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Genetics Home Reference: your guide to understanding genetic conditions
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Congenital insensitivity to pain with anhidrosis

(often shortened to CIPA)
Reviewed May 2011

What is CIPA?

Congenital insensitivity to pain with anhidrosis (CIPA) has two characteristic features: the inability to feel pain and temperature, and decreased or absent sweating (anhidrosis). This condition is also known as hereditary sensory and autonomic neuropathy type IV. The signs and symptoms of CIPA appear early, usually at birth or during infancy, but with careful medical attention, affected individuals can live into adulthood.

An inability to feel pain and temperature often leads to repeated severe injuries. Unintentional self-injury is common in people with CIPA, typically by biting the tongue, lips, or fingers, which may lead to spontaneous amputation of the affected area. In addition, people with CIPA heal slowly from skin and bone injuries. Repeated trauma can lead to chronic bone infections (osteomyelitis) or a condition called Charcot joints, in which the bones and tissue surrounding joints are destroyed.

Normally, sweating helps cool the body temperature. However, in people with CIPA, anhidrosis often causes recurrent, extremely high fevers (hyperpyrexia) and seizures brought on by high temperature (febrile seizures).

In addition to the characteristic features, there are other signs and symptoms of CIPA. Many affected individuals have thick, leathery skin (lichenification) on the palms of their hands or misshapen fingernails or toenails. They can also have patches on their scalp where hair does not grow (hypotrichosis). About half of people with CIPA show signs of hyperactivity or emotional instability, and many affected individuals have intellectual disability. Some people with CIPA have weak muscle tone (hypotonia) when they are young, but muscle strength and tone become more normal as they get older.

How common is CIPA?

CIPA is a rare condition; however, the prevalence is unknown.

What genes are related to CIPA?

Mutations in the NTRK1 gene cause CIPA. The NTRK1 gene provides instructions for making a receptor protein that attaches (binds) to another protein called NGFβ. The NTRK1 receptor is important for the survival of nerve cells (neurons).

The NTRK1 receptor is found on the surface of cells, particularly neurons that transmit pain, temperature, and touch sensations (sensory neurons). When the NGFβ protein binds to the NTRK1 receptor, signals are transmitted inside the cell that tell the cell to grow and divide, and that help it survive. Mutations in the NTRK1 gene lead to a protein that cannot transmit signals. Without the proper signaling, neurons die by a process of self-destruction called apoptosis. Loss of sensory neurons leads to the inability to feel pain in people with CIPA. In addition, people with CIPA lose the nerves leading to their sweat glands, which causes the anhidrosis seen in affected individuals.

Related Gene(s)

Changes in this gene are associated with congenital insensitivity to pain with anhidrosis.

  • NTRK1

How do people inherit CIPA?

This condition is inherited in an autosomal recessive pattern, which 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 CIPA?

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

  • Gene Review: Hereditary Sensory and Autonomic Neuropathy Type IV (http://www.ncbi.nlm.nih.gov/books/NBK1769/)
  • Genetic Testing Registry: Hereditary insensitivity to pain with anhidrosis (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0020074)

You might also find information on the diagnosis or management of CIPA in Educational resources (http://www.ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain-with-anhidrosis/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain-with-anhidrosis/show/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 CIPA?

You may find the following resources about CIPA helpful. These materials are written for the general public.

  • MedlinePlus - Health information

    • Encyclopedia: Osteomyelitis (http://www.nlm.nih.gov/medlineplus/ency/article/000437.htm)
    • Encyclopedia: Sweating - absent (http://www.nlm.nih.gov/medlineplus/ency/article/003219.htm)
    • Health Topic: Degenerative Nerve Diseases (http://www.nlm.nih.gov/medlineplus/degenerativenervediseases.html)
    • Health Topic: Peripheral Nerve Disorders (http://www.nlm.nih.gov/medlineplus/peripheralnervedisorders.html)

  • Additional NIH Resources - National Institutes of Health

    • National Institute of Neurological Disorders and Stroke: Hereditary Neuropathies (http://www.ninds.nih.gov/disorders/neuropathy_hereditary/neuropathy_hereditary.htm)
    • National Institute of Neurological Disorders and Stroke: Peripheral Neuropathy (http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm)
    • National Institutes of Health Rare Diseases Clinical Research Network: The Inherited Neuropathies Consortium (http://rarediseasesnetwork.epi.usf.edu/INC/professional/disorders/HSAN/)

