{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:40:22Z","timestamp":1791049222039,"version":"4.1.0"},"reference-count":53,"publisher":"American Society for Clinical Investigation","issue":"14","license":[{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"vor","delay-in-days":35,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["SNF 320030-146127"],"award-info":[{"award-number":["SNF 320030-146127"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"name":"McKeefrey Pediatric Genetics Foundation","award":["Grant for Pediatric Genetics"],"award-info":[{"award-number":["Grant for Pediatric Genetics"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,22]]},"abstract":"<jats:p>\n                    Genetic defects affecting steroid biosynthesis cause cortisol deficiency and differences of sex development; among these defects are recessive mutations in the steroidogenic enzymes CYP11A1 and CYP11B, whose function is supported by reducing equivalents donated by ferredoxin reductase (\n                    <jats:italic>FDXR<\/jats:italic>\n                    ) and ferredoxin. So far, mutations in the mitochondrial flavoprotein FDXR have been associated with a progressive neuropathic mitochondriopathy named FDXR-related mitochondriopathy (FRM), but cortisol insufficiency has not been documented. However, patients with FRM often experience worsening or demise following stress associated with infections. We investigated 2 female patients with FRM carrying the potentially novel homozygous FDXR mutation p.G437R with ambiguous genitalia at birth and sudden death in the first year of life; they presented with cortisol deficiency and androgen excess compatible with 11-hydroxylase deficiency. In addition, steroidogenic\n                    <jats:italic>FDXR<\/jats:italic>\n                    -variant cell lines reprogrammed from 3 patients with FRM fibroblasts displayed deficient mineralocorticoid and glucocorticoid production. Finally,\n                    <jats:italic>Fdxr<\/jats:italic>\n                    -mutant mice allelic to the severe p.R386W human variant showed reduced progesterone and corticosterone production. Therefore, our comprehensive studies show that human\n                    <jats:italic>FDXR<\/jats:italic>\n                    variants may cause compensated but possibly life-threatening adrenocortical insufficiency in stress by affecting adrenal glucocorticoid and mineralocorticoid synthesis through direct enzyme inhibition, most likely in combination with disturbed mitochondrial redox balance.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.179071","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T14:22:48Z","timestamp":1718634168000},"source":"Crossref","is-referenced-by-count":12,"title":["FDXR variants cause adrenal insufficiency and atypical sexual development"],"prefix":"10.1172","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5372-5692","authenticated-orcid":true,"given":"Emanuele","family":"Pignatti","sequence":"first","affiliation":[{"name":"Division of Pediatric Endocrinology, Diabetology and Metabolism, 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