Arthrogryposis Multiplex Congenita

Relation to Impaired Intrauterine Motility

In arthrogryposis, the joints themselves are usually normal, but the lack of fetal movements results in the development of extra connective tissue around the joints. Thus the development of fixed joints with limitation of movement in most cases is secondary to impaired intrauterine motility, almost invariably the result of muscle weakness . The postural deformities are caused by contractures of muscle with fibrous (not bony) ankylosis of the joints. The time of onset of the paralytic process determines in part the severity of the arthrogryposis; onset in the first trimester may be associated with pterygium formation at the neck and elbows. The positions of the deformities are related in large part to muscle imbalance around the joints involved; neuropathological data support this notion. The intrauterine position of the fetus may also play a role in determining the configuration of the deformities.

The basic concept that impaired motility secondary to muscle weakness is the critical common denominator is supported by experiments with developing chicks and with fetal rats, in which infusion of the neuromuscular blocker curare either into incubating eggs or into the fetal animals resulted in fixed postures of the neck and limbs that corresponded to intrauterine position. Pulmonary hypoplasia, micrognathia, polyhydramnios, short umbilical cord, and fetal growth retardation were documented in the fetal rats as in the human —findings further supporting the notion that intrauterine impairments of movement underlie many of the congenital anomalies often observed with arthrogryposis (see Table 35.1 ). An illustrative example is the Pena-Shokeir syndrome (see Box 35.1 ), characterized by (1) arthrogryposis, (2) polyhydramnios, (3) pulmonary hypoplasia, (4) short umbilical cord, (5) intrauterine growth restriction, (6) osteoporosis, and (7) craniofacial abnormalities. Pena-Shokeir syndrome is lethal because, as a result of the fetal akinesia, the lungs are hypoplastic, thus leading to respiratory failure and death after birth. However, because the causes of the Pena-Shokeir phenotype are multiple, the designation of such a syndrome appears to serve little clear purpose.

Other supporting clinical data linking reduced fetal movement to arthrogryposis include the usual association of the disorder with neuromuscular diseases of intrauterine onset (see following discussion) as well as the occurrence of the disorder after the administration of drugs to a pregnant woman that cause diminished motor activity. Disturbance of intrauterine movement is also presumed to be the cause of those unusual cases of arthrogryposis multiplex congenita occurring with intrauterine mechanical restrictions, such as amniotic band, small or malformed maternal pelvis or uterus, or oligohydramnios.

Amyoplasia

Amyoplasia accounts for as many as one-third of all newborns with arthrogryposis and occurs once in approximately 10,000 live births. In a large series of infants with arthrogryposis, of 16 with anterior horn cell involvement, 14 had amyoplasia. Clinically, these infants are distinctive and exhibit symmetrical involvement of all four limbs, with the upper extremities characteristically in a “waiter’s tip” position ( Fig. 35.2 ). The latter relates to internally rotated, adducted shoulders; extended elbows; pronated forearms; and flexed wrists and fingers. Talipes equinovarus is nearly invariable. The electromyogram (EMG) shows a reduced number of motor units but no fasciculations. Muscle biopsy (see later) is nondiagnostic, with affected muscles replaced by fatty and fibrous tissue. Patients have normal cognitive function without signs of central nervous system involvement. Common associations are facial hemangioma, gastrointestinal involvement (abdominal wall defects, inguinal hernia, gastroschisis, bowel atresia), dimples overlying involved joints, and digital defects.

Distal Arthrogryposes

The distal arthrogryposes are a heterogeneous group of genetic disorders in which the joint contractures primarily involve the distal limbs (see Table 35.2 ). Distal arthrogryposis type 1 is an autosomal condition due to mutations in various sarcolemmal proteins (troponin I [TNNI2] gene; troponin T3, fast skeletal type [TNNT3] gene; myosin binding protein C, slow type [MYBPC1] gene; and tropomyosin 2, beta [TPM2] gene). Common clinical features include medially overlapping fingers, clenched fists, ulnar deviation of the fingers when extended, contractures of the fingers (camptodactyly), and foot contractures ( Fig. 35.3 ). These deformities appear to be owing to misplaced tendons. Mutation in piezo-type mechanosensitive ion channel component 2 (PIEZO2) gene causes distal arthrogryposis type 3 (Gordon syndrome), an autosomal dominant condition characterized by distal arthrogryposes of hands and feet, short stature, and cleft palate. Distal arthrogryposis type 4 is complicated by severe scoliosis. Distal arthrogryposis type 5 is heterogeneous and can have both dominant and recessive inheritance. In addition to arthrogryposis, these patients have ocular abnormalities (ptosis, ophthalmoplegia, and/or strabismus). Some may have pulmonary hypertension as a result of restrictive lung disease. Distal arthrogryposis type 6 is similar to types 3 and 4 but is very rare and associated with deafness. It is caused by a mutation of the fibroblast growth factor receptor 3 (FGFR3) gene. Distal arthrogryposis type 7 is characterized by trismus, pseudocamptodactyly, palmar flexion at the wrists, extension at the metacarpophalangeal joints, short stature, and flexion contractures at the knees. This disorder is caused by a mutation of the myosin heavy chain 8 (MHY8) gene. Distal arthrogryposis type 8 is described as autosomal dominant multiple pterygium syndrome. Distal arthrogryposis type 9 (Beals syndrome) causes contractual arachnodactyly, an autosomal dominant condition with clinical overlap with Marfan syndrome caused by mutation in the fibrillin-2 gene (FBN2) (see later). Distal arthrogryposis type 10 (congenital plantar syndrome) is characterized by plantar flexion contractures with variable milder contractures of the hip, elbow, wrist, and finger joints.