Gavin S. MacColl

Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism

Idiopathic hypogonadotropic hypogonadism (IHH) due to defects of gonadotropin-releasing hormone (GnRH) secretion and/or action is a developmental disorder of sexual maturation. To date, several single-gene defects have been implicated in the pathogenesis of IHH. However, significant inter- and intrafamilial variability and apparent incomplete penetrance in familial cases of IHH are difficult to reconcile with the model of a single-gene defect. We therefore hypothesized that mutations at different IHH loci interact in some families to modify their phenotypes. To address this issue, we studied 2 families, one with Kallmann syndrome (IHH and anosmia) and another with normosmic IHH, in which a single-gene defect had been identified: a heterozygous FGF receptor 1 (FGFR1) mutation in pedigree 1 and a compound heterozygous gonadotropin-releasing hormone receptor (GNRHR) mutation in pedigree 2, both of which varied markedly in expressivity within and across families. Further candidate gene screening revealed a second heterozygous deletion in the nasal embryonic LHRH factor (NELF) gene in pedigree 1 and an additional heterozygous FGFR1 mutation in pedigree 2 that accounted for the considerable phenotypic variability. Therefore, 2 different gene defects can synergize to produce a more severe phenotype in IHH families than either alone. This genetic model could account for some phenotypic heterogeneity seen in GnRH deficiency.

Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization*

OBJECTIVE The association of idiopathic hypogonadotrophic hypogonadism (IHH) with congenital olfactory deficit defines Kallmanns syndrome (KS). Although a small proportion of IHH patients have been found to harbour defined genetic lesions, the genetic basis of most IHH cases remains to be elucidated. Genes currently recognized to be involved comprise KAL (associated with X‐linked‐KS), the GnRH receptor (associated with resistance to GnRH therapy), DAX 1 (associated with adrenohypoplasia congenita) and three loci also associated with obesity, leptin (OB), leptin receptor (DB) and prohormone convertase (PC1). Because of the rarity of the condition and the observation that patients are almost universally infertile without assistance, familial transmission of IHH is encountered infrequently and pedigrees tend to be small. This has constrained the ability of conventional linkage studies to identify other candidate loci for genetic IHH. We hypothesized that a systematic clinical evaluation of a large patient sample might provide new insights into the genetics of this rare disorder. Specifically, we wished to examine the following propositions. First, whether normosmic (nIHH) and anosmic (KS) forms of IHH were likely to be genetically discrete entities, on the basis of quantitative olfactory testing, analysis of autosomal pedigrees and the prevalence of developmental defects such as cryptorchidism and cleft palate. Second, whether mirror movements and/or unilateral renal agenesis were specific phenotypic markers for X‐linked‐KS.

GnRH neuronal development: insights into hypogonadotrophic hypogonadism

Pulsatile secretion of the hypothalamic decapeptide gonadotrophin-releasing hormone (GnRH) regulates activity of the pituitary-gonadal reproductive axis. Defects of this neuroendocrine axis necessarily result in hypogonadotrophic hypogonadism. In many vertebrate species studied, the main population of GnRH neurones originates extracranially within the olfactory system. In humans, both olfactory and GnRH systems are affected in Kallmanns syndrome--resulting in isolated hypogonadotrophic hypogonadism (IHH) combined with anosmia (loss of sense of smell). Familial IHH is also caused by other genetic conditions, which prevent GnRH from activating luteinizing hormone/follicle-stimulating hormone release from pituitary gonadotrophs. However, many cases of IHH have no defined chromosomal abnormality and, in the absence of pedigree analysis, studying the biological mechanisms controlling migration of GnRH neurones through the olfactory system into the developing central nervous system might reveal additional genetic pathways that play a role in the pathogenesis of IHH.

Kallmann Syndrome: Adhesion, Afferents, and Anosmia

Three new studies into the function of human anosmin-1 and related proteins in C. elegans and rodents show that these influence axon branching and axon targeting. The rodent anosmin appears to work at two stages of development, initially promoting axon outgrowth from the olfactory bulb and then stimulating branching from axons into the olfactory cortex. CeKal-1 further influences morphogenesis, and, as the human and nematode anosmins are functionally conserved, these studies provide insights into the pathogenesis of Kallmann syndrome (KS).

Recent advances in the pathogenesis of Kallmann's syndrome.

Publisher Summary This chapter discusses recent advances in the pathogenesis of Kallmanns syndrome (KS: olfactogenital dysplasia). Kallmanns syndrome represents the prototype of a human developmental defect caused by a disorder of axonal pathfinding and defective gonadotropin-releasing hormone (GnRH) neuronal ontogeny. Affecting 1 in 8,000 males and 1 in 40,000 females, olfactogenital dysplasia is characterized by absence of olfaction (anosmia) due to olfactory bulb and tract agenesis and hypogonadotropic hypogonadism (HH, the functional consequence of failed hypothalamohypophyseal GnRH secretion). The pathophysiology of X-KS is the most extensively studied hitherto. Endocrine profiling, histological/ histopathological explorations and observations on comparative GnRH ontogeny, and, finally, magnetic resonance imaging (MRI) and electrophysiological investigations have given insights into the pathogenesis of this disease. Endocrine profiling demonstrates very low or absent gonadotropin secretion in KS patients. It also demonstrates preserved pituitary responsiveness to exogenous GnRH, indicating hypothalamic GnRH deficiency, which is the consequence of a critical reduction in the 2,000 or so hypothalamic GnRH neurons, which normally discharge pulsatile GnRH into the median eminence capillary loops. Moreover, detailed immunohistochemical examination of a 19-week K4Ll deleted fetus revealed that GnRH neurons and olfactory nervus terminalis and vomeronasal nerve axonal terminals (cranial nerve 1 complex) failed to reach the brain, instead terminating their journey from their olfactory placodal origin at the upper nasal sub-cribriform area. GnRH neuronal ontogeny is also described in the chapter.

Kallmann's syndrome: bridging the gaps.

Reproductive success in mammals depends greatly on the interplay between olfactory, terminalvomeronasal (pheromonal) and gonadotropin-releasing hormone (GnRH) neural systems. Although this physiological relationship is much less robust in humans, the anatomical linkage is perfectly illustrated by Kallmanns syndrome (KS), in which hypogonadotrophic hypogonadism (HH) (low luteinising hormone [LH]/follicle stimulating hormone [FSH] and sex steroids) and anosmia are developmentally related. In all vertebrate species studied, GnRH-secretory neurons have been found to originate in the olfactory placode, along with the olfactory and (except in avians) the terminalvomeronasal nerve. Nerve fibres aggregate into discrete fascicles that project i,nto the developing forebrain. Initially migrating along these nerve fascicles, GnRH cell bodies then follow a complex route into the central nervous system (CNS), where they eventually take up residence within the hypothalamus. There they establish a neural network able to synchronise pulsatile release of GnRH into the hypophyseoportal circulation the GnRH pulse generator. This is demonstrably active from the third trimester of intrauterine development and, with the exception of a period of quiescence between the ages of around 1 and 10 years in humans, continues to function throughout life.