Primary adrenal insufficiency in patients with CPOX gene mutations

KELEŞTEMUR E., Yarar M. H., Tosun B. G., Karaca M., Goler A. M. Y., Yilmaz B. K., ...More

European Journal of Endocrinology, vol.192, no.5, 2025 (SCI-Expanded, Scopus) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 192 Issue: 5
  • Publication Date: 2025
  • Doi Number: 10.1093/ejendo/lvaf089
  • Journal Name: European Journal of Endocrinology
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, PASCAL, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Keywords: children, CPOX, mitochondria, porphyria, primary adrenal insufficiency
  • Istanbul University Affiliated: Yes

Abstract

Background: Harderoporphyria arises from biallelic CPOX gene mutations, leading to coproporphyrinogen oxidase deficiency in the inner mitochondrial membrane. The impact of CPOX gene mutations on adrenal function remains poorly understood. Objective: Characterizing primary adrenal insufficiency (PAI) in 2 siblings with harderoporphyria. Methods: Clinical data were recorded, and genetic analysis was performed by whole genome sequencing (WGS). Plasma steroids and urinary porphyrins were measured by liquid chromatography-mass spectrometry and high-performance liquid chromatography, respectively. Mitochondrial function was assessed using the mitochondrial membrane potential (MMP) assay in peripheral blood mononuclear cells. Results: Patients were diagnosed with PAI at 4.5 years (P1, 46,XY) and 7 months (P2, 46,XX). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. WGS revealed a homozygous c.83_85del, p.S28* variant in CPOX. Oxidative damage to mitochondria was shown by decreased MMP in patients compared with controls (P < .0001). Hormonal assessment indicated severe PAI, suggestive of combined CYP11A1 and CYP11B1 deficiency. Conclusions: CPOX gene mutations cause a mixed model of PAI, affecting mitochondrial steroidogenic enzymes. Clinical manifestations of harderoporphyria may overlap with PAI signs.