Congenital insensitivity to pain with anhidrosis

a case report of a 33-year-old patient

Abstract

Congenital insensitivity to pain with anhidrosis is a type IV hereditary sensory and autonomic neuropathy, presenting early in life. This disorder results from defective neural crest differentiation with loss of the first-order afferent system, which is responsible for sensations of pain and temperature; a neuronal loss in the sympathetic ganglia is also present. A case of a 33-year-old patient with congenital insensitivity to pain with anhidrosis is presented. From the time of birth, he did not sweat and did not respond to painful stimuli, although unexplained bouts of fever were often observed in infancy; an extensive workup during childhood helped establish the diagnosis. Throughout childhood and adulthood, the patient presented multiple infections and fractures in various sites of his body, growth disturbances, and avascular necrosis, and Charcot arthropathies and joint dislocations mainly affected his elbow and hip joint. At the final follow-up, at the age of 33 years, he was found to be obese, with a limited social life. A Charcot elbow restricted the activity of his left upper limb, and the dislocated hips combined with the instability of the ankle joints limited the ambulation distance. A specific treatment protocol has not been established in the literature; the main principles that can be applied in patients with normal intelligence include training programs to prevent self-mutilation and accidental injuries and an early diagnosis and treatment of the infections.

Introduction

Congenital insensitivity to pain is a rare condition that may affect various tracts in the peripheral nervous system. An indifference to painful stimuli is observed, although in most patients, the autonomic nervous system is affected. This condition has been described as hereditary sensory and autonomic neuropathy (HSAN) ¹ and is divided into various subtypes. In 1993, Dyck et al. ² described five types of HSAN: sensory radicular neuropathy (HSANI), congenital sensory neuropathy (HSANII), familial dysautonomia or Riley–Day syndrome (HSANIII), congenital insensitivity to pain with anhidrosis (HSANIV), and congenital indifference to pain (HSANV).

Congenital insensitivity to pain with anhidrosis (CIPA), a HSAN type IV disorder, is a rare autosomal-recessive condition of the nervous system characterized by the absence of a pain sensation, painless injuries of the extremities and oral structures such as scarring of the tongue, lips, and gums, fever secondary to anhidrosis during hot weather, loss of unmyelinated and reduction of small myelinated fibers in the sural nerve, and mental retardation; keratoderma palmoplantaris is found in older patients. A defective development of the small, nociceptive neurons in the dorsal root ganglia could be responsible for the pain insensitivity observed. Morphologic studies have yielded contradictory results regarding the sympathetic innervation of the eccrine sweat glands despite the fact that anhidrosis is a constant finding in CIPA. The presence of innervated sweat glands in the dermis was verified by Rosemberg et al. ³. The contrasting viewpoint was reported by Ismail et al.⁴ and Langer et al.⁵.

A case report of a 33-year-old male patient with CIPA is presented; he had multiple musculoskeletal problems that included infections, fractures, growth disturbances, and Charcot arthropathy. The patient was informed that data from his medical record and photographs of him would be submitted for publication and he gave his consent.

Report of the case

The patient, a 33-year-old white man, was the second child of nonrelated parents. His older sister and his parents were not affected by the congenital disease; pregnancy and labor were uneventful.

He did not sweat and did not respond to painful stimuli in the normal way from birth, whereas unexplained recurrent bouts of fever were often observed in infancy. The febrile period was characterized by an absence of sweating, whereas the skin was warm and dry.

He was diagnosed with congenital insensitivity to pain during childhood after an extensive workup.

From that period of time to date, the patient has been regularly examined by the Orthopaedic Department because of a wide range of musculoskeletal disorders, affecting both the upper and the lower limbs.

