Section of Child and Adolescent Neuropsychiatry, Department of Public Health and Pediatric Sciences, Università Degli Studi Di Torino, Regina Margherita Hospital, Piazza Polonia 94, 10126, Turin, Italy.
Section of Child and Adolescent Neuropsychiatry, Department of Neurosciences, Università Degli Studi Di Torino, Turin, Italy.
Eur J Pediatr. 2022 Aug;181(8):2919-2926. doi: 10.1007/s00431-022-04497-6. Epub 2022 May 16.
Noonan syndrome (NS) and related disorders encompass a phenotypically heterogeneous group of conditions due to mutations in the Ras/Mitogen-activated protein kinase pathway. The main objective of this study was to assess the presence and characteristics of epilepsy in children and adolescents affected by NS and related disorders. The study included all the patients aged 5-21 years who had been diagnosed with NS or of one of three Noonan-like syndromes (i.e., cardio-facio-cutaneous syndrome, Noonan syndrome with multiple lentigines, and Noonan-like syndrome with loose anagen hair) at a university pediatric hospital. Clinical, EEGs, brain MRIs, and genotype data were extracted from the medical records, and follow-up telephone interviews were conducted to obtain updated information about epilepsy and its course. Out of a total of 75 patients (38 [50.7%] males, median age at assessment 12.0 years [q1 9.0-q3 17.0]; 61 [81.3%] with NS; and 14 [18.7%] with a Noonan-like syndrome), 13 (17.3%) had epilepsy, with median age at onset of 4.0 years (q1 2.0-q3 8.0, min 0.1-max 17.0). Epilepsy was more common among Noonan-like patients (50.0%) than in NS (9.8%, p < 0.001), and its presence was associated with neurodevelopmental delay (p < 0.001, OR 14.6 95% CI 3.6-59.4), cognitive impairment (p = 0.002, OR 11.2 95% CI 2.5-51.0), need for educational support (p < 0.001, OR 21.8, 95% CI 2.6-179.1), and lower adaptive functioning (median [q1-q3]: 54.0 [q1 40.0-q3 77.5] vs 97.0 [q1 76.5-q3 107.0] of the non-epileptic subgroup, p = 0.004). In 10 out of 13 cases (76.9%), the epilepsy outcome was good (i.e., seizure-free for more than 12 months with or without anti-seizure medication).
Epilepsy was more common in NS than reported in the general population, with a significantly higher rate in Noonan-like syndromes. Epilepsy was associated with neurodevelopmental delay, cognitive impairment, and lower adaptive functioning.
• Neurological abnormalities have been reported in NS and related disorders. • There is evidence of a phenotype-genotype relationship for neurological abnormalities.
• Epilepsy was found to be more common in NS and related disorders than typically reported in the general population and associated with neurodevelopmental delay, cognitive, and functional impairment. • The Noonan-like phenotype had a higher frequency of epilepsy than typical NS.
努南综合征（Noonan syndrome，NS）及相关疾病是一组表型异质性疾病，其病因与 Ras/丝裂原活化蛋白激酶通路中的突变有关。本研究的主要目的是评估儿童和青少年 NS 及相关疾病患者癫痫的发生情况和特征。
该研究纳入了在一所大学儿科医院诊断为 NS 或三种努南样综合征（即心面四肢综合征、多发性黑子 NS 及具有疏松型生长期毛发的努南样综合征）的 5-21 岁患者。从病历中提取临床、脑电图、脑 MRI 和基因分型数据，并通过电话随访获取有关癫痫及其病程的最新信息。
在 75 例患者中（38 例[50.7%]为男性，评估时的中位年龄为 12.0 岁[四分位距（quartile range，QR）9.0-17.0]；61 例[81.3%]为 NS；14 例[18.7%]为努南样综合征），13 例（17.3%）患有癫痫，发病中位年龄为 4.0 岁（QR 2.0-8.0，最小值 0.1-最大值 17.0）。与 NS（9.8%，p<0.001）相比，努南样综合征患者癫痫更为常见（50.0%），且癫痫的存在与神经发育迟缓（p<0.001，OR 14.6，95%置信区间 3.6-59.4）、认知障碍（p=0.002，OR 11.2，95%置信区间 2.5-51.0）、需要教育支持（p<0.001，OR 21.8，95%置信区间 2.6-179.1）和适应性功能降低（中位数[QR]：54.0[40.0-77.5]比非癫痫组的 97.0[76.5-107.0]，p=0.004）相关。在 13 例患者中，有 10 例（76.9%）癫痫结局良好（即抗癫痫药物治疗或未治疗时，无癫痫发作超过 12 个月）。
NS 患者癫痫比一般人群中更为常见，努南样综合征患者癫痫发生率更高。癫痫与神经发育迟缓、认知障碍和适应性功能降低有关。
