Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement

Abstract

This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.

Fig. 1. Molecular defects in the PTH–PTHrP signalling pathway in PHP and related disorders.

Upon ligand binding (parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) are shown on the figure), the G protein coupled PTH/PTHrP receptor type 1 (PTHR1) activates the heterotrimeric G_s protein. The G_sα subunit triggers the activation of adenylyl cyclase, which leads to cAMP synthesis. cAMP then binds to the regulatory 1 A subunits (R) of protein kinase A (PKA), the predominant effector of cAMP. Upon cAMP binding, the catalytic subunits (C) dissociate from the R subunits and phosphorylate numerous target proteins, including cAMP-responsive binding elements (CREB) and the phosphodiesterases (PDEs; such as PDE3A and PDE4D). CREB activates the transcription of cAMP-responsive genes. Intracellular cAMP is then deactivated by PDEs, including PDE4D and PDE3A. The main clinical features of pseudohypoparathyroidism (PHP) and related disorders are due to molecular defects within the PTH–PTHrP signalling pathway, with the exception, perhaps, of ectopic ossification. The diseases caused by alterations in the genes that encode the indicated proteins are shown in blue boxes. Differential diagnoses are shown in grey boxes. CRE, cAMP response element; HDAC4, histone deacetylase 4; G protein, trimer α, β and γ; HTNB, autosomal dominant hypertension and brachydactyly type E syndrome; PHP, pseudohypoparathyroidism; PHP1A, pseudohypoparathyroidism type 1A; PHP1B, pseudohypoparathyroidism type 1B; PHP1C, pseudohypoparathyroidism type 1C; POH, progressive osseous heteroplasia; PPHP, pseudopseudohypoparathyroidism; PTHLH, parathyroid hormone-like hormone; TF, transcription factor; TRPS1, zinc-finger transcription factor TRPS1.

Fig. 2

Molecular algorithm for the confirmation of diagnosis of PHP and related disorders. If patients present with Albright hereditary osteodystrophy (AHO), genetic alterations at GNAS should be studied, including point mutations (sequencing) and genomic rearrangements (such as multiplex ligation-dependent probe amplification (MLPA) and comparative genomic hybridization arrays (aCGH)). Once the variant is found, its pathogenicity should be confirmed according to guidelines, and, when possible, the parental origin should be determined. In the absence of AHO, epigenetic alterations should be analysed first. According to the results obtained for the methylation status, further tests are needed to reach the final diagnosis: if the methylation defect is restricted to transcription start site (TSS)–differentially methylated region (DMR) at exon A/B of GNAS (GNAS A/B:TSS-DMR), STX16 deletions should be screened for, and, if present, the diagnosis of autosomal dominant-pseudohypoparathyroidism type 1B (AD-PHP1B) is confirmed; if the methylation is modified at the four DMRs, paternal uniparental disomy of chromosome 20 (UPD(20q)pat) should be screened for; in absence of UPD(20q)pat, deletions at NESP should be screened for; if no genetic cause is identified as the cause of the methylation defect, the sporadic form of the disease (sporPHP1B) is suspected. After exclusion of the GNAS locus as the cause of the phenotype, and in patients with AHO, pseudohypoparathyroidism (PHP)-related genes (that is, at least PDE4D and PRKAR1A) should be sequenced. Squares in light red indicate the technology; blue, the final molecular confirmation; red, no molecular alteration; and grey, future or research steps are suggested. ICRs, imprinting control regions; MLID, multilocus imprinting disturbance; NGS, next-generation sequencing; PHP1A, pseudohypoparathyroidism type 1A; PHP1B, pseudohypoparathyroidism type 1B; POH, progressive osseous heteroplasia; PPHP, pseudopseudohypoparathyroidism; RT-PCR, reverse-transcription PCR; SNP, single-nucleotide polymorphism; STRs, short tandem repeats (microsatellites); UPD, uniparental disomy; VUS, variant of unknown significance; WES, whole-exome sequencing; WGS, whole-genome sequencing.