Recommendations for Diagnosis and Treatment of Pseudohypoparathyroidism and Related Disorders: An Updated Practical Tool for Physicians and Patients

Abstract

Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.

Keywords: Acrodysostosis; Bone disorders; Brachydactyly; Calcium and phosphate metabolism; Consensus; Diagnosis; Management; Ossification; Parathyroid hormone; Pseudohypoparathyroidism; Treatment.

Conflict of interest statement

Conflict of Interest Statement

The authors declare no competing interests.

© 2020 S. Karger AG, Basel.

Figures

Fig. 1.

Molecular defects in the PTH-PTHrP signaling pathway in PHP and related disorders. The main clinical features of PHP and related disorders are due to molecular defects within the PTH-PTHrP signaling pathway, with the exception, perhaps, of ectopic ossification. Some of the clinical features result from the impaired signaling of other GPCR such as TSHR. The diseases caused by alterations at the genes codifying the indicated proteins are shown within square boxes. PTHR1, PTH/PTHrP receptor type 1; G protein, trimers α, β, and γ; PKA, tetramers R (regulatory subunit 1A; dark grey) and C (catalytic subunit; light grey); HTNB, autosomal dominant hypertension and brachydactyly type E syndrome; TF, transcription factor. Phosphodiesterases: ovals (PDE4D and PDE3A). cAMP: grey diamond.

Fig. 2.

Main clinical features of PHP and related disorders. PHP and related disorders affect many organs unequally. The clinical and biochemical features of the main diseases have been represented with their frequency when known. ACRDYS1, acrodysostosis due to a pathogenic variant in PRKAR1A; ACRDYS2, acrodysostosis due to alterations in PDE4D.

Fig. 3.

Molecular algorithm for confirmation of the diagnosis of PHP and related disorders. If patients present with AHO, genetic alterations at GNAS should be studied, including point variants (sequencing) and genomic rearrangements (such as MLPA and aCGH). In the absence of AHO, epigenetic alterations should be analyzed 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 GNAS A/B:TSS DMR, STX16 deletions should be screened for, and, if present, the diagnosis of AD-PHP1B is confirmed; if the methylation is modified at the 4 DMR, paternal uniparental disomy of chromosome 20 (UPD[20q] pat) should be screened for; in the 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 (spor-PHP1B) is suspected. After exclusion of the GNAS locus as the cause of the phenotype, and in patients with AHO, PHP-related genes (i.e., at least PDE4D and PRKAR1A) should be sequenced. RT-PCR, reverse transcription polymerase chain reaction; SNP, single-nucleotide polymorphism; NGS, next-generation sequencing; A/B: GNAS A/B:TSS-DMR; STR, short tandem repeats (microsatellites); UPD, uniparental disomy; WES, whole exome sequencing; WGS, whole genome sequencing; ICR, imprinting control region; VUS, variant of unknown significance.