Hereditary sensory and autonomic neuropathies: types II, III, and IV

Abstract

The hereditary sensory and autonomic neuropathies (HSAN) encompass a number of inherited disorders that are associated with sensory dysfunction (depressed reflexes, altered pain and temperature perception) and varying degrees of autonomic dysfunction (gastroesophageal reflux, postural hypotention, excessive sweating). Subsequent to the numerical classification of four distinct forms of HSAN that was proposed by Dyck and Ohta, additional entities continue to be described, so that identification and classification are ongoing. As a group, the HSAN are rare diseases that affect both sexes. HSAN III is almost exclusive to individuals of Eastern European Jewish extraction, with incidence of 1 per 3600 live births. Several hundred cases with HSAN IV have been reported. The worldwide prevalence of HSAN type II is very low. This review focuses on the description of three of the disorders, HSAN II through IV, that are characterized by autosomal recessive inheritance and onset at birth. These three forms of HSAN have been the most intensively studied, especially familial dysautonomia (Riley-Day syndrome or HSAN III), which is often used as a prototype for comparison to the other HSAN. Each HSAN disorder is likely caused by different genetic errors that affect specific aspects of small fiber neurodevelopment, which result in variable phenotypic expression. As genetic tests are routinely used for diagnostic confirmation of HSAN III only, other means of differentiating between the disorders is necessary. Diagnosis is based on the clinical features, the degree of both sensory and autonomic dysfunction, and biochemical evaluations, with pathologic examinations serving to further confirm differences. Treatments for all these disorders are supportive.

Figure 1

Histamine test. Dysautonomic reaction (forearm on top) demonstrates a narrow areola surrounding the wheal. Normal reaction (lower forearm) displays diffuse axon flare around a central wheal.

Figure 2

Facial features. Facial features of a patient with HSAN over time. Note flattening of upper lip. By age 10 years prominence of lower jaw is apparent and by age 19 years there is mild erosion of right nostril due to inadvertent self-mutilation.

Figure 3

Kyphoscoliosis in a 10-year-old girl with HSAN III.

Figure 4

A. Normal tongue with fungiform papillae present on the tip. B. Dysautonomic tongue. Note the absence of the highly vascularized fungiform papillae from the tongue tip, which gives the appearance of a smooth tongue.

Figure 5

Charcot joints are demonstrated in this boy with HSAN IV or congenital insensitivity to pain with anhidrosis (CIPA). The left knee and left ankle are enlarged and distorted. The skin over the medial aspect of the ankle is darkened with a draining would secondary to superimposed osteomyelitis. There are other areas of trauma and ulcers including a site on the left heel.