A case of hereditary sensory autonomic neuropathy type IV.

Hereditary sensory autonomic neuropathy type IV (HSAN -IV), also known as congenital insensitivity to pain with anhidrosis, is a very rare condition that presents in infancy with anhidrosis, absence of pain sensation and self -mutilation. Developmental delay and mental retardation are usually present. Ultrastructural study of the peripheral nerves demonstrates loss of the unmyelinated and small myelinated fibers. We here report a 8 year -old boy with HSAN IV with typical clinical features where the diagnosis was supported by nerve biopsy findings. However, our case was unusual since mental development was normal.

Introduction

Hereditary sensory and autonomic neuropathy type IV (HSAN IV), also called as congenital insensitivity to pain with anhidrosis (CIPA) or Nishida syndrome[1] is a rare autosomal recessive condition seen in children.[23] We present clinical and nerve biopsy images of a 13-year-old boy with classical manifestations of CIPA.

Case Report

A 8-year-old boy, born to a healthy non-consanguineous South Indian couple, presented with history of self-mutilation starting in infancy soon after primary dentition. There were repeated episodes of high fever in summer which was poorly responding to antipyretics. His developmental milestones were normal. There was no similar history in the family, with one younger sibling being healthy. On examination, there were signs of self-mutilation in the form of ulcerations of the lower lip, tongue, and oral mucosa. Skin, especially over the palms and soles was dry, coarse and mildly hyperkeratotic. Neurological examination revealed a generalized absence of response to temperature and painful stimuli. Touch, position, and vibration senses were intact. Tendon reflexes and plantar responses were normal. There was no cranial nerve palsy except for absent corneal reflex. Tests for autonomic function were normal.

On investigation, serum uric acid levels and the nerve conduction studies (motor and sensory) were normal. A bedside sweat test using pilocarpine showed the total absence of sweating. A full-thickness skin biopsy showed normal sweat glands. Sural nerve biopsy findings were consistent with hereditary sensory autonomic neuropathy [Figure 1]. IQ assessment using Binet-Kamat test showed a normal mental development for age (IQ=97). The child was lost to follow-up and presented to us 5 years later with extensive ulcers over upper limbs and neck [Figure 2]. There was substantial loss of tissue around the lips [Figure 3]. His left lower leg was amputated for non-resolving osteomyelitis 6 months back. The boy succumbed to fulminant sepsis with shock with profound DIC and massive upper GI bleed.

Figure 1

Mutilation of upper limb and fingers. Also note extensive ulcers involving the hand

Figure 2

Clinical photograph showing self-mutilation of lower lip with skin changes

Figure 3

Sural nerve biopsy showing reduced small myelinated fibers (unmyelinated fibers are shown in the subset). Large myelinated nerve fibers are normal

Discussion

Neuropathy in HSAN IV involves small-caliber (A-delta and C) nerve fibers which normally transmit nociceptive inputs along sensory nerves. Sensory testing of thermal and vibratory perception is abnormal and there is absence of sweating in response to sympathetic stimulation though autonomic perturbations are mild to absent. More than 37 different mutations in the neurotrophic tyrosine kinase receptor (NTRKA) gene, encoding a high-affinity NGF receptor, on chromosome 1q21-22 are described in HSAN IV.[45]

The reported patient had severe anhidrosis, absence of pain sensation, and self-mutilating behavior [Figure 3], starting in infancy. Due to absent pain sensation, HSAN IV patients frequently develop extensive skin ulcers [Figure 2]. The absence of sweating makes the skin dry, hyperkeratotic and parchment-like further making it susceptible to recurrent, refractory infection. Osteomyelitis and recurrent bone fractures may lead to development of Charcot joints. In the present case, the left leg was amputated below knee and he also had non-healing fracture of right femur. Up to 43% mortality in such patients has been attributed to hyperpyrexia and sepsis combined.[46] Inadequate response to stress might contribute to significant mortality, morbidity.[7] In our case, the patient developed fulminant septicemia due to extensive skin ulceration and died of DIC with uncontrolled bleeding.

Impairment of pain sensation and self-mutilation may also be seen in rare syndromes such as Lesch Nyhan syndrome and de Lange syndrome. In our patient, there was striking loss of pain perception and profound anhidrosis. There was no peripheral nerve thickening. These findings along with the absence of dysmorphic features, a normal serum uric acid level, electrophysiological studies and nerve biopsy histopathological findings of reduced small sympathetic myelinated and unmyelinated nerve fibers [Figure 1] confirmed the diagnosis of sensory autonomic neuropathy in our case.

Our patient did not have mental retardation on formal assessment, unlike typical cases of HSAN IV.[5] However, classical features of type IV HSAN, generalized loss of pain sensation, and profound anhidrosis were present. Therefore, our case could represent a unique variant of HSAN type IV without mental retardation.[25] Due to lack of availability of genetic tests, mutational studies could not be done in our case. The present case history and clinical images illustrate that HSAN type IV, rarely seen in pediatric population, is one of the most debilitating neuropathies of childhood with a high morbidity and a shortened life span.