Endocrine Abstracts

Introduction: Heterozygous inactivating mutations in the maternal allele of the GNAS gene typically result in pseudohypoparathyroidism (PHP). GNAS variants were recently described in 1% of patients, not known to have PHP, in the UK Genetics of Obesity cohort, resulting in reduced MC4R signalling and variable effects on PTH-R and GHRH-R signalling.

Methods: NGS (Cambridge Obesity Gene Panel) and in vitro functional analysis using cAMP biosensor assays.

Case: A six-year-old female (BMI +4.3SD, height +1.9SD) presented with hyperphagia and obesity from age 3. She had subtle brachydactyly. Developmental milestones were mildly delayed. Her 12-year-old brother (height +2.1SD, BMI +2.9SD) was followed in an obesity clinic and had hyperphagia, obesity, mildly delayed development and autism, with progressing puberty. He had subtle brachydactyly, as did the mother (BMI 38.9kg/m2, height 160.2cm).

Results: In the proband, 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). The brother and mother had mildly raised PTH but otherwise normal endocrinology. Brother’s bone age was 3 yrs advanced. A novel heterozygous (c.791A>C, p.(Asn264Thr) variant in exon 10 of GNAS was detected in the proband, mother and brother. The variant is in a highly conserved region and has been classified as pathogenic (ACMG and ACGS), and is not present in control databases. Functional effect of p.(Asn264Thr) was assessed by heterologously expressing GSWT or GSAsn264Thr in HEK293 cells, together with GPCRs 3xHA-GHRHR, 3xHA-MC4R or 3xHA-PTHR. After stimulation with GHRH, α-MSH and PTH, cAMP generation was significantly impaired in GSAsn264Thr compared to GSWT, supporting the pathogenic nature of the variant for all 3 signalling pathways.

Discussion: GNAS variant p.Asn264Thr leads to impaired MC4R, GHRH-R and PTH-R signalling in vitro but a clinical presentation dominated by obesity without a classical PHP phenotype. The obesity may compensate for the impaired GHRH-R signalling resulting in normal growth in height although pubertal growth could still be impaired. Patients with obesity should be assessed for subtle clinical and biochemical features of PHP for early diagnosis. Whether Setmelanotide is effective in improving MC4R signalling in these patients remains unanswered currently.