Arthrogryposis is presumed to be multifactorial in etiology. [8] In most cases, arthrogryposis multiplex congenita (AMC) is not a genetic condition. However, in approximately 30% of cases, a genetic cause can be identified. [9]
Arthrogryposis is a physical sign in many specific medical conditions. It can be a component of numerous conditions caused by environmental agents, single gene defects (autosomal dominant, autosomal recessive, X-linked recessive), chromosomal abnormalities, known syndromes, or unknown conditions. The principal cause is persistently decreased fetal movements (fetal akinesia) due to either fetal or maternal abnormalities.
The molecular basis of most genetic causes is not yet determined. However, the following 5 genetic loci associated with autosomal recessive arthrogryposis multiplex congenita have been described to date using a linkage analysis approach [10, 11] :
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Lethal congenital contracture syndrome (OMIM 253310) (9q34) - This is characterized by early fetal hydrops and akinesia, Pena-Shokeir phenotype, multiple pterygia and fractures, and a specific neuropathology in the spinal cord
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Neurogenic type of arthrogryposis multiplex congenita (OMIM 208100) (5q35) - This is a nonprogressive, nonlethal, multiple joint contracture described in a large Israeli-Arab inbred kindred
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Arthrogryposis-renal dysfunction-cholestasis syndrome (OMIM 208085) (15q26.1) - This is a neurogenic arthrogryposis multiplex congenita with renal tubular dysfunction and neonatal cholestasis, with bile duct hypoplasia and low gamma glumyl transpeptidase activity, leading to death within the first year of life
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Lethal congenital contracture syndrome (LCCS) type 2 (OMIM 607598) (12q13) - This is a lethal arthrogryposis multiplex congenita characterized by multiple joint contractures and micrognathia, normal duration of pregnancy, markedly distended urinary bladder, and lack of hydrops, pterygia, and fractures; it is prevalent in a large inbred Israeli-Bedouin kindred
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A novel autosomal recessive LCCS type 3 - This is similar to LCCS2 but lacks the urogenic bladder defect; the genetic defect leading to this syndrome was mapped to 3.4 Mb on chromosome 19p13, and it was shown that LCCS3 results from a mutation in PIP5K1C (GenBank accession number NM_012398)
Neuropathic abnormalities are the most common cause of arthrogryposis. They may include malformations or malfunctions of the central and peripheral nervous systems. Abnormalities include meningomyelocele, anencephaly, hydranencephaly, holoprosencephaly, spinal muscular atrophy, cerebrooculofacial-skeletal syndrome, and Marden-Walker syndrome.
Muscle abnormalities (malformations or malfunctions) are relatively rare causes of arthrogryposis. Some associated diseases include congenital muscular dystrophies, congenital myopathies, intrauterine myositis, and mitochondrial disorders.
Wallach et al, in a study of 42 children with arthrogryposis, found that in 19.1% of patients, the condition had a neurologic etiology, mainly involving polymicrogyria, while in 9.5% of the group, the disease arose myopathically. [12]
Connective tissue abnormalities in tendon, bone, joint, or joint lining may develop in such a way that restricts fetal movements, resulting in congenital contractures. Examples include synostosis, lack of joint development, aberrant fixation of joints (as in diastrophic dysplasia and metatropic dwarfism), aberrant laxity of joints with dislocations (as in Larsen syndrome), and aberrant soft tissue fixations (as in popliteal pterygium syndrome). In some forms of distal arthrogryposis, the tendon develops normally but fails to attach to the appropriate place around the joint or bone. This results in abnormal lack of movement of the joints with secondary contractures at birth.
Limited space for fetal movement inside the uterus may contribute to the development of contractures. Examples include multiple births, uterine structural abnormalities, oligohydramnios in renal agenesis, and early persistent leakage of amniotic fluid.
Intrauterine vascular compromise may result in a loss of function in nerve and muscle with development of fetal akinesia and secondary joint contractures. Examples include severe maternal bleeding during pregnancy and failed attempts at termination of pregnancy.
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An infant with amyoplasia. Note internally rotated and adducted shoulders, fixed extended elbows, pronated forearms, flexed wrists and fingers, and severe talipes deformity.
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An infant with distal arthrogryposis type I. Note medially overlapping fingers, tightly clenched fists, and positional foot contractures.
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The hands of a patient with contractural arachnodactyly (Beals syndrome). Note the long, thin fingers with interphalangeal joint contractures.
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A girl with an autosomal recessive type of multiple pterygium syndrome. Note the multiple joint contractures at the knees with marked pterygia, including intercrural webbing, affecting her stance and ambulation.
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A mother and child both affected with trismus pseudocamptodactyly. Note the small mouth (with limited ability to open) and flexion contractures of fingers on dorsiflexion.
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Twins with a lethal type of autosomal recessive multiple pterygium syndrome. Note the multiple joint contractures with marked pterygia, cardiac and lung hypoplasia, and characteristic facies.
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An infant with a lethal type of multiple pterygium syndrome. Note multiple joint contractures with marked pterygia and a cystic hygroma on the posterior aspect of the head and the neck.
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The photograph on the left shows an infant with fetal akinesia. Note depressed nasal bridge, micrognathia, flexion contractures of elbows, bilateral clubhands, and arthrogryposis of fingers. The radiograph on the right shows an infant with fetal akinesia. Note gracile ribs; thin, long bones with multiple fractures at mid diaphyses of the humeri, distal diaphyses of the femora, and proximal diaphyses of both tibiae and left fibula; and clubhands.
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An infant with Pena-Shokeir syndrome. Note characteristic facies (ocular hypertelorism; short nose with depressed bridge; small and markedly recessed jaw; low-set, malformed ears), short neck, mild contracture at the hip, moderate contractures at elbows and knees, severe ankle contractures, and camptodactyly with ulnar deviation of the hands.