Saletti Veronica, Viganò Ilaria, Melloni Giulia, Pantaleoni Chiara, Vetrano Ignazio Gaspare, Valentini Laura Grazia
Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via G. Celoria 11, 20133, Milan, Italy.
Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Childs Nerv Syst. 2019 Oct;35(10):1727-1739. doi: 10.1007/s00381-019-04319-5. Epub 2019 Jul 30.
Chiari malformation type I (CMI) is a common pediatric neurologic anomaly that can be associated with a variety of genetic disorders; however, it is not always clear whether the observed associations are real or random. The knowledge of the real associations could provide useful guidance to clinicians. Furthermore, it could be of help to better understand the still unknown genetic etiology of CMI.
With the aim of implementing such insights, we retrospectively reviewed clinical, neuroradiological, and genetic data of patients harboring CMI evaluated at the Child Neurology Unit of our institution between January 2008 and December 2018.
The cohort consists of 205 patients (111 males and 94 females), with a mean age at diagnosis of 6.3 years (range 0-18 years). 188 patients completed an average follow-up period of 5.2 years (range one month-18 years). Mean age at last assessment was 11.4 years (range nine months-23 years). 127 (62%) children have been classified as syndromic due to the presence of neurodevelopmental disorders, phenotypic anomalies, or malformations. Among syndromic CMI children, a molecular diagnosis was identified in 35/127 (27.6%) (20 males and 15 females). The most common diagnoses were syndromic craniosynostosis in 8/35 children (22.9%), among which sevenare FGFR-related and one ERF-related craniosynostosis; disorders of the RAS/MAPK pathway, termed RASopathies or RAS/MAPK syndromes in 9/35 (25.7%); disorders of the PTEN-PI3K/AKT signal transduction cascade, termed PTENopathies in 3/35 children (8.6%); and chromosomal rearrangements in 6/35 patients (17.1%), two of whom with del16p11.2.
We polarized our attention on the defined genetic diagnoses focusing not only on the phenotypic hallmarks but also on the phenotypic overlapping features. In addition, we discussed the pathophysiological mechanisms leading to progressive cerebellar ectopia and the involved molecular pathways. Along with the recent literature evidence, we suppose that interactions between FGFR and RAS/MAPK pathway and between RAS/MAPK and PTEN-PI3K/AKT pathways could explain some phenotypic overlapping features and could have a significant role in the pathogenesis of CMI.
I型Chiari畸形（CMI）是一种常见的儿科神经学异常，可与多种遗传疾病相关；然而，观察到的关联是真实的还是随机的并不总是很清楚。了解真实的关联可为临床医生提供有用的指导。此外，这可能有助于更好地理解CMI仍未知的遗传病因。
为了实现这些见解，我们回顾性地分析了2008年1月至2018年12月在我们机构儿童神经科接受评估的CMI患者的临床、神经放射学和遗传数据。
该队列由205名患者组成（111名男性和94名女性），诊断时的平均年龄为6.3岁（范围0-18岁）。188名患者完成了平均5.2年的随访期（范围1个月-18年）。最后一次评估时的平均年龄为11.4岁（范围9个月-23岁）。127名（62%）儿童因存在神经发育障碍、表型异常或畸形而被归类为综合征型。在综合征型CMI儿童中，35/127（27.6%）（20名男性和15名女性）有分子诊断。最常见的诊断是8/35名儿童（22.9%）的综合征型颅缝早闭，其中7例与FGFR相关，1例与ERF相关的颅缝早闭；RAS/MAPK途径障碍，在9/35（25.7%）中称为RAS病或RAS/MAPK综合征；PTEN-PI3K/AKT信号转导级联障碍，在3/35名儿童（8.6%）中称为PTEN病；6/35名患者（17.1%）存在染色体重排，其中2例有16p11.2缺失。
我们将注意力集中在明确的遗传诊断上，不仅关注表型特征，还关注表型重叠特征。此外，我们讨论了导致进行性小脑异位的病理生理机制以及涉及的分子途径。结合最近的文献证据，我们推测FGFR与RAS/MAPK途径之间以及RAS/MAPK与PTEN-PI3K/AKT途径之间的相互作用可以解释一些表型重叠特征，并且可能在CMI的发病机制中起重要作用。
