What is congenital insensitivity to pain with anhidrosis?

Congenital insensitivity to pain with anhidrosis (CIPA) is the inability to feel pain and temperature as well as having a reduction or complete absence of sweating [1].  CIPA is also known as hereditary sensory and autonomic neuropathy type IV (HSAN type IV) [1].  CIPA is an extremely rare condition with an unknown prevalence[1].  CIPA is inherited in an autosomal recessive pattern, which means both copies of the gene must be abnormal in order for a genetic disease to occur [1].  The characteristics of CIPA become evident in infancy when the child fails to respond to painful stimuli.  Secondary consequences of CIPA include self-mutilation of the tongue, lips, cheeks, fingers and eyes, recurrent bone fractures, chronic bone infections (osteomyelitis), joint trauma and the potential to develop Charcot joints [1,2].  Anhidrosis causes extremely high recurrent fevers, which result in febrile seizures [1].  Other physical symptoms of CIPA include misshapen fingernails or toenails, patches on their scalp where hair fails to grow (hyperpyrexia) and thick,  leathery skin on the palms of their hands [1].  Approximately half of all affected individuals show signs of hyperactivity and emotional instability [2].  Many affected individuals also have severe learning disabilities [1]. 

NTRK1

Congenital insensitivity to pain with anhidrosis (CIPA) is caused by a mutation in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) [3].  The NTRK1 gene mutation is detected in CIPA patients all over the world [4].  The NTRK1 gene makes a protein that is essential for the development and survival of sensory neurons; if this gene is defective, it can set off a chain of events that can lead to sensory neuron death.  The NTRK1 protein is an enzyme that changes the activity of other proteins by adding a cluster of oxygen or phosphorus atoms at specific positions, which is know as phosphorylation.  The NTRK1 protein is activated when a nerve growth factor beta (NGFβ) binds to it  and signals the NTRK1 protein to phosphorylate itself.  Many of the NTRK1 gene mutations lead to the production of a NTRK1 protein that cannot be activated by phosphorylation.  When the NTRK1 protein fails to be activated by phosphorylation it is unable to transmit growth and survival signals to the neurons.  Without signals  from the NTRK1 protein the neurons die by a process of self destruction (apoptosis).  People with CIPA lose the ability to feel pain due to the loss of these sensory neurons.  Some people with CIPA also lose the nerves leading to their sweat glands, which causes anhidrosis [3].

The NTRK1 gene is located on the long (q) arm of chromosome one between positions 21 and 22 and between base pairs 156,785,541 and 156,851,641.

Management

There is no treatment for congenital insensitivity to pain with anhidrosis (CIPA) because the survival and maintenance of specific neurons takes place during embryogenesis [4].  However the secondary consequences of CIPA need to be addressed in order to regulate body temperature, prevent self-mutilation and prevent orthopedic problems.  There are number of techniques that can be used to try to combat the secondary consequences of CIPA.  It is important to conduct daily evaluations to check for early signs of an unrecognized injury.  Braces may need to be warn to prevent injury to weight-bearing joints.  Sedation may be required to avoid further injuries.  Smoothing or removal of the teeth can help prevent self-mutilation of the tongue, lips and cheeks.  To protect the eyes it may be necessary wear protective eye wear or to partially sew the eyelids together (tarsorrhaphy).  Monitoring temperature carefully can help to prevent febrile seizures and using acetaminophen and/or ibuprofen and cooling baths or cooling blankets can bring down fevers [2].

References

[1] "Congenital Insensitivity to Pain with Anhidrosis." CIPA. U.S. National Library of Medicine, 28 Jan. 2013. Web. 04 Feb. 2013. <http://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain-with-anhidrosis>.
[2] Axelrod FB, Gold-von Simson G, Oddoux C. Hereditary Sensory and Autonomic Neuropathy IV. 2008 Aug 5 [Updated 2009 Nov 24]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1769/
[3] "NTRK1." - Neurotrophic Tyrosine Kinase, Receptor, Type 1. U.S. National Library of Medicine, 28 Jan. 2013. Web. 04 Feb. 2013. <http://ghr.nlm.nih.gov/gene/NTRK1>.
[4] Indo, Y. (2001), 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., 18: 462–471. doi: 10.1002/humu.1224