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.

Physiological Aspects of Female Fertility: Role of the Environment, Modern Lifestyle, and Genetics

“…After exclusion of excessive exercise, extreme stress, or an eating disorder, and after ensuring pituitary function, other than secretion of LH and FSH, is normal, and pituitary imaging is normal the condition is considered idiopathic HH (IHH) (194). The most common cause of GnRH insufficiency is the failure of migration of the GnRH secretory neurons to the forebrain which may also result in olfactory disorder (Kallman's syndrome); in the absence of olfactory, the condition is described as normosmic IHH (354). The inheritance is either X-linked (KAL genes), autosomal dominant or autosomal recessive, and the condition is usually detected in adolescence with a delay or absence of pubertal development, with in excess of 20 genes implicated in this condition to date (194 (194).…”

Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform

“…In addition, nonreproductive phenotypes, such as midline facial defects, dental agenesis, hearing loss, renal agenesis, synkinesis, and digital bone abnormalities, are commonly observed in patients with IHH (2,3). About one third of patients with IHH reveal a genetic defect in genes that regulate the embryonic development or migration of GnRH neurons, or the synthesis, secretion, or action of GnRH (4,5). One of the most frequently implicated genes is the fibroblast growth factor receptor 1 (FGFR1, OMIM 136350) gene, which is located at chromosome 8p11.2, and comprises 18 coding exons (6,7).…”

Genetikai tényezők a hypopituitarismus kialakulásában. A transzkripciós faktorok szerepe az agyalapimirigy-elégtelenség hátterében

“…IHH és hallászavar esetén a "chromodomainhelicase-DNA-binding protein 7" (CHD7) gén mutáció-ja merülhet fel. Az adenohypophysisben és a gonádok-ban is expresszálódó szteroidogenetikus faktor-1 (SF1 vagy NR5A1) génhibái esetén a változatos klinikai kép egyik megjelenési formája lehet, amikor a veleszületett centralis hypogonadismus primer mellékvesekéreg-elég-telenséggel együtt jelentkezik [26].…”