  • Educational resources - Information pages

    • Orphanet: Hereditary Sensory and Autonomic Neuropathy Type 4 (http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=935&Disease_Disease_Search_diseaseGroup=Hereditary-sensory-and-autonomic-neuropathy-type-2&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Hereditary-sensory-and-autonomic-neuropathy-type-4&title=Hereditary-sensory-and-autonomic-neuropathy-type-4&search=Disease_Search_Simple)
    • University of Chicago Center for Peripheral Neuropathy (http://peripheralneuropathycenter.uchicago.edu/)

  • Patient support - For patients and families

    • National Organization for Rare Disorders: Hereditary Sensory and Autonomic Neuropathy, Type IV (http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1144/viewAbstract)
    • The Neuropathy Association (http://www.neuropathy.org/site/PageServer)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

  • Gene Reviews - Clinical summary (http://www.ncbi.nlm.nih.gov/books/NBK1769/)

  • Genetic Testing Registry - Repository of genetic test information

    • Genetic Testing Registry: Hereditary insensitivity to pain with anhidrosis (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0020074)
  • PubMed - Recent literature (http://www.ncbi.nlm.nih.gov/pubmed?term=(Hereditary%20Sensory%20and%20Autonomic%20Neuropathies%5BMAJR%5D)%20AND%20((congenital%20insensitivity%20to%20pain%20with%20anhidrosis%5BTIAB%5D)%20OR%20(hsan%20type%20iv%5BTIAB%5D)%20OR%20(hereditary%20sensory%20autonomic%20neuropathy%20type%20iv%5BTIAB%5D)%20OR%20(hsan4%5BTIAB%5D)%20OR%20(cipa%5BTIAB%5D))%20AND%20english%5Bla%5D%20AND%20human%5Bmh%5D%20AND%20%22last%203600%20days%22%5Bdp%5D)
  • OMIM - Genetic disorder catalog (http://omim.org/entry/256800)

What other names do people use for CIPA?

  • hereditary sensory and autonomic neuropathy, type 4
  • hereditary sensory and autonomic neuropathy type IV
  • HSAN4
  • HSAN type IV

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 CIPA?

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

What glossary definitions help with understanding CIPA?

absent sweating ; anhidrosis ; apoptosis ; autosomal ; autosomal recessive ; cell ; chronic ; congenital ; gene ; hyperactivity ; hypotonia ; hypotrichosis ; injury ; muscle tone ; neuropathy ; osteomyelitis ; prevalence ; protein ; receptor ; recessive ; spontaneous ; tissue ; trauma

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano T, Mitsubuchi H, Tonoki H, Awaya Y, Matsuda I. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet. 1996 Aug;13(4):485-8. (http://www.ncbi.nlm.nih.gov/pubmed/8696348?dopt=Abstract)
  • Indo Y. Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Hum Mutat. 2001 Dec;18(6):462-71. Review. (http://www.ncbi.nlm.nih.gov/pubmed/11748840?dopt=Abstract)
  • Kaplan DR, Miller FD. Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol. 2000 Jun;10(3):381-91. Review. (http://www.ncbi.nlm.nih.gov/pubmed/10851172?dopt=Abstract)
  • Miranda C, Di Virgilio M, Selleri S, Zanotti G, Pagliardini S, Pierotti MA, Greco A. Novel pathogenic mechanisms of congenital insensitivity to pain with anhidrosis genetic disorder unveiled by functional analysis of neurotrophic tyrosine receptor kinase type 1/nerve growth factor receptor mutations. J Biol Chem. 2002 Feb 22;277(8):6455-62. Epub 2001 Nov 21. (http://www.ncbi.nlm.nih.gov/pubmed/11719521?dopt=Abstract)
  • Verhoeven K, Timmerman V, Mauko B, Pieber TR, De Jonghe P, Auer-Grumbach M. Recent advances in hereditary sensory and autonomic neuropathies. Curr Opin Neurol. 2006 Oct;19(5):474-80. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16969157?dopt=Abstract)
  • Verpoorten N, De Jonghe P, Timmerman V. Disease mechanisms in hereditary sensory and autonomic neuropathies. Neurobiol Dis. 2006 Feb;21(2):247-55. Epub 2005 Sep 23. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16183296?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: May 2011
Published: May 20, 2013