Dupuytren Contracture
Description
Dupuytren contracture is the most common heritable disorder of connective tissue. It is a disease of the soft tissues of the palm and fingers characterized by a progressive thickening and shortening of the fascial structures that normally provide support to the glabrous skin of the palm. Although it can also be a sporadic disorder, the inherited form is most frequently observed among people of Nordic descent. There is a male: female ratio of greater than 3:1 (Hu et al., 2005).
Dupuytren contracture has been associated with multiple fibroproliferative conditions, including Peyronie disease (171000), knuckle pads (149100), congenital generalized fibromatosis (228550), juvenile fibromatosis (228600), and frozen shoulder, suggesting a common underlying defect in wound repair (Hu et al., 2005).
Clinical FeaturesManson (1931) described affected father and 3 sons with contractures of fingers. Autosomal dominant inheritance with incomplete penetrance was likely.
Under the designation 'familial fibromatosis,' Young and Fortt (1981) described a family in which at least 5 members had Dupuytren contractures. The proband was first observed to have several small lumps on his trunk at the age of 4 months. At 10 months, discrete, painless, smooth, nonfluctuant lumps were noted over the left scapula, right axilla, and lower anterior abdomen. These subsequently subsided and, at age 3 years, he showed only 2 small swellings on the back of the neck. The histologic changes were those of fibromatosis. The father had thickening of the palmar fascia bilaterally from at least age 10 years, but no contracture. A paternal uncle of the proband had extensive palmar and plantar fibrosis dating from childhood with contracture of the right fifth finger. His 15-year-old daughter had thickening in the right palm. The proband's paternal grandfather had thickening of the right palmar fascia from age 11 years, resulting in a contracture of the fifth finger by age 45. This family illustrates nosologic uncertainty, showing similarities to congenital generalized fibromatosis and juvenile fibromatosis. In a review of disorders associated with knuckle pads, Ramer et al. (1994) referred to the condition in the family of Young and Fortt (1981) as 'Touraine polyfibromatosis.'
Warren (1985) noted that plantar fibromas have also been observed with familial Dupuytren contractures.
In a 3-generation family, Ranta et al. (1990) observed hypodontia associated with Dupuytren contracture. Contracture was observed in 5 individuals, 4 of whom had hypodontia.
Nagai et al. (1996) described plantar fibromatosis in 4 of 7 Japanese sibs. The proband was a 68-year-old man who had noted subcutaneous plantar nodules for 5 years. The nodules recurred after surgical excision; a 58-year-old brother had noted nodules in his left sole 20 years earlier and had 2 operations, but the nodules recurred each time. A 53-year-old brother had nodules from the age of 20 years. A 48-year-old sister had noted nodules at the age of 20 years. None of them had diabetes mellitus, epilepsy, alcoholism, or Dupuytren contracture. Nagai et al. (1996) cited the report of recurrent plantar fibromatosis in twins (Schindler and Schindler, 1986).
CytogeneticsWurster-Hill et al. (1988) performed chromosome studies on the nodular growth in 8 patients. All showed chromosome abnormalities that included numerical and structural clones, random numerical and structural aberrations, and premature centromere separation. Transverse fascial tissue unexpectedly showed the same types of abnormalities as the nodular tissue.
MappingIn a 5-generation Swedish family in which at least 17 members had Dupuytren contracture with autosomal dominant inheritance, Hu et al. (2005) identified a 6-cM candidate disease locus, referred to here as DUPC1, between markers D16S419 and D16S3032 on chromosome 16q (maximum 2-point lod score of 3.18 at marker D16S415). Haplotype analysis suggested incomplete penetrance.
Dolmans et al. (2011) conducted a genomewide association study of 960 Dutch individuals with Dupuytren disease and 3,117 controls to test for association between the disease and genetic markers. They tested 35 SNPs most strongly associated with Dupuytren disease (P less than 1 x 10(-4)) in the discovery set in 3 additional, independent case series comprising a total of 1,365 affected persons and 8,445 controls from Germany, the UK, and the Netherlands. Dolmans et al. (2011) observed a significant genomewide association between Dupuytren disease and 8 SNPs at 3 loci. Tests of replication and joint analysis of all data from 2,325 patients with Dupuytren disease and 11,562 controls yielded an association with 11 SNPs from 9 different loci (P less than 5.0 x 10(-8)). Six of these loci contain genes known to be involved in the Wnt signaling pathways: WNT4 (603490) (rs7524102) (P = 2.8 x 10(-9); odds ratio, 1.28), SFRP4 (606570) (rs16879765) (P = 5.6 x 10(-39); odds ratio, 1.98), WNT2 (147870) (rs4730775) (P = 3.0 x 10(-8); odds ratio, 0.83), RSPO2 (610575) (rs611744) (P = 7.9 x 10(-15); odds ratio, 0.75), SULF1 (610012) (rs2912522) (P = 2.0 x 10(-13); odds ratio, 0.72), and WNT7B (601967) (rs6519955) (P = 3.2 x 10(-33); odds ratio, 1.54). Dolmans et al. (2011) concluded that their study implicated 9 different loci involved in genetic susceptibility to Dupuytren disease. The fact that 6 of these 9 loci harbor genes encoding proteins in the Wnt signaling pathway suggested that aberrations in this pathway are key to the process of fibromatosis in Dupuytren disease. Balaji et al. (2011) commented on the paper by Dolmans et al. (2011) and proposed that the presence of susceptibility WNT variants confers a risk of disease through enhanced T cell and B cell activation rather than the WNT canonical pathway. Ophoff et al. (2011) responded that their preliminary data did not support an immunologic cause of Dupuytren disease, but that testing of hypotheses such as that of Balaji et al. (2011) would lead to a greater understanding of the disorder.