Hereditary sensory and autonomic neuropathy type 4 (ORPHA:642)
A rare hereditary sensory and autonomic neuropathy characterized by anhidrosis, insensitivity to pain, self-mutilating behavior and episodes of fever.
Epidemiology
Whilst several hundred cases have been reported worldwide, the exact prevalence is unknown. Most of the cases described were from the Israeli Bedouin population and Japan where the prevalence is estimated at 1/600,000-950,000.
Clinical description
The disease typically presents in early infancy, but may occasionally present during the neonatal period. Consanguinity has been reported in 50% of patients. Episodic fevers without obvious infections, extreme hyperpyrexia and febrile convulsions due to inability to dissipate heat as a result of anhidrosis as well as self-mutilation are usually the earliest signs of the disease. The cardinal feature is absence of sweating on the trunk and extremities, with occasional patients producing some moisture on the forehead, tip of the nose and gluteal sulcus. The skin becomes thick and callused with lichenification of palms, areas of hypotrichosis on the scalp and dystrophic nails. Deep tendon reflexes are usually present. Pain insensitivity is profound resulting in self-mutilation, auto-amputation, and corneal scarring but some patients retain temperature perception. Vibration sense and proprioception are normal or moderately decreased Bone fractures are slow to heal and large weight bearing joints are 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 sometimes normalize with age. Speech is usually clear, but patients have severe learning difficulties, irritability, hyperactivity, and cognitive impairment. Normal intelligence, however, has been reported in a few patients. Mild postural hypotension with compensatory tachycardia may be present, but not episodic hypertension. Around 20% of patients have scoliosis.
Etiology
The disease is due to mutations in the gene NTRK1 (1q21-22).
Diagnostic methods
Diagnosis requires two clinical criteria: anhidrosis and decreased pain perception, and is confirmed by genetic testing identifying variants in NTRK1. Skin biopsy reveals deficient C and A-delta fibers in the epidermis and hypoplastic dermal sweat glands without innervation. Plasma concentration of norepinephrine is extremely low or undetectable but epinephrine, vasopressin and plasma renin activity are normal.
Differential diagnosis
Differential diagnosis includes other hereditary sensory and autonomic neuropathies from which it is distinguished by absent or markedly decreased sweating.
Genetic counseling
The pattern of inheritance is autosomal recessive. Where both parents are unaffected carriers, the risk of disease transmission to offspring is 25%. Offspring of affected individuals are obligate carriers.
Management and treatment
Management is supportive and oriented to control hyperthermia, prevention of self-mutilation and treatment of orthopedic problems that potentially can cause severe and invalidating deformities. It is necessary to help families cope with behavioral and educational issues.
Prognosis
The prognosis for independent functions depends on the degree of disease expression and the ability to control the secondary clinical problems.

                            Last update: 
                            August 2019


                            - Expert reviewer(s): 
                            Pr Horacio KAUFMANN  - Pr Jose-Alberto PALMA