Ophthalmological manifestations in a cohort of Cowden syndrome patients in a large tertiary healthcare system.

BACKGROUND/OBJECTIVES: Cowden syndrome (CS) is a rare genetic disorder caused by mutations in the PTEN gene associated with multisystem hamartomas and predisposition to malignancies. Although ocular involvement has been reported in case studies, systematic data are lacking. This study aimed to evaluate the prevalence, characteristics, and genotypic associations of ocular manifestations in CS patients within a large tertiary healthcare system.

SUBJECTS/METHODS: We conducted a retrospective cohort study using the Mass General Brigham (MGB) Research Patient Data Registry, encompassing over 6 million patients from 2005 to 2024. Patients meeting clinical or genetic criteria for CS were identified. Ophthalmic findings, genotype-phenotype correlations, and clinical follow-up were extracted and analysed. A comprehensive literature review on CS-related ocular findings was performed to contextualize findings.

RESULTS

Of the 6,026,276 patients in the RPDR, 144 patients carried the diagnostic codes for CS. After a manual review of all charts, 77 met the clinical or genetic criteria for CS. Of these, 17 (22%) underwent ophthalmologic evaluation, and 4 (5%) exhibited CS-related ocular findings, including retinal hamartoma, eyelid hemangioma, trichilemmoma, and a peripapillary hamartoma-like lesion. Most patients maintained excellent vision over a median follow-up of four and a half years. Retinal imaging was limited, with OCT and OCTA available in only one case. Genotype analysis revealed that truncating PTEN variants were more likely associated with central nervous system involvement. Literature review identified a broader spectrum of ocular anomalies in CS, underscoring phenotypic variability.

CONCLUSIONS

The prevalence of CS in a large US tertiary setting is 1.28/100,000. Ocular manifestations in CS are rare and typically benign, with preserved vision in most cases. However, variability in presentation and mutation types may influence the risk. Notably, three of the four patients with ocular findings, possibly associated with CS, carried truncating variants. The fourth was PTEN-positive, but the specific variant was not retrievable. Multicentre studies are warranted to better define the full ocular phenotype of CS and to guide screening recommendations.