十二个患有X连锁先天性肾上腺发育不全的巴西家庭：NR0B1基因的新重排和新变异

摘要(中文译文)

为表征巴西多中心队列中与X连锁先天性肾上腺发育不良(X-hypoAC)相关的NR0B1变异分子谱,并强调早期分子诊断的临床意义。作者研究了12个无亲缘关系的家系,这些家系因临床诊断为早发性肾上腺功能不全而被转诊至巴西各地的儿科内分泌中心。收集了临床资料、生化特征及随访信息。通过Sanger测序对NR0B1基因进行遗传检测,以发现单核苷酸变异及小插入/缺失变异,并辅以MLPA以识别大片段缺失或重排。变异按照美国医学遗传学与基因组学学会(ACMG)指南进行分类。所有先证者均在出生后数月或数年内出现肾上腺功能不全,常需住院并终身接受糖皮质激素和盐皮质激素替代治疗。分子分析揭示了NR0B1致病变异的异质性谱,包括移码变异、无义变异和错义变异,以及大片段和小片段缺失,这些变异合计占近半数病例。临床随访证实,除肾上腺功能不全外,受累个体在青春期常出现低促性腺激素性性腺功能减退症,成年期记录到不育。新变异的发现有助于扩展NR0B1的突变谱,并进一步证实X-hypoAC中基因型-表型的变异性。本研究是巴西最大的X-hypoAC系列之一。本研究结果拓宽了NR0B1变异的分子图谱,并强调了早期遗传检测在将X-hypoAC与先天性肾上腺增生相鉴别、优化长期临床管理以及为受累家庭提供准确遗传咨询方面的重要意义。

Abstract

To characterize the molecular spectrum of NR0B1 variants associated with X-linked congenital adrenal hypoplasia (X-hypoAC) in a multicenter Brazilian cohort and to highlight the clinical implications of early molecular diagnosis. The authors investigated 12 unrelated families referred to pediatric endocrinology centers across Brazil with a clinical diagnosis of early-onset adrenal insufficiency. Clinical data, biochemical profiles, and follow-up information were collected. Genetic testing of the NR0B1 gene was performed by Sanger sequencing to detect single-nucleotide and small insertion/deletion variants, complemented by MLPA to identify large deletions or rearrangements. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. All probands presented with adrenal insufficiency within the first months or years of life, often requiring hospitalization and lifelong glucocorticoid and mineralocorticoid replacement. Molecular analysis revealed a heterogeneous spectrum of NR0B1 pathogenic variants, including frameshift, nonsense, and missense variants, as well as large and small deletions, which together accounted for nearly half of the cases. Clinical follow-up confirmed that, in addition to adrenal insufficiency, affected individuals frequently developed hypogonadotropic hypogonadism during puberty, with infertility documented in adulthood. The identification of novel variants contributes to expanding the mutational spectrum of NR0B1and reinforces the genotype-phenotype variability in X-hypoAC. This study represents one of the largest Brazilian series of X-hypoAC. The present findings broaden the molecular landscape of NR0B1 variants and underscore the relevance of early genetic testing to differentiate X-hypoAC from congenital adrenal hyperplasia, optimize long-term clinical management, and provide accurate genetic counseling for affected families.

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