Endocrinology :: 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.

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