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Kallmann syndrome is a condition characterized by delayed or absent puberty and an impaired sense of smell.
This disorder is a form of hypogonadotropic hypogonadism (HH), which is a condition affecting the production of hormones that direct sexual development. Males with hypogonadotropic hypogonadism are often born with an unusually small penis (micropenis) and undescended testes (cryptorchidism). At puberty, most affected individuals do not develop secondary sex characteristics, such as the growth of facial hair and deepening of the voice in males. Affected females usually do not begin menstruating at puberty and have little or no breast development. In some people, puberty is incomplete or delayed.
In Kallmann syndrome, the sense of smell is either diminished (hyposmia) or completely absent (anosmia). This feature distinguishes Kallmann syndrome from most other forms of hypogonadotropic hypogonadism, which do not affect the sense of smell. Many people with Kallmann syndrome are not aware that they are unable to detect odors until the impairment is discovered through testing.
The features of Kallmann syndrome vary, even among affected people in the same family. Additional signs and symptoms can include a failure of one kidney to develop (unilateral renal agenesis), a cleft lip with or without an opening in the roof of the mouth (a cleft palate), abnormal eye movements, hearing loss, and abnormalities of tooth development. Some affected individuals have a condition called bimanual synkinesis, in which the movements of one hand are mirrored by the other hand. Bimanual synkinesis can make it difficult to do tasks that require the hands to move separately, such as playing a musical instrument.
Researchers have identified four forms of Kallmann syndrome, designated types 1 through 4, which are distinguished by their genetic cause. The four types are each characterized by hypogonadotropic hypogonadism and an impaired sense of smell. Additional features, such as a cleft palate, seem to occur only in types 1 and 2.
Kallmann syndrome is estimated to affect 1 in 10,000 to 86,000 people and occurs more often in males than in females. Kallmann syndrome 1 is the most common form of the disorder.
Mutations in the KAL1, FGFR1, PROKR2, and PROK2 genes cause Kallmann syndrome. KAL1 mutations are responsible for Kallmann syndrome 1. Kallmann syndrome 2 results from mutations in the FGFR1 gene. Mutations in the PROKR2 and PROK2 genes cause Kallmann syndrome types 3 and 4, respectively.
The genes associated with Kallmann syndrome play a role in the development of certain areas of the brain before birth. Although some of their specific functions are unclear, these genes appear to be involved in the formation and movement (migration) of a group of nerve cells that are specialized to process smells (olfactory neurons). These nerve cells come together into a bundle called the olfactory bulb, which is critical for the perception of odors. The KAL1, FGFR1, PROKR2, and PROK2 genes also play a role in the migration of neurons that produce a hormone called gonadotropin-releasing hormone (GnRH). GnRH controls the production of several other hormones that direct sexual development before birth and during puberty. These hormones are important for the normal function of the gonads (ovaries in women and testes in men).
Studies suggest that mutations in the KAL1, FGFR1, PROKR2, or PROK2 gene disrupt the migration of olfactory nerve cells and GnRH-producing nerve cells 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 of GnRH-producing neurons prevents the production of certain sex hormones, which interferes with normal sexual development and causes the characteristic features of hypogonadotropic hypogonadism. It is unclear how gene mutations lead to the other possible signs and symptoms of Kallmann syndrome. Because the features of this condition vary among individuals, researchers suspect that additional genetic and environmental factors may be involved.
Together, mutations in the KAL1, FGFR1, PROKR2, and PROK2 genes account for 25 percent to 30 percent of all cases of Kallmann syndrome. In cases without an identified mutation in one of these genes, the cause of the condition is unknown. Researchers are looking for other genes that can cause this disorder.
Changes in these genes are associated with Kallmann syndrome.
Kallmann syndrome 1 (caused by KAL1 mutations) has an X-linked recessive pattern of inheritance. The KAL1 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
Most cases of Kallmann syndrome 1 are described as simplex, which means only one person in a family is affected. Some affected people inherit a KAL1 mutation from their mothers, who carry a single mutated copy of the gene in each cell. Other people have the condition as a result of a new mutation in the KAL1 gene.
Other forms of Kallmann syndrome can be inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.
In several families, Kallmann syndrome has shown an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
These resources address the diagnosis or management of Kallmann syndrome and may include treatment providers.
You might also find information on the diagnosis or management of Kallmann syndrome in Educational resources and Patient support.
General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).
To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.
You may find the following resources about Kallmann syndrome helpful. These materials are written for the general public.
You may also be interested in these resources, which are designed for healthcare professionals and researchers.
For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.
Ask the Genetic and Rare Diseases Information Center (https://rarediseases.info.nih.gov/gard).
agenesis ; anosmia ; autosomal ; autosomal dominant ; autosomal recessive ; cell ; chromosome ; cleft palate ; cryptorchidism ; gene ; hormone ; hypogonadism ; hypogonadotropic ; hypothalamus ; idiopathic ; inherit ; inheritance ; inherited ; kidney ; micropenis ; mutation ; new mutation ; olfactory bulb ; palate ; pattern of inheritance ; perception ; puberty ; recessive ; renal ; sex chromosomes ; syndrome ; synkinesis ; testes ; unilateral ; X-linked recessive
You may find definitions for these and many other terms in the Genetics Home Reference Glossary.
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