Homozygous variegate porphyria: Two cases misdiagnosed as erythropoietic protoporphyria

Abstract

Homozygous variegate porphyria (HVP) is an ultra-rare porphyria caused by biallelic pathogenic variants in PPOX. It typically presents with early childhood onset of cutaneous photosensitivity, including blistering, skin fragility, scarring, and poorly defined neurologic symptoms. We report two unrelated patients with childhood-onset photosensitivity, blistering, scarring, modest zinc-predominant erythrocyte protoporphyrin elevation, elevated plasma porphyrins that were predominantly protoporphyrin, and homozygous novel PPOX variants, findings consistent with homozygous variegate porphyria. Both patients had initially been diagnosed with erythropoietic protoporphyria because of photosensitivity and elevated total erythrocyte protoporphyrin, despite fractionation demonstrating a slight zinc predominance rather than metal-free predominance. Genetic testing revealed that both patients were homozygous for PPOX variants: c.223G>T p.Val75Phe in Case 1 and c.1070A>C p.Asp357Ala in Case 2. Neither variant was present in population genetic datasets nor previously reported in patients with variegate porphyria, and both were classified as variants of uncertain significance. A plasma fluorescence scan was performed for Case 2 and showed a peak at 624 nm, specific for variegate porphyria. A comprehensive porphyria gene panel, ideally with plasma fluorescence scanning, should be performed when total erythrocyte protoporphyrin is substantially elevated but predominantly zinc-chelated, to ensure accurate diagnosis of homozygous porphyrias such as HVP.