Magnetic resonance imaging of the endophenotype of a novel familial Möbius-like syndrome.

INTRODUCTION: Möbius syndrome typically presents as a sporadic trait with congenital facial palsy and abduction impairment. We used high-resolution magnetic resonance imaging (MRI) and genetic analysis to examine a family with features of Möbius syndrome.
METHODS: We examined 3 related family members having congenital complete opthalmoplegia with ptosis and facial diplegia. Orbits were imaged in quasi-coronal and sagittal planes of 2 mm thickness. Subarachnoid cranial nerves were imaged in planes of 1 mm thickness. Linkage and mutation analysis were performed to determine whether the pedigree harbored mutations in 4 candidate genes.
RESULTS: In affected subjects, MRI showed marked hypoplasia of extraocular muscles and intraorbital motor nerves. In the anterior orbit, rectus extraocular muscles were less hypoplastic but markedly curved toward insertion. Oblique extraocular muscles were hypoplastic and abnormally inserted. Posterior bony orbits were hypoplastic. Optic nerves were markedly straightened. Brainstems and cranial nerves III, VI, VII, and VIII were normal bilaterally. No pathogenic mutations were detected in affected individuals.
CONCLUSIONS: Previous MRI studies have demonstrated brainstem hypoplasia and cranial nerve aplasia in Möbius syndrome. The current family had normal brainstems and subarachnoid portions of motor cranial nerves innervating the orbit but marked extraocular muscle hypoplasia. These clinical and MRI findings are atypical for Möbius syndrome and other congenital cranial dysinnervation disorders. Congenital facial weakness and complete ophthalmoplegia may occur despite MRI evidence of normal brainstem anatomy. The endophenotype appears to result from a genetic defect distinct from the congenital cranial dysinnervation disorders defined thus far, rather than a global brainstem insult.