Journal of Pediatric Orthopaedics B:
Congenital insensitivity to pain with anhidrosis is an autosomal recessive disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene, which encodes the receptor for nerve growth factor. We report the clinical and radiological pitfalls in the diagnosis and treatment of two brothers, aged 5 and 8 years, with congenital insensitivity to pain with anhidrosis, the older brother having a proven NTRK1 mutation. In the neonatal period, both presented with recurrent episodes of fever of unknown origin, but their clinical problems changed later. In addition to severe mental retardation and self-harming behaviour, the older brother developed recurrent nonbacterial destructive infections of both the calcaneus and later the talus. No immunodeficiency was found. The younger brother had three complex fractures with a long history of healing problems: overwhelming production of callus, osteomyelitis and movement restrictions. He has less mental retardation than his older brother and shows no self-mutilation.
aDepartment of Child and Adolescence Health
bDepartment of Human Genetics
cDepartment of Pediatric Surgery, University of Lübeck, Lübeck, Germany
Correspondence to Marion Rapp, MD, Department of Child and Adolescence Health, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany Tel: +49 451 500 2127; fax: +49 451 500 6206; e-mail: firstname.lastname@example.org
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy (HSAN) type IV, is an autosomal recessive disorder characterized by anhidrosis and the absence of any reaction to pain stimuli 1,2. It is a rare disorder and only a few hundred cases have been reported in the literature 3. As in all known HSAN (type I–V), the development of small nerve fibres is disturbed: in CIPA the C and Aδ fibres are absent, leading to the absence of pain perception 3,4. The patients are unable to control their body temperature through sweating because their eccrine sweat glands are not innervated 5. This anhidrosis causes recurrent life-threatening episodes of fever of unknown origin in the neonatal period. Other autonomic manifestations are mild or missing, unlike in HSAN types II and III 3. The insensitivity to pain, combined with mental retardation, leads to severe injuries and to behavioural problems such as self-harm in infancy 6. In the clinical context, patients with CIPA suffer not only from their injuries; complications such as infections, the overwhelming production of callus, osteitis, avascular necrosis, corneal ulcers and the destruction of joints (Charcot joints) occur during the healing of wounds and fractures 1,7. Fractures are difficult to treat and wound healing take a long time.
Although CIPA is a genetic disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1), which is coded on chromosome 1q21–q22 8, the clinical presentation varies considerably between patients. This makes the treatment of complications even more difficult 9.
This paper presents the various surgical problems experienced by the two brothers during their childhood with CIPA.
The brothers are the third and fourth children of their consanguineous Kurdish parents (Fig. 1). Their oldest daughter died at the age of 1 year of an unexplained fever in Iraq, the family’s country of origin. Their second child has severe behavioural problems, but seems to be somatically healthy otherwise. At the time of the birth of the third child, neither parent was able to read, write or speak German. The father subsequently started to learn German but there remained many social and compliance problems.
The older brother was born at full term by normal vaginal delivery. He presented with neonatal seizures with a complete loss of muscle tone. By the age of 6 months, he had experienced recurrent episodes of fever with high inflammatory markers without positive blood, stool or throat cultures (sepsis-like episodes). Further diagnostics showed a glucose-6-phosphate dehydrogenase deficiency. Although a brain MRI scan was normal, a lumbar puncture indicated low dopamine levels. Because of this, he was treated with dopamine but his mental development was retarded, with noticeable ability loss. After his second year of life, he repeatedly presented with ulcers, haematoma and burns on his hands. The boy’s skin had a thick and calloused appearance, with dystrophic nails and trauma scars on the fingers. Nonaccidental injuries were suspected. During his time in hospital, the boy never cried with tears; he showed no sign of pain while scratching his wounds and he showed self-harming behaviours by putting his fingers into his eyes.
In childhood, the older brother’s milestones were delayed; he began to walk at the age of 2½ years and is still not using active speech. Owing to his severe mental retardation and self-harming behaviour, by the age of 3 years, he had suffered three open finger fractures, one proximal humeral epiphysiolysis and multiple burns. At the age of 3½ years, he was admitted with fever and a swollen right lower leg and ankle. Soft-tissue infections but no ulcerations of the foot were noted. Although radiograph and MRI suggested osteomyelitis of the calcaneus, no microorganisms were isolated from blood cultures, bones or aspirations from the calcaneus. Following multiple debridements, the boy received a long-term treatment with wide-spectrum antibiotics, but the destruction of the calcaneus continued; bone grafting was also unsuccessful. The experimental combination of foreign bone grafting and platelet-rich plasma as a growth stimulus (GPS; Biomet Merck Biomaterials, Berlin, Germany) halted the destruction and the boy was able to walk again. Just 3 months later, the boy presented with a swollen left ankle. Radiographs and MRI tests confirmed the diagnosis of osteomyelitis of the left calcaneus, but debridement and treatment with antibiotics were again unsuccessful. The combination of debridement, foreign bone grafting and GPS improved the local bone healing and the boy was again able to walk without aids. The boy developed no further complications of the musculoskeletal system for over 2 years, but during that time, he presented with recurrent corneal ulcers that led to visual impairment. Two years ago, at the age of 6, the boy again presented with a swollen right ankle. Radiograph and MRI indicated a necrosis of the right talus (Fig. 2). Debridement, local and intravenous antibiotics failed to improve the situation, but anti-inflammatories and orthopaedic splint immobilization reduced bone destruction. Investigations of the humoral and cellular immune systems showed that the natural killer cell and the macrophage activity (phagocytosis) were slightly lower than the reference, but immunodeficiency was not the cause for the recurrent inflammation in our patient (Table 1).
