Clinical Genetic Testing for Kallmann Syndrome

During the past 20 years, remarkable advances have been made regarding the molecular basis of many disorders affecting reproduction. This is particularly true for patients who present with delayed puberty due to GnRH deficiency. These affected males and females manifest low serum levels of sex steroids, low or normal gonadotropins, and no other pituitary pathology. The pathophysiology of GnRH deficiency is complex, but 2 major phenotypes are observed. When hypothalamic GnRH gene regulation or GnRH synthesis, secretion, or signaling is impaired, the resulting phenotype is normosmic hypogonadotropic hypogonadism (nHH). However, it is also known that GnRH neurons originate outside of the brain and migrate along with olfactory neurons from the nasal region into the hypothalamus. If this migratory pathway of GnRH and olfactory neurons is disrupted, anosmia accompanies hypogonadotropic hypogonadism, known as Kallmann syndrome (KS). KAL1, the first gene for KS, was identified more than 20 years ago in affected males with X-linked recessive KS. Valuable families with Xp deletions and chromosomal translocations permitted the localization of this gene on chromosome Xp22.32 (1, 2). Confirmation that KAL1 mutations cause KS was obtained by the demonstration of intragenic deletions and point mutations segregating within families, which were absent in unaffected controls (3, 4). About 7 years later, mutations in GNRHR (GnRH receptor) were identified in nHH patients (5, 6). The GNRHR gene was the first gene in which mutations were found to cause nHH and autosomal recessive disease. Therefore, GNRHR was the first causative gene identified to be involved in GnRH deficiency in women (5, 6).