Serur Yaffa, McGhee Chloe Alexa, Avital Noam, Russo Odeya, Raman Mira Michelle, Green Tamar
Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University, School of Medicine, 1520 Page Mill Road, Palo Alto, CA 94304, United States.
Cereb Cortex. 2025 Aug 1;35(8). doi: 10.1093/cercor/bhaf217.
Noonan syndrome is the most common RASopathy and is associated with high rates of neurodevelopmental disorders. Prior neuroimaging studies in children with Noonan syndrome have identified structural effects on subcortical regions, though most focus on volumetric differences, overlooking finer morphological changes. These studies also tend to examine common genetic variants, excluding rarer forms within the Noonan syndrome spectrum. Shape analysis offers a sensitive approach to detecting subtle alterations, and when applied across variants, may reveal distinct neuroanatomical signatures. We acquired anatomical magnetic resonance imaging scans from 104 children with Noonan syndrome spectrum (ages 5 to 17, mean = 10.0) and 80 age- and sex-matched typically developing children (ages 4 to 16, mean = 9.54). Our comprehensive analysis examined local thickness and surface dilation/contraction (Jacobian), including genetic variant-specific analyses. Noonan syndrome spectrum showed widespread subcortical alterations beyond volume reduction, including thinning and surface contraction in the putamen, pallidum, thalamus, and caudate, and expansion in the accumbens. Distinct regional effects were found for PTPN11, SOS1, and other Noonan syndrome spectrum-associated variants. These findings confirm subcortical volume reductions in several regions and highlight complex, region-specific shape alterations. Importantly, neuroanatomical patterns varied across genetic variants, suggesting distinct mechanisms of brain development. Understanding these variant-specific structural profiles may provide insights into genotype-based approaches and inform future precision medicine strategies.
努南综合征是最常见的RAS病，与高发性神经发育障碍相关。先前针对努南综合征患儿的神经影像学研究已确定了对皮质下区域的结构影响，不过大多数研究聚焦于体积差异，而忽略了更细微的形态变化。这些研究还倾向于检测常见的基因变异，排除了努南综合征谱系内较罕见的类型。形状分析提供了一种检测细微改变的灵敏方法，当应用于各种变异类型时，可能会揭示出不同的神经解剖学特征。我们对104名患有努南综合征谱系的儿童儿童解剖磁共振成像扫描（年龄5至17岁，平均年龄 = 10.0岁）以及80名年龄和性别匹配的发育正常儿童（年龄4至16岁，平均年龄 = 9.54岁）进行了扫描。我们的综合分析检查了局部厚度和表面扩张/收缩（雅可比行列式），包括特定基因变异分析。努南综合征谱系显示出广泛的皮质下改变，不仅仅是体积减小，还包括壳核、苍白球、丘脑和尾状核的变薄和表面收缩，以及伏隔核的扩张。发现PTPN11、SOS1和其他与努南综合征谱系相关的变异具有不同的区域效应。这些发现证实了几个区域的皮质下体积减小，并突出了复杂的、区域特异性的形状改变。重要的是，神经解剖学模式因基因变异而异，表明大脑发育的机制不同。了解这些特定变异的结构特征可能有助于深入了解基于基因型的方法，并为未来的精准医学策略提供参考。
