Congenital insensitivity to pain with anhidrosis (CIPA) is caused by a defect in the neurotrophin signal transduction system and is classified under hereditary sensory and autonomic neuropathy (HSAN)1. The defect lies in the NTRK1 gene coding for neurotrophic tyrosine kinase on chromosome 1q21-q222. Its incidence within the global population has been estimated to be 1 in 25,0003. First described in 1846 by Leplat4, the diagnosis of CIPA or HSAN IV is based on the clinical presentation, skin and nerve biopsies, and molecular DNA analysis1,5.
Dyck has classified HSAN into five types1. Type I is relatively mild, mainly affects the lower limbs, and manifests in the second to fourth decade. Type II is more severe and presents in infancy. Type III is familial dysautonomia or Riley-Day syndrome, a multisystem disease predominantly affecting Ashkenazi Jews. Type IV features insensitivity to pain, heat intolerance, and mental deficiency. Type V selectively affects nociception.
“Painless whitlows,” “mal perforant du pied,” and “Morvan syndrome” are some of the many names used to describe a wide range of conditions that have been grouped under the HSAN classifications. Common to these conditions is insensitivity to pain, but in addition, proprioception, temperature sensitivity, and sense of vibration may also be affected, along with wider systemic problems2. Charcot arthropathy may complicate fractures and osteomyelitis6.
The classical clinical presentation of CIPA in childhood is apathy, refusal to feed, absence of sweating, and unexplained hyperpyrexia. There may be a mild degree of mental retardation and delayed motor activities7. The tongue may appear bifid as a result of biting. There may be autoextraction of teeth and scarring of the lips as well as rounded fingertips with dystrophic nails.
We present the case of a young man who had been followed for eleven years after having been diagnosed with HSAN Type IV. He had manifested almost all of the described musculoskeletal problems associated with this condition. He has been a challenging case ever since the original diagnosis. The patient and his guardians were informed that data concerning the case would be submitted for publication, and they provided consent.
A right-handed boy, the eldest of three siblings born to parents in a nonconsanguineous marriage, initially had presented to the orthopaedic outpatient unit at the age of eleven years in 2002. He gradually had developed increased swelling in both knees, which was associated with a painless limp. The swelling of the left knee had increased steadily to a massive size, at which point the child had been brought to the hospital. The medical history revealed that he had experienced episodes of flushing of the skin, which tended to remain warm and needed to be wiped cool with a wet cloth. He had occasional high fevers, and he never sweated. He was also academically slow. He had been empirically treated with antituberculosis medications for two months but had experienced no improvement. Destructive changes seen in the radiographs of both knees suggested a diagnosis of neuropathic joints. A nerve conduction velocity study, sweat tests, and sural nerve and skin biopsies confirmed a diagnosis of CIPA. An intradermal injection of 0.1 mL of 1:1000 solution of histamine produced a wheal, but there was no pain and no axon flare around the wheal. He had been provided a brace but was noncompliant. Although he had continued to walk with a progressively increasing painless limp, he had been unable to continue schooling after 2003.
In September 2003, a trivial fall led to an undisplaced fracture of the left tibia and fibula, which healed normally after being treated conservatively in a below-the-knee cast. However, the patient presented a year later with a massive swelling around the same knee. There were areas of skin hyperpigmentation (Fig. 1). There was an ulcer over the lower thigh with ill-defined borders, and the knee had abnormal mobility. Radiographs suggested osteomyelitis of the distal part of the femur and septic arthritis of the knee, for which he was treated with drainage of the joint and multiple bone debridements. He responded well to the treatment.
In September 2008, at the age of seventeen, the patient presented with a high-grade fever and a swelling similar to the one experienced in 2003, which extended from the left thigh to the proximal third of the leg (Fig. 2). The clinical presentation and blood parameters suggested septicemia. Given the gross destruction of the neuropathic joint and extremely poor bone quality (Figs. 3 and 4), it was decided to perform an above-the-knee amputation as a lifesaving measure. He recovered well, and at discharge he was able to sit up on the bed and stand and walk with support on the right leg, despite the concurrent destruction of the right knee joint.
At the age of twenty-one, he had been bedridden for six months and was admitted to the hospital with a decubitus ulcer over the left ischial tuberosity (Fig. 5), which had been present for two weeks, and increased swelling of the right knee joint. Radiographs of the right knee joint were obtained (Figs. 6 and 7). The plastic surgery team treated the ulcer with a muscle flap.
On the latest physical examination, the patient was found to be poorly nourished and demonstrated a below-average IQ. There were flexion deformities of the distal interphalangeal joints of the fingers of both hands, as well as dystrophic nails (Fig. 8). The amputation stump of the left knee showed a well-healed surgical scar. There was severe wasting of the musculature of the right thigh and leg, with gross deformity of the right knee. There was a prominence of the veins over the knee (Fig. 9), with grossly abnormal but pain-free mobility. The femoral and tibial condyles, as well as the patella, were not palpable. There was abnormal bone growth all around the bones. There was a superficial ulceration over the medial malleolus (Fig. 10) and a 5 × 5 × 3-cm ulcer over the left ischial tuberosity. The edges of the decubitus ulcer were sloping and whitened, and there was a muscle base. The margins showed no surrounding erythema or induration (Fig. 5).
Although the patient had generalized insensitivity to pain, he was able to appreciate fine and crude touch, hot and cold sensations, vibration, and proprioception. He had grade-4 power in the muscles of the right lower limb, and grade-5 power in the muscles of both upper limbs. Deep reflexes were diminished, and peripheral pulses were palpable.
Most children with CIPA die before the third year of life as a result of high fevers, which makes the reporting of this condition infrequent. With survival up to the age of twenty-one years, our case is a rarity. Almost all of the signs and symptoms had been present before the boy first presented to the outpatient clinic. The reason our patient presented at the later age of eleven years was because of lack of awareness of the condition and the poor socioeconomic status of his family. Findings of self-mutilation were not seen in this twenty-one-year-old patient, who had been counseled over the last ten years to avoid this behavior.
Theodorou et al. suggested that fractures, dislocations, and neuropathic joints in patients with CIPA often are best treated with amputation7. In our case, life took predominance over limb; hence, the patient underwent an above-the-knee amputation of the left leg at the age of seventeen.
In patients with CIPA, fractures are more common in the lower limbs, with consequent neuropathy of the adjacent joints, and should be properly immobilized. It is essential to apply a well-padded cast. Krettek et al. encourage initial treatment with nonoperative methods and, if there are signs of hypertrophic nonunion, they suggest treating with internal fixation8. Ulcerations are best prevented. In the unfortunate event of their occurrence, they are best managed by local care of the wounds and thick aseptic dressings.
Bar-On et al. have suggested preventive measures for orthopaedic complications in these patients4. These include special protective footwear and clothing, periods of non-weight-bearing, avoidance of injuries, prompt treatment of wounds, wide surgical debridement, and curative osteotomy for deformities2.
CIPA is a condition that poses many therapeutic dilemmas. In our experience, this rare condition has been difficult to diagnose and complicated to explain to the patient’s parents, especially since it has not affected their other two children. Considering the number of investigations, hospital admissions, and surgical procedures this patient has undergone, it is an expensive disease to manage with a poor long-term outcome. It is best to counsel both the patient and the caregivers on ways to avoid injuries and prevent complications. It should be stressed that even the earliest of infections in the skin, bones, or joints in patients with CIPA should be aggressively treated in order to potentially salvage a limb.
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