Abstract of a paper due to be published in February’s issue of the
Journal of Clinical Investigation.
The more mutations the worse the disease in idiopathic hypogonadotropic hypogonadism
Idiopathic hypogonadotropic hypogonadism
(IHH) is an inherited genetic disorder that results in impaired sexual
development due to a deficiency in a sex hormone known as GnRH. Although
individuals are thought to inherit IHH by having just one gene defect (in any
one of a number of genes), not all the evidence supports this hypothesis, for
example, not all family members with a given gene defect have the same
symptoms.
In a study that appears online on January 18 in advance of
publication in the February print issue of the Journal of Clinical
Investigation, Nelly Pitteloud and colleagues from
Massachusetts General Hospital in Boston show that in two separate families
with distinct forms of IHH (Kallman syndrome and normosmic IHH, respectively) different combinations of
several gene defects result in different disease symptoms. In the first family,
the individual with the most severe phenotype had mutations in two different
genes (FGFR1 and NELF). By contrast, his parents and siblings
with only one or other of the mutations exhibited less severe disease.
Similarly, in the second family, the most severely affected individual had 2
mutations in her GNRHR genes and 1 mutation in her FGFR1 gene,
whereas the less severely affected family members did not have all 3 genetic
mutations. This study indicates that IHH is not caused by a defect in a single
gene, something that has implications for the genetic counseling of IHH.
TITLE: Digenic mutations account for variable
phenotypes in idiopathic hypogonadotropic
hypogonadism
AUTHOR CONTACT:
Nelly Pitteloud
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: (617) 724-1830; Fax: (617) 726-5357; E-mail: npitteloud@partners.org.
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