Kallmann syndrome

At least seven mutations in the FGF8 gene have been identified in people with Kallmann syndrome, a disorder characterized by the combination of hypogonadotropic hypogonadism (a condition affecting the production of hormones that direct sexual development) and an impaired sense of smell. This condition can also affect other body systems, and its features vary among affected individuals. Researchers estimate that mutations in the FGF8 gene account for a small percentage of all cases of Kallmann syndrome.

Most of the FGF8 gene mutations that cause Kallmann syndrome change single protein building blocks (amino acids) in the FGF8 protein. These mutations reduce or eliminate the protein's function, including its ability to bind to FGFR1. Studies suggest that a shortage of functional FGF8 disrupts the migration and survival of olfactory neurons and GnRH-producing neurons in the developing brain. If olfactory nerve cells do not extend to the olfactory bulb, a person's sense of smell will be impaired or absent. Misplacement or premature loss of GnRH-producing neurons prevents the production of sex hormones, which interferes with normal sexual development and causes puberty to be delayed or absent.

Some people with Kallmann syndrome resulting from FGF8 gene mutations have additional features, such as a split in the lip (cleft lip) with an opening in the roof of the mouth (a cleft palate), and a condition called bimanual synkinesis, in which the movements of one hand are mirrored by the other hand. It is unclear how mutations in the FGF8 gene lead to these other signs and symptoms. Because these features vary among individuals, researchers suspect that other genetic and environmental factors may be involved. Some affected individuals have mutations in one of several other genes in addition to FGF8, and these genetic changes may contribute to the varied features of the condition.

Nonsyndromic holoprosencephaly

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Nonsyndromic holoprosencephaly

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Other disorders

Several mutations in the FGF8 gene have been found to cause a form of hypogonadotropic hypogonadism that occurs without an impaired sense of smell. This condition is often called normosmic isolated hypogonadotropic hypogonadism (nIHH). 

Like most of the FGF8 gene mutations that cause Kallmann syndrome (described above), the mutations that cause nIHH change single amino acids in the FGF8 protein. These mutations reduce or eliminate the function of FGF8, including its ability to bind to FGFR1. A shortage of functional FGF8 disrupts the migration of GnRH-producing nerve cells in the developing brain, which affects the production of sex hormones and leads to delayed or absent puberty. 

It is unclear why some FGF8 gene mutations affect the sense of smell (resulting in Kallmann syndrome) and others do not (resulting in nIHH). At least one mutation has been found to cause Kallmann syndrome in some people and nIHH in others; this genetic change replaces the amino acid arginine with the amino acid glycine at position 127 of the FGF8 protein (written as Arg127Gly or R127G).