Endocrine Abstracts

Heterozygous mutations in GNAS1, which encodes the Gαs protein involved in multiple signalling pathways, are classically associated with Albright’s Hereditary Osteodystrophy (AHO). GNAS1 is one of few genetic loci that undergo allelic-specific methylation resulting in the parent-specific expression of at least four different transcripts. The classic constellation of phenotypic features includes short stature, round face, brachydactyly, obesity, dental hypoplasia and subcutaneous calcifications. These features have been reported with both paternally and maternally inherited mutations. Additionally, maternally inherited mutations can result in resistance to parathyroid hormone, thyroid stimulating hormone, growth hormone releasing hormone and gonadotrophins. Here we describe the identification of 24 patients with GNAS1 mutations from the whole exome and targeted resequencing of 5000 patients with severe early onset obesity. We describe the clinical spectrum in mutation carriers which includes hyperphagia as well as low basal metabolic rate, short stature in some but not all children and mild learning difficulties. These clinical characteristics may in part be explained by the ability of mutant forms of GNAS to impair receptor-dependent and receptor independent signalling by GPCRs such as MC4R, Beta-2 and Beta-3R. We conclude that mutations in GNAS1 present with a highly variable phenotype. Our ascertainment by studying a large number of children with severe obesity, has revealed a degree of clinical variability that is greater than reported. This may have contributed to under-diagnosis of patients who lack the classic phenotypic features. Broader recognition of the spectrum of features seen in GNAS1 mutations could aid diagnosis and patient care.