Otofaciocervical Syndrome 2

A number sign (#) is used with this entry because of evidence that otofaciocervical syndrome-2 (OTFCS2) is caused by homozygous mutation in the PAX1 gene (167411) on chromosome 20p11. One such family has been reported.

Description

Otofaciocervical syndrome (OTFCS) is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies including vertebral defects, low-set clavicles, winged scapulae, sloping shoulders, and mild intellectual disability (summary by Pohl et al., 2013).

For a discussion of genetic heterogeneity of otofaciocervical syndrome, see OTFCS1 (166780).

Clinical Features

Pohl et al. (2013) studied a large consanguineous Turkish family segregating autosomal recessive otofaciocervical syndrome, with 4 affected members from 2 different branches of the family. All affected individuals presented with cup-shaped ears, bilateral mixed hearing loss, bilateral preauricular fistulas, lacrimal duct abnormalities, commissural lip clefting, retrognathia, protruding shoulders, and winged scapulae. The index patient was a boy with moderately delayed motor and mental milestones who had long eyelashes, blue sclerae, downslanting palpebral fissures, malocclusion and dental caries, tapering fingers with bilateral clinodactyly, and bilateral cutaneous syndactyly of the second and third toes. Bone x-rays showed anterior scalloping of the lower thoracic and lumbar vertebral bodies and a fusion defect in L5/S1. Brain MRI revealed periventricular white matter gliosis and bilateral mastoiditis. Pohl et al. (2013) stated that the clinical findings of all affected family members were consistent with a diagnosis of OTFC syndrome.

Mapping

In a large consanguineous Turkish family segregating autosomal recessive OTFC syndrome, Pohl et al. (2013) performed microsatellite marker analysis and haplotyping, which defined a 1.5-Mb shared interval on chromosome 20, between markers D20S54 and D20S477 and encompassing the PAX1 gene (167411).

Molecular Genetics

By whole-exome sequencing in affected members of a large consanguineous Turkish family segregating autosomal recessive OTFC syndrome, Pohl et al. (2013) identified homozygosity for a missense variant in the PAX1 gene (G166V; 167411.0001). Sanger sequencing confirmed that homozygosity for the variant segregated with disease in the family, and the variant was not listed in more than 13,000 alleles from the Exome Variant Server database.