The fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous constellation of features including fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism (Vogt et al., 2009). It ... The fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous constellation of features including fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism (Vogt et al., 2009). It shows phenotypic overlap with the lethal form of multiple pterygium syndrome (see 253290).
Pena and Shokeir (1974, 1976) described patients with a lethal congenital syndrome comprising camptodactyly, multiple ankyloses, facial anomalies, and pulmonary hypoplasia. Affected sibs born of consanguineous parents indicated autosomal recessive inheritance. Punnett et al. (1974) and Mease et ... Pena and Shokeir (1974, 1976) described patients with a lethal congenital syndrome comprising camptodactyly, multiple ankyloses, facial anomalies, and pulmonary hypoplasia. Affected sibs born of consanguineous parents indicated autosomal recessive inheritance. Punnett et al. (1974) and Mease et al. (1976) observed cases with this sequence, and noted that the features were secondary to fetal neuromuscular dysfunction. Chen et al. (1983) reported 5 cases, including 3 sibs. The other 2 cases had a history of affected sibs including a pair of concordant twins. In addition to multiple ankyloses, camptodactyly, facial anomalies, and pulmonary hypoplasia, one fetus had pterygia of the neck and axillae and cardiac hypoplasia. Chen et al. (1983) suggested that pterygium may be a feature of the Pena-Shokeir syndrome, and that the lethal form of a recessively inherited syndrome described by Chen et al. (1980) and Hall et al. (1982) may represent a severe form of the Pena-Shokeir syndrome. Moerman et al. (1983) reported 2 unrelated infants who died perinatally with severe arthrogryposis multiplex congenita, pulmonary hypoplasia, and characteristic facies. They counted a total of 15 reported cases. They confirmed the suggestion of Smith (1982) that the Pena-Shokeir syndrome I is a primary motor neuropathy. Postmortem examination showed a marked paucity of anterior horn cells in the spinal cord and diffuse muscle atrophy. Pulmonary hypoplasia resulted from involvement of the respiratory muscles. In addition, both patients showed adrenal hypoplasia of the 'miniature' type; the histologic appearance was that of 'miniature' adult glands with atrophy of the fetal cortex, as seen in anencephaly. Polyhydramnios was due to impaired swallowing of amniotic fluid. Lindhout et al. (1985) reported 9 cases in 7 sibships. The parents were consanguineous in all but 1 of the 7. Toriello et al. (1985) reported 2 female infant sibs. Bisceglia et al. (1987) described the pathologic findings in affected male and female sibs. Hageman et al. (1987) observed a variety of brain pathology in 6 unrelated new cases and in a review of 28 previously reported cases. Katzenstein and Goodman (1988) reported a case of survival to the age of 20 months. Out of about 60 reported cases, only 5 others surviving beyond 28 days were found. Lammer et al. (1989) described affected brothers who were unusual because they had macrocephaly and normal intrauterine growth. Autopsy, performed only in the second sib, showed no detectable neuromuscular abnormalities underlying the contractures. Abnormalities were detected by ultrasonography during the 18th week of gestation of the second fetus. Erdl et al. (1989) described 2 sibs with the Pena-Shokeir phenotype and major malformations of the central nervous system. The cases illustrated again the heterogeneity of this phenotype. Gyr et al. (1992) described a consanguineous family in which 3 male sibs were affected; 2 died antepartum and the third shortly after delivery. Chen et al. (1995) described 2 unrelated infants with fetal akinesia sequence who as newborns were noted to have multiple perinatal fractures of the long bones. Radiographs showed gracile ribs and thin long bones with multiple diaphyseal fractures. Osseous hypoplasia associated with decreased use was thought to predispose to fracture. Vogt et al. (2009) reported 3 sibs from a consanguineous Bengali family with a severe lethal form of myasthenia due to DOK7 mutation (610285.0009). The first fetus was stillborn at 32 weeks' gestation and had signs of a neuromuscular developmental abnormality. The second fetus miscarried spontaneously at 22 weeks' gestation. Postmortem examination showed downslanting palpebral fissures, short neck, small jaw, overlapping fingers, and rocker-bottom feet. The third fetus showed no fetal movements at 24 weeks' gestation. None had evidence of pterygia. Muscle biopsy in 1 fetus showed muscle denervation with immature irregularly shaped muscle cells. The findings were consistent with a clinical diagnosis of FADS. Vogt et al. (2009) concluded that complete loss of DOK7 results in a lethal fetal akinesia phenotype that is at the more severe end of a spectrum of disorders involving acetylcholine receptors.
In 3 offspring of consanguineous parents with fetal akinesia deformation sequence, Vogt et al. (2008) identified homozygosity for a frameshift mutation in the RAPSN gene (601592.0012). The mutation was demonstrated to severely impair protein stability.
In ... In 3 offspring of consanguineous parents with fetal akinesia deformation sequence, Vogt et al. (2008) identified homozygosity for a frameshift mutation in the RAPSN gene (601592.0012). The mutation was demonstrated to severely impair protein stability. In 3 sibs from a consanguineous Bengali family with a severe form of myasthenia resulting in fetal death, Vogt et al. (2009) identified a homozygous truncating mutation in the DOK7 gene (610285.0009).