European journal of endocrinology · 2025
Primary adrenal insufficiency in patients with CPOX gene mutations.
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Kelestemur Elif, Yarar Murat Hakki, Gurpinar Tosun Busra, Karaca Meryem, Goler Ayse Mine Yilmaz, Yilmaz Betul Karademir, Yapici Ozge, Gokcay Gulden, Guran Tulay
Аннотация
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.
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.