MON-484 - What'S Up, DOC? Adrenal Insufficiency in Ferredoxin Reductase Mutation Disorders

Background: Ferredoxin reductase (FDXR) mutation associated mitochondrial dysfunction syndrome is a rare autosomal recessive disorder characterized by neurological sequelae. We describe a case of FDXR-related adrenal insufficiency and compare the diagnostic and clinical outcomes to previously reported neonatal cases.

Case: A 9-month-old male born at 36 weeks GA with heterozygous pathogenic FDXR mutations (c.1156C>T, p.R386W; c.221C>T, p.P74L), bilateral optic nerve atrophy, and auditory neuropathy spectrum disorder presented with abnormal movements during feeds and decreased oral intake. He developed hypertension (maximum systolic blood pressure 160 mmHg) requiring amlodipine. Endocrinology evaluation revealed normal genitourinary exam and normal morning cortisol levels (11.9 ug/dL) with mildly elevated ACTH (117 pg/mL). ACTH stimulation test results were pending, and family was discharged with as needed stress dose steroids. Four days post-discharge, he was admitted to the PICU with fever, lethargy, and acute hypoxemic respiratory failure. ACTH stimulation test returned with peak cortisol of 15.9 mcg/dL and elevated basal/stimulated DHEA (177/328 ng/dL), androstenedione (87/202 ng/dL) and testosterone (21/28 ng/dL). Notably, basal deoxycorticosterone (DOC) was normal with an only mildly elevated stimulated level (17/110 ng/dL) but 11-deoxycortisol levels were markedly high (231/2151 ng/dL). Collectively, these labs indicated 11-betahydroxylase (CYP11B1) dysfunction. Whole genome sequencing excluded concurrent CYP11B1 mutations. His thyroid function studies and growth factors were normal. Treatment included stress dose steroids with transition to hydrocortisone (HC) 12mg/m2/day. His hospital course has been complicated by recurrent metabolic strokes, infection, and tracheostomy.

Discussion: Endocrine sequalae of FDXR mutation have been newly described, with previous reports documenting two female siblings with homozygous pathogenic FDXR variants presenting with severe sensorial neuropathy, ambiguous genitalia, and steroid profile consistent with compensated CYP11B1 defect3. Both infants died within the first year of life from infections. Studies have shown FDXR is a reducing partner to steroidogenic enzymes CYP11A1, CYP11B1, and CYP11B2, therefore pathologic variants of FDXR affect aldosterone, cortisone, and androgen production1-3. However, current literature lacks specific treatment and monitoring guidelines for patients with FDXR-related adrenal dysfunction. HC treatment was initiated in our patient to facilitate, if possible, the discontinuation of amlodipine and attenuate the steroidogenic abnormalities due CY11B1 dysfunction. We suggest early screening for adrenal dysfunction in children identified to have FDXR mutations.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*