Hereditary sensory and autonomic neuropathy type IV
Related Terms
Anhidrosis, autosomal recessive disorders, CIPA, ectodermal dysplasia, familial dysautonomia type II, hereditary sensory and autonomic neuropathy type IV, HSAN-IV, NGF, nerve growth factor, neurotrophic tyrosine kinase receptor type 1, NTRK1 gene, RTK gene, TRKA gene.
Background
Congenital insensitivity to pain with anhidrosis (CIPA) is one of several ectodermal dysplasias, disorders that affect the outer layer of a developing embryo. This layer, called the ectoderm, develops into body parts such as the eyes, nails, hair, and skin, including pain receptors and sweat glands.
In CIPA, the nerves that sense heat and pain are abnormal or absent. As a result, those who suffer from CIPA are insensitive to heat and pain. People with CIPA are also unable to sweat, a condition called anhidrosis, which affects the ability to regulate body temperature and may lead to fevers in hot weather.
Because people with CIPA do not sense pain, they often injure themselves. Self-mutilating behavior is also common among CIPA patients, who may bite their own tongues, lips, and fingers. Numerous injuries can result in excessive scarring, infection, and deformities. Damaged limbs may even lose function or have to be amputated.
CIPA is caused by a mutation or defect in the NTRK1 gene. It is inherited, or passed down in families, as an autosomal recessive trait. A person must inherit two copies of the defective NTRK1 gene (one copy from each parent) for the disease to appear. People who inherit a mutated gene from only one parent are called "carriers" of the disease, and they can pass the mutation to their children.
CIPA is extremely rare. While actual incidence is unknown, there are fewer than 100 known cases in the United States. CIPA is more common among people from northern Israel, Ecuador, Sweden, and Japan. Incidence of the disease is higher among people whose parents are closely related to one another (also known as consanguineous).
While there is no cure for CIPA, treatment focuses on the relief of symptoms and the prevention of injury and infection. Many people with CIPA die prematurely because of injuries, fever, or infections.
Signs and symptoms
People with congenital insensitivity to pain with anhidrosis (CIPA) are insensitive to heat and pain. They are also unable to sweat, a condition called anhidrosis, which affects their ability to regulate body temperature and may lead to fevers in hot weather.
People with CIPA usually have intellectual disabilities, but some are of average intelligence.
Diagnosis
General: People with congenital insensitivity to pain with anhidrosis (CIPA) should receive a complete physical exam and provide a family history. During the patient interview, a clinician should focus on the patient's receptiveness to pain and history of injuries.
Biopsy: In a biopsy, a sample of tissue is removed from the body and the cells are examined in a laboratory. A biopsy from a person with CIPA may reveal decreased numbers of nerve fibers and a lack of sweat glands.
Genetic (DNA) testing: DNA tests may also be performed to confirm the presence of a mutated NTRK1 gene. Genetic testing is often performed to confirm the results of other tests.
Amniotic fluid (prenatal) genetic testing: CIPA may be diagnosed in a developing fetus using blood samples taken from the fetus. Diagnosis of CIPA may also be performed on a fetus through amniocentesis, in which the amniotic fluid surrounding the fetus is sampled through a needle. Genetic tests may be performed on blood or amniotic fluid. Because taking a blood sample may cause harm to a developing fetus, taking samples of amniotic fluid is generally preferred. It is important to note, however, that any prenatal test carries a risk of miscarriage.
Chorionic villus sampling (CVS): CVS is another type of prenatal diagnosis that can detect genetic problems in a fetus. Samples are taken from the chorionic villus, or placental tissue. It is important to note that any prenatal test carries a risk of miscarriage.
Pre-implantation genetic diagnosis (PGD): PGD is a new procedure that may be performed on embryos produced by in vitro (artificial) fertilization. This test allows parents to implant and bring to term only the embryos that do not carry the mutated genes that cause CIPA.
Complications
Fever and burns: Individuals with congenital insensitivity to pain with anhidrosis (CIPA) lack the ability to sweat (anhidrosis). Body temperature cannot be regulated, and people with CIPA may develop fevers during hot weather and be unresponsive to heat exposure. Because they are not sensitive to pain, people with CIPA may sustain burns to various parts of their bodies. For example, individuals with CIPA may sustain sunburns, cooking burns, and chemical burns.
Infection: Because people with CIPA are insensitive to pain, they may not attend to injuries to the skin and bone, which may lead to infection. Osteomyelitis, an infection of the bone or bone marrow, is a common problem in people with CIPA. Injury to the mouth, lips, gums, and teeth may be caused by self-mutilating behavior that is common in individuals with CIPA.
Injury: People with CIPA may be accident-prone, may sustain injuries to the arms and legs without sensing pain, and may injure themselves or self-mutilate parts of their body such as biting the tongue and/or finger tips. These injuries can lead to excessive scarring and infection. People with CIPA are also at an increased risk for broken bones, joint deformities, and osteomyelitis, a type of bone infection.
Other: Due to their insensitivity to pain, people with CIPA commonly sustain eye injuries known as corneal lacerations or scratches on the surface of the eye, painless bone fractures, joint deformities, and arthritis caused by repetitive injury.
Treatment
General: There is currently no known cure for congenital insensitivity to pain with anhidrosis (CIPA). Treatment is instead focused on the management of symptoms and prevention of injury and infection.
Antibiotics: Antibiotics may be taken by mouth or applied to the skin to treat infections of the mouth or skin.
Behavioral therapy: Several different types of behavioral therapy are available to help people with CIPA improve their communication and social skills, and strengthen learning abilities and adaptive behaviors. Evidence suggests that behavioral therapy is most effective if it is started early in life.
