Kallmann’s syndrome and normosmic isolated hypogonadotropic hypogonadism: two largely overlapping manifestations of one rare disorder

Excerpt

Central hypogonadism (CHg) is a disorder caused by an insufficient GnRH stimulation of an otherwise intact pituitary–gonadal axis. It is also called isolated or congenital gonadotropin-releasing hormone (GnRH) deficiency or isolated hypogonadotropic hypogonadism (IHH). CHg may be either congenital or acquired, and can either be secondary to hypothalamic or pituitary dysfunctions. Isolated CHg is a rare disease with an incidence of 1:8,000 males and 1:40,000 females. It can either be associated with a normal or defective sense of smell, respectively, identifying the normosmic CHg (nCHg or nIHH) or the Kallmann’s syndrome (KS). Males frequently present with defective androgenization and growth at peripubertal age but micropenis and cryptorchidism may already be evident in the neonatal period, indicating a defective HPG activation during the prenatal development. Females generally present with primary amenorrhea and growth retardation. Additional neurological (e.g., anosmia, bimanual synkinesia) and non-neurological defects (e.g., the midline or kidney defects) may frequently co-exist and be linked to specific modes of inheritance. Indeed, KS was originally described as caused by mutations in a specific X-chromosome gene, KAL-1 (reviewed in ref. [1]), with a consequent altered targeting of olfactory axons and migration of neurons producing GnRH, the key central regulator of the reproductive axis, but this genetic defect was soon found to be present in a minority of the patients. Thus the causal event of the isolated CHg was often missing and the classification of “idiopathic” IHH or CHg was consequently adopted. Nevertheless, the observation of familial cases with variable modes of inheritance (X-linked or autosomal dominant or recessive) soon indicated that IHH or CHg retains a highly heterogeneous genetic component. The application of conventional linkage studies to investigate the genetic basis has proven difficult, because most pedigrees tend to be of small size, since the majority of patients remain infertile in the absence of therapeutic treatment. In the last decade, however, the knowledge on the pathogenesis of CHg has been profoundly deepened thanks to the utilization of animal and cellular models; these, together with the application of modern techniques of genetic investigation, brought evidence of previously unknown genetic determinants of IHH (either nCHg or KS). These new insights have played a significant role in disclosing the physiological complexities of the HPG axis and therefore in elucidating the pathophysiology of IHH. Association with a multitude of candidate genes has nowadays been identified [1]. Some genes are determinant for the correct embryonic differentiation of the GnRH-secreting neurons, such as the receptor-ligand pair fibroblast growth factor receptor 1; fibroblast growth factor 8 (FGFR1/FGF8), nasal embrionic LH releasing hormone factor (NELF) and heparan sulfate 6-O-sulfotransferase 1 (HS6HST1). Other genes encode the signals essential for the correct migration of the GnRH neurons form their embryonic origin to the hypothalamus, such as the KAL-1, the ligand–receptor complex prokineticin 2 and its receptor (PROK2/PROKR2), the chromodomain helicase DNA binding protein 7 (CHD7) and SEMA3A (members of the class 3 Semaphorins). Other genes encode the elements of upstream signals contributing to the activation of GnRH neuron, such as the two ligand–receptor couples formed either by the TAC3/TACR3 (tachykinin 3 and its receptor also named neurokinin B, NKB, and/or neurokinin 3 receptor, NK3) or the KISS1/KISS1R (kisspeptin1 and its receptor, previously known as GPR54). Finally, candidate genes for IHH also include the GnRH gene itself (GnRH1) and its receptor (GNRHR). …