ESPE Abstracts

Introduction: Heterozygous inactivating mutations in the maternal allele of the GNAS gene typically result in pseudohypoparathyroidism (PHP), characterised by developmental delay, short stature, obesity, hormone resistance and bone abnormalities. GNAS variants were recently described in 1% of patients in the UK Genetics of Obesity cohort, resulting in reduced MC4R signalling. Here, we report another novel GNAS variant in a family with hyperphagia and obesity and only mild features of PHP.

Case: A six-year-old female presented with hyperphagia and obesity from the age of three years. BMI was 30.4 (4.1 SDS) with height +1.9 SDS, and head circumference (HC) + 3.0 SDS. She had subtle brachydactyly, short toes and a café au lait patch. Developmental milestones and cognitive achievements were mildly delayed. Her 12-year-old brother [ height +2.1 SDS, weight +3.1 SDS, BMI 29.55 (2.9 SDS), HC +3.6 SDS] had been followed in an obesity clinic with hyperphagia, obesity, delayed developmental milestones and a diagnosis of autism. He also had subtle brachydactyly, as did the mother, who was obese (BMI 38.9) with normal height and cognition.

Results: In the proband, initial investigations did not suggest hormone resistance. At 8.7 years, PTH was mildly raised [9.5 pmol/L (0.7-5.6)] with normal calcium and Vitamin D; TSH 6.6 mU/L (<6), FT4 11.8 pmol/L (10.8 - 19.0) in the proband. She had hyperlipidaemia, fatty liver, and generalised mild brachydactyly with a short right fifth metacarpal on X-ray. In the brother, biochemistry at 12.9 years showed: PTH18.4 pmol/L (1.6-6.9), normal calcium, Vitamin D and TFTs. Next Generation Sequencing using the Cambridge Obesity gene panel detected a novel heterozygous (c.791A>C, p.(Asn264Thr) variant in exon 10 of GNAS in the proband and subsequently in the mother and brother, confirming maternal inheritance. This variant has not been reported in control databases (1000 Genomes, ESP, ExAC and gnomAD, Human Gene Mutation Database and ClinVar). The variant is in a highly conserved region susceptible to missense mutations and has been classified as pathogenic using ACMG and ACGS guidelines.

Discussion: In conclusion, we describe a novel heterozygous inactivating GNAS variant c.791A>C, p.Asn264Thr resulting in hyperphagia, obesity, developmental delay, macrocephaly, mild brachydactyly, tall stature and variable biochemical mild hormone resistance in two siblings and obesity, mild brachydactyly, normal height, without cognitive impairment in the mother. We recommend that screening for PHP and GNAS variants should be performed in patients presenting with obesity, even in the absence of classical signs of PHP.