An episode of the television medical drama “House” featured 16-year-old Hannah and her mother, who were in a severe automobile accident. Hannah saw her mother unconscious and dialed 911. She looked down and noticed a metal rod jammed in her own thigh. At the hospital, Hannah soon ran a 105 degree fever, although she neither sweated nor shivered. She then collapsed, and ice water and cooling packs were applied. Later, Hannah underwent a PET scan and stuck her hand in and out of a container of very hot water while doctors observed her brain activity. During the test, she got distracted and forgot to remove her hand from the hot water. By the time the doctor pulled it out, Hannah had second-degree burns. Throughout her hospital stay, Hannah never winced, never complained of any pain at all.
Though Hannah is a fictional character on a television show, she displays all the signs of one of the rarest disorders on record: congenital insensitivity to pain with anhidrosis, or CIPA. As of 2000, only 56 cases had been identified worldwide, all in the pediatric age range, according to an article written by Dr. Stanley A. Shatsky and colleagues in the American Journal of Medical Genetics. Despite its rarity, CIPA has gained some recognition after being featured in episodes of both “House” and “Grey’s Anatomy.”
CIPA, also referred to as hereditary sensory and autonomic neuropathy type IV (HSAN-IV), is an autosomal recessive hereditary disorder characterized by recurrent episodic fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation,” writes Dr. Yasuhiro Indo in an issue of Human Mutuation: Variation, Informatics and Disease.
According to the American Journal of Medical Genetics study, it is especially common to those of Israeli Bedouin backgrounds, who make up 28 of the 56 known cases. This prevalence is probably due to a high rate of consanguineous marriage, and thus increased homozygosity for the genetic mutation allele.
What does CIPA look like?
One of the first obstacles CIPA patients must overcome is teething, as they often bite holes through their tongue and gums without realizing they are doing so. Such dangers have led some parents of CIPA patients to remove their children’s teeth, knowing that by the time their adult teeth come in, their children will be old enough to control their biting. The removal of teeth does, however, often cause difficulties eating. While their peers are learning to eat hard foods, they must eat soft foods and are thus often left developmentally behind.
People with CIPA also have difficulties with behaviors that involve paying attention to bodily cues. For example, they have trouble becoming toilet-trained, since they are unable to recognize the feelings associated with going to the bathroom. Often, they set timers reminding themselves to use the restroom. Timers are also helpful in reminding themselves to eat, as they do not feel hunger pains. Additionally, they must be wary of eye injuries that may come from scratching or rubbing their eyes too hard and wear goggles or glasses to prevent such injuries.
Maintaining a healthy body temperature is problematic for individuals with CIPA, and in fact, can be a dangerous problem. One of the most dangerous characteristics of CIPA is the common fever associated with it. Patients are unable to sweat and are therefore unable to regulate their body temperature the way most people can. During exercise and time spent outside, they must be cautious of overheating because otherwise they may experience febrile seizures or even death. Many parents of children with CIPA choose to live in cooler climates in order to prevent overheating.
The Molecular Basis of CIPA
According to molecular genetic studies by Indo, CIPA is a Mendelian autosomal recessive disorder caused by a mutation to a specific gene called the TRKA gene, on chromosome 1. With this mutation, there is a signal transduction problem at the TRKA receptor for nerve growth factor (NGF), so it cannot phosphorylate an enzyme called RTK. Therefore, there is a failure of the sympathetic ganglion neurons — neurons that send signals out of the spinal cord to the brain — and pain receptors to survive. They undergo cell death, and, thus, affected individuals are unable to feel pain.
Indo found that in addition to pain perception, these same cells are components of sweating and are implicated in brain plasticity and learning. Perhaps the most pressing problem of those affected with CIPA is the characteristic anhidrosis. Without the ability to sweat, overheating is a deadly threat. Mutations of the TRKA gene may also lead to loss of innervation to eccrine sweat glands. Eccrine sweat glands are present all over the body and are innervated primarily by cholinergic fibers of the sympathetic nervous system, Indo writes. The mutation to TRKA engenders the death of cholinergic neurons in the basal forebrain, so sweat glands are not innervated and thus do not work. The exact cause of the mental retardation exhibited by CIPA patients is still unknown, but, as Indo speculates, writing in the 2010 journal Pain, the death of these cholinergic neurons may also be the cause of it, since cholinergic neurons are involved in learning and memory.
The Future of CIPA
CIPA is a Mendelian recessive autosomal disorder with no evidence for heterogeneity; i.e., there is no range of severity. While there is currently no cure, Indo suggests that CIPA patients offer an opportunity for pharmacological research to understand pain disorders and what might happen when the TRKA receptors are targeted in those with chronic pain, as Doctor House hopes he can find with Hannah.