Endocrine Abstracts

Introduction: Pseudohypoparathyroidism type 1A (PHP1A) is a rare genetic disease characterized by resistance to parathyroid hormone along with hormonal resistance and features of Albright hereditary osteodystrophy (AHO). This is caused by heterozygous inactivating mutations in the maternal allele of the GNAS gene, which encodes the stimulatory G-protein alpha subunit (Gsα) and regulates production of second messenger cyclic AMP. Here, we report a previously undescribed GNAS variant in a child with hyperphagia, obesity, mild brachydactyly and normocalcaemia.

Case: A 6-year-old female presented with hyperphagia and significant weight gain from 3 years of age. Her weight was 47.1 kg (3.72 SDS), BMI 30.39 (4.05 SDS) with height (1.89 SDS) and HC 56 cm (3.01 SDS). She had brachydactyly with short fourth and fifth metacarpals, short toes and a café au lait patch on the chest. Birth weight was 3.79 kg (1.12 SDS). Developmental milestones including cognitive achievements were delayed. Parents were non-consanguineous; her older brother had a similar phenotype with hyperphagia.

Results: PTH was slightly high [9.5 pmol/l (0.7-5.6)] with normal calcium and Vitamin D, TSH 6.6 mU/l (<6), T3 10.3 pmol/l (6.2-9.5), FT4 11.8 pmol/l (10.8 - 19.0) and raised triglycerides. Ultrasound abdomen revealed mild diffuse fatty liver. X-ray hand showed generalised mild brachydactyly with short right fifth metacarpal. Next Generation Sequencing (NGS) of the coding region of the genes in the Obesity gene panel detected a novel heterozygous (c.791A>C, p.(Asn264Thr) mutation in the GNAS gene. This mutation was also identified in her mother and brother confirming maternal inheritance of the familial GNAS variant. This variant has not been reported in control databases (1000 Genomes, ESP, ExAC and gnomAD, Human Gene Mutation Database and ClinVar) and has been classified as pathogenic using ACMG and ACGS guidelines.

Discussion: In conclusion, the novel heterozygous GNAS variant c.791A>C, p.(Asn264Thr) results in altered Gsα function, which furthers our understanding of the pathogenesis of this disease. Screening for GNAS mutations should be considered in suspected cases of PHP1A even if the classical signs are not present. The obesity gene panel is able to detect GNAS variants as a cause of obesity.