Serur Yaffa, Fuhrman Naomi, Russo Odeya, Green Tamar
Stanford University.
Res Sq. 2024 Dec 19:rs.3.rs-5428038. doi: 10.21203/rs.3.rs-5428038/v1.
Rasopathies, including Noonan Syndrome (NS) and Neurofibromatosis type 1 (NF1), are developmental disorders caused by germline mutations in genes of the RAS/mitogen-activated protein kinase pathway (RAS-MAPK). This study investigates irritability, a highly prevalent transdiagnostic construct, in children with Rasopathies and the impact of Rasopathy status on the associations between irritability, emotional dysregulation-related disorders, and social skills impairments. The sample comprise 174 children aged 4-17 (age mean = 9.49; 98 females), including 113 children with Rasopathies (NS n = 85, NF1 n = 28) and 61 age-sex-matched typically developed (TD) children. We used parent questionnaires (CBCL, SRS) to assess irritability, symptoms of ADHD, defiance, anxiety/depression, and social skills impairments while controlling for cognitive measures (IQ). Children with Rasopathies exhibited higher irritability than TD children (mean difference = 1.09; p < 0.001). Children with NS showed a weaker association between irritability and ADHD symptoms compared to TD children ( = .032, η = .03) and a stronger association between irritability and social skills impairments compared to both TD ( = .033, η = .03), and NF1 groups ( = .009, η = .06). We present novel and clinically significant findings showing high irritability in children with Rasopathies. Our study provides syndrome-specific results, suggesting differences in the mechanisms involved in irritability, ADHD, and social processes in children with NS and NF1. In essence, children with Rasopathies showed a highly irritable profile associated with ADHD symptoms and social skills impairments, with a significantly stronger association between irritability and social processes in NS. Our results suggest that developing prevention and treatments targeting irritability can distinctly affect the trajectories of neurodevelopmental disorders in children with Rasopathies.
RAS 病，包括努南综合征（NS）和 1 型神经纤维瘤病（NF1），是由 RAS/丝裂原活化蛋白激酶通路（RAS-MAPK）基因的种系突变引起的发育障碍。本研究调查了 RAS 病患儿中易怒这一高度普遍的跨诊断概念，以及 RAS 病状态对易怒、情绪调节相关障碍和社交技能缺陷之间关联的影响。样本包括 174 名 4 - 17 岁的儿童（平均年龄 = 9.49；98 名女性），其中 113 名患有 RAS 病（NS 组 n = 85，NF1 组 n = 28），61 名年龄和性别匹配的发育正常（TD）儿童。我们使用家长问卷（CBCL、SRS）评估易怒、注意力缺陷多动障碍（ADHD）症状、违抗行为、焦虑/抑郁以及社交技能缺陷，同时控制认知测量指标（智商）。患有 RAS 病的儿童比 TD 儿童表现出更高的易怒程度（平均差异 = 1.09；p < 0.001）。与 TD 儿童相比，NS 患儿中易怒与 ADHD 症状之间的关联较弱（r = 0.032，η² = 0.03），与 TD 组（r = 0.033，η² = 0.03）和 NF1 组（r = 0.009，η² = 0.06）相比，易怒与社交技能缺陷之间的关联更强。我们展示了新的且具有临床意义的发现，即 RAS 病患儿存在高度易怒的情况。我们的研究提供了综合征特异性的结果，表明 NS 和 NF1 患儿在易怒、ADHD 和社交过程所涉及的机制上存在差异。本质上，患有 RAS 病的儿童表现出与 ADHD 症状和社交技能缺陷相关的高度易怒特征，且在 NS 中易怒与社交过程之间的关联明显更强。我们的结果表明，针对易怒制定预防和治疗措施可以显著影响 RAS 病患儿神经发育障碍的发展轨迹。
