Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles

Abstract

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Keywords: congenital cranial dysinnervation disorders; congenital fibrosis of extraocular muscles; development; optic nerve hypoplasia; optical coherence tomography; retinal ganglion cells.

Figure 1

(A) Pedigrees of families (F1–F4) and singletons (S1–S4) diagnosed with congenital fibrosis of the extraocular muscles. Genotypes are shown below the pedigrees. (B) Eye position in subjects with congenital fibrosis of extraocular muscles when observing a target located centrally (primary position) and superiorly (upgaze). Subject F1:I-1 has bilateral blepharoptosis, left esotropia, and no elevation in both eyes. However, his son (subject F1:II-3) has CFEOM3 phenotype limited to the right eye; he is unable to elevate the eye above the midline. There was no blepharoptosis and ductions were normal for the left eye. Subject F3:I-2 and subject S1:II-1 exhibited a CFEOM1 phenotype with bilateral blepharoptosis and inability to elevate either eye. Subject F3:I-2 also had a left exotropia and hypotropia. (C–H) Congenital pathologic synkinesis showing Marcus Gunn jaw winking phenomenon and synergistic divergence. Subject F2:I-2 had bilateral blepharoptosis, face turn to the left, and left exotropia with hypotropia (C). Retraction of the left upper eyelid is observed with mouth opening (D). Eye positions on central fixation (E) and downgaze (F) are shown. Synkinetic abduction of the left eye is observed on infraversion. Similar to F2:II-1, there is synkinetic abduction from central fixation (G) to downgaze (H). (I–P) Abnormal head postures observed when fixing at a target centrally in family F4 (I–L). Subjects F4:I-2 (I) and F4:II-1 (J) exhibit chin up and face turn to the left. Subject F4:II-2 has a head turn to the right with chin up position (K). Subject F4:II-3 has head tilt to the right with chin up position (L). All subjects had large angle exotropia. Facial weakness is demonstrated in all subjects when asked to smile (M–O). Drooping of the corner of the mouth and flattening of forehead and nasolabial folds are seen. Subject F4:II-3 had severe blepharoptosis of the left eye and frequently raised his upper left eyelid and brow using his finger in order to fixate with the left eye (P).

Figure 2

Fundus photos of subjects with CFEOM. In subject F3:1-2, the disc appears tilted with a small cup and inferior yellowish mottled halo (blue arrows). There is situs inversus of the blood vessels. Subject S1:II-1 has a faint halo surrounding the disc, which is a subtle incomplete double ring (yellow arrows). This is also seen in the left eye of subject F3:III-1, with an abnormal course of retinal vessels seen in both eyes. Subject F3:II-2 has hypoplastic optic nerves with significant inferior peripapillary scleral halos (blue arrows). Abnormal course of retinal vessels is seen. Subject F1:I-1 has tilted disc with myopic crescent (white arrow) and significant disc excavation and pallor. Scale bar represents 500 microns.

Figure 3

Optical coherence tomograms with corresponding disc photos. Dotted white line represents location of the OCT B-scan overlaid on the disc photo. Schematic shows borders of disc (orange) with the cup centrally (yellow), double ring (pale yellow), and peripapillary atrophy (hatched). Partial double ring/atrophy (F3:I-2 and F3:II-2) is seen below disc border (white arrows). In subject F3:I-2, the first scan (1) shows thin temporal neuro-retinal rim (yellow arrow); this is not evident on the disc photo as the borders of the cup are not clear and the cup appears significantly smaller. The location of the neuro-retinal rim on the fundus photo is highlighted with the yellow arrow. The second scan (2) is through a region of yellow mottled appearance. The OCT shows a hyper-reflective region posteriorly (white arrow). Disc photo of subject F3:II-2 shows appearance of a small cup. However, on OCT (3) the rim is very thin (yellow arrow), and the cup is deep and appears larger than on the fundus photo. The OCT through the inferior aspect of the disc (4) shows an optic cup that is not evident on the fundus photo. Disc photo in F3:III-1 shows a small cup with large neuro-retinal rims. However, OCT (5) shows thin neuro-retinal rim temporally (yellow arrow). OCT (6) below the inferior border of the presumed cup (from the fundus photo and illustration) shows a well-formed cup, although not as deep as the OCT through the center of the cup (5). In subject F1:I-1, this abnormal sloping is evident in the region of peripapillary atrophy (white arrow) in both scans (7,8). There is also a thin neuro-retinal rim with good correlation between disc photos and the OCT (yellow arrow).

Figure 4

Schematic representation based on average measurements of disc parameters in CFEOM (A) and controls (B). Examples of disc optical coherence tomograms in CFEOM patients and controls (C–E). Yellow lines represent the horizontal disc diameters measured from the termination of the retinal pigment epithelium. Graphs show mean and error bars representing the standard error of mean for disc diameter (F), rim width (G), rim area (H), cup width (I), cup depth (J), cup area (K), cup/disc ratio (L), nasal nerve fiber layer (NFL), thickness (M), and temporal NFL thickness (N). p values are shown above error bars.

Figure 5

Schematic representation of average thickness of each retinal layer in CFEOM (A) and controls (B). Significant differences were observed for nasal retinal thickness (C), retinal nerve fiber layer (RNFL) (D), ganglion cell complex (GCC) (E), and photoreceptor layer (PRL) thickness (F). Bar charts represent mean and standard error (µm). p values are shown above each bar. Abbreviations: RNFL = retinal nerve fiber layer, GCL = ganglion cell layer, IPL = inner plexiform layer, INL = inner nuclear layer, OPL = outer plexiform layer, ONL = outer nuclear layer, IS = inner segment, OS = outer segment, COST = cone outer segment tip, and RPE = retinal pigment epithelium.