Education: Patients with CIPA who suffer from intellectual disabilities must have access to education tailored to their specific strengths and weaknesses. According to the Individuals with Disabilities Education Act, all children with disabilities must receive free and appropriate education. This law states that staff at the patient's school must consult with the patient's parents or caregivers to design and write an individualized education plan based on the child's needs. The school faculty should document the child's progress in order to ensure that the child's needs are being met.
Educational programs vary depending on a child's specific learning disabilities. In general, most experts believe that children with disabilities should be educated alongside their nondisabled peers. The idea is that nondisabled students will help the patient learn appropriate behavioral, social, and language skills. For this reason some people with CIPA are educated in mainstream classrooms. Other patients attend public schools but take special education classes. Others attend specialized schools that are designed to teach children with disabilities.
Occupational therapy: Patients with CIPA may benefit from occupational therapy. During sessions, a therapist helps the child learn the skills needed to perform basic daily tasks, such as feeding, dressing, and communicating with others. Some patients work with therapists who specialize in disorders and disabilities. Parents and caregivers can ask their children's pediatricians to recommend a therapist.
Integrative therapies
Currently, there is a lack of scientific data on the use of integrative therapies for the treatment or prevention of congenital insensitivity to pain with anhidrosis (CIPA).
Prevention
General: Because congenital insensitivity to pain with anhidrosis (CIPA) is inherited, there is currently no known way to prevent it. Options do exist to prevent injury and infection.
Genetic testing and counseling: Individuals who have CIPA may meet with a genetic counselor to discuss the risks of having children with the disease. Individuals from high-risk populations or those with family histories of CIPA may also meet with a genetic counselor to determine whether they are at risk of having a child with the disease. Carriers can be identified through detailed family histories or genetic testing.
Known carriers of CIPA may undergo genetic counseling before they conceive a child. A genetic counselor can explain the options and the associated risks of various tests, including pre-implantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS).
Pre-implantation genetic diagnosis (PGD) may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for the NTRK1 gene (also called the TRKA gene), and only the embryos that are free of the mutations are implanted. Because CIPA can be detected in an unborn baby, parents may choose whether to continue the pregnancy. A genetic counselor can assist parents with these difficult decisions.
Author information
This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
Bibliography
American Academy of Pediatrics (AAP). .
Bonkowsky JL, Johnson J, Carey JC, et al. An infant with primary tooth loss and palmar hyperkeratosis: a novel mutation in the NTRK1 gene causing congenital insensitivity to pain with anhidrosis. Pediatrics. 2003;112:e237-e241.
Courtney KB, Freedenberg DL. A new variant of hereditary sensory neuropathy type IV: anhidrosis, pain insensitivity, and normal intelligence. Am J Hum Genet. 1990;47(suppl):A53.
Ectodermal Dysplasia Society. .
Lab Tests Online. .
Mardy S, Miura Y, Endo F, et al. Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor. Anesth Analg. 2007;104:1561-1562.
Natural Standard: The Authority on Integrative Medicine. .
Okuda K, Toshimi A, Miwa T, et al. Anaesthetic management of children with congenital insensitivity to pain with anhidrosis. Pediatr Anaesthesia. 2000;10:545-548.
Online Mendelian Inheritance in Man. .
Shatzky S, Moses S, Levy J, et al. Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies. Am J Med Genet. 2000;92:353-360.
Causes
Congenital insensitivity to pain with anhidrosis (CIPA) is caused by a mutation in the human NTRK1 gene, which is also called the TRKA gene. This gene provides instructions for making a protein in the neurotrophic tyrosine kinase receptor (NTKR) family. The NTKR family comprises receptors that are found on the surface of nerve cells.
The NTKR receptors respond to nerve growth factor (NGF), which is needed by nerve cells for proper function and survival. In CIPA, the NTKR1 receptor is abnormal and cannot recognize NGF. As a result, the nerves cannot survive or function properly, and people affected with CIPA cannot feel pain or heat.
CIPA is an inherited recessive genetic disorder. Therefore, a person must inherit two copies of the defective NTRK1 gene (one copy from each parent) to develop the disease. People who inherit a mutation from only one parent are called "carriers" of the disease, and they may pass the mutation to their children.
If one parent is a carrier, or has only one copy of the defective gene, then each child will have a 50% chance of inheriting one defective gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two defective genes, a 50% chance of inheriting only one defective gene, and a 25% chance of not inheriting either defective gene. Therefore, if both parents are carriers, about one out of four children will have CIPA. As with most recessive disorders, CIPA occurs more often in families that are closely related or consanguineous, meaning that they share a blood line.
Risk factors
General: Because congenital insensitivity to pain with anhidrosis (CIPA) is inherited, the only known risk factor is a family history of CIPA. CIPA is very rare, with fewer than 100 known cases in the United States and about 300 known cases in Japan. However, it occurs more frequently among certain ethnic populations, including people from northern Israel, Ecuador, Sweden, and Japan.
Inheritance: CIPA is caused by a mutation, or genetic error, in the NTRK1 gene. This mutation is inherited as an autosomal recessive trait, meaning that a person must inherit two copies of the defective NRTK1 gene (one copy from each parent) for the disease to appear. People who inherit only one mutated gene are called "carriers" of the disease, and they can pass the mutation to their children.
If one parent is a carrier, or has only one copy of the defective gene, then each child will have a 50% chance of inheriting one defective gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two defective genes, a 50% chance of inheriting only one defective gene, and a 25% chance of not inheriting either defective gene. Therefore, if both parents are carriers, about one out of four children will have CIPA. As with most recessive disorders, CIPA occurs more often in families that are closely related or consanguineous, meaning that they share a blood line.
Random occurrence: It is unknown whether random mutations in the NTRK1 gene can cause CIPA in people with no family history of the disease.