October 7, 2021
Evidence of disrupted rhombic lip development in the pathogenesis of Dandy–Walker malformation
Haldipur P, Bernardo S, Aldinger KA, Sivakumar T, Millman J, Sjoboen AH, Dang D, Dubocanin D, Deng M, Timms AE, Davis BD, Plummer JT, Mankad K, Oztekin O, Manganaro L, Guimiot F, Adle‑Biassette H, Russo R, Siebert JR, Kidron D. Petrilli G, Roux N, Razavi F, Glass IA, Gioia CD, Silvestri E, Millen KJ
In this multi-institutional collaborative study, Haldipur et al. shine light on the pathogenesis of Dandy-Walker malformation (DWM) and cerebellar vermis hypoplasia (CVH). The authors studied a cohort of 54 pathological specimens: 26 DWM, 5 CVH, and 23 age-matched controls. All cases with DWM and CVH had a standard autopsy, and all 54 cases had a brain MRI.
The authors focused on the rhombic lip, a transient highly proliferative stem cell zone that drives the growth of the posterior cerebellar vermis during fetal life. The rhombic lip is an elongated tail-like structure along the ventral inferior cerebellum that undergoes internalization at about 14 weeks of gestation. With internalization of the rhombic lip, the fastigium of the cerebellar vermis reaches a normal acute angle.
Study highlights include:
- Aberrations in rhombic lip development are likely responsible for posterior vermis hypoplasia in DWM
- A blunted and obtuse fastigial angle was seen in all cases of DWM, indicating a disruption of rhombic lip internalization
- Cases of CVH demonstrate an acute fastigial point, suggesting a developmental disruption after 14 weeks, when normal internalization of the rhombic lip occurs
- There is significant reduction in the rhombic lip progenitor pool in cases of DWM
The study also reaffirmed previously described morphological abnormalities of DWM: upward rotation of the hypoplastic cerebellar vermis with an enlarged tegmental-vermian angle; disproportionate hypoplasia of the cerebellar posterior lobules; and presence of the “tail sign”. To that end, the tail sign was observed in 75% of all DWM in this cohort. The pathological analysis of the “tail sign” demonstrates a partially formed unpaired cerebellar lobule associated with an absent versus hypercellular rhombic lip.
This constellation of morphological and molecular findings suggests an early insult, prior to 14 weeks, to the cerebellar rhombic lip as a key mechanism to the pathogenesis of DWM.
Carolina V. Guimaraes, MD
Lucile Packard Children’s Hospital Stanford