Kallman syndrome pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
==Pathophysiology== | |||
Under normal conditions, GnRH travels from the hypothalamus to the [[pituitary gland]] via the [[hypophyseal portal system]], where it triggers production and release of [[gonadotropin]]s ([[luteinizing hormone|LH]] and [[follicle stimulating hormone|FSH]]) from the [[gonadotrope]]s. When GnRH is low, the pituitary does not create the normal amount of gonadotropins. The gonadotropins normally increase the production of [[sex steroid|gonadal steroids]], so when they are low, these steroids will be low as well. | |||
In Kallmann syndrome, the GnRH neurons do not migrate properly from the olfactory [[placode]] to the hypothalamus during development. The olfactory bulbs also fail to form or have hypoplasia, leading to anosmia or hyposmia. | |||
===Genetics=== | |||
Kallmann syndrome can be inherited as an X-linked recessive trait, in which case there is a defect in the [[KAL1 gene|KAL1]] gene, which maps to chromosome Xp22.3.<ref name="pmid12062015">{{cite journal |author=MacColl G, Bouloux P, Quinton R |title=Kallmann syndrome: adhesion, afferents, and anosmia |journal=Neuron |volume=34 |issue=5 |pages=675–8 |year=2002 |pmid=12062015 |doi=10.1016/S0896-6273(02)00720-1}}</ref> KAL encodes a neural cell adhesion molecule, [[anosmin-1]]. Anosmin-1 is normally expressed in the [[brain]], [[face|facial]] [[mesenchyme]], [[mesonephros]] and [[metanephros]]. It is required to promote migration of [[GnRH]] neurons into the [[hypothalamus]]. It also allows migration of olfactory neurons from the [[olfactory bulbs]] to the hypothalamus. | |||
An autosomal dominant gene on chromosome 8 {8p12} (KAL-2 or FGFR-1 (fibroblast growth factor receptor 1)) is thought to cause about 10% of cases. There is some recent evidence to suggest a degree of linkage between the KAL-1 and FGFR-1 genes. | |||
An additional autosomal cause of Kallmann syndrome has been reported<ref>Dode C, et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet.2: e175, 2006.</ref> by a mutations in the prokineticin receptor-2 gene (PROKR2)(KAL-3) at position 20p13 and its ligand prokineticin 2 (PROK2)(KAL-4) at position 3p21.1. It was noted that mutations in these genes brought about various degrees of olfactory and reproductive dysfunction, but not the other symptoms seen in KAL-1 and KAL-2 forms of Kallmann Syndrome. The authors of the paper suggested that up to 30% of all Kallmann Syndrome cases can be linked to known genetic mutations. | |||
Autosomal dominant mutations have been described with the FGFR-1 (8p12) gene, sometimes referred to as the KAL-2 gene. This is thought to cause about 10% of cases. However, the majority of KS cases (70%) would seem to be the result of autosomal dominant genes even though the identity of those genes is not yet known. | |||
Autosomal recessive mutations of the GnRH receptor gene (4q13.2) have also been reported.<ref name="Quinton"> </ref> This defect appears to produce a wider spectrum of physical symptoms than with the other gene defects, and the defect lies in the ability of the pituitary gland to recognize GnRH, rather than the ability of the hypothalamus to produce GnRH. It is debatable as to whether this is in fact Kallmann syndrome since the GnRH receptor development is not related to anosmia. | |||
There may also be no obvious family history of inheritance (sporadic cases). However, it is possible for Kallmann syndrome genes to be passed on to children of a sporadic case. | |||
==References== | ==References== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Under normal conditions, GnRH travels from the hypothalamus to the pituitary gland via the hypophyseal portal system, where it triggers production and release of gonadotropins (LH and FSH) from the gonadotropes. When GnRH is low, the pituitary does not create the normal amount of gonadotropins. The gonadotropins normally increase the production of gonadal steroids, so when they are low, these steroids will be low as well.
In Kallmann syndrome, the GnRH neurons do not migrate properly from the olfactory placode to the hypothalamus during development. The olfactory bulbs also fail to form or have hypoplasia, leading to anosmia or hyposmia.
Genetics
Kallmann syndrome can be inherited as an X-linked recessive trait, in which case there is a defect in the KAL1 gene, which maps to chromosome Xp22.3.[1] KAL encodes a neural cell adhesion molecule, anosmin-1. Anosmin-1 is normally expressed in the brain, facial mesenchyme, mesonephros and metanephros. It is required to promote migration of GnRH neurons into the hypothalamus. It also allows migration of olfactory neurons from the olfactory bulbs to the hypothalamus.
An autosomal dominant gene on chromosome 8 {8p12} (KAL-2 or FGFR-1 (fibroblast growth factor receptor 1)) is thought to cause about 10% of cases. There is some recent evidence to suggest a degree of linkage between the KAL-1 and FGFR-1 genes.
An additional autosomal cause of Kallmann syndrome has been reported[2] by a mutations in the prokineticin receptor-2 gene (PROKR2)(KAL-3) at position 20p13 and its ligand prokineticin 2 (PROK2)(KAL-4) at position 3p21.1. It was noted that mutations in these genes brought about various degrees of olfactory and reproductive dysfunction, but not the other symptoms seen in KAL-1 and KAL-2 forms of Kallmann Syndrome. The authors of the paper suggested that up to 30% of all Kallmann Syndrome cases can be linked to known genetic mutations.
Autosomal dominant mutations have been described with the FGFR-1 (8p12) gene, sometimes referred to as the KAL-2 gene. This is thought to cause about 10% of cases. However, the majority of KS cases (70%) would seem to be the result of autosomal dominant genes even though the identity of those genes is not yet known.
Autosomal recessive mutations of the GnRH receptor gene (4q13.2) have also been reported.[3] This defect appears to produce a wider spectrum of physical symptoms than with the other gene defects, and the defect lies in the ability of the pituitary gland to recognize GnRH, rather than the ability of the hypothalamus to produce GnRH. It is debatable as to whether this is in fact Kallmann syndrome since the GnRH receptor development is not related to anosmia.
There may also be no obvious family history of inheritance (sporadic cases). However, it is possible for Kallmann syndrome genes to be passed on to children of a sporadic case.
References
- ↑ MacColl G, Bouloux P, Quinton R (2002). "Kallmann syndrome: adhesion, afferents, and anosmia". Neuron. 34 (5): 675–8. doi:10.1016/S0896-6273(02)00720-1. PMID 12062015.
- ↑ Dode C, et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet.2: e175, 2006.
- ↑