Congenital insensitivity to pain with anhidrosis is a rare autosomal-recessive disorder of the nervous system. Lack of pain sensation, painless injuries of the extremities and oral structures with self mutilation, fever secondary to anhidrosis (lack of sweating) during hot weather, mental retardation, and loss of unmyelinated and diminution of small myelinated fibers in sural nerve specimens are the main features of the disease. Infection and scarring of the tongue, lips, and gums occur frequently, and keratoderma palmo-plantaris is a typical feature in older patients. Chronic infections of bones and joints represent additional complications.

In congenital insensitivity to pain with anhidrosis the insensitivity to pain is associated with the defective development of the small, nociceptive neurons in the dorsal root ganglia. These nociceptive neurons and the cells of the sympathetic ganglia derive from the neural crest, and their survival is stimulated by the nerve growth factor through the neuronal tyrosine kinase receptor. Mutations in the tyrosine kinase receptor A gene, described recently in patients with congenital insensitivity to pain with anhidrosis, correlate well with the defective development of the nociceptive neurons. Human tyrosine kinase receptor A is a receptor tyrosine kinase which is phosphorylated in response to nerve growth factor. The binding of the nerve growth factor to tyrosine kinase receptor A stimulates homodimer formation and activation of tyrosine kinase activity. Phosphorylated tyrosine residues in tyrosine kinase receptor A cytoplasmic domain serve as anchors for binding downstream signaling molecules.