Irreversible Ocular and Systemic Damage in ROSAH Syndrome

Introduction: This study aimed to describe the clinical, genetic, and pathophysiologic features of four Italian patients from two unrelated families with retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache (ROSAH) syndrome, highlighting novel ocular and systemic manifestations and therapeutic considerations. Methods: We report detailed phenotypic, ophthalmologic, and systemic findings in four genetically confirmed cases (eight eyes). Special attention was given to ocular and systemic manifestations and complications, inflammatory markers, systemic complications, and treatment responses. Results: All eyes exhibited bilateral optic disc and peripapillary involvement, cone-rod retinal dystrophy confirmed by full-field electroretinography and multimodal retinal imaging, low-grade uveitis and retinal vasculitis. Novel findings included keratoconus in one patient and dry eye in all patients. Acute angle-closure glaucoma was also observed in four eyes (two patients) with short axial lengths. Systemically, in addition to the previously described features of fever, splenomegaly, headache, dental anomalies, and anhidrosis, we report the first case of reactive amyloidosis in ROSAH syndrome, leading to severe renal failure and dialysis dependence. Splenectomy resolved recurrent fever in two patients. Conventional immunosuppressants were largely ineffective, whereas interleukin-6 inhibition provided systemic benefit but limited ocular improvement. Conclusions: ROSAH syndrome presents with distinctive ocular features, and recognition of ocular surface, corneal and anterior segment anomalies further broadens its phenotypic spectrum. Reactive amyloidosis is a possible complication of ROSAH syndrome, as in other autoinflammatory disorders. Early diagnosis is critical to prevent irreversible ocular and extraocular organ damage, and to guide timely, targeted therapeutic interventions.