![]() Finally, a variety of other disorders are present in only a fraction of KS patients. In addition, a few cases of seeming reversal of hypogonadism after discontinuation of hormonal treatment have been reported. The degree of hypogonadism and of smell deficiency may vary significantly within affected families, even between monozygotic twins. Some years later, the hypogonadism was ascribed to GnRH deficiency, which can be estimated in the patients by using endocrinological tests. The occasional presence of various cerebral or cranial anomalies was also reported. These olfactory anomalies can now be shown by magnetic resonance imaging (MRI). ![]() He described the underdevelopment or absence of the olfactory bulbs and tracts in several male patients with hypogonadism. In the 1950s, de Morsier, an anatomist from Switzerland, further documented this syndrome. He showed the cosegregation of anosmia and hypogonadism in all the affected individuals, and therefore established that this syndrome can be hereditary. The syndrome was identified as a clinical entity in 1944 by an American medical geneticist, Kallmann, who carried out a study on the occurrence of hypogonadism accompanied by anosmia in three affected families. Maestre de San Juan, a Spanish anatomist, was probably the first to report the association of the absence of olfactory structures in the brain and the presence of small testes in an individual. It is believed that anosmin-1 acts as an enhancer of FGF signalling and perhaps of prokineticin signalling too. Finally, KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked form of the disease. These two genes are likely to be involved both in monogenic recessive and digenic or oligogenic KS transmission modes. Mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous or compound heterozygous states. Mutations in FGFR1, encoding fibroblast growth factor receptor 1, underlie an autosomal dominant form of the disease. Mutations in these genes, however, account for barely 30% of all KS cases. To date, five KS genes have been identified, namely, FGFR1, FGF8, PROKR2, PROK2, and KAL1. Defects in GnRH cell fate specification, differentiation, axon elongation or axon targeting to the hypothalamus median eminence may, however, also contribute to GnRH deficiency, at least in some genetic forms of the disease. This failure could be a consequence of the early degeneration of olfactory nerve and terminal nerve fibres, because the latter normally act as guiding cues for the migration of GnRH cells. Hypogonadism is due to gonadotropin-releasing hormone (GnRH) deficiency, which presumably results from a failure of the embryonic migration of neuroendocrine GnRH cells from the olfactory epithelium to the forebrain. Anosmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Nature Genetics, 36(9), 955–957.Kallmann syndrome (KS) combines hypogonadotropic hypogonadism and anosmia. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nussbaum: Thompson & Thompson genetics in medicine (7th ed.). American Journal of Human Genetics, 78(2), 303–314. ![]() Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation. Journal of the American Academy of Child and Adolescent Psychiatry, 49(8), 794–809. Autism spectrum disorders and epigenetics. Grafodatskaya, D., Chung, B., Szatmari, P., & Weksberg, R. Cohen (Eds.), Handbook of autism and pervasive developmental disorders (3rd ed., Vol. Developmental Medicine and Child Neurology, 41(4), 270–272.įilipek, P. Autistic disorders in children with CHARGE association. A., Karlgren-Leitner, C., Norlin, B., Hagberg, B., & Gillberg, C.
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