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At a glance

Genetic neurodegenerative disorder (peripheral nerve degeneration involving small fibers) characterized by congenital insensitivity to pain (resulting in painless injuries), episodic fever (hot weather) as a consequence of anhidrosis, autonomic disorders, mental retardation, short stature, self-mutilation, and joint deformities.

Synonyms

Congenital Sensory Neuropathy with Anhidrosis; Familial Dysautonomia Type II; Congenital Insensitivity to Pain with Anhidrosis (CIPA) of Swanson; Swanson Syndrome.

Incidence

Very rare disease. High prevalence reported in Israeli-Bedouin Arabs.

Genetic inheritance

Autosomal recessive. Gene map location is chromosome 1q21-q22. Mutations in the same gene are associated with familial medullary thyroid carcinoma. The protein has a single extracellular domain (nerve growth factor binding) that acts as a signal peptide and a single intracellular domain (tyrosine kinase).

Pathophysiology

Nociceptive neurons in the dorsal root ganglia derive from the neural crest, and they can survive only if they are stimulated by the nerve growth factor through the tyrosine kinase (TrkA) receptor. Mutations in the TrkA gene have shown a correlation with the defective development of the nociceptive neurons. It results in the loss of small “C” nerve fibers responsible for carrying pain, temperature, and autonomic control. HSAN IV is a result of a defect of the high-affinity TrkA receptor (neurotrophin signal transduction system) for nerve growth factor. Consequently, there is a defect in neural crest differentiation and the system responsible for pain and temperature sensation, the first-order afferent system, is lost. The Lissauer spinothalamic tract is absent. Temperature regulation and sensation are inexistent, which may represent a life-threatening condition. Nerve growth factor modulates synaptic plasticity and nervous transmission and plays a modulating role among the nervous, immune, and endocrine systems. It may interfere with the skeletal cell metabolism.

Diagnosis

Clinically evocated by progressive insensitivity to pain, associated with anhidrosis. Nerve biopsy shows a loss of unmyelinated fibers. Small myelinated and unmyelinated axons are almost absent (0-5% of normal); large myelinated axons are mildly reduced (45-65% of normal). Absence of innervation of sweat glands. Provocative sweating tests are negative. Presence of normal sweat glands in the skin, with absence of sweating.

Clinical aspects

Symptoms present from birth. There is a progressive insensitivity to pain, associated with anhidrosis. HSAN IV shares some clinical similarities with HSAN III, but instead of profuse sweating there is complete anhidrosis. Children present with unexplained fever up to 43°C (109.4°F) because of loss of thermal regulation. Self-mutilating behavior, with numerous trauma, tongue bites, and burns. Mental retardation with IQ in the 60s is often observed. Other features include fingernail dystrophy and various neurogenic joint disorders. Prognosis is poor; 30% of children die before 3 years of age due to uncontrolled fever and/or massive infection.

Precautions before anesthesia

Patients often require anesthesia ...

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