Congenital insensitivity to pain with anhidrosis and progressing acro-osteolysis: a case report with 7-year follow-up

Congenital insensitivity to pain is a rare disorder, first described by Dearborn¹ in 1932. Since the discovery of congenital insensitivity to pain with anhidrosis or hereditary sensory neuropathy type IV in 1983,² fewer than 60 cases have been reported.³ Congenital insensitivity to pain with anhidrosis and progressing acro-osteolysis is a very rare disorder characterized by absence of painful perception after birth. Severe problems may arise if pain sensation is absent, causing injury to oral structures as teeth, lips and the tongue by self mutilation. The patient is at a risk of late presentation with systemic illnesses associated with pain, such as fracture and joint dislocation. Importantly, the patient may suffer from acro-osteolysis with growth, for instance, osteolysis of the distal extremities.

We report the clinical characteristics of a boy with congenital absence of pain with anhidrosis and progressing acro-osteolysis after a 7-year follow-up，and address the necessity of early intervention as an alternative of conservative treatment.

A 12-year-old boy was brought to our hospital on October 12th, 1999, owing to the restriction of his right leg movement. The leg could not move without any pain when he was playing games 2 days before. He could neither stand nor walk after rest in bed for 2 days. Pelvic radiograph indicated right hip joint dislocation, and reduction was taken by manipulation technique without anesthesia. In the mean time, no tips of fingers and toes but ulcer of distal parts of fingers and palms of hands and scar of lips were found.

The boy, the first son of non-consanguineous parents of Han ethnic nationality, had no familial history of the disease. Pregnancy and labour were uneventful. He was delivered vaginally with birth weight of 3100 g. He could stand at 12 months, walked without support at 18 months, and spoke at the age of 24 months. His parents found him never sweat after birth. His hands and feet were normal during 2 years after birth. At the 6th month after birth his abdominal wall was burned by his father's aflame cigarette, but amazingly, he had no response. From then on, the parents found that the child showed no response to any kind of injury including pin-pricking, poking, burning, hitting and cutting. The boy had never complained of painful sensation. He bit his tongue and lips unconsciously. His hands and feet began to change at 2 years old. The tips of toes and fingers were missing. His right femur was fractured without reason when he was 3 years old. Open reduction and plate internal fixation were performed in another hospital. One year later, the fracture was cured and the plate was removed.

His father was 36 years old and his mother 33. They were both peasants and they had no kinships. They were healthy with moderate height and normal intelligence. The father had 3 brothers and the mother had 3 brothers and 2 sisters, and they were also healthy, and their children showed no sign of hereditary disease. Neurologic examination revealed normal function of the cranial nerve. The pupils responded to light normally. Cardiovascular reflexes were normal. Muscle tone and power were reduced and deep tendon reflexes preserved. The boy was absent of painful stimuli. No normal feeling island could be found by pin-pricking in the skin of his whole body.

Oral examination showed scar in his lips and tongue because of self biting, and several teeth were absent. His fingers and toes were short (Fig. 1). Two ulcers were seen on the palms of his hands.

The results of routine blood counts, urine acid, serum glucose, liver, renal thyroid and parathyroid function tests were normal. Iodine-starch test revealed no sweating. The parents did not give consent to sural nerve biopsy. Electromyography of the extremities showed normal nerve conduction velocity, and heart color Doppler showed nothing abnormal. He was 103 cm in height and 28 kg in weight. The boy was very shy and not cooperative during all the tests. His language was very poor but understandable. The psychometric evaluation showed a low IQ of 40.

Lateral radiography of the cranium showed an absence of his six teeth. Plain X-ray of the pelvis showed a right hip dislocation, a small sheet of acetabular fracture and acetabular dysplasia. Hands radiography showed that all the distal phalanx disappeared except little fingers. Feet radiography showed that all the distal phalanx almost disappeared (Fig. 2). Spine radiography showed no scoliosis, kyphosis and osteolysis. No abnormal evidence was found by X-ray of knee, ankle, shoulder, elbow, and wrest joint.

He had unexplainedly recurrent fever constantly. When he was 15 years old, his right hip joint dislocated again and left proximal femur fracture occurred. Because of far distance to our hospital, the boy was sent to a nearby hospital for treatment by open reduction for right hip dislocation and internal fixation with a plate for the left femur. Unfortunately, the right hip joint dislocated again and the left proximal femur revealed osteolysis complicated with plate and screw loosening. The plate was removed and the right hip joint dislocation was untreated. From then on, the boy could not stand.

At the time of the latest follow-up, the boy was sent to our hospital. On examination he was 110 cm in height and 33 kg in weight. Sexual development was normal. Neurologic and oral examinations were the same as the first time. Routine hematologic and blood chemical measurements were normal. Negative or normal results were noted in urinalysis, creatinine clearance, erythrocyte sedimentation rate, excretion of mucopolysaccharides and hydroxy- proline, antinuclear antibody, C-reactive protein, serum thyroxine and triiodothyronine. Roentgenographic examination showed progressing osteolysis of the distal phalanx of the right thumb, middle finger, left index finger and first left toe. Osteolysis of the right femoral head and parts of the left femoral head and neck was outstanding. Pseudarthrosis in the left proximal femur was induced by osteolysis. On the other hand, osteoporosis of the feet and pelvis was aggravated because of the disuse (Fig. 2).