During childhood, multiple infections were observed, usually starting as infected decubitus ulcers on weight-bearing areas in the feet. Treatment consisted of a combination of antibiotics and relief of pressure from weight-bearing areas by custom-made shoes, relieving splints, or periods of non-weight-bearing. Persistent cases of infection required surgical intervention consisting of drainage of the affected area and thorough surgical debridement of necrotic tissue. Multiple infections (bursitis) around the hip joints were frequent, progressing to septic arthritis in some cases, treated either with the administration of antibiotics or with surgical debridement. The diagnosis was complicated by concomitant infections at multiple sites as well as defective temperature control of systemic manifestations. No amputations of any extremity were performed.

Gait capability was limited because of structural deformities. The patient presented bilateral dislocation of the hip joints and genu varum deformity of the knees, which could have been because of fractures of the growth plate. The patient’s intelligence was normal and he had no behavioral problems.

At the age of 16 years, he suffered from a spiral fracture of the left femur that was surgically treated by external fixation. This technique was chosen because it is less traumatic to the tissues, with lower incidences of infection, and it also takes a shorter time than the other techniques, which was a major advantage as the operation was performed without anesthesia. The varus deformity of the affected limb was corrected at the same time. A few days later, taking advantage of the patient’s immobilization, a corrective osteotomy was performed to the bilateral varus knee (at the proximal tibia). The fracture and the osteotomy united uneventfully and wound healing was uneventful.

Four months later, he presented a Salter-Harris II fracture of the upper tibial epiphysis. The limb was immobilized on a splint for a 4-week period, sufficient for the formation of profuse callus.

A fracture of the proximal end of the right femur occurred at the age of 17 years. The fracture was reduced and stabilized by three half pins, placed at the proximal end, and three others placed at the distal end of the fractured femur. A transparent, flexible anesthetic tube was placed alongside by transfixing it on the projecting parts of the pins. After that, the methyl methacrylate was mixed and injected into the tube. The fracture was reduced under radiographic control and stabilized at the same time by hardened methyl methacrylate ⁶. During the surgical manipulations, the femoral head was dislocated and reduced at the same time. The half pins’ insertion well as the reduction were performed without anesthesia; he did not show any response to the manipulations performed. Two months later, the external fixation was removed and the fracture healed successfully.

Avascular necrosis of both tali was responsible for the cavovarus deformity of the feet, which consisted of hindfoot varus and plantar flexion of the first ray with pronation of the forefoot. The malformation of the right foot (Fig. 1) was responsible for the recurrent ulcers of the plantar surface, which were treated with consecutive surgical debridement; analgesia was not necessary during these procedures.

Fig. 1: A lateral radiograph of the neuropathic right ankle joint, showing avascular necrosis of the talus. The tibia is found to be submerged into the calcaneus and the talus is completely destroyed.

The patient’s BMI increased in the subsequent years; the clinical and radiological views (Fig. 2) of the right ankle aggravated throughout that period of time, with the tibia being submerged into the calcaneus and complete destruction of the talus. An excessive arthrodesis of the joint was performed, at the age of 20 years, consisting of surgical fusion of the tibiotalocalcaneal, talonavicular, and calcaneocuboid joint; during the surgical procedure, no anesthetic agents were administered.

Fig. 2: A postoperative lateral radiograph of the right ankle where an excessive arthrodesis is shown. Surgical fusion of the tibiotalocalcaneal, talonavicular, and calcaneocuboid joint was performed to correct the deformity.

The subsequent decade was characterized by multiple bone and joint infections, mainly at the hip, requiring many surgical procedures.

A surgical stabilization and concurrent correction of the deformity of the left ankle by a tibiotalocalcaneal fusion combined with talonavicular and calcaneocuboid joint fusion was performed when he was 30 years of age; the results were not satisfactory. Stability did not improve with surgery and the patient was managed by below-the-knee braces that often had to be modified because of pressure ulceration.

A year later, the patient experienced numbness of the upper limbs, followed by a slightly diminished strength and paresthesia of the extremities. The radiographic control (plain radiographs and MRI) revealed instability and kyphosis of the C5–C6 vertebrae. An anterior, 1-level fusion with cage was performed (Fig. 3a and b). Upon mobilization postoperatively, he complained of minor pain, lack of numbness, and his overall recovery was satisfactory.

