Figure 1.

Clinical spectrum and cranial nerve imaging of the TUBB3-CFEOM syndromes. (A–I) Photographs of individuals harboring TUBB3-CFEOM variants. R262C can cause bilateral ptosis and severe CFEOM3 with the resting position of both eyes infraducted and abducted (A), moderate CFEOM3 that can be unilateral (B), and mild CFEOM3 (not shown). A similar spectrum is seen with D417N; severe CFEOM3 is shown in (E). A302T (C) and R380C (D) cause moderate to severe CFEOM3. Participants in (A–E) have full facial movements. The axonal neuropathy in the participant with D417N (E) results in atrophy of the intrinsic foot muscles and a high arch (F). E410K (G) and R262H (H) result in severe CFEOM3 and facial weakness, and R262H also results in congenital joint contractures, including ulnar deviation of the hand with joint contractures of the thumbs and fingers (I). (J,K) MRI of the brainstem at the level of the oculomotor (CN III) nerve in control (J) and E410K (K). (L,M) Orbital contents posterior to the globe in control (L) and in an individual with the E410K substitution. Note atrophy of the levator palpebrae superioris (LPS), superior rectus (SR), and medial rectus (MR) muscles in (M). The inferior rectus (IR), lateral rectus (LR), and superior oblique (SO) muscles appear normal. ON denotes optic nerve. (N,O) MRI of the brainstem at the level of the superior internal auditory meati to visualize the facial (CN VII, blue arrows) and vestibulocochlear (CN VIII, red arrows) nerves. In a control individual (N), CN VII courses parallel and ventral to CN VIII on each side. The anterior inferior cerebellar artery flow void is seen between the cranial nerves on the right (yellow arrowhead). In an individual with R262H substitution, CN VII appears hypoplastic and is faintly visualized coursing ventral and parallel to the cranial nerves VIII. (A–L) Reproduced with permission from Tischfield et al. (2010); (N,O) reproduced with permission from Whitman et al. (2021).