Dandy-Walker malformation and Wisconsin syndrome: novel cases add further insight into the genotype-phenotype correlations of 3q23q25 deletions

Abstract

Background: The Dandy-Walker malformation (DWM) is one of the commonest congenital cerebellar defects, and can be associated with multiple congenital anomalies and chromosomal syndromes. The occurrence of overlapping 3q deletions including the ZIC1 and ZIC4 genes in few patients, along with data from mouse models, have implicated both genes in the pathogenesis of DWM.

Methods and results: Using a SNP-array approach, we recently identified three novel patients carrying heterozygous 3q deletions encompassing ZIC1 and ZIC4. Magnetic resonance imaging showed that only two had a typical DWM, while the third did not present any defect of the DWM spectrum. SNP-array analysis in further eleven children diagnosed with DWM failed to identify deletions of ZIC1-ZIC4. The clinical phenotype of the three 3q deleted patients included multiple congenital anomalies and peculiar facial appearance, related to the localization and extension of each deletion. In particular, phenotypes resulted from the variable combination of three recognizable patterns: DWM (with incomplete penetrance); blepharophimosis, ptosis, and epicanthus inversus syndrome; and Wisconsin syndrome (WS), recently mapped to 3q.

Conclusions: Our data indicate that the 3q deletion is a rare defect associated with DWM, and suggest that the hemizygosity of ZIC1-ZIC4 genes is neither necessary nor sufficient per se to cause this condition. Furthermore, based on a detailed comparison of clinical features and molecular data from 3q deleted patients, we propose clinical diagnostic criteria and refine the critical region for WS.

Figure 1

Faces and toe dysmorphisms from patients CCM067 and CCM095. Note the distinct coarse face with unusually shaped eyebrows (arched or upsweeping, full or thick, with synophrys), wide and prominent nasal tip, full and everted lower lip, and the digital anomalies with recessed 4th toes.

Figure 2

Brain MRIs. Brain imaging of patients CCM067, CCM095 (with Dandy-Walker malformation) and CCM001 (with normal cerebellum and posterior fossa). A: sagittal midline T1-weighted images. B: axial T2-weighted images.

Figure 3

Schematic representation of overlapping 3q deletions in DWM and WS patients. Extension of 3q deletions in the present three and 21 previously published subjects (only patients with molecular characterization have been included). Vertical grey and blue areas represent the proposed critical regions for DWM and WS, respectively. Horizontal bars are grouped by color according to the presence/absence of either condition, as specified in the columns on the left. Red and purple shaded bars represent patients with unknown status for WS or DWM, respectively. Vertical black lines indicate the position of FOXL2 gene (causative of BPES), and ZIC1-ZIC4 genes, as indicated. *previously described by Sudha et al. [26]; **previously described by Ko et al. [23].