Other entities represented in this entry:
SNOMEDCT: 57406009; ICD10CM: G56.0, G56.00; ICD9CM: 354.0; DO: 0070466;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q12.1 | Carpal tunnel syndrome, familial | 115430 | Autosomal dominant | 3 | TTR | 176300 |
A number sign (#) is used with this entry because of evidence that carpal tunnel syndrome-1 (CTS1) is caused by heterozygous mutation in the TTR gene (176300), which encodes transthyretin, on chromosome 18q12.
Carpal tunnel syndrome-1 (CTS1) is characterized by hand pain and numbness in the distribution of the median nerve, with onset in the sixth decade of life. Amyloid deposits are observed in synovial tissue of the wrist and in the transverse carpal ligament (Murakami et al., 1994).
Genetic Heterogeneity of Carpal Tunnel Syndrome
CTS2 (619161) is caused by mutation in the COMP gene (600310) on chromosome 19p13.
Susceptibility to the development of mononeuropathy of the median (MNMN; 613353) may be conferred by heterozygous mutation in the SH3TC2 gene (608206) on chromosome 5q32.
Carpal tunnel syndrome has been described as a feature in amyloid neuropathy (see 176300) and in mucopolysaccharidoses (e.g., 253200) and mucolipidoses (252600).
Murakami et al. (1994) studied a 68-year-old Japanese woman and her 67-year-old brother with carpal tunnel syndrome and mutation in the TTR gene. At the time of surgical carpal tunnel release, Congo-red stained biopsy material was obtained demonstrating the presence of amyloid. There were no other neurologic abnormalities, no orthostatic hypotension, no gastrointestinal problems or sphincter disturbances, and no vitreous opacities. The father, who had symptoms of carpal tunnel syndrome, died at the age of 76 of pneumonia.
Reports of Carpal Tunnel Syndrome without Known Mutations
Danta (1975) reported carpal tunnel syndrome (constrictive median neuropathy) in 4 persons in 3 generations with male-to-male transmission. Symptoms began in the first decade in father and son, and in both the median nerve at operation was found to be constricted under a thickened transverse carpal ligament.
Gray et al. (1979) described bilateral carpal tunnel syndrome in 19 of 43 living members of a nonconsanguineous family, with male-to-male transmission. Sixty-three percent of the affected persons also had symptomatic digital flexor tenosynovitis, often polytendinous, which required surgery in 4. Age of onset was most often in the twenties but was at age 10 in 1 patient.
Vallat and Dunoyer (1979) reported carpal tunnel syndrome in father and daughter.
Kishi et al. (1975) and Kishi and Folkers (1976) used the level of erythrocyte glutamic oxaloacetic transaminase (EGOT) as a measure of vitamin B6 deficiency. Ellis et al. (1977) demonstrated severe deficiency of B6 in CTS. Administration of pyridoxine corrected the B6 deficiency and alleviated the neurologic disorder (Ellis et al., 1979). Further documentation of the improvement, which may obviate surgery, was presented by Ellis et al. (1982). They concluded that, since K(m) values of EGOT were identical in patients with and without CTS but with identical specific activities, CTS is a primary deficiency of B6, not a dependency state.
Serratrice et al. (1985) described familial occurrence and onset at an early age (before 12 years) especially in the right hand (see also Lettin, 1965). McDonnell et al. (1987) described 5 definite and 3 possible cases of carpal tunnel syndrome in 3 generations of a family. A remarkable feature was the development of symptoms as early as age 4 years.
Swoboda et al. (1998) described the case of a 7-month-old son of consanguineous Indian parents who presented with the recurrent chewing of his fingers in a median nerve distribution as the primary manifestation of carpal tunnel syndrome, in conjunction with features consistent with congenital insensitivity to pain. Electromyography (EMG) demonstrated severe median nerve entrapment at the wrist bilaterally, but other nerves were normal. In spite of clinical evidence of diffuse pain insensitivity, sural nerve and skin biopsies were normal, and he had no evidence of autonomic dysfunction. Hand findings evolved with scarring and infection of median innervated digits and loss of fine motor skills. Carpal tunnel release resulted in complete clinical resolution and significant EMG improvement. Milder symptoms and EMG evidence of median nerve entrapment were demonstrated in both parents, paternal grandparents, and several of his father's sibs. Swoboda et al. (1998) suggested that the child was homozygous for a mutant allele that in its heterozygous state predisposed to familial autosomal dominant carpal tunnel syndrome. Homozygosity for this or another mutant allele may have been responsible for his congenital insensitivity to pain.
Stoll and Maitrot (1998) studied the family of an otherwise healthy 35-year-old woman with carpal tunnel syndrome and found that 7 other members of the family in 4 generations were affected. Only 2 of the 8 were male. None of the secondary causes of carpal tunnel syndrome, such as amyloidosis, were found in the family.
