Ophthalmoplegia, External, With Rib And Vertebral Anomalies

A number sign (#) is used with this entry because of evidence that external ophthalmoplegia with rib and vertebral anomalies (EORVA) is caused by homozygous mutation in the MYF5 gene (159990) on chromosome 12q21.

Description

External ophthalmoplegia with rib and vertebral anomalies is characterized by congenital nonprogressive external ophthalmoplegia and ptosis, with torticollis and scoliosis developing during childhood. In addition, patients exhibit hypoplastic or missing ribs with fusion anomalies (Di Gioia et al., 2018).

Clinical Features

Traboulsi et al. (2000) described 2 Yemeni girls, born of first-cousin parents, with bilateral congenital nonprogressive external ophthalmoplegia. Examination of the 15-month-old proband showed bilateral large-angle exotropia and mild left hypotropia in primary gaze with the head held straight. She had severely limited ocular motility, consisting of moderate bilateral abduction with minimal adduction and depression. She underwent corrective surgery, with recession of the bilateral lateral rectus and resection of the left medial rectus; microscopic examination of muscle biopsies showed normal muscle tendon. Intraoperative forced duction testing was positive, with limitation in all directions of attempted movement. The proband's affected 4-year-old sister had a very small exotropia in primary gaze and severely limited ocular motility similar to the proband's, with no upgaze and minimal residual abduction, adduction, and depression.

Di Gioia et al. (2018) restudied the Yemeni sisters reported by Traboulsi et al. (2000) (family BX) and observed scoliosis in the older sister that had developed between age 4 and young adulthood, and mild left ptosis in the younger sister. The authors also reported 3 additional similarly affected individuals from 2 Turkish families (ALO and CHO). In family ALO, an affected sister and brother were born with nonprogressive ptosis and ophthalmoplegia, and developed torticollis and scoliosis by 6 years of age. In family CHO, the proband was a 16-year-old boy who had nonprogressive bilateral ptosis and ophthalmoplegia from birth, and developed torticollis in infancy and pectus carinatum in childhood, both of which progressed with age. MRI of his orbits showed absence of the extraocular muscles. Chest x-rays and CT images in the Turkish patients revealed a spectrum of dysmorphic ribs, including hypoplasia, fusion anomalies, pseudoarthrosis, missing ribs, and failure of some remaining ribs to extend anteriorly toward the sternum.

Mapping

Di Gioia et al. (2018) performed genomewide linkage analysis in the Yemeni family (BX) with external ophthalmoplegia originally reported by Traboulsi et al. (2000), as well as homozygosity mapping in 2 similarly affected Turkish families (ALO and CHO), and identified a 42.6-Mb overlapping region of homozygosity on chromosome 12. Within that region, the Turkish families shared a 1.2-Mb region of haploidentity (chr12:80,696,475-81,927,644; GRCh37).

Molecular Genetics

In affected individuals from the Yemeni family (BX) originally reported by Traboulsi et al. (2000) and 2 Turkish families (ALO and CHO) with external ophthalmoplegia and rib and vertebral anomalies mapping to chromosome 12, Di Gioia et al. (2018) performed whole-exome sequencing and identified homozygosity for mutations in the MYF5 gene: the 2 Yemeni sisters were homozygous for a missense mutation (R95C; 159990.0001) and the 3 affected individuals from the 2 Turkish families were homozygous for the same 10-bp deletion (159990.0002). The mutations segregated with disease in the families and were not found in public variant databases. Analysis of the MYF5 gene in probands from 28 recessive, 26 dominant, and 51 simplex pedigrees with congenital ophthalmoplegia did not reveal any rare homozygous or compound heterozygous variants. Noting the phenotypic variability exhibited by affected individuals, even among the 3 Turkish patients with the same mutation, the authors suggested that genetic or environmental modifiers might play a role.