![]() ![]() The degree of the hypogonadism and that of the smell deficiency can, however, vary significantly, not only between unrelated patients, but also within affected families 5, 6 (and see pedigrees in references 7, 8, 9, 10, 11, 12, 13, 14), even between monozygotic twins. The Kallmann syndrome typically combines severe HH with a complete absence of the sense of smell (anosmia). Moreover, primary amenorrhea in females often remains unexplored. In girls, the prevalence is thought to be five times lower, but is probably underestimated because some affected females only have mild hypogonadism (see below). It has been roughly estimated at one out of 8000 in boys. 3 Some years later, the hypogonadism was ascribed to gonadotropin-releasing hormone (GnRH) deficiency. In the 1950s, the Swiss anatomist de Morsier further documented the disease by describing the underdevelopment or absence of the olfactory bulbs and tracts in several male patients with hypogonadism. 2 He showed the cosegregation of the anosmia and the hypogonadism in all the affected individuals, and therefore established that this syndrome can be hereditary. 1 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 was probably the first to report, in 1856, the association of the absence of olfactory structures in the brain and the presence of small testes in an individual. In both sexes, hormone replacement therapies are used to stimulate the development of secondary sexual characteristics at the time of puberty, and later to induce fertility. ![]() There is currently no treatment for olfactory deficit. Treatment of KS is that of the hypogonadism. Genetic testing strategy (Figure 1) is based on patient's gender, familial history (if any) and putative mode of disease inheritance, and the presence of additional clinical anomalies that may direct the geneticist towards a particular disease gene or occasionally a contiguous gene syndrome. Mutations in any of the five known disease genes ( KAL1, FGFR1, FGF8, PROKR2, PROK2) have been identified in a relatively small proportion (less than 30%) of the patients.Īs many as 30% of the mutations found in FGFR1 might be de novo mutations, certainly a possibility to be considered before assessing recurrence risk of this genetic form in a family. Main differential diagnoses are normosmic idiopathic hypogonadotropic hypogonadism and CHARGE syndrome.ĭifferent modes of KS transmission include X chromosome-linked recessive, autosomal recessive, autosomal dominant with incomplete penetrance, and most probably digenic/oligogenic inheritance. Some non-reproductive non-olfactory anomalies can also be present, depending on the genetic form of the disease.ĭisease prevalence has been roughly estimated at 1:8000 males and 1:40000 females, but might be underestimated especially in females. KS is a genetically heterogeneous developmental disease that most often manifests as absent spontaneous puberty combined with a defective sense of smell (hyposmia or anosmia). ![]()
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