ESPEYB15 7 PUBERTY Genetic architecture of hypogonadotropic hypogonadism and delayed puberty (3 abstracts)
7.8 Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures
Cassatella D , Howard SR , Acierno JS , Xu C , Papadakis GE , Santoni FA , Dwyer AA , Santini S , Sykiotis GP , Chambion C , Meylan J , Marino L , Favre L , Li J , Liu X , Zhang J , Bouloux PM , Geyter C , Paepe A , Dhillo WS , Ferrara JM , Hauschild M , Lang-Muritano M , Lemke JR , Flück C , Nemeth A , Phan-Hug F , Pignatelli D , Popovic V , Pekic S , Quinton R , Szinnai G , l'Allemand D , Konrad D , Sharif S , Iyidir ÖT , Stevenson BJ , Yang H , Dunkel L & Pitteloud N
Service of Endocrinology Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerlan
To read the full abstract: Eur J Endocrinol. 2018 Apr;178(4):377-388
[Comments on 7.7 and 7.8] Familial self-limited delayed puberty is highly heritable and has a clear genetic basis as described in the review written by Sasha Howard. Recent studies suggest that the genetic basis of self-limited delayed puberty is likely to be highly heterogeneous and involve abnormalities of GnRH neuronal development, function, and its downstream pathways, metabolic and energy homeostatic derangements, and transcriptional regulation of the hypothalamic-pituitary-gonadal axis. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder affecting approximately 1:4000 births1. It is caused by GnRH deficiency, and subsequently results in altered activation of the hypothalamic–pituitary–gonadal axis that controls sexual maturation and fertility. Congenital delay of growth and puberty (CDGP) and CHH are part of a continuum of GnRH deficiency, ranging from transiently delayed to a complete absence of puberty. Therefore, CDGP, also termed self-limited delayed puberty, and CHH appear to be part of the same clinical spectrum2. In contrast to CHH, CDGP is a common disease, observed in 2–2.5% of the population. Currently, the differential diagnosis between CHH and CDGP at early adolescence remains challenging, as both conditions present with isolated delay in puberty.
Cassatella et al. studied a cohort of 116 CHH probands of European descent (n=61 Kallmann Syndrome, n=55 normosmic CHH) and 72 unrelated probands with CDGP of primarily Finnish European origin. Ethnically matched controls were used to compare individual variant and gene mutation frequencies. They found that the genetic profiles of CHH and CDGP were different. CHH and CDGP differed in the number of patients harboring mutations in individual CHH genes (51% vs 7%). Nearly two-thirds of familial CHH probands carried mutations in CHH genes (61%), while the frequency in sporadic CHH probands was lower (44%). FGFR1 and CHD7 were the most frequently mutated genes in CHH probands. CHH and CDGP patients also differed in their overall mutational load of CHH genes (oligogenicity). The majority of CHH genes were inherited in an oligogenic fashion in CHH probands, a trend not observed in CDGP probands. Larger studies examining gene pathways, rather than individual genes identified by genome-wide association studies, are required to further elucidate the genetic overlap between CHH and CDGP.
1. Mitchell AL, Dwyer A, Pitteloud N & Quinton R. Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory. Trends in Endocrinology and Metabolism 2011; 22: 249–258.
2. Boehm U, Bouloux PM, Dattani MT, de Roux N, Dode C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism – pathogenesis, diagnosis and treatment. Nature Reviews Endocrinology 2015 ; 11: 547–564.
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ESPE Yearbook of Paediatric Endocrinology
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