Homozygous p.R31H GNRH1 mutation and normosmic congenital hypogonadotropic hypogonadism in a patient and self-limited delayed puberty in his relatives.
Cécile Brachet: Paediatric Endocrinology Unit, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Bruxelles, Belgium.
Caroline Gernay: Paediatric Endocrinology Unit, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Bruxelles, Belgium.
Emese Boros: Paediatric Endocrinology Unit, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Bruxelles, Belgium.
Julie Soblet: Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, ULB Center of Human Genetics, Université Libre de Bruxelles, Bruxelles, Belgium.
Catheline Vilain: Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, ULB Center of Human Genetics, Université Libre de Bruxelles, Bruxelles, Belgium.
Claudine Heinrichs: Paediatric Endocrinology Unit, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Bruxelles, Belgium.
Objectives congenital hypogonadotropic hypogonadism (CHH) is a rare condition resulting from GnRH deficiency. Gonadotropin Releasing Hormone 1 (GNRH1) homozygous mutations are an extremely rare cause of normosmic CHH (nCHH). Most heterozygous individuals are asymptomatic, with the notable exception of individuals heterozygous for a p.R31C GNRH1 mutation. Case presentation The patient is an index case from a consanguineous family, presenting with severe CHH and his parents presenting with late puberty and normal fertility. The index case is homozygous for a p.R31H GNRH1 variant, both parents being heterozygous. The analysis of a panel of genes implicated in CHH does not show any other clinically relevant variant in any other gene tested. Conclusions GNRH1 mutations are a rare cause of nCHH. Five different mutations have been reported so far in homozygous individuals. Most are frameshift in nature but the one reported here causes an amino acid change in the Gonadotropin-releasing hormone (GnRH) decapeptide. Both independently reported patients with the p.R31H mutation are from Turkish origin. The question of the possible role of this mutation in the late puberty of the heterozygous parents needs further documentation. An analogy is made with the heterozygous individuals carrying the p.R31C and displaying partial CHH. No nonreproductive disorder is noted.
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