Evidence of disrupted rhombic lip development in the pathogenesis of Dandy–Walker malformation

Parthiv Haldipur*, Silvia Bernardo, Kimberly A. Aldinger, Tarika Sivakumar, Jake Millman, Alexandria H. Sjoboen, Derek Dang, Danilo Dubocanin, Mei Deng, Andrew E. Timms, Brian D. Davis, Jasmine T. Plummer, Kshitij Mankad, Ozgur Oztekin, Lucia Manganaro, Fabien Guimiot, Homa Adle-Biassette, Rosa Russo, Joseph R. Siebert, Debora KidronGiulia Petrilli, Nathalie Roux, Ferechte Razavi, Ian A. Glass, Cira Di Gioia, Evelina Silvestri, Kathleen J. Millen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Dandy–Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses. This was supplemented by laser capture microdissection and RNA-sequencing of the cerebellar rhombic lip, a transient progenitor zone, to assess the altered transcriptome of DWM vs control samples. Our radiological findings confirm that the cases studied fall within the accepted biometric range of DWM. Our histopathological analysis points to reduced foliation and inferior vermian hypoplasia as common features in all examined DWM cases. We also find that the rhombic lip, a dorsal stem cell zone that drives the growth and maintenance of the posterior vermis is specifically disrupted in DWM, with reduced proliferation and self-renewal of the progenitor pool, and altered vasculature, all confirmed by transcriptomics analysis. We propose a unified model for the developmental pathogenesis of DWM. We hypothesize that rhombic lip development is disrupted through either aberrant vascularization and/or direct insult which causes reduced proliferation and failed expansion of the rhombic lip progenitor pool leading to disproportionate hypoplasia and dysplasia of the inferior vermis. Timing of insult to the developing rhombic lip (before or after 14 PCW) dictates the extent of hypoplasia and distinguishes DWM from CVH.

Original languageEnglish
Pages (from-to)761-776
Number of pages16
JournalActa Neuropathologica
Issue number4
StatePublished - Oct 2021


  • Cerebellar vermis hypoplasia
  • Cerebellum
  • Dandy–Walker malformation
  • Development
  • Rhombic lip


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