Indifference To Pain, Congenital, Autosomal Recessive

A number sign (#) is used with this entry because autosomal recessive congenital indifference to pain and autosomal recessive hereditary sensory neuropathy type IID (HSN2D) are both caused by homozygous or compound heterozygous mutations in the SCN9A gene (603415) on chromosome 2q24.

Description

Congenital indifference to pain is a rare autosomal recessive disorder characterized by the complete absence of pain perception typically associated with noxious stimuli. Affected individuals are aware of a stimulus, but have lost the ability to perceive pain. Most patients are hyposmic or anosmic. Other sensory modalities are unaffected, and there is an absence of overt autonomic symptoms. Sural nerve biopsy and nerve conduction velocity studies are normal (summary by Cox et al., 2006; and Goldberg et al., 2012).

Hereditary sensory and autonomic neuropathy type IID (HSAN2D) is an autosomal recessive disorder characterized by congenital or childhood-onset distal loss of pain and temperature sensation as well as autonomic dysfunction accompanied by hyposmia, hearing loss, hypogeusia, and sometimes bone dysplasia. The phenotype is highly variable, even within families. Two Japanese families have been reported (summary by Yuan et al., 2013).

For a discussion of genetic heterogeneity of HSAN, see HSAN1 (162400).

Nomenclature

Dyck et al. (1983) stated that congenital 'indifference' to pain is characterized by an absence of nerve pathology on histologic examination and can be distinguished from congenital 'insensitivity' to pain, which is associated with pathologic changes in peripheral nerves, as found in hereditary sensory and autonomic neuropathies, such as HSAN4 (256800) or HSAN5 (608654). Many cases reported as congenital indifference to pain or congenital analgesia were reported before the development of methods to assess the physiologic function of nerve fibers; therefore, Dyck et al. (1983) suggested that some of these cases may actually have been cases of HSAN.

Another interpretation of the distinction was provided by Cox et al. (2006) who noted that the term 'indifference' implies a lack of concern to a stimulus that is received and perceived through normal sensory pathways, whereas 'insensitivity' describes the absence of painful sensation or failure to receive perception due to a detectable defect in sensory pathways. Cox et al. (2006) thus suggested that congenital indifference to pain due to mutations in the SCN9A gene is actually a form of insensitivity to pain since the defect is due to a channelopathy that is not normally detected by routine histopathology. The authors proposed the term 'channelopathy-associated insensitivity to pain' for the disorder described here.

Clinical Features

Individuals with congenital indifference to pain have painless injuries beginning in infancy but otherwise normal sensory modalities. Perception of passive movement, joint position, and vibration are normal, as are tactile thresholds and light touch perception. Reflexes and autonomic responses are also normal. The axonal flare response after intradermal injection of histamine is normal, a finding that is in contrast to HSAN (Nagasako et al., 2003).

The first case of congenital analgesia is said to have been reported by Dearborn (1932). The patient made a living as a human pincushion act. A crucifixion had to be called off when a woman in the audience fainted after a spike was driven through one hand.

Fanconi and Ferrazzini (1957) described an affected brother and sister from consanguineous parents, and parental consanguinity has been noted in other cases (Ogden et al., 1959; Bertoye et al., 1964; Thiemann, 1961), suggesting autosomal recessive inheritance. Silverman and Gilden (1959) described a family in which 2 of 8 children of consanguineous parents were affected. Winkelmann et al. (1962) reviewed the subject of absence of pain, with a useful discussion of differential diagnosis.

Saldanha et al. (1964) described one family in which 3 brothers out of 10 sibs were affected and another family in which 2 sibs out of 11 were affected. The parents of the probands were normal and in 1 case were consanguineous. Gilly et al. (1964) described 2 affected sibs who were born of normal parents and were of normal intelligence. Osuntokun et al. (1968) described brother and half sister with congenital indifference to pain, who presumably had different fathers, both normal. They referred to the condition as 'pain asymbolia' and noted the association of auditory imperception. Gaudier et al. (1969) described affected brothers.

Baxter and Okzewski (1960) reported no anatomic abnormalities at autopsy. In several patients with congenital indifference to pain, Becak et al. (1964) found mosaicism of cells with normal karyotype and cells trisomic for a chromosome in the 13-15 group; Blau and Mutton (1967) could demonstrate no chromosomal abnormality.

Cox et al. (2006) described individuals from 3 Pakistani families with congenital inability to perceive any form of pain, in whom all other sensory modalities were preserved and the peripheral and central nervous systems were apparently otherwise intact. The trait was segregating as an autosomal recessive in the family. The index case was a 10-year-old child well known to the medical service after regularly performing 'street theater.' He placed knives through his arms and walked on burning coals, but experienced no pain. He died on his 14th birthday after jumping off a house roof. All affected individuals had injuries to their lips (some requiring plastic surgery) and/or tongue (with loss the distal third in 2 cases), caused by biting themselves in the first 4 years of life. The children were considered of normal intelligence by their parents and teachers. All could correctly perceive sensations of touch, warm and cold temperature, proprioception, tickle, and pressure, but not painful stimuli. Cox et al. (2006) referred to the disorder as 'channelopathy-associated insensitivity to pain.'

