Arthrogryposis, Distal, Type 1a
A number sign (#) is used with this entry because of evidence that distal arthrogryposis type 1A (DA1A) and type 2B4 (DA2B4) are caused by heterozygous mutation in the TPM2 gene (190990) on chromosome 9p13.
Heterozygous mutation in the TPM2 gene can also cause nemaline myopathy-4 (NEM4; 609285), which shows similar features and may be identical to DA1A.
DescriptionIn general, the distal arthrogryposes are a group of disorders characterized by contractures mainly involving the distal parts of the limbs. The hands have a characteristic position with medially overlapping fingers, clenched fists, ulnar deviation of fingers, and camptodactyly, and the feet have deformities. Contractures at other joints are variable; there are no associated visceral anomalies, and intelligence is normal. Bamshad et al. (1996) revised the classification by Hall et al. (1982) of the common mendelian arthrogryposis syndromes. 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).
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 (summary by Bamshad et al., 1996). Classically, DA was defined as being without overt neurologic or muscle disease (Lin et al., 1977 and Hall et al., 1982), although more recent evidence suggests that DA1A results from muscle dysfunction (Robinson et al., 2007; Mokbel et al., 2013; Davidson et al., 2013) (summary by Bamshad et al., 2009).
The congenital contractures in distal arthrogryposis type 2B (Sheldon-Hall syndrome; see 601680) are similar to those observed in DA1, but affected individuals tend to have more prominent nasolabial folds, downslanting palpebral fissures, and a small mouth. DA2B is thought to be the most common of the distal arthrogryposis disorders (summary by Bamshad et al., 2009).
A review of patients diagnosed with DA1 or DA2B by Beck et al. (2013) found that the same mutation caused DA1 in some famlies and DA2B in others. There were no significant differences among the clinical characteristics of DA by locus or between each locus and DA1 or DA2B. The authors suggested that DA1 and DA2B might represent phenotypic extremes of the same disorder.
Genetic Heterogeneity of Distal Arthrogryposes
Other forms of distal arthrogryposis include DA1B (614335), caused by mutation in the MYBPC1 gene (160794) on chromosome 12q23; DA2A (Freeman-Sheldon syndrome, 193700), caused by mutation in the MYH3 gene (160720) on chromosome 17p13; DA2B1 (601680), caused by mutation in the TNNI2 gene (191043) on 11p15; DA2B2 (618435), caused by mutation in the TNNT3 gene (600692) on chromosome 11p15; DA2B3 (618436), caused by mutation in the MYH3 gene (160720) on chromosome 17p13; DA3 (Gordon syndrome, 114300) and DA5 (108145), caused by mutation in the PIEZO2 gene (613629) on chromosome 18p11; DA4 (609128), which has not been mapped; 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; DA9 (121050), caused by mutation in the FBN2 gene (612570) on chromosome 5q23; and DA10 (187370), which maps to chromosome 2q.
Distal arthrogryposis-8 (DA8) has been reclassified as contractures, pterygia, and variable skeletal fusions syndrome-1A (CPSKF1A; 178110).
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.
There are other forms of arthrogryposis multiplex congenita (AMC), including a lethal congenital form (see LCCS1, 253310).
Clinical FeaturesDistal Arthrogryposis, Type 1A1
Bamshad et al. (1994) reported a large multigenerational family from Utah (family F) with distal arthrogryposis. One or more diagnostic features were present in all affected individuals. In the upper extremities, these features included ulnar deviation, camptodactyly, absent flexion creases, and overriding fingers. In the lower extremities, these features included metatarsus varus, talipes equinovarus, vertical talus, and a calcaneovalgus deformity. There was intrafamilial variability, and some patients also had hip dislocation. Bamshad et al. (1996) provided follow-up of family F. There were 15 affected family members showing 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. Muscle weakness and/or atrophy were not mentioned. Bamshad et al. (1996) suggested that the findings in this family expanded the phenotypic range in DA1.
Distal Arthrogryposis, Type 2B4
Tajsharghi et al. (2007) reported a mother and daughter, aged 65 and 28 years, with a form of distal arthrogryposis most consistent with type 2B. Both had presented with distal joint contractures at birth. At the time of examination, both complained of muscle weakness in proximal and distal muscles, most prominent in the hands and feet. Other notable features in both patients included hearing impairment, high-arched palate, short neck, short stature, contractures in proximal joints, smooth palms, and scoliosis. Neither had cardiac involvement. Muscle biopsies showed type 1 fiber predominance but no other major abnormalities.
Ko et al. (2013) reported a Korean mother and daughter with distal arthrogryposis type 2B4. The proband was an infant who at birth showed camptodactyly, overlapping fingers, and adducted thumbs. She had a calcaneovalgus deformity with congenital vertical talus in the right foot and an equinovarus deformity in the left foot. She also displayed subtle facial dysmorphism, including a triangular face, downslanting palpebral fissures, and a small mouth. She had feeding difficulties and died at several months of age, presumably from aspiration pneumonia. The proband's 25-year-old mother had multiple congenital contractures of the distal limbs, camptodactyly with ulnar deviation of all fingers, and bilateral talocalcaneal coalition, with left clubfoot. She also had mild bilateral knee contractures. Facial features included a triangular face with downslanting palpebral fissures, low-set ears with attached earlobes, small mouth, high-arched palate, receding chin, prominent nasolabial folds, broad and long nasal bridge and root, and long philtrum. She had a short neck and sloping shoulders. She also had mild bilateral sensorineural hearing impairment. Electromyography revealed generalized myopathy with relative sparing of the slow-twitch muscle fibers.
