17α-羟化酶/17,20-裂解酶缺陷症扩展的基因型-表型谱：九例系列报道，包括一种新发突变、疑似TART样病变及多系统受累

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中文摘要

背景： 17α-羟化酶/17,20-裂解酶缺陷症（17-OHD）是一种由CYP17A1双等位基因变异驱动的罕见先天性肾上腺增生，具有广泛的临床和分子异质性；关于罕见表型和基因型-表型模式的数据很少。
目的： 描述来自单中心的九例中国17-OHD患者的临床、激素、性腺病理和遗传学特征，扩展人群特异性CYP17A1变异谱，探索基因型-亚型趋势，并记录罕见的偶然表现，以指导临床诊疗和遗传咨询。
方法： 一项回顾性病例系列纳入九例经基因验证的患者（七例46,XY，两例46,XX）。应用SWISS-MODEL同源建模和美国医学遗传学与基因组学学会（ACMG）标准评估新发变异的致病性。
结果： 纯合c.985_987delTACinsAA（p.Y329Kfs*90）变异在完全型患者中占主导。一种新发无义变异c.1218G>A，p.W406X，预测会截断103个C端氨基酸，基于一例部分型病例中的PVS1/PM2/PM3/PM4证据被暂定为致病性。我们观察到一种描述性趋势：双等位基因截短型功能丧失变异与完全型17-OHD相关，而部分型携带具有残余酶活性的错义变异。两例46,XX完全型患者有双侧卵巢萎缩和低抗苗勒管激素（AMH）；两例46,XY患者表现为偶然的单侧感音神经性听力损失。一例46,XY患者存在类似睾丸肾上腺残余肿瘤（TART）的性腺类固醇生成细胞巢，但无肾上腺特异性免疫组织化学（IHC）以确认细胞来源。一名先证者患有两种独立的单基因疾病：17-OHD和左心室心肌致密化不全心肌病，同时携带CYP17A1和肌节基因（MYBPC3/ACTN2/TTN）变异。所有患者均有促肾上腺皮质激素（ACTH）升高，多数皮质醇降低，11-脱氧皮质酮（11-DOC）和皮质酮水平不同程度升高。
结论： 本队列扩展了中国致病性CYP17A1变异谱，并揭示了初步的基因型-亚型关联以及罕见的共存表型。需要更大规模的多中心队列和功能实验来验证非典型表现与17-OHD之间的因果联系。建议对高血压、低钾血症和性发育异常患者进行早期肾上腺类固醇谱分析和CYP17A1测序。46,XX患者需要连续卵巢储备功能检测，而46,XY性腺发育不全患者需要长期性腺影像学随访。

英文摘要

CONTEXT: 17α-hydroxylase/17,20-lyase deficiency (17-OHD), a rare congenital adrenal hyperplasia driven by biallelic CYP17A1 variants, shows extensive clinical and molecular heterogeneity; data on rare phenotypes and genotype-phenotype patterns are scarce.
OBJECTIVE: To characterize clinical, hormonal, gonadal pathological, and genetic features of nine Chinese patients with 17-OHD from a single center, expand the population-specific CYP17A1 variant spectrum, explore genotype-subtype trends, and document rare incidental manifestations to inform clinical care and genetic counseling.
METHODS: A retrospective case series included nine genetically verified patients (seven 46,XY, two 46,XX). SWISS-MODEL homology modeling and American College of Medical Genetics and Genomics (ACMG) criteria were applied to assess the novel variant's pathogenicity.
RESULTS: The homozygous c.985_987delTACinsAA (p.Y329Kfs*90) variant predominated in complete-type patients. A novel nonsense variant c.1218G>A, p.W406X, predicted to truncate 103 C-terminal amino acids, was tentatively classified as pathogenic based on PVS1/PM2/PM3/PM4 evidence in one partial-type case. We observed a descriptive trend: biallelic truncating loss-of-function variants correlated with complete 17-OHD, while partial forms carried missense variants with residual enzyme activity. The two 46,XX complete-type patients had bilateral ovarian atrophy and low anti‑Müllerian hormone (AMH); two 46,XY patients presented with incidental unilateral sensorineural hearing loss. One 46,XY patient harbored gonadal steroidogenic cell nests resembling testicular adrenal rest tumors (TART), without adrenal-specific immunohistochemistry (IHC) to confirm cellular origin. One proband had two independent monogenic diseases: 17-OHD and left ventricular non-compaction cardiomyopathy, carrying concurrent CYP17A1 and sarcomeric gene (MYBPC3/ACTN2/TTN) variants. All patients had elevated adrenocorticotropic hormone (ACTH), most had low cortisol, and 11-deoxycorticosterone (11-DOC) and corticosterone levels were variably elevated.
CONCLUSIONS: This cohort extends the Chinese pathogenic CYP17A1 variant spectrum and reveals tentative genotype-subtype associations plus rare co-occurring phenotypes. Larger multicenter cohorts and functional experiments are needed to validate causal links between atypical manifestations and 17-OHD. Early adrenal steroid profiling and CYP17A1 sequencing are recommended for patients with hypertension, hypokalemia, and disorders of sex development. Serial ovarian reserve testing is required for 46,XX patients, and long-term gonadal imaging follow-up for 46,XY patients with gonadal dysgenesis.