ESPE Abstracts

Context: Inherited mitochondrial diseases are a group of disorders in which redox homeostasis is disrupted. The adrenal gland is particularly susceptible to oxidative stress associated with mitochondrial dysfunction. Furthermore, all adrenal steroid hormones are synthesized within the mitochondria. Therefore, novel genetic mitochondrial diseases emerge as rare causes of primary adrenal insufficiency (PAI).

Objective: Characterization of PAI in two siblings with biallelic CPOX mutations.

Design and Setting: Clinical and molecular characteristics of 2 siblings (P1:8.9 years 46,XY, P2:6.2 years 46,XX) from a consanguineous family were investigated for the etiology of PAI.

Methods: Clinical data were recorded. Molecular etiologies were determined using mitochondrial and whole genome sequencing (WGS): Plasma steroids and urinary porphyrins were measured using mass spectrometry methods. Mitochondrial function was tested using the mitochondrial membrane potential (MMP) assay.

Results: A boy (P1) and his sister (P2) was diagnosed with PAI at the age of 4.5 years and at 7 months due to diffuse hyperpigmentation, respectively. P1 had a history of proximal hypospadias and micropenis. He developed gynecomastia and primary gonadal insufficiency since the ages of 6 and 11, respectively. Both patients had a history of early-onset microcytic anemia, cholestasis, hepatosplenomegaly, nystagmus, optic atrophy, mild lactic acidosis. WGS revealed a novel homozygous mutation in the coproporphyrinogen oxidase (CPOX) gene (c.83_85del, p.Ser28_Gln29delins*) in affected siblings. Urinary porphyrin profiling supported the diagnosis of hereditary coproporphyria caused by homozygous CPOX mutation in patients. Oxidative damage to mitochondria was demonstrated by decreased MMP in patients compared to controls (P <0.0001). Adrenal MRI showed bilateral atrophic adrenals with calcifications. Hypothalamo-pituitary-adrenal assessment showed severe PAI with very low cortisol and androgens and relatively high 11-deoxycortisol, corticosterone and deoxycorticosterone concentrations. Steroid hormone profiling revealed a mixture of characteristics of 17-hydroxylase deficiency and adrenal destruction in both patients.

Conclusion: Mitochondrial disorders may cause a multi-hit model of PAI affecting mitochondrial steroidogenic enzymes and adrenal cortex integrity. In patients with coproporphyria, it should not be overlooked that clinical findings may mask PAI findings.