May 15, 2020
Years published: 2004, 2007, 2014, 2017, 2020
NORD gratefully acknowledges Ingo Kurth, MD, Institute for Human Genetics, RWTH Aachen University Aachen, Germany, for assistance in the preparation of this report.
Hereditary sensory and autonomic neuropathy type IV (HSAN4 or HSAN IV) is a rare genetic disorder that usually begins in infancy and is characterized by an inability to feel pain and an inability to sweat (anhidrosis). Affected individuals also cannot feel temperature and cannot distinguish between hot and cold. The sensory loss in individuals with HSAN IV is due to abnormal functioning of the sensory nerves that control responses to pain and temperature. Anhidrosis can cause recurrent episodes of fever and high body temperature. An inability to feel pain can lead to unintentional self-mutation, repeated fractures, and joint damage. Affected individuals and especially children or infants may be unaware of injury delaying treatment. HSAN IV is caused by changes (mutations) in the NTRK1 gene. The disorder is inherited in an autosomal recessive manner.
The hereditary sensory and autonomic neuropathies (HSAN), also known as the hereditary sensory neuropathies, include distinct inherited degenerative disorders of the nervous system (neurodegenerative) that frequently progress to loss of feeling, especially in the hands and feet. Some of these disorders have several subtypes based upon the specific associated genes and about 20 genes have been identified as disease-causative. Some types of HSAN are related to or identical with some forms of Charcot-Marie-Tooth disease, and others are related to or identical with familial dysautonomia (Riley-Day syndrome). The classification of the HSANs is complicated, and the experts to not always agree on it. Furthermore, HSANs are classified more broadly as peripheral neuropathies or disorders or the peripheral nervous system, which encompasses all of the nerves outside of the central nervous system (i.e. brain and spinal cord). HSAN IV is also known as congenital insensitivity to pain with anhidrosis (CIPA).
Infants cannot or have a markedly decreased ability to sweat (anhidrosis). Sweating is the body’s way of cooling itself and maintaining proper body temperature. The inability to sweat can cause recurrent episodes of fever including extremely high fevers that result in a significant elevation of body temperature (hyperpyrexia). When someone has a significantly increased body temperature it is known as hyperthermia and this can be the initial sign of the disorder. The inability to sweat can affect the entire body, but the trunk and arms are mostly affected. Seizures are sometimes associated with fever episodes. The skin may become abnormally thickened and callused with an exaggeration of normal skin lines (lichenification). There may be areas of hair loss of the scalp (hypotrichosis) and malformation of the fingernails and toenails.
Affected infants fail to feel pain in response to stimuli that normally should produce pain such as failing to respond to routine injections that are part of pediatric immunizations. Pain is essential to protect people from injury and to alert the body of injury. Because of the inability to feel pain, affected infants and children may suffer repeated injuries and may demonstrate behaviors that cause injury to themselves (self-mutilation) including biting one’s tongue, lips and the lining of the inside of the mouth (buccal mucosa). Affected infants often develop ulcers on their tongues from repeatedly biting their tongues. When the primary teeth first erupt, affected children often bite their fingertips or toes; in severe cases, they can chew or bite off the tips of their fingers or toes.
Affected individuals will be unable to distinguish between cold or warm stimuli and be unable to feel pain in the affected area. Because of the loss of sensation, affected individuals may be unaware of injury. For example, affected individuals may develop chronic skin erosions, ulcers (open sores), or blisters that are slow to heal. These normally painful conditions do not hurt because of the loss of sensation. If unrecognized and left untreated, these painless injuries can progress to cause more serious complications such as recurrent infections. Eventually, affected individuals can develop infection of the surrounding bone (osteomyelitis), loss of bone and tissue in the fingers and toes (acroosteolysis), and spontaneous, repeated fractures. Repeated trauma to joints results in progressive inflammation, damage, and deformity of the affected joints (Charcot joint or neuropathic arthropathy). The large, weight-bearing joints are especially prone to this complication.
Children with HSAN IV may show delays in attaining developmental milestones (developmental delays) and learning disabilities are common. Intellectual disability has been reported in some cases, but the severity of this finding has varied widely and some children are only mildly affected. Behavioral problems including irritability, hyperactivity, an inability to control one’s emotions (emotional lability), and episodes of anger or rage have also been reported.
Diminished muscle tone (hypotonia) may be present at birth or during infancy. Hypotonia, also known as a “floppy baby,” may cause affected infants to be abnormally limp. Although hypotonia is common at birth, strength and tone improves with age.
