Congenital insensitivity to pain and anhidrosis: a case report from South India.

Congenital insensitivity to pain with anhidrosis, also known as hereditary sensory and autonomic neuropathy type IV, is an autosomal recessive disorder characterized by the congenital lack of pain sensation, inability to sweat, episodes of recurrent hyperpyrexia, mental retardation, and self-mutilating behavior. It is an extremely rare disorder with only a handful of reports from India. A five- year- old boy, born to second-degree consanguineous parents after uneventful antenatal period, presented to us with history of recurrent unexplained fever, recurrent ulcers in the lower limbs, insensitivity to painful stimuli (like injections, vaccination) and self-mutilating behavior from early childhood. Cutaneous examination showed multiple ulcers, loss of teeth, loss of tip of the tongue (due to biting), scarring of finger tips, xerosis and lichenification. Sensory examination showed complete loss of pain and temperature sensations, but fine touch and vibration were preserved. Deep tendon reflexes were normal. Evaluation for Hansen's disease was non-contributory. An intradermal injection of histamine did not show any flare response. Based on clinical as well as compatible histological features a diagnosis of congenital insensitivity to pain with anhidrosis was made. The ulcers were treated with appropriate antibiotics and daily dressings. The parents were counseled about appropriate care of the child.

What was known?

CIPA, an autosomal recessive disorder presents with congenital lack of pain sensation, inability to sweat, episodes of recurrent hyperpyrexia, mental retardation and self-mutilation

Introduction

Congenital insensitivity to pain and anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV, is an autosomal recessive disorder characterized by the congenital lack of pain sensation, inability to sweat, episodes of recurrent hyperpyrexia, mental retardation, and self-mutilating behavior. It is due to mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene in chromosome 1.[1] It is an extremely rare disorder with only a handful of reports from India.[2-7] Herein we report a rare case of CIPA from South India and highlight its cutaneous findings.

Case Report

A five-year-old boy was brought to our dermatology department for recurrent ulcers in the lower limbs for the past 2 years. He was the only child born to second-degree consanguineous parents. He was born by normal vaginal delivery after an uneventful antenatal period and showed no abnormality at birth. But, during infancy he was repeatedly hospitalized for recurrent unexplained fever from which he used to recover normally. His mother also noticed delay in milestones in his infancy. His parents noted that he did not respond to painful stimuli like injection of vaccines or any other accidental trauma. They also noticed self- mutilating behavior like biting of his tongue, chewing his fingers, bruising, and manipulation the wounds. There was no history of similar illness in the family. On general examination pallor was present. His systemic examination was normal. Cutaneous examination revealed generalized xerosis with areas of lichenification over his ankles and dorsa of feet [Figure 1]. Palms showed thickening while there was fissuring of both the soles. Both the heels showed deep ulcers, measuring 3 × 3 cm on the left and 2.5 × 2 cm on the right side [Figure 2]. There was another ulcer of 4 × 3 cm in size over the right knee. There was scarring of left little finger and right index finger (healed ulcers due to biting) [Figure 3]. Oral cavity showed loss of tip of the tongue, many missing teeth and angular cheilitis [Figure 4]. Sensory examination showed complete loss of pain and temperature sensations, but fine touch and vibration were preserved. Deep tendon reflexes were normal. Lacrimation was normal. There were no hypopigmented patches or thickened, palpable nerves. Complete hemogram revealed iron deficiency anemia. Other hematological and biochemical investigations including serum uric acid levels were normal. An intradermal injection of histamine did not show any flare response. Histological examination of the skin showed normal epidermis and dermal structures including presence of normal sweat glands. Based on the clinical and histological features the diagnosis of CIPA was made. The ulcers were treated with appropriate antibiotics and daily dressings. The xerosis was managed with emollients. The parents were counseled about appropriate care of the child.

