NORD gratefully acknowledges Ingo Kurth, MD, Institute for Human Genetics, University Hospital RWTH Aachen, Germany, for assistance in the preparation of this report.
Hereditary sensory and autonomic neuropathy type II (HSAN2) is a rare genetic disorder that usually begins in childhood, affecting the nerves that serve the lower legs and feet and the lower arms and hands. Symptoms start with inflamed fingers or toes, especially around the nails. Numbness and tingling sensations in the hands and feet may also occur. Eventually, affected individuals lose feeling (sensation) in the hands and feet. This sensory loss is due to abnormal functioning of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body processes. Chronic infection of the affected areas is common and worsens as ulcers form on the fingers or the soles of the hands and feet. The loss of sensation in the hands and feet often leads to neglect of the wounds. This can become serious even leading to amputation in extreme cases if left untreated. The disorder affects many of the body’s systems, is characterized by early onset (infancy or childhood) and follows an autosomal recessive pattern of inheritance. HSAN2 occurs due to changes (mutations) in specific genes. There are a few subtypes designated A through D, each one associated with a different gene.Introduction
The hereditary sensory and autonomic neuropathies (HSAN), also known as the hereditary sensory neuropathies, include at least eight similar but 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. Some types of HSAN are related to or identical with some forms of Charcot-Marie-Tooth disease, congenital insensitivity to pain (CIP), and others are related to or identical to 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 as 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).
The symptoms of HSNs are highly variable, even among members of the same family. HSNs of various types may attack a single nerve (mononeuropathy) or many nerves simultaneously (polyneuropathy). The resulting symptoms may involve sensory, motor, reflex or blood vessel (vasomotor) function.
Although researchers have been able to establish HSANs as a distinct group of disorders with characteristic or “core” symptoms, much about these disorders is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis of all subtypes. Many of the reported individuals of HSAN2 are inconsistent in terms of symptomology and progression. This is partially caused by case reports that include cases that are not molecularly confirmed to be HSAN2. Consequently, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms, and overall prognosis.
HSAN2 is characterized by sensory loss of the distal portions of the legs. Distal refers to those areas that are farther from the center of the body and includes the lower arms and legs and the hands and feet. The legs and feet are more severely affected than the arms and hands. Onset is usually shortly after birth or during childhood.
Affected individuals may experience progressive numbness and tingling in the hands and feet. They may also experience reduced sensation to temperature, pain and touch. Eventually, 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 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), spontaneous, painless fractures, and inflammation and damage to the surrounding joints (neuropathic arthropathy).
Most reports describe autonomic problems as less pronounced than sensory abnormalities in individuals with HSAN2. Many affected individuals have sweating abnormalities including episodes of excessive sweating (hyperhidrosis), reduced sweating (hypohidrosis), or an inability to sweat (anhidrosis). Individuals can experience hyperhidrosis along with patchy areas of anhidrosis. Hyperhidrosis can also lead to excessive tear production. Additional autonomic findings include backflow of the stomach contents into the esophagus (gastroesophageal reflux) and low blood pressure upon standing (postural hypotension) causing lightheadedness or dizziness.
Some individuals with HSAN2 exhibit self-mutilation, usually around the time of the eruption of primary teeth. Additional symptoms have been reported in some patients including dry scaly patches on the skin of the palms and soles (hyperkeratosis), diminished taste sensation, diminishment of certain reflexes, and abnormal sideways curvature of the spine (scoliosis). Some infants and children may have difficulty swallowing. Sleep apnea, in which breathing slows or stops briefly during sleep, may also occur. Later in the course of the disorder, urinary incontinence or signs of spasticity may develop.
HSAN2 is caused by a mutation in the one of four genes. HSAN2A is caused by mutations in the WNK1 gene, HSAN2B is caused by mutations in the FAM134B gene, lately renamed to RETREG1. HSAN2C is caused by mutations in the KIF1A gene, HSAN2D is caused by mutations in the SCN9A 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.
HSAN2 is an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 non-working 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 working genes from both parents is 25%. The risk is the same for males and females.
HSAN2 affects males and females in equal numbers. The exact incidence and prevalence is unknown. HSAN2 may go misdiagnosed or undiagnosed, making it difficult to determine the disorder’s true frequency in the general population.
A diagnosis of HSAN2 is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Congenital or early onset of sensory deficits and a family history consistent with autosomal recessive inheritance are indicative of HSAN2.
Clinical Testing and Workup
Electromyography (EMG) and nerve conduction studies may be abnormal. During EMG, a thin electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscles at rest and during contraction. This record, called an electromyogram, shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. Nerve conduction studies, which measure the speed of conduction of an electrical impulse through a nerve, may be reduced in individuals with HSAN2.
Surgical removal and microscopic examination (biopsy) of affected nerve fibers / skin may be used to aid in the diagnosis of HSAN2 by revealing characteristic changes to nerves.
An axonal flare test is sometimes used to aid in diagnosing HSAN2. During this test, a small amount of diluted histamine is injected underneath the skin. Histamine is a chemical compound produce 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 (neuron) to another). An injection of histamine causes a distinctive skin eruption around the site of injection. In affected individuals, the skin eruption is different and indicative of HSAN2. In mild cases of HSAN2, however, this test may be normal.
Molecular genetic testing can confirm a diagnosis in some cases. Molecular genetic testing can detect mutations in the specific genes known to cause HSAN2, but is available only as a diagnostic service at specialized laboratories.
The treatment of HSAN2 is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, orthopedic surgeons, dermatologists, physiotherapists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families.
Prompt recognition and treatment of wounds on affected areas (e.g. the feet) is critically important. Ulceration of the feet of individuals with HSAN2 is extremely similar to ulcers found on the feet of individuals with diabetic neuropathy. Therefore, the treatment of foot ulcerations and infections may follow similar guidelines. Such treatment can include medical removal of diseased skin and tissue (debridement), applying medications and dressing to the wound, and keeping the wound clean and bandaged. Antibiotics may be used to treat infection.
Affected individuals should receive instruction on proper care of their feet including avoiding risk factors for developing foot ulceration such as removing sources of pressure (e.g. shoes with pressure points). It is recommended that affected individuals receive routine foot care from a diabetic clinic or a podiatrist familiar with the treatment of diabetic foot ulcers.
Additional treatment is symptomatic and supportive.
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
University RWTH Aachen
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