Fetal Akinesia Deformation Sequence 1
A number sign (#) is used with this entry because of evidence that fetal akinesia deformation sequence-1 (FADS1) is caused by homozygous mutation in the MUSK gene (601296) on chromosome 9q31.
Mutation in the MUSK gene can also cause a form of congenital myasthenic syndrome (CMS9; 616325).
DescriptionThe 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).
Genetic Heterogeneity of Fetal Akinesia Deformation Sequence
FADS2 (618388) is caused by mutation in the RAPSN gene (601592), FADS3 (618389) is caused by mutation in the DOK7 gene (618389), and FADS4 (618393) is caused by mutation in the NUP88 gene (602552).
As mutations in the MUSK, RAPSN, and DOK7 genes have been associated with congenital myasthenic syndromes (see, e.g., CMS1A, 601462), the disorders in these patients likely represent extreme phenotypes of CMS (Vogt et al., 2009).
NomenclatureAlthough early descriptions by Pena and Shokeir (1974, 1976) resulted in the eponym, Moessinger (1983), Hall (1986), and Hageman et al. (1987) noted that Pena-Shokeir is not a specific unitary diagnosis or syndrome, but rather a description of a clinically and genetically heterogeneous phenotype resulting from fetal akinesia or decreased in utero movement; hence the term 'fetal akinesia deformation sequence.'
See also type II Pena-Shokeir syndrome, which is also known as COFS syndrome (214150); the separate delineation of types I and II was given by Shokeir (1982) and Houston and Shokeir (1981).
Clinical FeaturesPatients with Mutations in the MUSK Gene
Tan-Sindhunata et al. (2015) reported 14 affected fetuses from a Dutch genetic isolate with FADS associated with a homozygous missense mutation in the MUSK gene (see MOLECULAR GENETICS). All died in utero or shortly after birth. Clinical features included polyhydramnios, decreased fetal movements, joint contractures, and pulmonary hypoplasia. Dysmorphic features included hypertelorism, low-set ears, micrognathia, and reduced muscle bulk. All males had undescended testes, but most were born prematurely. Muscle biopsies showed myopathic features associated with denervation, such as variation in muscle fiber diameter, rounded and atrophic fibers, and internal nuclei. AChR clusters and tyrosine kinase activity at motor endplates were significantly decreased compared to controls, suggesting a defect in synaptogenesis.
Wilbe et al. (2015) reported 5 fetuses, born of Swedish parents, with FADS associated with a homozygous truncating mutation in the MUSK gene (see MOLECULAR GENETICS). All fetuses showed akinesia and joint contractures on prenatal ultrasound, and all died in utero or in the perinatal period. Autopsy confirmed muscle atrophy and multiple joint contractures. Additional features included polyhydramnios, micrognathia, low-set ears, and lung hypoplasia. Muscle biopsy showed a large variation in fiber size, fiber atrophy, and a predominance of type II fibers.
Early Reports of Patients with FADS
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.
DiagnosisVogt et al. (2012) proposed a diagnostic pathway for the molecular investigation of FADS.
Prenatal Diagnosis
Muller and de Jong (1986) commented on the similarities in prenatal ultrasonographic features between Pena-Shokeir syndrome type I and the trisomy 18 syndrome. They studied 2 cases of each, referred because of polyhydramnios. All had multiple ankyloses, camptodactyly, and rocker-bottom feet. Distinguishing sonographic features were scalp edema and lung hypoplasia in Pena-Shokeir syndrome, and cardiac arrhythmias, prominent occiput, micrognathia, and omphalocele in trisomy 18.
Ohlsson et al. (1988) reviewed the ultrasonographic prenatal diagnosis of this disorder. They reported a pregnancy in which the diagnosis was made by this means, having been suspected antenatally because the first-cousin parents had normal chromosomes and had had 2 previously affected offspring with a clinical picture compatible with the diagnosis. Furthermore, ultrasound had shown hydramnios, ankyloses, and decreased chest movements in the fetus.
Davis and Kalousek (1988) presented the morphologic findings in 16 previable fetuses with the fetal akinesia deformation sequence.
PathogenesisMoessinger (1983) suggested that the Pena-Shokeir I phenotype is not specific but rather the result of a deformation sequence caused by fetal akinesia; hence the term 'fetal akinesia deformation sequence.' The work of Moessinger (1983) was an extension of that of Drachman and Coulombre (1962), which focused on the essentiality of fetal (and probably embryonic) movement to joint development.
