A number sign (#) is used with this entry because of evidence that carpal tunnel syndrome-2 (CTS2) is caused by heterozygous mutation in the COMP gene (600310) on chromosome 19p13.

Carpal tunnel syndrome-2 (CTS2) is characterized by the relatively early onset of symptoms of median nerve compression in the wrist. Patients experience pain and numbness in the thumb, index, and middle fingers, correlating with the median nerve distribution in the hand. In addition to thickening of the tendons and ligaments of the wrist, thickening of other tendons has been observed (Li et al., 2020).

For a general phenotypic description and discussion of genetic heterogeneity of carpal tunnel syndrome, see CTS1 (115430).

Li et al. (2020) reported 2 large families segregating autosomal dominant carpal tunnel syndrome (CTS). In family 1, they studied 17 affected individuals, who experienced onset of CTS symptoms between 20 and 30 years of age. Median nerve entrapment caused pain, paresthesias, and numbness in the thumb, index, and middle fingers; symptoms were exacerbated by overuse and exercise and were more severe at night. CTS was confirmed by the Tinel and Phalen signs and 2-point discrimination testing, as well as by electrophysiologic evaluation showing increased distal motor latency and reduced nerve conduction velocity. Thenar atrophy, digital trophic ulcers, and digital necrosis were observed in some patients. MRI showed swelling of carpal tunnel flexor tendons and smaller median nerves, and transverse carpal ligaments (TCLs) were significantly thickened. At surgery, soft connective tissue swelling and thickening in the carpal tunnels was observed, which the authors noted was similar to but more severe than that found in sporadic CTS patients. Severe enlargement of TCLs and flexor tendons, further compressing the median nerve, was confirmed. Histologic analysis of TCL tissue showed collagen fragmentation, edema, neovascular structures, and lipomatosis, as well as an increased number of myofibroblasts and thickening of vascular walls. Transmission electron microscopy (TEM) showed ectopic small fibrils and contrast differences in the extracellular matrix (ECM) of patient TCLs. Immuno-TEM revealed that the ectopic fibrils contained components of ECM, such as type I collagen (see 120150), type III collagen (see 120180), and COMP. The authors noted that flexor pollicis longus tendons and Achilles tendons of family 1 patients also tended to be bigger than those of controls, suggesting a systemic change in patients' tendons and ligaments. In addition, the affected individuals exhibited significantly reduced mobility of the wrists, ankles, thumbs, and fifth fingers compared to controls; however, no joint or growth plate defects were observed. In family 2, there were 11 living CTS patients, whose symptoms were less severe than those of family 1 and had a later age of onset, between 30 to 50 years. MRI findings were similar to those of family 1. Family 2 patients also experienced joint pain, and orthopedic examination suggested a diagnosis of multiple epiphyseal dysplasia (see EDM1, 132400), which is characterized by epiphyseal deformity with joint pain and stiffness.

The transmission pattern of carpal tunnel syndrome in the families reported by Li et al. (2020) was consistent with autosomal dominant inheritance.

In a large 5-generation family (family 1) with carpal tunnel syndrome, Li et al. (2020) performed linkage analysis and obtained a maximum multipoint lod score greater than 6 for a locus at chromosome 19p13.11-p12. Microsatellite analysis and haplotype reconstruction confirmed segregation of a specific haplotype in affected individuals.

In a large 5-generation family (family 1) with carpal tunnel syndrome mapping to chromosome 19p12, Li et al. (2020) sequenced the targeted locus and identified a heterozygous missense mutation in the COMP gene (V66E; 600310.0019) that segregated with disease. In a second family (family 2), in which affected individuals exhibited both CTS and EDM, whole-exome sequencing revealed heterozygosity for the R718W substitution in COMP (600310.0017), a known recurrent mutation associated with EDM1 (132400). Functional analysis revealed that secretion of the R718W mutant was reduced in both primary tendon cells and chondrocytes, whereas secretion of V66E was reduced only in tendon cells; the authors noted that this might account for the different phenotypes in the 2 families.