Familial ROSAH Syndrome Associated with the ALPK1 p.Thr237Ala Variant: Divergent Ocular Phenotypes and Partial...

To report phenotypic variability and treatment response in familial ROSAH syndrome associated with the ALPK1 p.Thr237Ala variant.

Longitudinal observational familial case series of a mother-daughter pair with ALPK1-associated ROSAH syndrome. The daughter carried a heterozygous ALPK1 p.Thr237Ala variant, whereas her mother showed an apparent homozygous genotype. Both underwent multimodal ophthalmic imaging, visual field testing, systemic assessment, genetic analysis, and 24 months of follow-up, including 17 months after starting tocilizumab.

The daughter presented with bilateral optic disc edema, peripheral retinal vascular leakage, cytopenias, splenomegaly, anhidrosis, headache, and short dental roots, with preserved visual acuity. Her mother showed advanced inflammatory-degenerative retinopathy with profound visual loss and fewer systemic manifestations. In the daughter, tocilizumab was associated with resolution of systemic inflammation, reduced optic nerve head edema, and preserved visual acuity. In the mother, inflammatory markers normalized and macrocystic intraretinal fluid resolved, but retinal atrophy and severe visual impairment remained unchanged.

Familial ALPK1 p.Thr237Ala-associated ROSAH syndrome may show marked intrafamilial variability. The different clinical courses observed in these two related patients raise the possibility that inflammatory and degenerative mechanisms may progress, at least in part, independently. Interleukin-6 inhibition may improve inflammatory activity but appears limited once advanced retinal degeneration is established.