ESPE Abstracts

Background: Assessment in childhood obesity includes looking for obesity syndromes. Dysmorphic features should guide investigations. When clinical signs are subtle, genetic investigations aide diagnosis. A case (S) of progressive childhood obesity is described. He was found to have a pathogenic GNAS mutation which was also present in his mother. Both mother and son had a similar phenotype and did not have hypocalcaemia or PTH resistance described in pseudohypoparathyroidism type 1a (PHP1a).

Case: S was referred at 6 years old for a growth assessment because of escalating weight from the age of 1 year. Birth weight at full term was normal at 3.66 kg. His height tracked along the 75th centile in his growth records and weight was above the 99.8th centile. S was well behaved and did not appear to have learning difficulties. On examination, S had mild rhizomelic limb shortening, brachyphalangy and no obvious shortening of the third or fourth metacarpals, no subcutaneous calcifications were palpable. His phenotype and digits were similar to his mother’s. Mother’s BMI was 35.5 kg/m².

Investigations: Skeletal survey, oral glucose tolerance test, thyroid function, bone biochemistry, and PTH levels were requested. DNA was sent for the Genetics of Obesity Study and saved for further analysis.

Results: Skeletal survey showed generalised brachydactyly and brachymetacarpia, especially the fourth and fifth. Fasting glucose 4.5 mmo/l paired with insulin 153 pmol/l, glucose at 120 min 6.1 mmol/l. Calcium 2.36 mmol/l (2.12–2.55) and PTH 6.1 pmol/l (1.2–9.3). Leptin concentration was normal for his percentage of body fat. Plasma insulin was raised but proinsulin and split proinsulin were normal. GNAS mutation analysis showed that he was heterozygous for R342Q, also present in his mother but not father and sister.

Conclusion: PHP1a is usually caused by maternally inherited G(s)α loss of function mutations in the GNAS gene. This condition includes Albright’s hereditary osteodystrophy (AHO) and hypocalcaemia with PTH resistance. Maternal, but not paternal, G(s)α mutations lead to obesity, as in S. However bone biochemistry and PTH was normal in S, suggesting variable renal tubular expression of this imprinted gene. Mutation in exon 12 of GNAS appears to be associated with normocalcaemia and obesity.