Clinical evaluation and molecular analysis of genetic and epigenetic inactivation defects in GNAS in children: A multicenter experience in China

OBJECTIVE: We assessed pediatric patients with clinically diagnosed pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH) for genetic and epigenetic defects in GNAS and characterized their clinical features. DESIGN: We enrolled a total of 87 patients in our study, 70 patients underwent genetic analysis. We compared the clinical manifestations according to the previously reported inactivating PTH/PTHrP signaling disorder (iPPSD) classification combined with conventional clinical classification. RESULTS: We identified pathogenic variants within exons 1-13 of GNAS in 31 patients (iPPSD2), with the majority presenting as PHP1A, and 2 cases each of PPHP and POH. GNAS imprinting defects were found in 39 patients (iPPSD3), with the clinical types including 11 cases of PHP1A and 28 cases of PHP1B. Sluggish height growth and hypocalcemia-related symptoms were common presenting complaints in PHP1A, while hypocalcemia-related symptoms were typical in PHP1B. Both iPPSD2 and iPPSD3 patients had variable manifestations of Albright hereditary osteodystrophy (AHO), but heterotopic ossification was limited to iPPSD2. We compared the clinical characteristics of these iPPSD2 patients presented as PHP1A in different cohorts. The AHO phenotypes varied among the 4 cohorts. Three PHP1A patients were treated with recombinant human growth hormone and showed improved height and growth rates. CONCLUSION: Our findings suggest that molecular screening can be highly specific in patients with parathyroid hormone resistance. Furthermore, we found significant overlap in the clinical features between patients with iPPSD2 and iPPSD3, suggesting that a combination of molecular genetic diagnosis and clinical evaluation may be the better approach for fully understanding GNAS inactivation defects disorders.