Coproporphyrinogen oxidase deficiency causes primary adrenal insufficiency and 46,XY DSD.

Abstract

Context: Primary adrenal insufficiency (PAI) is a rare, life-threatening condition, and at times is associated with differences of sexual differentiation (DSD). Cytochrome P450 enzymes, which are essential for steroidogenesis in adrenals and gonads, have heme in their active center. CPOX encodes an enzyme coproporphyrinogen oxidase (CPOX) that is involved in the synthesis of heme.

Objective: This study aims to report the identification of biallelic inactivating CPOX variants in three unrelated patients with PAI and their clinical characteristics.

Methods: We reported three patients with childhood-onset PAI, including two patients with 46,XY DSD. All three had adrenal hypoplasia. Additionally, they commonly had severe neonatal jaundice; two of them developed skin blisters in the areas exposed to phototherapy, and two showed severe neonatal anemia requiring transfusions. Exome sequencing was performed to explore the genetic basis of the patients. The pathogenicity of the identified variants was confirmed with targeted mRNA and proteomic analyses of the patient-derived peripheral blood cells.

Results: We identified biallelic rare CPOX variants in each patient, including c.2T>G, p.Arg426*, c.1277G>A and p.Tyr429Cysfs33*. The three patients commonly had the start codon-altering c.2T>G variant. Analysis of the mRNA and proteome of peripheral blood cells from one patient (c.2T>G and p.Arg426*) showed that CPOX mRNA expression was comparable to controls, however CPOX protein expression was significantly decreased to 1%.

Conclusion: We provided genetic evidence linking CPOX deficiency and PAI with 46,XY DSD, suggesting that the heme synthesis pathway plays an important role in human steroidogenesis.