The etiology of renal artery stenosis (RAS) and abdominal aortic coarctation (AAC) causing the midaortic syndrome (MAS), often resulting in renovascular hypertension (RVH), remains ill-defined. Neurofibromatosis type 1 (NF-1) is frequently observed in children with RVH. Consecutive pediatric patients (N = 102) presenting with RVH secondary to RAS with and without concurrent AAC were prospectively enrolled in a clinical data base, and blood, saliva and operative tissue, when available, were collected. Among the 102 children, 13 were having a concurrent clinical diagnosis of NF-1 (12.5%). Whole exome sequencing was performed for germline variant detection, and RNA-Seq analysis of NF1, MAPK pathway genes and MCP1 levels were undertaken in five NF-1 stenotic renal arteries, as well as control renal and mesenteric arteries from children with no known vasculopathy or NF-1. In 11 unrelated children with sequencing data, 11 NF1 genetic variants were identified, of which 10 had not been reported in gnomAD. Histologic analysis of NF-1 RAS specimens consistently revealed intimal thickening, disruption of the internal elastic lamina and medial thinning. Analysis of transcript expression in arterial lesions documented an approximately 5-fold reduction in NF1 expression, confirming heterozygosity, MAPK pathway activation and increased MCP1 expression. In summary, NF-1-related RVH in children is rare but often severe and progressive and, as such, important to recognize. It is associated with histologic and molecular features consistent with an aggressive adverse vascular remodeling process. Further research is necessary to define the mechanisms underlying these findings.

中文翻译：

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1型神经纤维瘤病肾动脉狭窄腹主动脉缩窄所致小儿肾血管性高血压的分子遗传学评价

肾动脉狭窄 (RAS) 和腹主动脉缩窄 (AAC) 导致主动脉中部综合征 (MAS)，通常导致肾血管性高血压 (RVH)，其病因仍然不明确。在患有 RVH 的儿童中经常观察到 1 型神经纤维瘤病 (NF-1)。连续的儿科患者 (N = 102) 出现继发于 RAS 的 RVH 伴或不伴并发 AAC 被前瞻性纳入临床数据库，并收集血液、唾液和手术组织（如果有）。在 102 名儿童中，13 名同时临床诊断为 NF-1（12.5%）。进行全外显子组测序以检测种系变异，并在五个 NF-1 狭窄肾动脉中进行 NF1、MAPK 通路基因和 MCP1 水平的 RNA-Seq 分析，以及控制来自没有已知血管病变或 NF-1 的儿童的肾动脉和肠系膜动脉。在有测序数据的 11 名无关儿童中，鉴定出 11 种 NF1 基因变异，其中 10 种未在 gnomAD 中报道。NF-1 RAS 标本的组织学分析一致显示内膜增厚、内部弹性层破坏和内侧变薄。动脉病变中转录物表达的分析记录了 NF1 表达减少约 5 倍，证实了杂合性、MAPK 通路激活和 MCP1 表达增加。总之，儿童 NF-1 相关 RVH 很少见，但通常是严重的和进行性的，因此识别很重要。它与与侵袭性不利血管重塑过程一致的组织学和分子特征有关。