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Hereditary sensory and autonomic neuropathy type 4
Hereditary sensory and autonomic neuropathy, type 4 (HSAN4) is an inherited disorder characterized by anhidrosis, insensitivity to pain, self-mutilating behavior and episodes of fever.
- CIP-anhidrosis syndrome
- Congenital insensitivity to pain-anhidrosis syndrome
- Hereditary sensory and autonomic neuropathy type IV
- Prevalence: -
- Inheritance: Autosomal recessive
- Age of onset: Infancy, Neonatal, Childhood
- ICD-10: G60.8
- OMIM: 256800
- UMLS: C0020074
- MeSH: -
- GARD: 3006
- MedDRA: -
Several hundred cases have been published.
The disease has an onset in early infancy. Consanguinity has been reported in 50% of patients. Episodic fevers, extreme hyperpyrexia and recurrent febrile convulsions (due to anhidrosis) as well as self-mutilation are usually the earliest signs of the disorder. The cardinal feature of HSAN4 is absence of or markedly decreased sweating. It is present on the trunk and upper extremities in 100% of cases, other areas of the body are variably affected. The skin becomes thick and callused with lichenification of palms, areas of hypotrichosis on the scalp and dystrophic nails. Pain and temperature perception are absent. With time, the sensory insensitivity is much more profound resulting in self-mutilation, auto-amputation, and corneal scarring. Patients have definite problems in healing of ectodermal structures, fractures are slow to heal and large weight bearing joints appear particularly susceptible to repeated trauma and frequently go on to the development of Charcot joints and osteomyelitis. Hypotonia and delayed developmental milestones are frequent in the early years, but normalize with age. Postural hypotension with compensatory tachycardia may be present, but not episodic hypertension. Less than 10% of patients have depressed deep tendon reflexes. Vibration sense is normal or moderately decreased. Scoliosis may be present (20%). Irritability, hyperactivity, and susceptibility to rages are frequent. Speech is usually clear, however, there can be severe learning difficulties.
The HSAN4 gene, NTRK1 (TRKA), is localized to chromosome 1q21-22.
Diagnosis requires three clinical criteria: anhidrosis, decreased pain perception and intellectual deficit, and is confirmed by pharmacological tests and neuropathological findings. Due to numerous mutations, DNA diagnosis is not routinely used for clinical confirmation of diagnosis. Skin biopsy morphology of HSAN4 patients reveals deficient C and A-delta fibres in the epidermis and absent or hypoplastic dermal sweat glands without innervation.
Differential diagnosis includes other HSAN disorders. What distinguishes HSAN4 is the extensive involvement of ectodermal structures including skin, bone and nervous system, and especially absent or markedly decreased sweating.
The disease is transmitted as an autosomal recessive trait.
Management and treatment
Management is supportive of and oriented to control hyperthermia, prevention of self-mutilation and treatment of orthopaedic problems that potentially can cause severe and invalidating deformities. It is necessary to help families cope with behavioural and educational issues.
The prognosis for independent functions depends on the degree of disease expression and the ability to control the secondary clinical problems.