Gossett and Chance (1998) reviewed reports of families with familial carpal tunnel syndrome and the guidelines used for the diagnosis. They identified 7 new 'potential' familial CTS pedigrees on the basis of their having 4 or more members with symptoms. In all but 2 pedigrees, however, an explanation other than familial CTS was found. Gossett and Chance (1998) concluded that familial isolated CTS is a rare, but genetically distinct disorder.
Carpal tunnel syndrome-1 is caused by mutation in the TTR gene, which maps to chromosome 18q12.
Exclusion Studies
Sparkes et al. (1985) found no linkage between idiopathic carpal tunnel syndrome and 20 informative markers. For 8 of these, linkage was excluded by a lod score less than 2.0.
There are conditions that mimic the symptoms of CTS or predispose people to develop it. One such condition is hereditary neuropathy with liability to pressure palsies (HNNP; 162500). This disorder most frequently manifests initially as a peripheral nerve entrapment, including median nerve compression at the carpal canal with delayed nerve conduction velocities. Potocki et al. (1999) described a family with dominantly inherited CTS that was associated with the chromosome deletion in 17p12 that causes HNPP. HNPP is probably underdiagnosed because it typically has episodic and transient clinical manifestations. Stockton et al. (2001) evaluated 50 patients diagnosed with idiopathic CTS and found no instance of the chromosome 17 microdeletion that causes HNPP.
In 2 sibs from a Japanese family with carpal tunnel syndrome, Murakami et al. (1994) identified a heterozygous tyr114-to-his substitution in the TTR gene (Y114H; 176300.0033).
Exclusion Studies
Elstner et al. (2006) reported a large family in which 9 members over 3 generations had bilateral carpal tunnel syndrome. The pedigree was compatible with autosomal dominant inheritance, but there was some evidence for an X-linked dominant transmission that was lethal in the hemizygous male: there was an almost exclusive occurrence of CTS in females, a preponderance of female to male offspring, and several male miscarriages. The affected matriarch had 6 sisters, no brother, 5 daughters, and 2 male miscarriages. The phenotype in this pedigree was consistent with anticipation, since the onset of CTS was approximately 20 years earlier in the third generation than in the second. Elstner et al. (2006) analyzed the peripheral myelin protein-22 (PMP22; 601097) and transthyretin (TTR; 176300) genes but found no alterations in affected family members, and linkage to the connexin-32 (GJB1; 304040) locus was excluded by haplotype analysis.
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Ellis, J. M., Azuma, J., Watanabe, T., Folkers, K., Lowell, J. R., Hurst, G. A., Ahn, C. H., Shuford, E. H., Jr., Ulrich, R. F. Survey and new data on treatment with pyridoxine of patients having a clinical syndrome including the carpal tunnel and other defects. Res. Commun. Chem. Path. Pharm. 17: 165-177, 1977. [PubMed: 877401]
Ellis, J. M., Folkers, K., Levy, M., Shizukuishi, S., Lewandowski, J., Nishii, S., Schubert, H. A., Ulrich, R. Response of vitamin B-6 deficiency and the carpal tunnel syndrome to pyridoxine. Proc. Nat. Acad. Sci. 79: 7494-7498, 1982. [PubMed: 6961425] [Full Text: https://doi.org/10.1073/pnas.79.23.7494]
Ellis, J. M., Folkers, K., Watanabe, T., Kaji, M., Saji, S., Caldwell, J. W., Temple, C. A., Wood, F. S. Clinical results of a cross-over treatment with pyridoxine and placebo of the carpal tunnel syndrome. Am. J. Clin. Nutr. 32: 2040-2046, 1979. [PubMed: 484522] [Full Text: https://doi.org/10.1093/ajcn/32.10.2040]
Elstner, M., Bettecken, T., Wasner, M., Anneser, F., Dichgans, M., Meitinger, T., Gasser, T., Klopstock, T. Familial carpal tunnel syndrome: further evidence for a genetic contribution. (Letter) Clin. Genet. 69: 179-182, 2006. [PubMed: 16433699] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00555.x]
