Expanding phenotype of FDXR-related mitochondrial disorder: the role of ferredoxin reductase in steroidogenesis

Background: FDXR (ferredoxin reductase) encodes for a mitochondrial flavoprotein required for the biogenesis of iron–sulfur clusters and for the reduction of P450. Its deficiency is characterized by sensorineural hearing loss, optic atrophy, seizures, hypotonia, and developmental delay. Here we expand the known phenotype by presenting a new female who developed premature pubarche at 3 years of age.

Case Study: A term female with a history of intrauterine growth restriction presented with global developmental delay, hypotonia, and septo optic dysplasia (by brain MRI) at 12 months of age. At 14 months during a febrile illness, she experienced acute developmental regression with seizures. Brain MRI identified new abnormalities of the globi pallidi. Trio whole genome sequencing identified homozygosity for a pathogenic variant c.1285C>T (p. Arg429Trp) in the FDXR gene. Results/Course: She had multiple subsequent hospitalizations for febrile illnesses and further regression of skills. She became more stable after the placement of a tracheostomy and a GJ-tube at 2.5 years of age. At 3 years of age, she developed pubic hairs. Laboratory studies indicated elevated ACTH 73.6-81.6 pg/mL (normal range 7.2-63.3), Cortisol 10.5-17.9 mg/dL (5-10.8), Total testosterone 23-28 ng/dL (<19), Androstenedione 0.965-2.095 ng/mL (<0.159), DHEAS 175-204 mcg/dL (<0.29), Estradiol 3.3-9.2 pg/ml (<56), FSH 20.8 mIU/mL (0.6-5).

Discussion/Conclusion: FDXR deficiency causes a spectrum of neurological problems. Here we provide clinical evidence of the role of mitochondrial FDXR in steroid metabolism, which has been previously hypothesized, but never demonstrated. Our hypothesis is that insufficient FDXR activity results in decreased activity of all 5 mitochondrial P450-dependent enzymes involved in steroidogenesis, thereby increasing the supply of substrates to enzymes leading to increased androgen synthesis in the cytoplasm.