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