This article is part of the Research Topic Neurological and psychiatric disorders in endocrine diseases


Front. Endocrinol., 09 July 2014 | doi: 10.3389/fendo.2014.00109

Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes

imageHernan Valdes-Socin1*, imageMatilde Rubio Almanza1, imageMariana Tomé Fernández-Ladreda1, imageFrançois Guillaume Debray2, imageVincent Bours2 and imageAlbert Beckers1
  • 1Service of Endocrinology, CHU Liège, University of Liège, Liège, Belgium
  • 2Service of Human Genetics, CHU Liège, University of Liège, Liège, Belgium

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.

Keywords: reproduction, male, Kallman syndrome, hypogonadotropic hypogonadism, olfaction, kisspeptin, genetics

Citation: Valdes-Socin H, Rubio Almanza M, Tomé Fernández-Ladreda M, Debray FG, Bours V and Beckers A (2014) Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes. Front. Endocrinol. 5:109. doi: 10.3389/fendo.2014.00109

Received: 31 March 2014; Accepted: 24 June 2014;
Published online: 09 July 2014.

Edited by:

Gianluca Tamagno, St Columcille’s Hospital, Ireland

Reviewed by:

Alexandru Saveanu, Aix Marseille University, France
Thomas King, Mater Misericordiae University Hospital, Ireland

Copyright: © 2014 Valdes-Socin, Rubio Almanza, Tomé Fernández-Ladreda, Debray, Bours and Beckers. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Hernan Valdes-Socin, Service of Endocrinology, Centre Hospitalier Universitaire, Rue de l’Hôpital 1, Liège 4000, Belgium e-mail:

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