Fig. 3: (a) Anteroposterior radiograph of the cervical spine showing the 1-level (C5–C6) anterior fusion; (b) lateral plain radiograph showing the spine fusion and the intersomatic cage. One screw was found to be broken, without clinical symptoms.

The final follow-up was performed at the age of 33 years. He has no occupation as his social life is limited. The patient was found to be obese; a Charcot-type left elbow was identified during the clinical examination, which was stiff and had a reduced range of motion (Fig. 4a and b), whereas the collateral one was not affected (Fig. 4). Both Charcot-type hips were found to be dislocated as confirmed by the radiographic control (Fig. 5). A genu varum deformity was present while the patient ambulates short distances by using a below-the-knee ankle-brace in both limbs in order to stabilize the ankle joint.

Fig. 4: (a) Photograph of the left Charcot elbow showing severe swelling and deformity of the joint; (b) radiographic evaluation of the left elbow reveals characteristic findings of a neuropathic joint. The severe deformity that characterizes that elbow can be easily interpreted as the left hand is the dominant one and is exposed to multiple injuries; (c) the collateral elbow (R) is normal.

Fig. 5: Anteroposterior radiograph of Charcot hips. A bilateral dislocation with neoacetabulum formation is revealed.

Discussion

Children suffering from peripheral neuropathies are characterized by impairment of both the sensory-discriminative and the affective-motivational components of pain sensations. Most of those patients have a type of HSAN, with the main symptoms of absence of pain sensations and other sensory or autonomic abnormalities. In all of these cases, the main abnormality regards the small-diameter C and A-δ fibers responsible for pain transmission.

Various classification systems have been proposed on the basis of different parameters such as the inheritance pattern, natural history of the disease, pathological alterations, neurophysiological characteristics, and biochemical disorders. The ones widely used are those proposed by Pinsky and Di George ⁷ in 1966, and by Dyck ², who divided those neuropathies into five types (Table 1); type IV, also known as CIPA, is a severe form presenting early in life. CIPA is also known as ‘congenital sensory neuropathy with anhidrosis’ and ‘familial dysautonomia type II’.

Table 1: Types of hereditary sensory and autonomic neuropathy

CIPA is an extremely rare autosomal disorder – the incidence has been estimated to be one in 25 000 population ⁸ – where pain insensitivity and autonomic deficits are present; however, touch and pressure sensitivity are unimpaired. In CIPA, the lack of pain sensations is most likely the result of dorsal root ganglia absence, which is responsible for pain sensation. The absence of small-diameter centripetal neurons that are activated by tissue damaging stimuli result in the lack of pain ^9,10, and the phenomenon of anhidrosis can be explained by the loss of intervention of eccrine sweat glands by sympathetic neurons ^4,5. The clinical onset characteristics of CIPA are quite typical. The first sign of the disease is recurrent episodes of elevated body temperature during infancy ¹¹, hyperpyrexia, which is more frequent in high summer temperatures; during these bouts of hyperpyrexia, the skin does not sweat and remains, on the whole, warm and dry. This condition is responsible for the death of 20% of affected children ³. MRI and cerebrospinal fluid abnormalities, in a 9-month-old girl with CIPA and hyperpyrexia complicated by generalized tonic convulsions and coma, were reported by Iwanaga ¹². Mental retardation is usually present, although the patient reported in the present paper had normal intelligence.

In addition to problems with temperature control, patients with CIPA have various musculoskeletal problems. After teeth eruption, infection and scarring of the lips and gums occur frequently, followed by mutilation of the tip of the tongue; auto extraction of teeth is also common ¹³. The fingertips also appear scarred, smaller, and rounded with dystrophic nails. As they grow older, accidental injuries such as burns or falls may be responsible for multiple scars ¹⁴. Chronic infections of the bones and joints are additional complications.

