Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB-Mediated Autoinflammatory Disease with Retinal Dystrophy

Abstract

Purpose: We aimed to characterize the ocular phenotype of patients with ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome and their response to therapy.

Design: Single-center observational case study.

Participants: Eleven patients with a diagnosis of ROSAH syndrome and mutation in ALPK1 were included.

Methods: Patients with molecularly confirmed ROSAH syndrome underwent ophthalmic evaluation, including visual acuity testing, slit-lamp and dilated examinations, color fundus and autofluorescence imaging, fluorescein angiography, OCT, and electrophysiologic testing.

Main outcome measures: Visual acuity, electrophysiology, fluorescein angiography, and OCT findings.

Results: Eleven individuals (6 female and 5 male patients) from 7 families ranging in age from 7.3 to 60.2 years at the time of the initial evaluation were included in this study. Seven patients were followed up for a mean of 2.6 years (range, 0.33-5.0 years). Best-corrected visual acuity at baseline ranged from 20/16 to no light perception. Variable signs or sequelae of intraocular inflammation were observed in 9 patients, including keratic precipitates, band keratopathy, trace to 2+ anterior chamber cells, cystoid macular edema, and retinal vasculitis on fluorescein angiography. Ten patients were observed to show optic disc elevation and demonstrated peripapillary thickening on OCT. Seven patients showed retinal degeneration consistent with a cone-rod dystrophy, with atrophy tending to involve the posterior pole and extending peripherally. One patient with normal electroretinography findings and visual evoked potential was found to have decreased Arden ratio on electro-oculography.

Conclusions: Leveraging insights from the largest single-center ROSAH cohort described to date, this study identified 3 main factors as contributing to changes in visual function of patients with ROSAH syndrome: optic nerve involvement; intraocular inflammation, including cystoid macular edema; and retinal degeneration. More work is needed to determine how to arrest the progressive vision loss associated with ROSAH syndrome.

Financial disclosure(s): Proprietary or commercial disclosure may be found after the references.

Keywords: Cone–rod dystrophy; Optic disc elevation; Syndromic retinal dystrophy; Uveitis; Vasculitis.

Figure 1.

Optic disc elevation in retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache syndrome. Left column, Color fundus photographs showing disc elevation with only mild disc margin blurring in (A) (patient 8) and much more pronounced disc elevation and margin blurring in (B) (patient 9) and (C) (patient 3). Middle and right columns, with infrared image of the optic nerve and corresponding OCT imaging.

Figure 2.

Retinal findings on (Top row) ultra-widefield color images, (Middle row) fundus autofluorescence (FAF) images, and (bottom row) macular OCT images. Patients with early disease show disc elevation and normal-appearing retina on color imaging, FAF imaging, and OCT (A) (patient 3), whereas those with more advanced disease (B–D) (patients 7, 11, and 5, respectively) demonstrate a range of posterior pole nummular pigment (white arrowhead, magnified inset), vascular attenuation, and retinal pigment epithelium and photoreceptor atrophy. In patients with more advanced retinal degeneration, coarse lamination of the retinal layers are noted on OCT (C, D).

Figure 3.

Longitudinal ultra-widefield fluorescein angiography and OCT images of patient 3 showing changes in response to treatment. Fluorescein angiography and OCT images of the right eye (A, E) and left eye (B, F) obtained while the patient was receiving treatment with adalimumab weekly. Fluorescein angiography (A, B) revealed disc and peripapillary leakage as well as diffuse small-vessel leakage in both eyes, and cystoid macular edema (CME) was observed bilaterally (E, F). Improved disc retinal vascular leakage (C, D) and CME (G, H) was noted in both eyes after initiation of oral prednisone (1 mg/kg) in addition to methotrexate and adalimumab weekly. A recurrence of both retinal vascular leakage (I, J) and CME (M, N) was observed on tapering prednisone, while continuing anakinra 400 mg daily, adalimumab weekly, and methotrexate. A notable improvement in retinal vascular leakage (K, L) and almost complete resolution of CME (O, P) was noted after replacing anakinra with tocilizumab every 2 weeks subcutaneously.