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

Abstract

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: Kallman syndrome; genetics; hypogonadotropic hypogonadism; kisspeptin; male; olfaction; reproduction.

Figure 1

Schematic representation of the reproductive axis and the different genes invalidating mutations participating in Kallman syndrome and nIHH. GnRH neurons migrate from nasal placode to hypothalamus in the first weeks of fetal life. Several genes are represented in the left column: their invalidating mutations are responsible for Kallmann syndrome and olfactory dysfunction. Kiss1 neurons integrate different hormonal, metabolic, circadian inputs from other hypothalamic and brain areas and thus stimulate GnRH neurons firing. Several genes are represented in the right black column, including KISS1-GPR54 system, which invalidating mutations lead to normosmic idiopathic hypogonadotropic hypogonadism. GnRH secretion leads to gonadotropins FSH and LH pituitary release. LH and FSH control sex steroids secretion and gametogenesis [adapted from Valdes-Socin et al. (1), with permission].