Miller Walter L, Pandey Amit V, Flück Christa E
Department of Pediatrics, Center for Reproductive Sciences, and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland.
J Clin Endocrinol Metab. 2025 Feb 18;110(3):e574-e582. doi: 10.1210/clinem/dgae815.
Most disorders of steroidogenesis, such as forms of congenital adrenal hyperplasia (CAH) are caused by mutations in genes encoding the steroidogenic enzymes and are often recognized clinically by cortisol deficiency, hyper- or hypo-androgenism, and/or altered mineralocorticoid function. Most steroidogenic enzymes are forms of cytochrome P450. Most P450s, including several steroidogenic enzymes, are microsomal, requiring electron donation by P450 oxidoreductase (POR); however, several steroidogenic enzymes are mitochondrial P450s, requiring electron donation via ferredoxin reductase (FDXR) and ferredoxin (FDX). POR deficiency is a rare but well-described form of CAH characterized by impaired activity of 21-hydroxylase (P450c21, CYP21A2) and 17-hydroxylase/17,20-lyase (P450c17, CYP17A1); more severely affected individuals also have the Antley-Bixler skeletal malformation syndrome and disordered genital development in both sexes, and hence is easily recognized. The 17,20-lyase activity of P450c17 requires both POR and cytochrome b5 (b5), which promote electron transfer. Mutations of POR, b5, or P450c17 can cause selective 17,20-lyase deficiency. In addition to providing electrons to mitochondrial P450s, FDX, and FDXR are required for the synthesis of iron-sulfur clusters, which are used by many enzymes. Recent work has identified FDXR mutations in patients with visual impairment, optic atrophy, neuropathic hearing loss, and developmental delay, resembling the global neurologic disorders seen with mitochondrial diseases. Many of these patients have had life-threatening events or deadly infections, often without an apparent triggering event. Adrenal insufficiency has been predicted in such individuals but has only been documented recently. Neurologists, neonatologists, and geneticists should seek endocrine assistance in evaluating and treating patients with mutations in FDXR.
大多数类固醇生成障碍，如先天性肾上腺皮质增生症（CAH）的多种类型，是由编码类固醇生成酶的基因突变引起的，临床上常表现为皮质醇缺乏、雄激素过多或过少以及/或盐皮质激素功能改变。大多数类固醇生成酶是细胞色素P450的形式。大多数P450，包括几种类固醇生成酶，是微粒体酶，需要细胞色素P450氧化还原酶（POR）提供电子；然而，几种类固醇生成酶是线粒体P450，需要通过铁氧化还原蛋白还原酶（FDXR）和铁氧化还原蛋白（FDX）提供电子。POR缺乏是一种罕见但已充分描述的CAH形式，其特征是21-羟化酶（P450c21，CYP21A2）和17-羟化酶/17,20-裂解酶（P450c17，CYP17A1）活性受损；受影响更严重的个体还患有安特利-比克斯勒骨骼畸形综合征以及两性生殖器发育紊乱，因此很容易被识别。P450c17的17,20-裂解酶活性需要POR和细胞色素b5（b5），它们促进电子传递。POR、b5或P450c17的突变可导致选择性17,20-裂解酶缺乏。除了为线粒体P450提供电子外，FDX和FDXR是合成铁硫簇所必需的，许多酶都需要铁硫簇。最近的研究发现，患有视力障碍、视神经萎缩、神经性听力丧失和发育迟缓的患者存在FDXR突变，类似于线粒体疾病所见的全身性神经疾病。这些患者中的许多人曾发生危及生命的事件或致命感染，通常没有明显的触发事件。此前曾预测这些个体存在肾上腺功能不全，但直到最近才得到证实。神经科医生、新生儿科医生和遗传学家在评估和治疗FDXR突变患者时应寻求内分泌科的帮助。
