%A Valdes-Socin,Hernan %A Rubio Almanza,Matilde %A Tomé Fernández-Ladreda,Mariana %A Debray,François Guillaume %A Bours,Vincent %A Beckers,Albert %D 2014 %J Frontiers in Endocrinology %C %F %G English %K Reproduction,male,Kallmann Syndrome,Hypogonadism,Olfaction Disorders,Kisspeptins,lutheinizing hormone,Follicule stimulating hormone,GnRH,Genetics,FGFR1,Fgf8,FGF17,PROK2,PROKR2,NELF model,CHD7,DUSP6,SEMA3A,WDR11,Leptin,Hesx1,IL17RD,BLH,BFSH,KISS1,KISSR,GnRH receptor %Q %R 10.3389/fendo.2014.00109 %W %L %M %P %7 %8 2014-July-09 %9 Review %+ Dr Hernan Valdes-Socin,Service of Endocrinology, CHU Liège, University of Liège,Belgium,hg.valdessocin@chuliege.be %# %! Reproduction and Neurodevelopmental disorders: genetic defects in hypogonadotropic hypogonadism %* %< %T Reproduction, Smell, and Neurodevelopmental Disorders: Genetic Defects in Different Hypogonadotropic Hypogonadal Syndromes %U https://www.frontiersin.org/articles/10.3389/fendo.2014.00109 %V 5 %0 JOURNAL ARTICLE %@ 1664-2392 %X The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations [Kallmann syndrome (KS)] and idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH). KS is a heterogeneous disorder affecting 1 in 5000 males, with a three to fivefold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF, and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non-reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental, and genetic aspects of HH in human pathology.