Gossett, J. G., Chance, P. F. Is there a familial carpal tunnel syndrome? An evaluation and literature review. Muscle Nerve 21: 1533-1536, 1998. [PubMed: 9771681] [Full Text: https://doi.org/10.1002/(sici)1097-4598(199811)21:11<1533::aid-mus25>3.0.co;2-#]
Gray, R. G., Poppo, M. J., Gottlieb, N. L. Primary familial bilateral carpal tunnel syndrome. Ann. Intern. Med. 91: 37-40, 1979. [PubMed: 464452] [Full Text: https://doi.org/10.7326/0003-4819-91-1-37]
Hess, H., Baumann, F. Ueber das familiaere Vorkommen eines Karpaltunnelsyndroms. Ztschr. Orthop. Grenzgebiete 106: 565-569, 1969. [PubMed: 4242691]
Kishi, H., Folkers, K. Improved and effective assays of the glutamic oxaloacetic transaminase by the coenzyme-apoenzyme system (CAS) principle. J. Nutr. Sci. Vitaminol. 22: 225-234, 1976. [PubMed: 966077] [Full Text: https://doi.org/10.3177/jnsv.22.225]
Kishi, H., Kishi, T., Williams, R. H., Folkers, K. Human deficiencies of vitamin B6. I. Studies on parameters of the assay of the glutamic oxaloacetic transaminase by the CAS principle. Res. Commun. Chem. Path. Pharm. 12: 557-569, 1975. [PubMed: 1197932]
Lettin, A. W. F. Carpal tunnel syndrome in childhood: report of a case. J. Bone Joint Surg. Br. 47: 556-559, 1965. [PubMed: 14341079]
McArthur, R. G., Hayles, A. B., Gomez, M. R., Bianco, A. J., Jr. Carpal tunnel syndrome and trigger finger in childhood. Am. J. Dis. Child. 117: 463-469, 1969. [PubMed: 5773417] [Full Text: https://doi.org/10.1001/archpedi.1969.02100030465015]
McDonnell, J. M., Makley, J. T., Horwitz, S. J. Familial carpal-tunnel syndrome presenting in childhood: report of two cases. J. Bone Joint Surg. Am. 69: 928-930, 1987. [PubMed: 3597507]
Mochizuki, Y., Ohkubo, H., Motomura, T. Familial bilateral carpal tunnel syndrome. (Letter) J. Neurol. Neurosurg. Psychiat. 44: 367 only, 1981. [PubMed: 7241167] [Full Text: https://doi.org/10.1136/jnnp.44.4.367]
Murakami, T., Tachibana, S., Endo, Y., Kawai, R., Hara, M., Tanase, S., Ando, M. Familial carpal tunnel syndrome due to amyloidogenic transthyretin his-114 variant. Neurology 44: 315-318, 1994. [PubMed: 8309582] [Full Text: https://doi.org/10.1212/wnl.44.2.315]
Potocki, L., Chen, K. S., Koeuth, T., Killian, J., Iannaccone, S. T., Shapira, S. K., Kashork, C. D., Spikes, A. S., Shaffer, L. G., Lupski, J. R. DNA rearrangements on both homologues of chromosome on both homologues of chromosome 17 in a mildly delayed individual with a family history of autosomal dominant carpal tunnel syndrome. Am. J. Hum. Genet. 64: 471-478, 1999. [PubMed: 9973284] [Full Text: https://doi.org/10.1086/302240]
Serratrice, G., Roger, J., Guastalla, B., Saint-Jean, J. C. Amyotrophies thenariennes familiales d'origine carpienne. Rev. Neurol. 141: 746-749, 1985. [PubMed: 4089404]
Sparkes, R. S., Spence, M. A., Gottlieb, N. L., Gray, R. G., Crist, M., Sparkes, M. C., Marazita, M. Genetic linkage analysis of the carpal tunnel syndrome. Hum. Hered. 35: 288-291, 1985. [PubMed: 4043979] [Full Text: https://doi.org/10.1159/000153564]
Stockton, D. W., Meade, R. A., Netscher, D. T., Epstein, M. J., Shenaq, S. M., Shaffer, L. G., Lupski, J. R. Hereditary neuropathy with liability to pressure palsies is not a major cause of idiopathic carpal tunnel syndrome. Arch. Neurol. 58: 1635-1637, 2001. [PubMed: 11594922] [Full Text: https://doi.org/10.1001/archneur.58.10.1635]
Stoll, C., Maitrot, D. Autosomal dominant carpal tunnel syndrome. Clin. Genet. 54: 345-348, 1998. [PubMed: 9831348] [Full Text: https://doi.org/10.1034/j.1399-0004.1998.5440414.x]
Swoboda, K. J., Engle, E. C., Scheindlin, B., Anthony, D. C., Jones, H. R. Mutilating hand syndrome in an infant with familial carpal tunnel syndrome. Muscle Nerve. 21: 104-111, 1998. [PubMed: 9427229] [Full Text: https://doi.org/10.1002/(sici)1097-4598(199801)21:1<104::aid-mus13>3.0.co;2-3]
Vallat, J. M., Dunoyer, J. Familial occurrence of entrapment neuropathies. (Letter) Arch. Neurol. 36: 323 only, 1979. [PubMed: 444109] [Full Text: https://doi.org/10.1001/archneur.1979.00500410101026]