A Novel Maternally Inherited GNAS Variant in a Family With Hyperphagia and Obesity: 3 Cases.

GNAS variants were recently described in 1% of patients not known to have pseudohypoparathyroidism/inactivating PTH/PTHrP signalling disorder 2 in the UK Genetics of Obesity Study. We describe a new missense GNAS variant, c.791A > C, p.(Asp264Thr), in a family with obesity, hyperphagia and mild PTH resistance. A 6-year-old female (body mass index +4.3 SD score [SDS], height +1.9 SDS) presented with hyperphagia and obesity from age 3 years. She had subtle brachydactyly, macrocephaly, and mildly delayed development. The 12-year-old brother (height +2.1 SDS, body mass index +2.9 SDS) had hyperphagia, obesity, mildly delayed development, and autism. He had subtle brachydactyly, as did the affected mother. We assessed the functional effect of the mutant, measuring cAMP production in cells transfected with wild type and mutant GNAS after ligand stimulation. Cells with the mutant GNAS showed impaired cAMP generation through melanocortin receptor 4, GH releasing hormone receptor, and PTH receptor. These cases demonstrate the clinical heterogeneity of monogenic disease, suggesting a need to test for PHP1A in children with obesity even without classical signs of PHP1A.

Delayed puberty.

The onset of puberty may be late - in the latter part of the predicted normal range or truly delayed - beyond this range. The latest age to start is usually regarded as 13 years in girls and 14 years in boys. There may also be a delayed completion of puberty, 16 years in girls and 17 years in boys. The initial approach requires a detailed history and clinical examination to exclude other medical or psychological problems. The presence or absence or pubertal signs should be documented. Investigations should be targeted at ruling out any medical causes and determining whether the delay is due to central gonadotropin deficiency (hypogonadotropic hypogonadism) or a gonadal disorder (hypergonadotropic hypogonadism). Physiological or constitutional delay of growth and puberty (CDGP) is more common in boys but is a diagnosis of exclusion. Current research suggests that CDGP and congenital hypogonadotropic hypogonadism have distinct genetic profiles which may aid in the differential diagnosis. Treatment may be given using low doses of sex steroids, testosterone or estradiol initially in a short course of 3-6 months but continuing in escalating doses mimicking the normal course of puberty, watching regularly for the spontaneous resumption of progress and gonadotropin secretion. In gonadotropin deficiency, sex hormone treatment needs to be continued until completion of pubertal development and growth. Counselling, reassurance and support are key elements in the management of adolescents with delayed puberty.