Information on the following diseases can be found in the Related Disorders section of this report:

• Charcot-Marie-Tooth Disease, Axonal, Type 2b
• Hereditary Sensory Neuropathy Type I
• Peripheral Neuropathy
• Pure autonomic failure
• Syringomyelia

HSN type IV is most frequently recognized by associating the combination of (1) lack of sweating (anhidrosis) with (2) lack of response to stimuli that should produce pain and (3) developmental delays (mental retardation). Also, affected individuals often show signs of self-mutilating behavior and have periodic episodes of unexplained fever and infection.

Frequently, those affected have joint dislocations and deformities (Charcot joints); multiple, slowly healing bone fractures; skin infections; bruises; corneal ulcerations and aggressive behavior. In a few cases, body temperatures have become so elevated (hyperpyrexia) as to be life-threatening.

It is important to treat open sores with care. When these sores of the feet become infected, in combination with degeneration of the bones of the feet, amputation of toes and/or the foot may be necessary.

Hereditary sensory neuropathy type IV is inherited as an autosomal recessive trait. The gene identified with this disorder, known as TRKA, is involved in the production of an enzyme essential for the proper positioning of the nerve growth factor receptor. This gene is located on the long arm of chromosome 1 (1q21-q22).

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 1q21-22" refers to a region on the long arm of chromosome 1 between bands 21 and 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

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.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Recessive genetic disorders occur when an individual inherits the same abnormal 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.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

HSN type IV is present at birth (congenital). Its prevalence has not been determined but it does not appear to affect any particular ethnic group more than others.

Charcot-Marie-Tooth disease, axonal, type 2b (CMT2b) is a rare, hereditary, neurological disorder characterized by muscle atrophy and weakness most often affecting the legs and feet but sometimes progressing to the arms and hands. A decrease in vibration, pain, and thermal sensation in the hand, foot, and lower part of the leg may occur. Stretch reflexes are usually absent. Age of onset peaks between 10 and 20 years. This disorder is often mistaken for HSN Type I. (For more information on this disorder, choose "Charcot-Marie-Tooth Disease" as your search term in the Rare Disease Database.)

Hereditary sensory neuropathy type I is a rare genetic disorder characterized by a loss of sensation usually affecting the feet and legs more severely than the hands and forearms, and by perforating ulcers (open sores) on the feet. Pain and temperature sensations are affected more than are touch and pressure sensations. (For more information on this disorder, choose "Hereditary Sensory Neuropathy Type I" as your search term in the Rare Disease Database.)

The symptoms of peripheral neuropathy are produced by disease of a single nerve (mononeuropathy), several nerves in asymmetric areas of the body (mono-neuropathy multiplex), or many nerves simultaneously (polyneuropathy). These symptoms may involve sensory, motor, reflex, or blood vessel (vasomotor) function. (For more information on these disorders, choose "neuropathy" as your search term in the Rare Disease Database.)
Pure autonomic failure (PAF) is a sporadic disorder of unknown origin (idiopathic) characterized by dizziness upon rising from a prone or seated position (orthostatic hypotension) and usually associated with evidence of more widespread autonomic failure, such as excessive sweating or sexual dysfunction. It usually first appears in middle age and affects slightly more men than women. The symptoms may be so mild that they go unnoticed for years. They include weakness, dizziness, or faintness that are typically worse in the morning or after meals or exercise. Symptoms may be aggravated by hot weather, and are often associated with pain in the rear of the head or neck. A decreased ability to sweat may also be evident for some. Some affected individuals may also have bladder symptoms, constipation, or impotence. Some may develop a drooping eye lid and sinking in of the eyes (Horner's syndrome).

Syringomyelia is a rare neurological disorder characterized by a fluid- filled cavity (syrinx) within the spinal cord. People who have syringomyelia in the upper (cervical and thoracic) part of the spinal cord may first notice loss of feeling for pain and temperature in their fingers, hands, arms, and upper chest. In the early stages, a sense of touch is still present. A loss of feeling may spread over the shoulders and back. Chronic progressive degeneration of the stress-bearing part of a bone joint (Charcot joint) is another symptom. Reflexes in the upper extremities may be absent. When the lower (lumbar and sacral) segments of the spine are affected, spasticity, muscle weakness, and muscular incoordination in the lower extremities, as well as paralysis of the bladder, usually occur. Morvan disease is the name applied to a severe form of syringomyelia. (For more information on this disorder, choose "Syringomyelia" as your search term in the Rare Disease Database.)

Diagnosis
Diagnosis of HSN type IV is based on clinical, physiological and neuropathological criteria. Recently, a method of molecular analysis of the responsible gene has become available. Biopsy of nerve fibers may be used to confirm the diagnosis.

Treatment
Treatment of HSN type IV is symptomatic and supportive. Genetic counseling may be of benefit for patients and their families.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, go to:
www.centerwatch.com

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Insensitivity to Pain, Congenital, with Anhidrosis; CIPA. Entry Number; 256800: Last Edit Date; 5/24/2004.

TEXTBOOKS
Rowland LP, ed. Merritt’s Neurology. 10th ed. Lippincott Williams & Wilkins. Philadelphia, PA. 2000:611.

Menkes JH, Pine Jr JW, et al., eds. Textbook of Child Neurology. 5th ed. Williams & Wilkins. Baltimore, MD; 1995:184.

REVIEW ARTICLES
Auer-Grumbach M. Hereditary sensory neuropathies. Drugs Today (Barc). 2004;40:385-94.

Axelrod FB, Hilz MJ. Inherited autonomic neuropathies. Semin Neurol. 2003;23:381-90.

Hilz MJ. Assessment and evaluation of hereditary sensory and autonomic neuropathies with autonomic and neurophysiological examinations. Clin Auton Res. 2002;12 Suppl 1:I33-43

Indo Y. Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV. Clinical, biological and molecular aspects of mutations in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Clin Auton Res. 2002;12 Suppl 1:I20-32.

JOURNAL ARTICLES
Einarsdottir E, Carlsson A, Minde J, et al. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception, Hum Mol Genet. 2004;13:799-805.

Ohto T, Iwasaki N, Fujiwara J, et al. The evaluation of autonomic nervous function in a patient with hereditary sensory and autonomic neuropathy type IV with novel mutations of the TRKA gene. Neuropediatr. 2004;35:274-78.

Sakae N, Yamada T, Arakawa K, et al. Adult-onset hereditary sensory and autonomic neuropathy accompanied by anosmia but without skin ulceration. Acta Neurol Scand. 2001;104:316.

Verze L, Viglietta-Panzica C, Plumari L, et al. Cutaneous innervation in hereditary sensory and autonomic neuropathy type IV. Neurology. 2000;55:126-28.

Hilz MJ, Stemper B, Axelrod FB. Sympathetic skin response differentiates hereditary sensory and autonomic neuropathies III and IV. Neurology. 1999;52:1652.

Berkovitch m, Copeliovitch L, Tauber T, et al. Hereditary insensitivity to pain with anhidrosis. Pediatr neurol. 1998;19:227-29.

FROM THE INTERNET
Toscano E. Hereditary sensory and autonomic neuropathy type IV. Orphanet. Creation date: December 2003. 5pp.
www.orpha.net/data/patho/GB/uk-HSANIV.pdf

Hereditary sensory and autonomic neuropathy type IV. Orphanet. Update: 28/11/2004. 1p.
www.orpha.net/static/GB/hereditary_sensory_and_autonomic_neuropathy_4.html

Toth C. Autonomic Meuropathy. emedicine. Last Updated: August 17, 2004. 27pp.
www.emedicine.com/neuro/topic720.htm