DISCUSSION

Congenital insensitivity to pain with anhidrosis, a very rare and severe hereditary sensory autonomic neuropathies (HSAN), is characterized by mental retardation, congenital analgesia leading to self-mutilation, multiple scars and fractures, and anhidrosis with repeated episodes of fever, especially in hot weather. Death from hyperpyrexia occurs within the first 3 years of life in about 20% of patients.⁴ Dick et al⁵ recognized 5 types of HSAN in 1993: HSAN I-sensory radicular neuropathy, HSAN II-congenital sensory neuropathy, HSAN III- familial dysautonomia or Riley Day syndrome, HSAN IV-congenital insensitivity to pain with anhidrosis (CIPA), HSAN V-congenital indifference to pain. This kind of disease is known as a HSAN type IV or familiar or congenital sensory neuropathy with anhidrosis.

In our case, CIPA was diagnosed when the patient was 12 years old. He was brought to our hospital by his parents for the right hip joint dislocation with absence of pain. The impairment of pain and temperature sensation and the absence of sweating suggested a kind of neuropathy. Because of mental retardation of the boy, reliable quantitative sensory test for response ability to perceive cold, warm, and painful stimuli was difficult to perform. However, the diagnosis was confirmed by the history of pain absence during injury and by the lack of sweating after iodine-starch test. Normal cardiovascular reflexes in our patient were in agreement with the previous findings in CIPA.

The same clinical manifestations of this disease were reported. Because the patients were unaware of the danger and showed no signs of discomfort, serious injury could occur, like scar in lips and tongue tissues, premature teeth self-extraction, fracture and joint dislocation.

In dentistry, the most important characteristic of CIPA is the self-mutilating behavior that leads the child to injury of lips, tongue and cheeks, and self-extraction of teeth.⁶ Our patient presented scar in the lip and self-extraction of teeth, although the patient was absent of pain. Why he often did self-mutilation was unknown.

The disease was thought to be caused by a mutation in the TrkA gene, encoding for receptor of tyrosine kinase (Tyrosine kinase receptor A) for nerve growth factor (NGF), which is necessary for the survival of nociceptive sensory and autonomic neurons.⁷ Nerve conduction velocities of the patient are normal, but sympathetic skin response (SSR) is absent. There are few earlier reports on sural nerve biopsies in phenotypically classified HSAN IV, and no small myelinated fibers and very few unmyelinated fibers were found in the sural nerve. Skin biopsy in a case of HSAN IV showed absence of fibers immunoreactive to neuropeptide Y, nitric oxide, and vasoactive intestinal polypeptide, thus prompting developmental alterations of the peripheral nervous system. The lack of innervation of the skin by Aσ and C fibers is the basis of HSAN IV.⁸

In orthopedic surgery, the characteristic of CIPA is acro-osteolysis, fracture and joint dislocation. Pain is a protective mechanism for the body, and in the absence of pain, the patient is likely at the risk of injury. Our patient had the right hip joint dislocation when he first came to our hospital, and the left proximal femur fracture occurred after 3 years. It was reported that acro-osteolysis was due to self-mutilation. However, the parents of our patient said that the boy never had self-mutilation in the hands and feet, but the tips of all the fingers and toes disappeared, and scar in his lips and ulcer of distal parts of fingers and palms of hands displayed. Surprisingly, progressing osteolysis of the distal phalanx of the right thumb, middle finger, left index finger and the first left toe occurred and pseudarthrosis in the left proximal femur occurred because of osteolysis after a 7-year follow-up. The mechanism of the osteolysis was unknown.

Other diseases resulting in acro-osteolysis for differential diagnosis are follows: Winchester syndrome is characterized by normal intelligence, osteoporosis, corneal opacities, joint stiffness, skin changes and coarse face. Acro-maxillofacial dysplasia is characterized by prominent eyes, beaked profile of nose，face atrophy，sparse and dim hair，visible scalp vein, and progressive shrinking of the lower mandible. Radiologically, slow osteolysis of the lower mandible and micrognathia can be found. Hutchinson-Gilford progeria is characterized by normal intelligence, high-pitched voice, hearing loss，alopecia，unusual facies，marked short stature and normal sweating gland secretion. X-ray shows progressive osteolysis of phalanx ends, even shortened and thinned to punctiform, and osteolysis in clavicle. Pyknodysostosis is characterized by normal sense and increased densities of all the bones in radiology. Hajdu-Cheney syndrome, which was first reported by Hajdu and Kauntze in 1948, and familiar cases was reported by Cheney in 1965, is autosomal dominantly inherited, with various clinical manifestations. Only 35 cases were reported up to now. Patients with this disease usually present with short stature，unusual facies，slowly progressing acro-osteolysis，normal sweat gland secretion, and no analgesia or mental defect. X-ray features show mandibular hypoplasia, frontal sinus absence, saddle hypoplasia, loss of tooth, occipital predominance, and distal ends osteolysis of hands and feet.⁹

Few cases of insensitivity to pain with anhidrosis and progressing acro-osteolysis are reported, and thus no standard treatment is available for this kind of disease. A patient should be protected from every dangerous condition. There is no evidence to indicate how long the life-expectancy of the patient would be. Our patient needs further follow-up.

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