Dandy-Walker Syndrome

Description

Dandy-Walker malformation is defined by hypoplasia and upward rotation of the cerebellar vermis and cystic dilation of the fourth ventricle. Affected individuals often have motor deficits such as delayed motor development, hypotonia, and ataxia; about half have mental retardation and some have hydrocephalus. DWM is a heterogeneous disorder. The low empiric recurrence risk of approximately 1 to 2% for nonsyndromic DWM suggests that mendelian inheritance is unlikely (summary by Murray et al., 1985).

The primary defect was thought to be atresia of the foramina of Luschka and Magendie by Dandy and Blackfan (1914) and Taggart and Walker (1942). Benda (1954) introduced the designation Dandy-Walker syndrome. Furthermore he reported familial occurrence. He considered it a developmental anomaly not necessarily due to foraminal atresia since some cases had patent foramina. Patients present early in life with hydrocephalus associated with bulging occiput. Posterior fossa signs such as cranial nerve palsies, nystagmus and truncal ataxia are common. Radiologically, patients show elevated imprint of the transverse sinuses with thinning and bulging of the bones of the posterior fossa. The definition of the syndrome used by Hart et al. (1972) was 3-fold: (1) hydrocephalus, (2) partial or complete absence of the cerebellar vermis, and (3) posterior fossa cyst contiguous with the fourth ventricle. D'Agostino et al. (1963) found the condition in sibs who also had polycystic kidneys.

Christian et al. (1980) reported the unusual case of an infant with both Ellis-van Creveld (EVC; 225500) and Dandy-Walker syndromes and with homozygosity for an unusually long heterochromatic segment of the long arm of chromosome 9 (9qh+). The 18-year-old mother was mentally retarded, the product of a first-cousin mating, and less than 4 feet tall. Although thelarche and menarche occurred on schedule, she developed no pubic or axillary hair. The authors suggested that she may have a previously unknown recessive disorder. The mating that resulted in the offspring with EVC and DW syndromes was presumably incestuous. Her father and 2 of her brothers, like the 18-year-old mother, had the 9qh+.

Murray et al. (1985) emphasized etiologic heterogeneity. Recurrence risk is low (on the order of 1 to 5%) when DWM is not associated with a mendelian disorder such as Warburg (see 236670) or Meckel (249000) syndrome. There appears to be an increased frequency of an association with congenital heart disease, cleft lip/palate and neural tube defects. Among the children of healthy, consanguineous parents, Stoll et al. (1990) observed brother and sister with hypoplasia of the cerebellar hemispheres and partial agenesis of the cerebellar vermis with normal communication between the fourth ventricle and arachnoid spaces, i.e., the manifestations of the Dandy-Walker variant malformation. Agenesis of the corpus callosum was also present. The clinical manifestations were dominated by spastic paraplegia from an early age and skull anomalies: bulging forehead, prominent occiput, large fontanels, and wide cranial sutures.

Barkovich et al. (1989) suggested that there is a continuum of posterior fossa developmental anomalies involving the cerebellum that might be called the Dandy-Walker complex (DWC). The DWC constitutes complete or partial agenesis of the vermis, cystic dilatation of the fourth ventricle with upper displacement of the lateral venous sinuses and tentorium. Cerebellar malformation appears to be the fundamental fault. Chitayat et al. (1994) gave an extensive tabulation of single gene disorders, chromosomal aberrations, teratogen-induced conditions and forms that are sporadic or of undetermined inheritance associated with DWM. They reported 2 brothers with an apparently new constellation or manifestations, including DWC, migrational brain disorder, macrocephaly, and facial abnormalities. The first brother presented at birth and his clinical features at the age of 9 years were discussed. The second brother was detected prenatally when fetal ultrasound demonstrated the presence of DWC. Fetal brain histopathology showed DWC associated with brainstem dysgenesis. Either autosomal or X-linked recessive inheritance of this combination might represent a 'new' disorder.

Lin et al. (2006) reported the familial occurrence of isolated Dandy-Walker variant in 2 consecutive male fetuses. At 26 years of age, the mother had delivered a 24-gestational-week male fetus with an isolated Dandy-Walker variant confirmed by postmortem examination. One year later, she had a normal baby girl. Her third pregnancy, at age 31, was terminated at 19 weeks; autopsy confirmed the isolated Dandy-Walker malformation that had been seen on ultrasound in the male fetus.

Grinberg et al. (2004) identified 7 individuals with de novo interstitial deletions of 3q. Magnetic resonance imaging (MRI) of computed tomography scans showed that they all had isolated DWM, with hypoplasia and upward rotation of the cerebellar vermis and a posterior fossa cyst. Typical of DWM, the cerebellar hemispheres were less affected than the vermis. Three of these individuals also had hydrocephalus. All 7 had substantial cognitive deficits. Three had large deletions that included 3q22.2 and had facial changes of the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES; 110100), presumably due to codeletion of the gene FOXL2 (605597). Grinberg et al. (2004) mapped the sizes and locations of the 7 deletions by extensive fluorescence in situ hybridization analysis on metaphase chromosomes and identified a 7-Mb critical region for DWM, defined by BACs at 3q24 and 3q25.1. Two good candidate genes, ZIC1 (600470) and ZIC4 (608948), are located 250 kb centromeric to the 1.9-Mb critical region. Both ZIC1 and ZIC4 were hemizygous in 7 of 8 individuals with deletions of 3q, and expression of both genes was altered by the adjacent deletion of the eighth individual, as determined by semiquantitative RT-PCR analysis of lymphoblast mRNA.

Based on the finding that some individuals with Dandy-Walker malformation have interstitial deletions of 3q2 encompassing the ZIC1 and ZIC4 genes, Grinberg et al. (2004) investigated the contributions of these genes in a mouse model. They found that mouse Zic4 is expressed in the dorsal central nervous system, including the developing cerebellum and spinal cord, in a pattern that overlaps with expression of Zic1. Grinberg et al. (2004) generated a targeted deletion in mouse embryonic stem cells, encompassing the first exons of Zic1 and Zic4, which are closely linked on mouse chromosome 9. Heterozygous loss of Zic1 and Zic4 were sufficient to cause DWM-like cerebellar vermis hypoplasia in mice.