1–2 µg/day with 500–1000 mg/day of calcium. Calcitriol has a labelled PHP indication in the USA from 6 years and is used off-label in Europe; alfacalcidol has labelled paediatric dosing in the United Kingdom. GH is used under approved indications, with different doses and ages in the USA and EU. Obesity, OSAS, cognitive impairment and ossifications require multidisciplinary surveillance and intervention, and investigational therapies (theophylline, setmelanotide, GLP-1 agonists, topical sodium thiosulfate) do not yet have practice-changing results. During pregnancy, calcium and active vitamin D requirements change unpredictably, and breastfeeding, contraindicated in the American calcitriol label, is accepted by the consensus with infant monitoring.

Genetic counselling depends on mechanism and the transmitting parent's sex: 50% transmission with GNAS variants, with phenotype determined by parental origin; 50% with maternal STX16 deletions, with healthy male carriers; population risk in sporadic PHP1B without a genetic cause and in de novo acrodysostoses. Main gaps are the absence of randomised trials with clinical outcomes, sparse epidemiological data outside Japan and some European countries, absence of Portuguese and Brazilian data in the sources consulted and lack of disease-specific paediatric intravenous calcium doses.

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