Division of Genetics, Department of Pediatrics, Oishei Children's Hospital, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, New York, USA.
Am J Med Genet A. 2022 Jan;188(1):364-368. doi: 10.1002/ajmg.a.62523. Epub 2021 Oct 14.
Noonan syndrome (NS) is the most common disease among RASopathies, characterized by short stature, distinctive facial features, congenital cardiac defects, and variable developmental delay. NS rarely presents with overt neurologic manifestations, in particular hydrocephalus. Recent evidence suggests that pathogenic variants in the gene RRAS2 are a rare cause of NS. Specifically, an RRAS2 pathogenic variant, p.Q72L, may be particularly severe, manifesting with lethal neurologic findings. Here, we report a NS patient with documented p.Q72L variant in RRAS2. The patient was identified in utero to have hydrocephalus and a Dandy Walker malformation. Postnatal examination revealed multiple dysmorphic features, some reminiscent of NS including low-set posteriorly rotated ears, redundant nuchal skin, widely spaced nipples, and cryptorchidism. Despite suspicion of NS, results of a 14-gene Noonan syndrome panel (Invitae) were negative. Follow-up rapid whole exome sequencing revealed a de novo p.Q72L variant in RRAS2, a poorly studied gene recently identified as a cause of NS. The patient herein reported brings to three the total number of cases reported with the RRAS2 p.Q72L pathogenic variant. All three documented patients presented with a particularly fulminant course of NS, which included hydrocephalus. RRAS2, specifically p.Q72L, should be considered in severe NS cases with neurologic manifestations.
努南综合征（Noonan syndrome，NS）是 RAS opathy 中最常见的疾病，其特征为身材矮小、特征性面部特征、先天性心脏缺陷和不同程度的发育迟缓。NS 很少表现出明显的神经表现，特别是脑积水。最近的证据表明，RRAS2 基因中的致病性变异是 NS 的罕见原因。具体来说，RRAS2 致病性变异 p.Q72L 可能特别严重，表现出致命的神经表现。在这里，我们报告了一例 NS 患者，其 RRAS2 基因中存在明确的 p.Q72L 变异。该患者在宫内被诊断为脑积水和 Dandy Walker 畸形。产后检查显示存在多种发育异常，其中一些与 NS 相似，包括低位后旋耳、多余的颈后皮肤、乳头间距宽和隐睾。尽管怀疑是 NS，但 14 基因 Noonan 综合征检测组（Invitae）的结果为阴性。后续快速全外显子组测序显示 RRAS2 中存在一个新发的 p.Q72L 变异，这是一个最近被确定为 NS 原因的研究较少的基因。本报告中的患者使携带 RRAS2 p.Q72L 致病性变异的病例总数达到 3 例。所有 3 例有记录的患者均表现出特别严重的 NS 病程，包括脑积水。RRAS2，特别是 p.Q72L，应在具有神经表现的严重 NS 病例中考虑。
