The distal arthrogryposes are a group of autosomal dominant disorders that mainly involve the distal parts of the limbs. They are characterized by congenital contractures of 2 or more different body areas without a primary neurologic or muscle ... The distal arthrogryposes are a group of autosomal dominant disorders that mainly involve the distal parts of the limbs. They are characterized by congenital contractures of 2 or more different body areas without a primary neurologic or muscle disease. The prototypic distal arthrogryposis is type 1 (DA1), which is characterized largely by camptodactyly and clubfoot. Hypoplasia and/or absence of some interphalangeal creases is common. The shoulders and hips are less frequently affected. While the pattern of affected joints is consistent, the degree to which the joints are affected is highly variable, with equinovarus deformities ranging from mild to severe and hand involvement ranging from isolated hypoplasia of the distal interphalangeal crease of the fifth digit to severely clenched fists and ulnar deviation of the wrist. The various phenotypic forms of distal arthrogryposis are classified hierarchically according to the proportion of features they share with one another and are designated DA1 through DA10 (summary by Bamshad et al., 2009). - Genetic Heterogeneity of Distal Arthrogryposes Distal arthrogryposis type 1 includes DA1A, caused by mutation in the TPM2 gene, and DA1B (614335), caused by mutation in the MYBPC1 gene (160794) on chromosome 12q23.2. Other forms include DA2A (Freeman-Sheldon syndrome, 193700), caused by mutation in the MYH3 gene (160720) on chromosome 17p13.1; DA2B (Sheldon-Hall syndrome, 193700), caused by mutation in MYH3, the TNNT3 gene (600692) on chromosome 11p15.5, the TNNI2 gene (191043), also on 11p15.5, or TPM2 (190990) on chromosome 9p13; DA3 (Gordon syndrome, 114300); DA4 (609128); DA5 (108145); DA5D (615065), caused by mutation in the ECEL1 gene (605896) on chromosome 2q36; DA6 (108200); DA7 (158300), caused by mutation in the MYH8 gene (160741) on chromosome 17p13.1; DA8 (178110); DA9 (121050), caused by mutation in the FBN2 gene (612570) on chromosome 5q23-q31; and DA10 (187370). See 277720 for discussion of a possible autosomal recessive form of DA2A. See 208155 for a description of Illum syndrome, which includes 'whistling face,' central nervous system dysfunction, and calcium deposition in central nervous system and muscle.
Arthrogryposis is a highly heterogeneous category (Hall et al., 1977). The classic form of peripheral AMC, called amyoplasia by Hall et al. (1977), is always sporadic. An overall recurrence risk of about 5% results from admixture of cases ... Arthrogryposis is a highly heterogeneous category (Hall et al., 1977). The classic form of peripheral AMC, called amyoplasia by Hall et al. (1977), is always sporadic. An overall recurrence risk of about 5% results from admixture of cases of mendelian types (see 208100, 301830, etc.). They concluded that there is at least one autosomal dominant form of distal AMC. The involvement in some persons can be very mild. Lin et al. (1977) and Hall et al. (1982) delineated the distal form of AMC by its autosomal dominant inheritance, intrafamilial variability, involvement primarily of the distal part of the limbs (especially hands and feet), a characteristic position of the hands (medially overlapping fingers, clenched fists, ulnar deviation of fingers, and camptodactyly), positional foot deformities, and relatively good response to physical therapy. Contractures at other joints are variable. There are no associated visceral anomalies; intelligence is normal. Daentl et al. (1974) described a father and his 2 daughters who had congenital contracture and deformity of the fingers, inguinal hernia, clubfoot, hip dislocation, small mandible, limitation of motion in the shoulders, elbows, wrist, knees and ankles, short neck, and elevated serum creatine phosphokinase. The authors reviewed familial forms of arthrogryposis and arthrogryposis-like disorders. McCormack et al. (1980) reported affected father, son and daughter. See digitotalar dysmorphism (126050). Baty et al. (1988) reported the prenatal diagnosis of distal arthrogryposis type I by ultrasound at 18 weeks' gestation in a family with 2 other affected members (mother and sister). The abnormality in the female infant was confirmed at birth. The diagnosis was based on the fact that the wrist remained extended and the fingers 'fisted' throughout a period of ultrasonic observation. Prenatal diagnosis in other forms of multiple joint contractures was reviewed. Klemp and Hall (1995) described a Maori family in which dominant distal arthrogryposis showed marked variability of expression. The index case was a Maori bushman who presented with severe congenital spinal stenosis and manifestations of distal arthrogryposis. One son and 2 sisters, as well as 2 sons of one sister and 2 daughters of the second, were definitely affected. Two affected members had severe hand and foot involvement as well as craniofacial changes compatible with a diagnosis of Freeman-Sheldon syndrome (193700). Bamshad et al. (1994) noted that distal arthrogryposis type 1 is a frequent cause of dominantly inherited clubfoot. Bamshad et al. (1996) reported a large kindred from Utah in which 15 members had DA1 with marked variability in phenotypic expression. The most consistent features were overlapping fingers at birth, abnormal digital flexion creases, and foot deformities, including talipes equinovarus and vertical talus. The clinical severity varied from limited range of motion at the shoulders and small calves without foot deformities in 1 family member, to overlapping fingers, camptodactyly, abnormal flexion creases, ulnar deviation, bilateral talipes equinovarus, and bilateral dislocated hips in another family member. Five individuals had a small mouth and mild limitation in opening of the mouth. All affected family members had normal intelligence. Bamshad et al. (1996) suggested that the findings in this family expanded the phenotypic range in DA1. Krakowiak et al. (1997) provided a useful classification of the distal arthrogryposes; see also 601680. Bamshad et al. (1996) revised the classification by Hall et al. (1982) of the common mendelian arthrogryposis syndromes. Gurnett et al. (2009) identified a patient with 4-extremity arthrogryposis and no evidence of facial abnormalities carrying the R63H mutation in TNNT3 (600692.0001); this mutation had previously been identified in a woman with DA2B and her 2 affected daughters. They classified the disorder in this child as distal arthrogryposis type 1 but noted 'it is admittedly difficult to diagnose mild forms of facial weakness, particularly in infancy, and thus it may be difficult to clearly distinguish patients with DA1 (affecting only the hands and feet) from other types of distal arthrogryposis.'
Sung et al. (2003) demonstrated that DA1 can be caused by substitution of a highly conserved amino acid residue in TPM2, the gene encoding beta-tropomyosin (190990.0001). The authors had found that DA2B (601680) can be caused by mutations ... Sung et al. (2003) demonstrated that DA1 can be caused by substitution of a highly conserved amino acid residue in TPM2, the gene encoding beta-tropomyosin (190990.0001). The authors had found that DA2B (601680) can be caused by mutations in the TNNI2 gene (191043), which encodes an isoform of troponin I specific to the troponin-tropomyosin complex of fast-twitch myofibers. That gene had come under suspicion because of its location in the same region to which the DA2B phenotype had been mapped. Because the distal arthrogryposes are genetically heterogeneous, Sung et al. (2003) sought additional candidate genes by examining modifiers of mutant Drosophila isoforms of troponin I. One of these modifiers, Tm2, encodes tropomyosin, another component of the troponin-tropomyosin complex. A human homolog of Tm2, TPM2 maps to the critical linkage interval of DA type 1 and encodes a protein that interacts directly with troponin I, and so was chosen for screening for disease-causing mutations.