Chiari I malformation in defined genetic syndromes in children: are there common pathways?

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.