Because of severe compliance problems with treatment strategies and frequent visits, most treatment took place in the hospital.
At the time that nonaccidental injuries were suspected in patient 1, the younger brother was born and showed recurrent episodes of unexplained high fever (42°C). Inflammatory markers were normal and all cultures were negative. The nurses realized that the boy did not sweat during fever, but lacrimation was normal. Neurological examination indicated generalized loss of pain and temperature sensation. MRI showed no pathology; no metabolic disorder or immunodeficiency was found. The characteristic clinical signs of insensitivity to pain and anhidrosis observed in this boy led to the clinical diagnosis of CIPA in the brothers. The genetic confirmation was performed later (see below).
The younger brother has mental retardation, but not as severe as his older brother (Table 2). He began to walk at the age of 2 years and uses some Kurdish words. He is able to express his feelings and wishes without words. At the age of 3, he had a closed dislocated transverse fracture of the lower leg – treated with elastic stable intramedullary nailing – followed by compartment syndrome and delayed bone and soft-tissue healing with skin transplantation. During the stay in hospital, a hypertrophic callus formed at the distal femur as a secondary fracture sign. An osteomyelitis of the tibia occurred, which required further surgical interventions and resulted in an enormous hypertrophic callus (Fig. 3). Soon afterwards, he broke his left elbow joint. At the first change of cast, the boy took out his K-wires. A second fall resulted in the break of another osteosynthesis (with one screw and K-wires) and a massive soft-tissue infection became visible (Fig. 4). More than 6 weeks of vacuum assisted closure-therapy was necessary to close the soft-tissue defect. One year after treatment, the movement is considerably reduced (elbow joint: extension/flexion elbow 0–30–90°, supination/pronation: 20–0–20°).
The diagnosis of CIPA was confirmed by the identification of a homozygous c.274dupG, p.Glu92GlysfsX81 mutation in the NTRK1 gene. This mutation changes a translation codon to a termination codon, stopping the synthesis of nerve growth factor (NGF). It leads to a loss of function of both copies of the NTRK1 gene.
Children with congenital insensitivity to pain and anhidrosis (CIPA) suffer from complex problems in almost every organ system. Because the disease is very rare, the diagnosis is difficult to make even for experts, and many life-threatening situations may occur before CIPA is identified. The boys presented with sepsis-like episodes or severe temperature dysregulation. However, it was only the coincidence of the different symptoms of the disease in both brothers that led to diagnosis. Retrospectively, their older sister probably died because of CIPA. Although no curative treatment is known, a diagnosis of CIPA helps avoid extensive diagnostic procedures in the children, such as repeated lumbar punctures, or antibiotic treatment associated with long-term hospital stays. Both boys suffered, in infancy, from characteristic problems of wound healing and fracture treatment: hypertrophic callus in the younger boy and avascular necrosis of the calcaneus and talus in the older boy.
The reasons for these complex problems of the musculoskeletal system of patients with CIPA are still unknown, but determination of the genetic background helps to characterize the disease and may improve the future treatment of these children. The diagnosis of CIPA in our patients was confirmed by the identification of the new homozygous c.274dupG, p.Glu92GlysfsX81 mutation in the NTRK1 gene on chromosome 1 (1q21–q22), which encodes for the NGF receptor. It regulates neural development and differentiation 10. The lack of NGF-dependent primary afferents (myelinated Aδ-fibres and unmyelinated C-fibres) leads to impaired pain perception and autonomic dysfunction with no stimulus for the production of sweat for thermal regulation 4. Research in the last decade has shown that CIPA is a multisystem disease, affecting not only the nervous but also the immune and other systems 9,11.
Because NGF is found on the surface of B lymphocytes, some authors favour a direct link between the NGF and the immunological system: the lack of NGF resulting in a reduced immunglobulin synthesis 12,13. Although circulating human B lymphocytes are known to express NGF receptors, no changes in immunoglobulin production and function occurred in our patients, in contrast to the reported case of a 7-year-old girl with CIPA 12. Recurrent ulceration of the palmar hand in one of our patients led to phagocytic immunodeficiency being suspected, but it was excluded by normal functional testing. Other investigations indicated that innate and adapted immune responses were normal; this contrasts with reported abnormal neutrophil chemotactic activity 14.
Other experimental studies have shown NGF expression on bone-producing cells in a mouse and rat model. If the NGF was disturbed, a hypertrophic new bone was produced 15,16. This might explain the massive bone hypertrophy in our younger patient. The neuroimmunological pathways that led to the disturbed wound healing and the necrosis of the calcaneus or taleus are unknown, but the fact that most osteomyelitis-like episodes are nonbacterial osteitis enabled us to alter our treatment guidelines from antibiotics to anti-inflammatory medication. Current management with immobilization is thus much less invasive.
An important differential diagnosis to CIPA is child abuse. Every physician has to consider the possibility of child abuse in cases of unexplained injury, but neurologic disorders such as CIPA should not be overlooked as a possible explanation – as in our cases.
The combination of paediatric, orthopaedic, surgical and ophthalmological problems means that these children should be treated in specialized multidisciplinary teams. Given the fact that CIPA is an autosomal recessive genetic disease, the teams need to include human geneticists.
These multidisciplinary teams also facilitate the exchange of knowledge, which is important in reducing postoperative complications in patients with the rare disease of CIPA. An improved treatment strategy for the patients and their family was only possible by a combination of therapies by a paediatric immunologist, a neurologist, a paediatric surgeon and social workers.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
calcaneus necrosis; congenital insensitivity to pain with anhidrosis; hereditary sensory and autonomic neuropathy type IV; immunodeficiency; multiple fractures; NTRK1 gene; osteitis; overwhelming callus