ESPEYB25 6. DSD and Gender Incongruence DSD Papers: DSD associated with Rare Mitochondrial Disorders (3 abstracts)
6.11. FDXR variants cause adrenal insufficiency and atypical sexual development
Pignatti E , Slone J , Gómez Cano MÁ , Campbell TM , Vu J , Sauter KS , Pandey AV , Martínez-Azorín F , Alonso-Riaño M , Neilson DE , Longo N , du Toit T , Voegel CD , Huang T & Flück CE
JCI Insight. 2024 Jun 17;9(14):e179071. doi: 10.1172/jci.insight.179071
Brief summary: This study identified biallelic variants in the ferredoxin reductase gene (FDXR), encoding mitochondrial flavoprotein, as a newly recognized cause of adrenal insufficiency and atypical sex development. Previously, FDXR mutations were linked to neurodegenerative disorders (ferredoxin reductase-related mitochondriopathy, FRM), but adrenal dysfunction was not documented. In two 46,XX siblings with FRM, homozygous p.G437R FDXR mutations led to ambiguous genitalia, cortisol deficiency, and androgen excess reminiscent of 11β-hydroxylase deficiency. Both infants died within their first year of life, likely due to adrenal crises triggered by infections.
Functional studies in patient-derived adrenal-like cells showed impaired glucocorticoid and mineralocorticoid synthesis, confirming FDXR’s role in steroidogenesis via its support of mitochondrial CYP enzymes such as CYP11A1, CYP11B1, and CYP11B2. Additionally, a mouse model carrying an orthologous Fdxr mutation (p.R389W) exhibited reduced corticosterone and progesterone levels, yet maintained normal adrenal zonation, indicating preserved structural integrity despite functional impairment.
Collectively, these findings expand FRM’s clinical spectrum to include a form of syndromic 46,XX adrenal insufficiency with steroidogenic defects. They highlight the importance of evaluating both sexes in mitochondrial-linked endocrine disorders and suggest that acute or subclinical adrenal insufficiency in FRM could be life-threatening under stress.
With the increasing use of advanced molecular diagnostic techniques, both the number of reported cases with mitochondriopathies, and the list of associated genes continue to expand (1).
Reference: 1. Miller WL, Pandey AV, Flück CE. Disordered Electron Transfer: New Forms of Defective Steroidogenesis and Mitochondriopathy. J Clin Endocrinol Metab. 2025 Feb 18;110(3):e574-e582. doi: 10.1210/clinem/dgae815. PMID: 39574227.
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ESPE Yearbook of Paediatric Endocrinology
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