Primary adrenal insufficiency in patients with CPOX gene mutations.

This article focuses on the characterization of primary adrenal insufficiency (PAI) in two siblings with harderoporphyria, a rare autosomal recessive porphyria caused by biallelic mutations in the CPOX gene, which encodes coproporphyrinogen oxidase involved in heme biosynthesis. The study identifies a homozygous truncating CPOX variant (c.83_85del, p.S28*) linked to severe PAI, likely due to impaired mitochondrial steroidogenic enzymes CYP11A1 and CYP11B1, and mitochondrial dysfunction evidenced by decreased mitochondrial membrane potential. Clinical features included hyperpigmentation, microcytic anemia, and adrenal insufficiency without mineralocorticoid deficiency, with hormonal profiles supporting combined steroidogenic enzyme deficiencies. The findings suggest that adrenal insufficiency is an under-recognized complication of harderoporphyria and related porphyrias affecting mitochondrial heme metabolism, highlighting the need to consider PAI in patients with porphyria.