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Kallmann syndrome

Reviewed August 2008

What is Kallmann syndrome?

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.

How common is Kallmann syndrome?

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.

What genes are related to Kallmann syndrome?

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.

Related Gene(s)

Changes in these genes are associated with Kallmann syndrome.

  • FGFR1
  • KAL1
  • PROK2
  • PROKR2

How do people inherit 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.

Where can I find information about diagnosis or management of Kallmann syndrome?

These resources address the diagnosis or management of Kallmann syndrome and may include treatment providers.

  • Gene Review: Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency (http://www.ncbi.nlm.nih.gov/books/NBK1334)
  • Genetic Testing Registry: Hypogonadism with anosmia (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0162809)
  • Genetic Testing Registry: Kallmann syndrome 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1563719)
  • Genetic Testing Registry: Kallmann syndrome 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1563720)
  • Genetic Testing Registry: Kallmann syndrome 3 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2930927)
  • Genetic Testing Registry: Kallmann syndrome 4 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1857720)
  • MedlinePlus Encyclopedia: Hypogonadotropic Hypogonadism (http://www.nlm.nih.gov/medlineplus/ency/article/000390.htm)
  • MedlinePlus Encyclopedia: Smell - Impaired (http://www.nlm.nih.gov/medlineplus/ency/article/003052.htm)

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.

Where can I find additional information about Kallmann syndrome?

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.

What other names do people use for Kallmann syndrome?

  • anosmic hypogonadism
  • anosmic idiopathic hypogonadotropic hypogonadism
  • hypogonadism with anosmia
  • hypogonadotropic hypogonadism and anosmia
  • hypogonadotropic hypogonadism-anosmia syndrome
  • Kallmann's Syndrome

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.

What if I still have specific questions about Kallmann syndrome?

Ask the Genetic and Rare Diseases Information Center (https://rarediseases.info.nih.gov/gard).

What glossary definitions help with understanding Kallmann syndrome?

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.

References

  • Cadman SM, Kim SH, Hu Y, González-Martínez D, Bouloux PM. Molecular pathogenesis of Kallmann's syndrome. Horm Res. 2007;67(5):231-42. Epub 2006 Dec 21. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17191030?dopt=Abstract)
  • Cariboni A, Maggi R. Kallmann's syndrome, a neuronal migration defect. Cell Mol Life Sci. 2006 Nov;63(21):2512-26. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16952059?dopt=Abstract)
  • Dodé C, Levilliers J, Dupont JM, De Paepe A, Le Dû N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pêcheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel JC, Delemarre-van de Waal H, Goulet-Salmon B, Kottler ML, Richard O, Sanchez-Franco F, Saura R, Young J, Petit C, Hardelin JP. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. 2003 Apr;33(4):463-5. Epub 2003 Mar 10. (http://www.ncbi.nlm.nih.gov/pubmed/12627230?dopt=Abstract)
  • Dodé C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P, Kottler ML, Lespinasse J, Lienhardt-Roussie A, Mathieu M, Moerman A, Morgan G, Murat A, Toublanc JE, Wolczynski S, Delpech M, Petit C, Young J, Hardelin JP. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2006 Oct 20;2(10):e175. Epub 2006 Sep 1. (http://www.ncbi.nlm.nih.gov/pubmed/17054399?dopt=Abstract)
  • Fechner A, Fong S, McGovern P. A review of Kallmann syndrome: genetics, pathophysiology, and clinical management. Obstet Gynecol Surv. 2008 Mar;63(3):189-94. doi: 10.1097/OGX.0b013e3181641278. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18279545?dopt=Abstract)
  • Gene Review: Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency (http://www.ncbi.nlm.nih.gov/books/NBK1334)
  • Kim SH, Hu Y, Cadman S, Bouloux P. Diversity in fibroblast growth factor receptor 1 regulation: learning from the investigation of Kallmann syndrome. J Neuroendocrinol. 2008 Feb;20(2):141-63. Epub 2007 Nov 22. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18034870?dopt=Abstract)
  • Legouis R, Hardelin JP, Levilliers J, Claverie JM, Compain S, Wunderle V, Millasseau P, Le Paslier D, Cohen D, Caterina D, et al. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell. 1991 Oct 18;67(2):423-35. (http://www.ncbi.nlm.nih.gov/pubmed/1913827?dopt=Abstract)
  • Pitteloud N, Meysing A, Quinton R, Acierno JS Jr, Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes F, Seminara S, Hughes VA, Ma J, Bouloux P, Mohammadi M, Crowley WF Jr. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol. 2006 Jul 25;254-255:60-9. Epub 2006 Jun 9. (http://www.ncbi.nlm.nih.gov/pubmed/16764984?dopt=Abstract)
  • Sato N, Katsumata N, Kagami M, Hasegawa T, Hori N, Kawakita S, Minowada S, Shimotsuka A, Shishiba Y, Yokozawa M, Yasuda T, Nagasaki K, Hasegawa D, Hasegawa Y, Tachibana K, Naiki Y, Horikawa R, Tanaka T, Ogata T. Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients. J Clin Endocrinol Metab. 2004 Mar;89(3):1079-88. (http://www.ncbi.nlm.nih.gov/pubmed/15001591?dopt=Abstract)
  • Trarbach EB, Silveira LG, Latronico AC. Genetic insights into human isolated gonadotropin deficiency. Pituitary. 2007;10(4):381-91. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17624596?dopt=Abstract)
  • Tsai PS, Gill JC. Mechanisms of disease: Insights into X-linked and autosomal-dominant Kallmann syndrome. Nat Clin Pract Endocrinol Metab. 2006 Mar;2(3):160-71. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16932275?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: August 2008
Published: August 24, 2015