From OMIMCongenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).'
Although HH was initially considered to be a monogenic disorder, the presence of marked locus heterogeneity, incomplete penetrance within pedigrees, and variable expressivity of pathogenic alleles, together with evidence for mutations in multiple genes in some affected individuals, resulted in a conceptual shift from monogenicity to an oligogenic framework in which a limited number of genes contribute pathogenic alleles to the genetic network responsible for the neuroendocrine control of human reproduction (Sykiotis et al., 2010).
Genetic Heterogeneity of Hypogonadotropic Hypogonadism with or without Anosmia
Other forms of autosomal hypogonadotropic hypogonadism with or without anosmia include HH3 (244200), caused by mutation in the PROKR2 gene (607123); HH4 (610628), caused by mutation in the PROK2 gene (607002); HH5 (612370), caused by mutation in the CHD7 gene (608892); HH6 (612702), caused by mutation in the FGF8 gene (600483); HH7 (146110), caused by mutation in the GNRHR gene (138850); HH8 (614837), caused by mutation in the KISS1R gene (604161); HH9 (614838), caused by mutation in the NELF gene (608137); HH10 (614839), caused by mutation in the TAC3 gene (162330); HH11 (614840), caused by mutation in the TACR3 gene (162332); HH12 (614841), caused by mutation in the GNRH1 gene (152760); HH13 (614842), caused by mutation in the KISS1 gene (603286); HH14 (614858), caused by mutation in the WDR11 gene (606417); HH15 (614880), caused by mutation in the HS6ST1 gene (604846); HH16 (614897), caused by mutation in the SEMA3A gene (603961); HH17 (615266), caused by mutation in the SPRY4 gene (607984); HH18 (615267), caused by mutation in the IL17RD gene (606807); HH19 (615269), caused by mutation in the DUSP6 gene (602748); HH20 (615270), caused by mutation in the FGF17 gene (603725); HH21 (615271), caused by mutation in the FLRT3 gene (604808); HH22 (616030), caused by mutation in the FEZF1 gene (613301); HH23 (228300), caused by mutation in the LHB gene (152780); HH24 (229070), caused by mutation in the FSHB gene (136530); HH25 (618841), caused by mutation in the NDNF gene (616506); and HH26 (619718), caused by mutation in the TCF12 gene.
There is also an X-linked form of the disorder (HH1; 308700), caused by mutation in the KAL1 gene (300836).
There is evidence that mutation in 2 or more of these genes can work in combination (oligogenicity) to produce GnRH-deficient conditions (summary by Chan, 2011). Sykiotis et al. (2010), for example, demonstrated that of patients with an identifiable coding sequence mutation in 1 of 8 genes responsible for isolated GnRH deficiency, 11% carried mutations in at least one other of these genes as well.
Reviews
Valdes-Socin et al. (2014) reviewed the reproductive, neurodevelopmental, and genetic aspects of hypogonadotropic hypogonadism in human pathology.
Young et al. (2019) reviewed the genetics, diagnosis, and clinical management of patients with congenital hypogonadotropic hypogonadism.
http://www.omim.org/entry/147950 From MedlinePlus GeneticsKallmann syndrome is a condition characterized by delayed or absent puberty and an impaired sense of smell.
This disorder is a form of hypogonadotropic hypogonadism, which is a condition resulting from a lack of production of certain hormones that direct sexual development. These hormones are normally made in a part of the brain called the hypothalamus. Males born with hypogonadotropic hypogonadism often have an unusually small penis (micropenis) and undescended testes (cryptorchidism). At puberty, most affected individuals do not develop secondary sex characteristics, such as the growth of facial hair and deepening of the voice in males, the start of monthly periods (menstruation) and breast development in females, and a growth spurt in both sexes. Without treatment, most affected men and women are unable to have biological children (infertile).
Kallmann syndrome can have a wide variety of additional signs and symptoms. These include a failure of one kidney to develop (unilateral renal agenesis), abnormalities of bones in the fingers or toes, a cleft lip with or without an opening in the roof of the mouth (a cleft palate), abnormal eye movements, hearing loss, and abnormalities of tooth development. Some affected individuals have a feature called bimanual synkinesis, in which the movements of one hand are mirrored by the other hand. Bimanual synkinesis can make it difficult to do tasks that require the hands to move separately, such as playing a musical instrument.
In Kallmann syndrome, the sense of smell is either diminished (hyposmia) or completely absent (anosmia). This feature distinguishes Kallmann syndrome from most other forms of hypogonadotropic hypogonadism, which do not affect the sense of smell. Many people with Kallmann syndrome are not aware that they are unable to detect odors until the impairment is discovered through testing.
https://medlineplus.gov/genetics/condition/kallmann-syndrome