PA03: Understanding phenotypic variations of pseudohypoparathyroidism and loss‐of‐function <i>GNAS</i> variants

N.-Y.C. Kang,1 J. Harrington,1,2 P. Kannu,1,3 E. Pope1,3 and I. Lara-Corrales1,4 1Faculty of Medicine, University of Toronto, Toronto, ON, Canada; and 2Department of Endocrinology, 3Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and 4Section of Dermatology, The Hospital for Sick Children, Toronto, ON, Canada Pseudohypoparathyroidism (PHP) refers to a heterogeneous group of endocrine disorders that occur as a result of loss-of-function (LOF) mutations in GNAS. There is a characteristic parental inheritance pattern, phenotype and hormone profile associated with each PHP subtype [PHP-1a, PHP-1b, pseudopseudohypoparathyroidism (PPHP) and progressive osseous heteroplasia (POH)]. However, not all patients with PHP and LOF GNAS mutations demonstrate the characteristic phenotype and hormone profile. The aim of this study was to describe the phenotypic variability of patients with PHP and LOF GNAS mutations and to explore the genotype–phenotype correlation. This was a single-centre retrospective review, which included patients with a positive genetic test for a LOF GNAS mutation. We collected patients’ baseline characteristics (sex, ethnicity, family and medical histories), diagnostic history (including age at diagnosis and clinical findings), available genetic, laboratory and radiology results, including genetic tests, biochemistry, X-ray findings and treatments. Twenty-five patients with LOF GNAS mutations were included in our study. PHP-1a, PPHP, PHP-1b and POH were diagnosed in 52%, 28%, 16% and 4% of patients, respectively. The most common mutations in PHP-1a, PHP-1b, PPHP and POH were splicing (38%), methylation defect (100%), missense (43%) and frameshift (100%) mutations, respectively. Of the 13 patients with PHP-1a, common findings were parathyroid hormone (PTH) and thyroid-stimulating hormone resistance (100%), short stature (85%), brachydactyly type E (77%), round faces (69%), obesity (61%) and speech/language delays (61%). Of the four patients with PHP-1b, 67% had PTH resistance, short stature and brachydactyly type E. The seven patients with PPHP did not have endocrine abnormalities, but 80% had short stature, atrophic skin lesions and osteoma cutis, and 75% had speech and language delays. The patient with POH had atrophic skin lesions but no hormone resistance. PHP subtypes are characterized by specific phenotypes: PHP-1a with Albright hereditary osteodystrophy (AHO), developmental delay and hormone resistance; PHP-1b with PTH resistance only; PPHP with AHO only; and POH with none of the above. However, we found that patients with PHP-1a did not demonstrate all AHO features, patients with PHP-1b had AHO and patients with PPHP had language delays and AHO. Furthermore, the same mutation – but not phenotype – was found among the different PHP subtypes. Thus, we concluded that there are phenotypic variations and a lack of a genotype–phenotype correlation in PHP.

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