Figure 1

Lichenification over dorsa of feet and ankles, xerosis and ulcer over right knee

Figure 2

Ulcers on the heels

Figure 3

Old scars on the finger tips

Figure 4

Loss of tip of the tongue with angular cheilitis

Discussion

CIPA was first described in 1963 by Swanson in two brothers who were affected by defect of temperature sensation and insensitivity to pain.[2] Half the cases reported have occurred in consanguineous marriages.[8] CIPA is caused by mutations in the NTRK1 gene, located on chromosome 1 that encodes the tyrosine kinase receptor for nerve growth factor (NGF). Mutations in this gene results in the failure of differentiation and migration of neural crest cells, leading to the complete absence of small myelinated and unmyelinated nerve fibres resulting in loss of pain and temperature sensations. Furthermore, the sweat glands are not innervated, leading to anhidrosis.[9]

The constant features of CIPA present in all patients are anhidrosis, episodes of unexplained fever (which is usually the earliest sign of the disorder[8]), mental retardation, insensitivity to pain, and self-mutilating behavior.[10] The other features that are frequently present are multiple fractures, joint dislocations and deformities, skin infections, bruises, corneal ulcerations, and aggressive behavior. Rarely, it also can present with features of impaired immune response, proteinuria, renal failure, anemia, hyperkeratosis, dry skin, and early primary tooth loss. Death from hyperpyrexia within the first three years of life may occur in 20% of these cases.[10] Insensitivity to pain is profound and results in deep ulceration on the knees and elbows, overuse of bones and joints leading to recurrent fractures, osteomyelitis, joint dislocations, and joint deformities (Charcot joints). All these children have self-inflicted injuries in the form of skin ulcers, burns, bone fractures, auto-amputations of the fingertips, and tongue.[11] However, no joint problem was noted in our patient.

Cutaneous features are due to anhidrosis and repeated trauma. Anhidrosis contributes to xerosis, thick and calloused appearance of the skin with lichenification of palms.[8] Skin infections, bruises, and scars occur as a result of repeated trauma or self-mutilation. Typical oral manifestations are ulcers on the ventral surface of the tongue due to repeated biting during infancy, which usually lead to absent tip of the tongue by the second year of life. Lip wounds are mostly noticed only on the lower lip. Multiple missing teeth because of auto-extraction may be seen in upto 50% of patients.[811]

Histology reveals otherwise normal skin and appendageal structures. There is absence of non-myelinated, small -myelinated nerve fibres with normal sweat glands that lack innervation by small-diameter neurons.[8] Motor and sensory peripheral nerve conduction velocities are usually normal in EMG examination.[12]

CIPA has to be differentiated from other hereditary sensory neuropathies. Type I (Hereditary sensory radicular neuropathy) is a relatively mild condition, manifesting in the second to fourth decade and mainly affecting the lower limbs. Type II (Congenital sensory neuropathy) is also associated with loss sweating, but temperature and control of blood pressure are normal. Type III (Familial dysautonomia or Riley-Day syndrome) has a multisystem presentation including postural hypotension, ataxia, kyphoscoliosis, oropharyngeal dyscordination, and abnormal gastro- esophageal motility resulting in feeding difficulties and recurrent aspiration pneumonia. Type V disease is similar to Type IV but is relatively mild without mental retardation and significant anhidrosis and it selectively affects nociception.[13] Lesch-Nyhan syndrome resulting from hypoxanthine-guanine-phosphoribosyl transferase (HGPRT) deficiency is characterized by hyperuricaemia, self-induced trauma, mental retardation, chorea, and athetosis.

Though CIPA is a totally painless disorder, it can have devastating effects. There is no specific treatment for this condition. Severe hyperpyrexia and traumatic complications require frequent medical attention. Close attention of children with CIPA is necessary to prevent injuries, burns, fractures, corneal ulceration, and self-mutilation. The parents need to be educated about simple measures like avoiding excessive wrapping, preventing dehydration, and measures to reduce hyperpyrexia, which reduce lot of preventable deaths. The treating pediatrician should be made aware of the diagnosis as it can help in avoiding unnecessary use of antibiotics and investigations during episodes of hyperpyrexia. Frequent operative intervention may be required for fractures and the operating surgeons should consider the possibility of inadequate analgesia if tachycardia and hypertension occur in the postoperative period due to an unconscious physiologic response to pain though the patient may not be consciously aware of pain because of decreased number of peripheral pain fibers.[14] Identification of the NTRK1 mutations is the only tool for prenatal diagnosis. Being an autosomal recessive disorder, genetic counseling may be given to discourage consanguineous marriages, especially when there is a positive family history for CIPA.

What is new?

Generalized xerosis, lichenification over ankles and dorsa of feet, palmar thickening and plantar fissures were the unusual cutaneous findings in our case.