Insensitivity To Pain, Congenital, With Anhidrosis

A number sign (#) is used with this entry because congenital insensitivity to pain with anhidrosis (CIPA) is caused by homozygous or compound heterozygous mutation in the NTRK1 gene (191315) on chromosome 1q23.

For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).

Clinical Features

Swanson et al. (1963, 1965) described 2 brothers with congenital insensitivity to pain and anhidrosis, despite normal-appearing sweat glands on skin biopsy. Temperature sensation was also defective. One of the brothers died after a 24-hour illness during which his temperature reached 109 degrees F. Almost complete absence of the first order afferent system considered responsible for pain and temperature was found at autopsy (Swanson et al., 1965). Pinsky and DiGeorge (1966) described the same disorder in 3 mentally retarded children, 2 of whom were sibs, with recurrent episodes of unexplained fever, repeated traumatic and thermal injuries, and self-mutilating behavior. Sweating could not be elicited by thermal, painful, emotional, or chemical stimuli, and histamine evoked no axonal flare. Subcutaneous administration of mecholyl or neostigmine in doses capable of producing lacrimation in normal children failed to do so in these patients, despite their occasional spontaneous lacrimation. Wolfe and Henkin (1970), who referred to the disorder in Pinsky and DiGeorge's sibs as type II familial dysautonomia, described unresponsiveness to methacholine despite the presence of taste buds. They suggested that it is the same as the disorder reported in 2 sibs of each of 2 families by Swanson (1963) and by Vassella et al. (1968).

Yanagida (1978) found that naloxone, a specific antagonist of opiate receptors, was effective in CIPA, suggesting that overproduction of brain endorphins is involved in the disorder.

Ishii et al. (1988) described a Japanese girl with CIPA who died at the age of 21 months. During the first few months of life, she suffered from recurrent episodes of unexplained high fever without sweating and hard breathing, and was found to lack sensation to pain. After the establishment of dentition, she bit off the apical part of her tongue and began self-mutilating her lips and the tips of her fingers. Courtney and Freedenberg (1990) described a patient who appeared to have HSAN4, but did not have developmental delay. Rosemberg et al. (1994) presented a 4-year-old girl, the second child of consanguineous parents, who had typical HSAN4. They provided a useful review of the literature, which included 31 patients, noting that 20% of the patients succumbed to hyperpyrexia, most of them before age 3. Most of the children were mentally retarded, with IQs varying from 41 to 78, the majority being in the 60s.

Ismail et al. (1998) described an 8-year-old girl who was 1 of 2 affected sibs from healthy first-cousin Kuwaiti parents. She first presented at the age of 24 hours with fever, which persisted for 8 weeks. Extensive investigations revealed no cause for the fever. Recurrent febrile convulsions occurred, with fever of 42 degrees C induced by environmental temperature in Kuwait. She had mild hypotonia and hyporeflexia, did not cry during blood sampling, had never sweated, and never developed sphincter control. Pictures of the child demonstrated severe mutilation of the hands and feet as well as of the tongue and lips.

Yagev et al. (1999) studied 15 Bedouin children with CIPA and found that all had absent corneal sensation, which led to corneal opacities in 10 (67%). Active corneal ulcers were found in 7 of the 15 children; 2 children had bilateral ulcers and 3 of the ulcers were recurrent. These corneal ulcers were characterized by very poor healing, and some required surgical interventions including lateral tarsorrhaphy, corneal patch graft, and/or penetrating keratoplasty. The authors concluded that congenital insensitivity to pain and anhidrosis, although rare, should be considered in the differential diagnosis of neurotrophic keratitis.

Bonkowsky et al. (2003) studied a 1-year-old male with an atypical presentation of CIPA, whose diagnosis was confirmed by molecular analysis. The clinical features included an abnormally high pain threshold and heat intolerance, normal nerve conduction, and the absence of epidermal and sweat gland innervation in a skin biopsy.

Hepburn et al. (2014) reported 4 patients from 3 unrelated families with genetically confirmed HSAN4, including 2 consanguineous Pakistani families. In addition to absent pain and temperature sensation and the presence of learning difficulties, all patients had a history of frequent severe Staphylococcus aureus infections of the skin, bone, or teeth, suggesting a pathogen-specific immune defect.

Pathologic Findings

In a biopsy of the cutaneous branch of the radial nerve from a 9-year old girl with CIPA, Rafel et al. (1980) found complete absence of small myelinated and unmyelinated fibers. They suggested that the disorder was not a hereditary sensory neuropathy, but rather a developmental defect. In a sural nerve biopsy from a 2-month-old boy with CIPA, Matsuo et al. (1981) found that unmyelinated fibers were essentially lacking, and that the number of small myelinated fibers was decreased.

Langer et al. (1981) and Ismail et al. (1998) demonstrated absence of eccrine sweat gland innervation.

In immunohistochemical studies of skin biopsies from a 10-year-old girl with CIPA, Verze et al. (2000) found greatly reduced numbers of nerve fibers compared to normal controls. In particular, the epidermis was free of nerve branches or endings, whereas rare nerve fibers were present in the dermis. No autonomic nerve fibers were visible around sweat glands or hair follicles, and blood vessel walls were completely devoid of nerve fibers. Degenerative changes were not found. Verze et al. (2000) concluded that HSAN4 patients have a hereditary developmental defect of nerve outgrowth.

Other Features

Kilic et al. (2009) reported a Turkish girl with HSAN4 confirmed by genetic analysis. In addition to the classic features, she had a humoral immune defect, with recurrent infections and decreased serum immunoglobulins. The infections responded well to intravenous Ig therapy. Kilic et al. (2009) postulated a role for the NTRK1 gene in B lymphocyte signaling.

Mapping

Shatzky et al. (2000) studied CIPA in consanguineous Israeli-Bedouin groups in which the disorder has a relatively high prevalence. They reported clinical studies of 28 patients. Using the linkage approach, they found that 9 of 10 unrelated families with CIPA were linked to the NTRK1 gene, which had been mapped to chromosome 1q23-q24; in 1 family, linkage was excluded, implying genetic heterogeneity.

Molecular Genetics

Based on the phenotypic features of a mouse model lacking the gene encoding the receptor tyrosine kinase (NTRK1; 191315) for nerve growth factor (NGF; 162030) (Smeyne et al., 1994), Indo et al. (1996) studied human NTRK1 as a candidate gene for the site of the mutation in CIPA. In 3 unrelated patients with CIPA, each of whom had consanguineous parents, Indo et al. (1996) identified a deletion (191315.0001), a splice site aberration (191315.0002), and a missense mutation (191315.0003) in the tyrosine kinase domain of NTRK1. Their findings strongly suggested that defects in NTRK1 cause CIPA and that the NGF-NTRK system has a crucial role in the development and function of the nociceptive reception system, as well as establishment of thermal regulation via sweating in humans. The results also implicated genes encoding other TRK and neurotrophin family members as candidates for developmental defects of the nervous system.

In patients with CIPA from an isolate of Bedouins in northern Israel, Shatzky et al. (2000) identified 2 mutations (191315.0010; 191315.0011) in the NTRK1 gene. They made the prenatal diagnosis in 8 cases, 2 by linkage analysis and 6 by direct checking for one of the novel mutations.