Hall (1986) suggested that at least 5 specific subgroups of Pena-Shokeir syndrome could be distinguished among 16 multiplex families. She noted that the original description by Pena and Shokeir (1974) was general in character and did not include unique features permitting identification with 1 of the 5 subtypes. In relation to pathogenesis, Hall (1986) stated: 'The 'use' of a structure in utero is necessary for its continuing and normal development. The old adage 'use it or lose it' seems to apply just as appropriately to prenatal normal development as it does in the crusty adult world of politics, business, and academia.'
Possible Relation to Maternal Myasthenia Gravis
Brueton et al. (1994) reported 8 cases (5 males and 3 females) of the Pena-Shokeir phenotype from 2 sibships. Antiacetylcholine receptor (AChR) (see ACHRA; 100690) antibody titers were increased in both mothers, although neither of them had any neurologic symptoms of myasthenia gravis (254200). The authors noted that several infants born of mothers with clinically evident myasthenia gravis have had a Pena-Shokeir phenotype. In the case of maternal myasthenia gravis, the recurrence risk for Pena-Shokeir syndrome is high; there has been no instance of a normal child being born following the affected pregnancy.
Vincent et al. (1995) and Riemersma et al. (1996), respectively, reported high levels of antibodies against human muscle AChR in 5 women with histories of arthrogryposis multiplex congenita recurring in successive pregnancies. The fetuses, which were mostly stillborn or terminated for fetal anomalies, showed dysmorphic facies and lung hypoplasia as well as joint contractures, consistent with the Pena-Shokeir syndrome. Anti-AChR antibodies are usually associated with acquired myasthenia gravis, and transient neonatal myasthenia gravis sometimes occurs in neonates born to mothers with this disorder due to placental transfer of the antibodies. However, 3 of the 5 mothers reported by Vincent et al. (1995) and Riemersma et al. (1996) were asymptomatic or had mild or unrecognized myasthenia gravis at the time that their babies were affected, suggesting that the anti-AChR antibodies were different from those usually associated with myasthenia gravis. Indeed, the serum and IgG from these women blocked, by more than 90%, the function of fetal AChR expressed in the human muscle-like cell line and in Xenopus oocytes. They did not, however, block the function of adult AChR, explaining the marked effects on the fetus and the relative sparing of their mothers. In humans, fetal AChR is replaced by the adult form by 33 weeks' gestation (Hesselmans et al., 1993). To investigate the pathogenesis further, Jacobson et al. (1999) injected pregnant mice with plasma from 4 anti-AChR antibody-positive women whose fetuses had severe AMC. They found that human antibodies could can be transferred efficiently to the mouse fetus during the last few days of fetal life. Many of the fetuses of dams injected with maternal plasmas or immunoglobulin were stillborn and showed fixed joints and other deformities. Moreover, similar changes were found in mice after injection of a serum from one anti-AChR antibody-negative woman who had had 4 AMC fetuses.
Brueton et al. (2000) reported a family in which 6 of 7 sibs had arthrogryposis multiplex congenita and a Pena-Shokeir phenotype; the healthy mother was found to have asymptomatic myasthenia gravis. They claimed that this was the first report of anti-AChR antibodies causing fetal akinesia/hypokinesia sequence in the offspring of an asymptomatic mother. The seventh child, the first born, may have been mildly affected.
Molecular GeneticsIn affected fetuses from a Dutch genetic isolate with FADS, Tan-Sindhunata et al. (2015) identified a homozygous missense mutation in the MUSK gene (I575T; 601296.0006).
In 5 affected fetuses, born of Swedish parents, with FADS, Wilbe et al. (2015) identified a homozygous truncating mutation in the MUSK gene (601296.0007). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The severe phenotype was similar to that observed in mice with homozygous knockdown of the MuSK gene (DeChiara et al., 1996) (see ANIMAL MODEL).
Animal ModelDeChiara et al. (1996) generated mice with a targeted disruption for the gene encoding MuSK. Neuromuscular synapses did not form in these mice, suggesting a failure in the induction of synapse formation. In connection with other findings, DeChiara et al. (1996) interpreted this to indicate that MuSK responds to a critical signal by agrin (103320) and that it, in turn, activates signaling cascades responsible for all aspects of synapse formation, including organization of the postsynaptic membrane, synapse-specific transcription, and presynaptic differentiation.