Mroczek et al. (2017) reported a female infant with congenital distal arthrogryposis, dysmorphic facial features, and myopathy. She required mechanical ventilation at birth and showed neither suck nor swallowing reflex. Dysmorphic features included hypertelorism, prominent eyes, hypertrichosis of the sacroiliac region, contractures of wrists, knees, fingers and toes, and bilateral clubfoot. She had persistent hypotonia. A muscle biopsy at age 7 months showed muscle fiber-type disproportion, with selective smallness of type 1 fibers. At age 13 months, she had contractures in the small joints of the hands and feet (with overlapping fingers and toes) as well as in the knee and at the hip joints, and she had reduced flexion of the wrist and elbow joint. She had an elongated face with bitemporal narrow forehead, low frontal hairline, short nose with depressed nasal bridge, underdeveloped nasolabial fold, and open mouth. She also had bilateral sensorineural hearing loss. She died suddenly at age 2 years and 8 months.
Li et al. (2018) reported 5 affected members of a 4-generation Chinese family (family 1) segregating distal arthrogryposis type 2B of varying severity. The proband was a 59-year-old man with bilateral and symmetric congenital contractures of the distal limbs, including severe ulnar deviation, camptodactyly, adducted thumbs, and overlapping fingers. He also had short stature and minor facial anomalies, including a triangular face, downslanting palpebral fissures, and a small mouth. His 2 affected daughters had finger contractures, camptodactyly, and clubfeet. One daughter was pregnant, and ultrasound of her fetus indicated extended wrists, clenched fists, and bilateral clubfeet.
DiagnosisPrenatal Diagnosis
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.
InheritanceThe transmission pattern of DA1 in the family reported by Bamshad et al. (1994) was consistent with autosomal dominant inheritance.
MappingUsing short tandem repeat (STR) polymorphisms in a genomewide search, Bamshad et al. (1994) mapped the DA1 gene to the pericentromeric region of chromosome 9 in a large kindred with distal arthrogryposis. Linkage analysis generated a lod score of 5.90 at theta = 0.0 with the marker GS-4. Analysis of an additional family demonstrated no linkage to the same locus, indicating probable locus heterogeneity.
By 2-point linkage analysis in a Chinese family segregating DA2B, Li et al. (2018) found linkage of the disorder to chromosome 9p13, near the TPM2 gene.
Molecular GeneticsDistal Arthrogryposis, Type 1A
In affected members of a large multigenerational family with DA1A (family K5), originally reported as family F by Bamshad et al. (1994) and linked to the pericentromeric region of chromosome 9, Sung et al. (2003) identified a heterozygous missense mutation in the TPM2 gene (R91G; 190990.0001). The findings indicated that this form of distal arthrogryposis has a myopathic origin, specifically in the contractile apparatus of fast-twitch myofibers. Functional studies of the variant and studies of patient cells were not performed. TPM2 mutations were not found in 13 additional probands with a similar disorder.
Distal Arthrogryposis, Type 2B4
In a mother and daughter with a form of distal arthrogryposis most consistent with type 2B, Tajsharghi et al. (2007) identified a heterozygous mutation in the TPM2 gene (R133W; 190990.0004).
In a Korean mother and daughter with distal arthrogryposis type 2B4, Ko et al. (2013) identified the same R133W mutation in the TPM2 gene that had been identified in an affected mother and daughter by Tajsharghi et al. (2007).
In a female infant, born to unrelated parents, with congenital distal arthrogryposis, dysmorphic facial features, and myopathy, Mroczek et al. (2017) identified a de novo heterozygous splice site mutation in the TPM2 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the parents or in 100 healthy controls.
In affected members of a Chinese family (family 1) segregating DA2B4, Li et al. (2018) identified heterozygosity for a missense mutation (Q103R; 190990.0010) in the TPM2 gene. The mutation was identified by linkage analysis and Sanger sequencing.
PathogenesisIn in vitro studies, Robinson et al. (2007) demonstrated that the TPM2 R91G mutation (190990.0001) resulted in a gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. Robinson et al. (2007) concluded that the mutation would cause increased tension in developing muscles, thus resulting in contractures and limb deformities via an active process rather than a passive process. These findings implicated disturbed muscle function as the pathogenic mechanism underlying DA1A.
HistoryArthrogryposis 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.
Lacassie et al. (1977) and Sack (1978) reported a man who was born with limited flexion of all joints of the upper limbs and neck and with absent flexion creases of the fingers. Talipes equinovarus was corrected by bilateral triple arthrodeses and later Achilles tendon extensions. As an adult he was short with scoliosis and 4 symmetric dimples over the posterior ilia. Gaze, especially upward, was generally limited, and the muscles below the knees were atrophic. Intelligence was normal. His 2-year-old daughter showed the same findings. Muscle biopsy was 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).
Hall et al. (1983) recognized a specific congenital contracture (arthrogryposis) syndrome in 135 of 350 patients with various kinds of congenital contractures. Always sporadic, this is the disorder that is usually meant when the term arthrogryposis multiplex congenita is used. Amyoplasia is the designation chosen by Hall et al. (1983) because absence of limb muscles, which are replaced by fibrous and fatty tissue, is the finding. At birth, characteristic positioning includes internal rotation at the shoulders, extension at the elbows, and flexion at the wrists. Severe equinovarus deformity of the feet is usually present. The face is typically round with a frontal midline capillary hemangioma and slightly small jaw. Intelligence is normal. About 63% had involvement of 4 limbs (usually symmetrically), 24% mainly of the lower limbs, and 13% mainly of the upper limbs. All cases are sporadic. Identical twins are always discordantly affected. Hall et al. (1983) found among 135 patients 11 who were the discordantly affected member of a pair of identical twins. As 8% of the total, this incidence seems to be a remarkable and probably biologically significant excess.