Some individuals experience postural hypotension, a condition in which there is a drop in blood pressure upon a change in body position such as upon standing. Sometimes, postural hypotension is accompanied by a faster than normal heart rate (compensatory tachycardia), in which the body attempts to compensate for the decreased blood pressure.
Eye abnormalities may develop, specifically neurotrophic keratitis, a condition characterized by damage to the corneas of the eyes. The cornea is the transparent membrane that covers the front of the eyes. Affected individuals can develop lesions (ulcerations) on the cornea; these lesions can cause corneal scarring. Infection can also occur.
HSAN IV is caused by mutations in the neurotrophic tyrosine kinase receptor type I (NTRK1) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
The NTRK1 gene creates (encodes) neurotrophic tyrosine receptor type 1, a protein that is found on the surface of certain cells, especially nerve cells (neurons) that transmit pain, temperature, and touch sensations. Another protein known as nerve growth factor (NGF) binds to the NTRK1 receptor, which allows nerve signals that are essential for the growth and survival of the cell to be transmitted into the cell. Mutations in the NTRK1 gene result in faulty or deficient neurotrophic tyrosine receptor type 1, which prevents the binding of NGF and, consequently, the transmission of nerve signals. Ultimately, the affected neurons die prematurely. The symptoms of HSAN IV result from this premature destruction of sensory nerve cells.
HSAN IV is inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
HSAN IV affects males and females in equal numbers. Several hundred cases have been reported in the medical literature. The exact incidence and prevalence is unknown. Many patients have been reported in Japan and the frequency of the disorder is higher in the Japanese and Israeli-Bedouin populations due to a founder effect. A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a particular genetic trait. Regions with a high rate of consanguinity also show a higher prevalence. Onset of the disorder is at birth.
A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests, mainly genetic testing. Characterized symptoms proposed as necessary for a diagnosis are insensitivity to pain, anhidrosis and intellectual disability. However, the severity of these symptoms is highly variable.
Clinical Testing and Workup
Surgical removal and microscopic examination of affected skin tissue (skin biopsy) may reveal a lack of functioning nerves supplying the sweat glands (eccrine sweat gland innervation). A biopsy of nerve tissue from the calf of the leg (sural nerve biopsy) may reveal characteristic findings including reduced numbers of myelinated and unmyelinated small-diameter fibers with normal numbers of large-diameter fibers, but is largely replaced by molecular genetic testing.
An axonal flare test is sometimes used to aid in diagnosing HSAN IV. During this test, a small amount of diluted histamine is injected underneath the skin. Histamine is a chemical compound produced by the body that helps the immune system and acts as a neurotransmitter (a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell to another). An injection of histamine causes a distinctive skin eruption around the site of injection.
Molecular genetic testing for mutations in the NTRK1 gene can confirm the diagnosis and is often done by next-generation sequencing (NGS) from a blood sample.
Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, neurologists, dental specialists, orthopedists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan for an affect child’s treatment. Psychosocial support for the entire family is essential as well.
Genetic counseling is recommended for affected individuals and their families.
Affected individuals may be treated with acetaminophen or ibuprofen when fevers are present. Direct cooling in a bath or with a blanket designed to lower body temperature (cooling blanket) may also be used.
Various orthopedic measures may be necessary to treat abnormalities affecting the bones and joints including surgery or the use of braces or orthopedic devices.
Various dental procedures may be used to treat individuals. Smoothing over or grinding down the sharp edges of teeth, prophylactic use of crowns, the use of a night-guard and other orthodontic treatments may be considered. Extracting teeth to prevent self-mutilation has also been done.
Treatment of neurotrophic keratitis can include a procedure in which the eyelids are sewn together to narrow the opening (tarsorrhaphy), plastic surgery to repair the cornea (keratoplasty), replacement of part or all of an affected cornea with healthy corneal tissue from a donor (scleral corneal graft), and special contact lenses that protect the cornea (scleral bandage lens). These contact lenses create a space between the front of the cornea and the back of the lenses that fills with a sterile saline solution.
Behavioral issues tend to improve with age. These issues have been treated with behavior modification techniques along with anti-psychotic medications or attention deficit hyperactivity disorder medications.
Regular, daily inspection for unrecognized or unrealized injury is important as well.
A group of researchers in Germany is interested in HSAN disorders and offers genetic testing on a research basis (free of charge) for individuals meeting the criteria for a diagnosis of HSAN. For more information, contact:
Prof. Dr. med. Ingo Kurth
Institut für Humangenetik
der RWTH Aachen
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