From infancy, fractures become frequent and the problem aggravates with time as the child becomes mobile. Fractures are commonly found in the lower limbs, particularly proximal to the knee and to the ankle and hip joints, with consequent neuropathy of the adjacent joints. Pathologic fractures of the mandible have also been described, although open reduction and internal fixation is the appropriate method of treatment ¹⁵. In many cases, for instance in complicated fractures, dislocations, neuropathic joints (Charcot arthropathy), and infections, amputation of the limb may be necessary. We believe that the most appropriate surgical technique in managing these fractures is external fixation. On the one hand, it is considered to be less traumatic compared with other techniques (plates and screws, intramedullary nails, etc.) as the few half pins that are inserted through the skin prevent extensive skin incisions that are performed in other methods. Moreover, the pin tract infection, a major issue especially in these patients, can be easily controlled with surgical skills and antibiotic administration. On the other hand, it should also be kept in mind that most surgical procedures are not performed under anesthesia; therefore, the fracture should be reduced and stabilized in a short period of time with the least invasive technique.

The skeleton, as a whole, may be affected including the spine ¹⁶. Nagayama et al.¹⁷ reported on a case of a spinal cord injury at birth in a neonate with CIPA. One of the main issues in those patients, during admission to the orthopedic department, remains the differentiation between fractures and infections. Both usually come along at an advanced stage with local swelling and warmth. Body temperature is not a reliable indicator, and the erythrocyte sedimentation rate and C-reactive protein are elevated because of concomitant infections at other sites of the body. Callus formation, at the radiographic evaluation, may aid the diagnosis of a fracture. Aspiration and cultures should be obtained before the decision of surgical debridement is made to prevent unnecessary surgery and damage to the growth plate. When the diagnosis of infection is established, a thorough debridement should be performed to control the infection ¹⁸.

The differential diagnosis of CIPA from other conditions presenting with absence of or reduced pain can be easily established on the basis of the distinct clinical picture; insensitivity to pain with anhidrosis, followed by frequent hyperpyrexia are not found in any other type of neuropathy.

The role of prevention of infections that characterize patients with CIPA is very important to provide them with a better quality of life. Custom-fitted shoes and periods of non-weight-bearing relieve pressure areas ¹⁹. In addition, education on the prevention of injuries, local foot care, and early medical attention is imperative as this can help avoid radical surgery. Ulceration of the posterior aspect of the elbows, knees, and upper and lower extremities as well as other parts of the body should be managed by local wound care, aseptic dressings, and avoidance of external pressure. Dislocated neuropathic joints are painless and mobile, which means that they should be manipulated in a ‘watchful neglect’ way. Roberts et al. ²⁰ described successful surgical stabilization of the hip joint; in contrast, Koster et al. ²¹ reported a failure. Furthermore, heterotopic ossification and joint stiffness could be disastrous for insensate patients. The braces and splints that are frequently used in different sites of the body should be enhanced with extra padding and periodically examined for infections because of the pressure. These preventive measures to improve longevity in patients with CIPA may be useful for individuals with normal intelligence as in the patient reported on in this paper.

Conclusion

CIPA is considered a rare autosomal developmental disorder of the nervous system caused by lack of maturation of small myelinated and unmyelinated fibers of the peripheral nerves that are responsible for sensations of pain and temperature. The absence of innervation of the sweat glands by these fibers causes the anhidrosis observed.

Early diagnosis of CIPA is essential for the survival of those suffering patients. Inappropriate correction of hyperpyrexia could be fatal in the first years of life; in older children, soft-skin infections and osteomyelitis may lead to severe surgical procedures, sometimes even to amputations. A specific treatment protocol has not been established, although the main principles, which can be followed by patients with normal intelligence, include training programs to prevent self-mutilation and accidental injuries as well as prevention and early diagnosis and treatment of infectious conditions.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.