ESPE Yearbook of Paediatric Endocrinology

Eur J Endocrinol. 2025 Apr 30;192(5):K31-K37. doi: 10.1093/ejendo/lvaf089

Brief summary: This case report describes2 siblings, one 46,XY and one 46,XX, with primary adrenal insufficiency (PAI) in the context of harderoporphyria, a porphyrin metabolism disorder caused by biallelic mutations in the CPOX gene. Both children presented early in life with microcytic anemia, cholestasis, hepatosplenomegaly, and neurological symptoms such as nystagmus and optic atrophy. They were later diagnosed with PAI at ages 4.5 years and 7 months. The patient with 46,XY karyotype also had DSD.

Whole-genome sequencing identified a homozygous frameshift variant (c.83_85del, p.S28⁺) in the CPOX gene, affecting coproporphyrinogen oxidase. Biochemical assays showed dysfunctional mitochondrial membrane potential in patient cells, suggesting that CPOX deficiency impairs mitochondrial steroidogenesis, leading to deficiencies in CYP11A1 and CYP11B1 activity and resulting in PAI and 46,XY DSD. The diagnosis of combined CYP11A1 and CYP11B1 deficiency remains inferred from hormonal profiles, without direct demonstration of impaired enzyme activity or reduced steroidogenic output in adrenal cells. Additionally, while mitochondrial dysfunction was observed in peripheral blood cells, there was no direct assessment of adrenal tissue, which limits interpretation of how CPOX mutation specifically disrupts steroidogenesis. A similar phenotype has been described by Honda M, et al. in 2 new patients with PAI and 46,XY DSD due to biallelic rare CPOX variants (1).

In summary, this report expands the phenotypic spectrum of CPOX-related harderoporphyria to include PAI and DSD, likely via impaired mitochondrial steroidogenesis and affecting adrenal and gonadal function. However, broader studies with functional adrenal assays and larger cohorts are needed to confirm causality and elucidate pathophysiological mechanisms. Any form of inherited mitochondrial dysfunction, whether caused by defects in mitochondrial DNA or autosomal genes encoding mitochondrial proteins, can cause impaired adrenal and gonadal steroidogenesis which can lead to adrenal insufficiency and DSD. It is important to recognize that the symptoms of the primary disease may overlap with or mask those of adrenal insufficiency. This is particularly critical in preventing mortality associated with unrecognized adrenal failure.

Reference: 1. Honda M, Narumi S, Hasegawa K, Goto Y, Kawashima Y, Ohara O, Fukuzawa R, Ishii T, Hasegawa T. Coproporphyrinogen oxidase deficiency causes primary adrenal insufficiency and 46,XY DSD. J Clin Endocrinol Metab. 2025 Jun 7:dgaf329. Epub ahead of print. PMID: 40481674.