Fetal Akinesia Deformation Sequence 2

A number sign (#) is used with this entry because of evidence that fetal akinesia deformation sequence-2 (FADS2) is caused by homozygous or compound heterozygous mutation in the RAPSN gene (601592) on chromosome 11p11.

Mutation in the RAPSN gene can also cause a form of congenital myasthenic syndrome (CMS11; 616326).

Description

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).

For a general phenotypic description and a discussion of genetic heterogeneity of FADS, see 208150.

Clinical Features

Vogt et al. (2008) described 3 fetuses with fetal akinesia deformation sequence from a consanguineous family. The family presented when FADS was detected at 19 weeks' gestation in male twins. On ultrasound examination, both fetuses had micrognathia and fixed position of the hands, elbows, and feet. There were no respiratory movements. The pregnancy was terminated at 23 weeks' gestation. Postmortem examination revealed monochorionic, monoamniotic twins with no evidence of growth retardation. A subsequent female singleton fetus was similarly affected. Fetal akinesia sequence was detected on ultrasound at 19 weeks of gestation, and the pregnancy was terminated at 23 weeks. Again, postmortem examination showed dysmorphologic features including short broad neck but no pterygia.

Michalk et al. (2008) described 2 sibs in a Pakistani family with fetal akinesia syndrome with congenital contractures. Respiratory distress resulted in the death of 1 sib at age 10 months.

Molecular Genetics

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 a Pakistani family, Michalk et al. (2008) found that compound heterozygosity for missense mutations in the RAPSN gene (601592.0014-601592.0015) caused fetal akinesia syndrome with congenital contractures in 2 sibs.