چکیده:
Congenital fibrosis of the extraocular muscles type 3 (CFEOM3) is a congenital cranial dysinnervation disorder marked by variable ophthalmoplegia and ptosis with considerable phenotypic heterogeneity. We report a large multigenerational Iranian family with autosomal dominant CFEOM3. Affected individuals underwent comprehensive ophthalmologic evaluation. Whole-exome sequencing in the proband, followed by Sanger sequencing in ten affected and four unaffected relatives, identified a heterozygous missense variant, c.784C>T (p.Arg262Cys), in exon 4 of TUBB3 (16q24.3), which co-segregated with the disease phenotype.
Cranial magnetic resonance imaging (MRI) in two affected individuals revealed asymmetric basal ganglia morphology, predominantly affecting the caudate nuclei and putamen. At the level of the anterior commissure, the bilateral CFEOM3 patient lacked a visible commissure, whereas the unilateral patient exhibited a thin but identifiable structure. Midline sagittal imaging demonstrated corpus callosum dysgenesis in both individuals, with slightly greater involvement of the corpus callosum body in the unilateral case, though this difference was not radiologically significant. Despite differences in ocular phenotype, overall cerebral involvement was largely comparable.
These findings confirm the pathogenic role of the TUBB3 p.Arg262Cys variant in CFEOM3A and extend the spectrum of ophthalmologic and neuroimaging abnormalities within an extended family. The results highlight the complex genotype–phenotype relationships in TUBB3-related disease and underscore the importance of integrated clinical and molecular evaluation for precise diagnosis.
Cranial magnetic resonance imaging (MRI) in two affected individuals revealed asymmetric basal ganglia morphology, predominantly affecting the caudate nuclei and putamen. At the level of the anterior commissure, the bilateral CFEOM3 patient lacked a visible commissure, whereas the unilateral patient exhibited a thin but identifiable structure. Midline sagittal imaging demonstrated corpus callosum dysgenesis in both individuals, with slightly greater involvement of the corpus callosum body in the unilateral case, though this difference was not radiologically significant. Despite differences in ocular phenotype, overall cerebral involvement was largely comparable.
These findings confirm the pathogenic role of the TUBB3 p.Arg262Cys variant in CFEOM3A and extend the spectrum of ophthalmologic and neuroimaging abnormalities within an extended family. The results highlight the complex genotype–phenotype relationships in TUBB3-related disease and underscore the importance of integrated clinical and molecular evaluation for precise diagnosis.
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