Weiss et al. (2011) found that individuals with channelopathy-associated insensitivity to pain caused by mutations in SCN9A were completely anosmic.

Clinical Variability

Ebermann et al. (2008) reported an 11-year-old boy, born of Egyptian consanguineous parents, with a phenotype suggestive of Navajo neurohepatopathy (MTDPS6; 256810), including short stature, frequent painless fractures, bruises, and cuts, hepatomegaly with elevated liver enzymes, corneal ulcerations, and mild hypotonia. His 22-month-old sister had short stature, hepatomegaly, increased liver enzymes, and hypotonia. A cousin had died at age 8 years from liver failure. After genetic analysis excluded a mutation in the MPV17 gene (137960), Ebermann et al. (2008) postulated 2 recessive diseases. Genomewide linkage analysis and gene sequencing of the proband identified a homozygous mutation in the AGL gene (610860), consistent with glycogen storage disease III (GSD3; 232400), and a homozygous mutation in the SCN9A gene, consistent with congenital insensitivity to pain. His sister had the AGL mutation and GSD3 only. Ebermann et al. (2008) emphasized that consanguineous matings increase the risk of homozygous genotypes and recessive diseases, which may complicate genetic counseling.

Hereditary Sensory and Autonomic Neuropathy, Type IID

Yuan et al. (2013) reported 2 Japanese sibs, born of consanguineous parents, and 1 unrelated Japanese patient with hereditary sensory and autonomic neuropathy. The phenotype was somewhat variable, even between the 2 sibs. A 50-year-old man developed decreased pain and temperature perception in the hands and feet in childhood, which progressed to the proximal limbs after age 40. He also had hyposmia, lack of sweating, skin lesions, including burn marks, and unilateral asymptomatic sensorineural hearing loss. There was mild weakness in the right lower limb, resulting in a steppage gait, and areflexia. His 55-year-old older sister had a history of recurrent fractures in childhood and had bone dysplasia with deformities of the elbow, foot, and lower limbs. She had no pain or temperature sensation in her feet as an adult. Other features included mild muscle weakness in the lower limbs and anhidrosis but not hyposmia or hearing loss. An unrelated 33-year-old man had decreased pain and temperature perception since birth, resulting in digital ulceration and deformities. Hyposmia and unilateral hearing loss were noted in early childhood. Other features included occasional urinary and fecal incontinence, reduced sweating, and reduced number of fungiform papillae on the tongue, consistent with autonomic dysfunction. He also had pigmentary skin lesions and left acetabular dysplasia resulting in asymmetric leg length. Vibration and joint position remained intact in all patients. Nerve conduction studies of the 2 unrelated men showed variably slowed sensory nerve conduction velocities (NCVs) and decreased sensory nerve action potential (SNAP) amplitudes in the median nerves. However, 1 patient had normal sural NCV and SNAP values. Sural nerve biopsy showed variable loss of myelinated fibers, which did not appear to correlate with symptoms in 1 patient. Both families were from the Kagoshima prefecture, but were unrelated.

Inheritance

The transmission pattern of HSAN2D in the families reported by Yuan et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

In 3 northern Pakistani families segregating autosomal recessive 'channelopathy-associated insensitivity to pain,' Cox et al. (2006) mapped the trait to 2q24.3, a region containing the SCN9A gene, which encodes the alpha subunit of the voltage-gated sodium channel, Nav1.7 (2-point lod of 3.2 at theta = 0.0).

Molecular Genetics

By sequence analysis of the SCN9A gene in 3 northern Pakistani families segregating autosomal recessive 'channelopathy-associated insensitivity to pain,' Cox et al. (2006) identified 3 distinct homozygous nonsense mutations (603415.0005-603415.0007). By coexpression of wildtype or mutant human Nav1.7 with sodium channel beta-1 and beta-2 subunits in cultured cells, Cox et al. (2006) showed that these mutations caused loss of function of Nav1.7. In cells expressing mutant Nav1.7, the currents were no greater than background. The data suggested that SCN9A is an essential and nonredundant requirement for nociception in humans. Cox et al. (2006) suggested that these findings should stimulate the search for novel analgesics to target this sodium channel subunit selectively.

Goldberg et al. (2007) identified 10 different mutations in the SCN9A gene (see, e.g., 603415.0014-603415.0015), 9 of which were truncating mutations, in affected members of 9 different families with congenital insensitivity to pain. The families were from Canada, the U.S., and Argentina as well as various countries in Europe.

Weiss et al. (2011) studied the individual reported by Nilsen et al. (2009). This individual was heterozygous for a frameshift and nonsense mutation in the NaV1.7 protein. Weiss et al. (2011) also studied 2 other individuals, sibs, who were compound heterozygous for nonsense and frameshift mutations. None of the affected individuals was able to smell. In the case of the sibs, both parents, who were heterozygous, had intact olfactory sensation.

In 3 Japanese patients from 2 unrelated families with HSAN2D, Yuan et al. (2013) identified a homozygous truncating mutation in the SCN9A gene (603415.0028). The mutation was predicted to result in nonsense-mediated mRNA decay and loss of SCN9A function in nociceptive neurons.