ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2017) 51 OC3.2 | DOI: 10.1530/endoabs.51.OC3.2

A novel syndrome of nephrogenic syndrome of inappropriate antidiuresis, precocious puberty, parathyroid insensitivity associated with a novel GNAS mutation, p.F376V

Ian Tully1,2, Sarah Kiff3, Detlef Bockenhauer4,5, Louise Wilson6, Jeremy Allgrove7, John Gregory8,9 & Mehul Dattani7,10

1Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK; 2Neurology and Mental Health Research Institute (NMHRI), Cardiff University, Cardiff, UK; 3Department of Endocrinology, Great Ormond Street Hospital, London, UK; 4Department of Nephrology, UCL Institute of Child Health, London, UK; 5Department of Nephrology, Great Ormond Street Hospital, London, UK; 6Department of Clinical Genetics, Great Ormond Street Hospital, London, UK; 7Department of Paediatric Endocrinology, Great Ormond Street Hospital, London, UK; 8Division of Population Medicine, Cardiff University, Cardiff, UK; 9Department of Paediatric Endocrinology, Noah’s Ark Children’s Hospital for Wales, Cardiff, UK; 10Department of Genetics and Epigenetics in Health and Disease, UCL Great Ormond Street Institute of Child Health, London, UK.

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.