Facial Palsy, Congenital, With Ptosis And Velopharyngeal Dysfunction

A number sign (#) is used with this entry because of evidence that congenital facial palsy with ptosis and velopharyngeal dysfunction (FPVEPD) is caused by heterozygous mutation in the TUBB6 gene (615103) on chromosome 18p11. One such family has been reported.

Clinical Features

Fazeli et al. (2017) reported a 5-generation family with congenital nonprogressive bilateral facial palsy and velopharyngeal dysfunction. Features included varying degrees of hypomimia, rhinophonia, impaired gag reflex, and bilateral ptosis. The proband was a 4-year-old girl who showed bilateral ptosis and facial palsy since infancy. Physical examination as a child showed reduced motility of the levator palpebrae muscles with compensatory chin up posture and velopharyngeal dysfunction with a wide uvula, absent gag reflex, and severe rhinophonia aperta with speech articulation defects. She had no additional neurologic, skeletal, muscular, or cognitive abnormalities. Family history revealed a similar phenotype on the paternal side of the family. The severity of the disorder was highly variable: some patients had a mild hypomotile upper lip or reduced gag reflex only, whereas others had varying degrees of rhinophonia aperta, impaired facial movement, and ptosis. Some of the patients required surgical intervention for nasal regurgitation or ptosis. None of the affected individuals had limitation of ocular abduction or limb abnormalities as described for Moebius syndrome (MBS; 157900). Cognition was normal in all patients. The phenotype was nonprogressive, and some patients reported improved symptoms with age or speech therapy. Brain imaging in 3 affected individuals showed no abnormalities.

Inheritance

The transmission pattern of FPVEPD in the family reported by Fazeli et al. (2017) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of a 5-generation family with FPVEPD, Fazeli et al. (2017) identified a heterozygous missense mutation in the TUBB6 gene (F394S; 615103.0001). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Expression of the mutation in the yeast ortholog Tub2p resulted in significantly increased sensitivity to a microtubule destabilizing drug compared to wildtype, indicating that the mutation disturbed microtubules. Brain imaging of 3 patients was normal, but Fazeli et al. (2017) postulated that the mutation may have adversely affected the development of certain cranial nerves, particularly VII, IX, and potentially X. The authors suggested that this was a congenital cranial dysinnervation disorder.