Hereditary sensory and autonomic neuropathy type 4 (HSAN 4) - also or more commonly known as Congenital insensitivity to pain with anhidrosis (CIPA) - has two characteristic features: the inability to feel pain and temperature, and decreased or absent sweating (anhidrosis). 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.
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.
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.
Axon flare after intradermal histamine phosphate injection is absent, a finding in all HSAN types that is not specific to HSAN IV. Mutations in NTRK1 (TRKA), the only gene known to be associated with HSAN IV, are identified by sequence analysis in almost all individuals meeting HSAN IV diagnostic criteria.
Treatments for CIPA do not always work; however, there are some cases where Naloxone may be used as a treatment. Naloxone is a chemical that acts within the nervous system of the body by blocking the nervous system from causing the inactions that occur within the group of cells that receives the message to initiate the sensation of pain, heat, or cold. Most treatments are hard to narrow down for this condition because each CIPA patient may have other conditions including the absence of a sweat gland, nerve fibers, ulcers[disambiguation needed], and other sub-conditions. It has been suggested that young CIPA sufferers have their baby teeth removed so they cannot chew through their tongue, lips or fingers until their full set of adult teeth grow through.
Prevention of secondary severe or debilitating orthopedic problems by daily evaluation for early signs of unrecognized injury; control of hyperthermia with acetaminophen and/or ibuprofen or direct cooling in a bath or cooling blanket; prevention of neurotrophic keratitis with tarsorrhaphy, corneal patch graft, keratoplasty, and/or scleral bandage lens. Antipsychotic and/or ADHD medications in conjunction with behavior modification as needed. Interventions for behavioral, developmental, and motor delays; educational and social support for school-age children and adolescents.