Introduction: Mutations in GNAS, affecting the alpha subunit of heterotrimeric G proteins, are implicated in several endocrinopathies. We report a patient with features of both receptor activation and inactivation in association with a novel de novo heterozygous somatic mutation.
Case report: Asymptomatic hyponatraemia (Na 117-123) was identified in a male neonate, and treated with sodium supplementation and fludrocortisone. Biochemical data were consistent with nephrogenic syndrome of inappropriate anti-diuresis (NSIAD), and this was confirmed on Tolvaptan challenge. Medication was stopped, and sodium concentrations regulated by fluid restriction. A skeletal survey showed appearances suggestive of increased PTH activation with an elevated PTH and a normal calcium. By the age of 2 years, he developed rapidly advancing gonadotrophin-independent precocious puberty. Commencement of spironolactone and anastrozole led to recurrent hyponatraemia and he was therefore commenced on bicalutamide and letrozole. Sanger sequencing revealed a de novo GNAS1 mutation (c.1126T>G; p.Phe376Val) on the maternally inherited allele. Whole exome sequencing did not identify any further mutations which could provide an alternative explanation for the constellation of features seen in our patient. We hypothesise that this specific mutation in GNAS, which has not been previously described, causes activation of the G protein receptors GnRHR and AVPR2, leading to the combination of NSAID and gonadotrophin-independent precocious puberty. As the maternal allele is expressed in the proximal tubules, we also suggest that this mutation leads to a paradoxical inhibition of the PTH response, leading to an increased circulating concentration of PTH causing the skeletal features.
Conclusion: We describe a previously undescribed condition in association with a novel germline mutation in GNAS, leading to a complex pattern of tissue-specific activation/inactivation. The unique spectrum of endocrinopathies could offer new insights into G-protein function.
22 - 24 Nov 2017
British Society for Paediatric Endocrinology and Diabetes