Systematic ophthalmologic evaluation in cardio-facio-cutaneous syndrome: A genotype-endophenotype correlation

Cardio-facio-cutaneous syndrome (CFCS) is a rare genetic disorder belonging to the RASopathies, a group of developmental syndromes caused by upregulated RAS/MAPK signaling. Pathogenic variants affecting four genes, KRAS, BRAF, MAP2K1 and MAP2K2, encoding core signal transducers of the pathway, underlie the condition. Major clinical features include a distinctive facies, ectodermal and cardiac anomalies, reduced postnatal growth, intellectual disability, and musculoskeletal abnormalities. Similar to other RASopathies, reports of visual impairment, high refractive error, optic nerve pallor, and other ocular abnormalities have been anecdotally reported in the literature. The aim of our study is to report the prevalence of ophthalmologic abnormalities in a large monocentric cohort of individuals affected by CFCS and explore the occurrence of genotype-endophenotype correlations in this series of patients. We observed that BRAF mutations are associated to a higher prevalence of anisometropia >3D (11.8% vs. 0%) and high astigmatism (29.4% vs. 0%; both p < 0.001) while patients with mutations in other genes had a significantly higher prevalence of myopia >6 D (60% vs. 5.9%; p = 0.012). Pale optic disc was associated with higher prevalence of inferior oblique muscle (IO) overaction (33.3% vs. 0%) and lower prevalence of ptosis (0% vs. 11.8%; both p < 0.001). Combined exotropia, IO overaction and nystagmus were frequent in patients with pale optic nerve. Our findings might suggest the need for earlier ophthalmologic referral for CFCS patients due to high risk of amblyopia, especially those expressing BRAF mutations.

Automated summary

Cardio-facio-cutaneous syndrome (CFCS) is a rare genetic disorder caused by upregulated RAS/MAPK signaling. This study investigates the prevalence of ophthalmologic abnormalities in CFCS patients and explores genotype-endophenotype correlations. The findings suggest that CFCS patients with BRAF mutations have a higher risk of visual impairment and refractive errors, while patients with mutations in other genes have a higher prevalence of myopia. Pale optic disc is associated with specific eye muscle abnormalities. Early ophthalmologic referral is recommended for CFCS patients, especially those with BRAF mutations, due to the high risk of amblyopia.