Dandy–Walker malformation (DWM), also known as Dandy–Walker syndrome (DWS), is a rare congenital brain malformation in which the part joining the two hemispheres of the cerebellum (the cerebellar vermis) does not fully form, and the fourth ventricle and space behind the cerebellum (the posterior fossa) are enlarged with cerebrospinal fluid. Most of those affected develop hydrocephalus within the first year of life, which can present as increasing head size, vomiting, excessive sleepiness, irritability, downward deviation of the eyes and seizures. Other, less common symptoms are generally associated with comorbid genetic conditions and can include congenital heart defects, eye abnormalities, intellectual disability, congenital tumours, other brain defects such as agenesis of the corpus callosum, skeletal abnormalities, an occipital encephalocele or underdeveloped genitalia or kidneys. It is sometimes discovered in adolescents or adults due to mental health problems.
DWM is usually caused by a ciliopathic or chromosomal genetic condition, though the causative condition is only identified in around half of those diagnosed before birth and a third of those diagnosed after birth. The mechanism involves impaired cell migration and division affecting the long period of development of the cerebellar vermis. The mechanism by which hydrocephalus occurs in DWM is not yet fully understood. The condition is diagnosed by MRI or, less commonly, prenatal ultrasound. There are other malformations that can strongly resemble DWM, and disagreement exists around the criteria and classifications used for the malformation.
Treatment for most involves the implantation of a cerebral shunt in infancy. This is usually inserted in the posterior fossa, but a shunt in the lateral ventricles may be used instead or in conjunction. Endoscopic third ventriculostomy (ETV) is a less invasive option for patients older than 1 year. Posterior fossa shunts are most effective (80% of the time) but carry the highest risk of complications, while ETV is least effective but has the least risk of complications. The mortality rate is roughly 15%, mostly due to complications from hydrocephalus or its treatment, which can include subdural haematomas or infection. The prognosis after successful hydrocephalus treatment is usually good but depends on any associated condition and its symptoms. Those without hydrocephalus are treated based on any associated symptoms or condition.
The prevalence of DWM is estimated at between 1 in 25,000 to 1 in 50,000. DWM is the cause of around 4.3% of cases of congenital hydrocephalus and 2.5% of all cases of hydrocephalus. At least 21% of those with DWM have a sibling with the malformation, and at least 16% have a parent with the malformation. The malformation was first described by English surgeon John Bland-Sutton in 1887, though it was named by German psychiatrist in 1954 after American neurosurgeons Walter Dandy and Arthur Earl Walker, who described it in 1914 and 1942, respectively.
Signs and symptoms
Hydrocephalus The most frequent and prominent symptoms of DWM are those associated with hydrocephalus in the postnatal period. Hydrocephalus occurs in an estimated 80% of patients with classic DWM. This usually presents within the first year of life (85% of the time), most often within the first three months. Signs of hydrocephalus in infants include increasing head size, vomiting, excessive sleepiness, irritability, downward deviation of the eyes (known as "sunsetting eyes") and seizures. In contrast to classic DWM, only around 30% of those with Dandy–Walker variant (DWV), in which the posterior fossa is not enlarged, have hydrocephalus.
Neurological Despite the hypoplastic cerebellar vermis, just over half of individuals with DWM (between 27% and 84%) do not appear to have significant intellectual disability or developmental delay. However, many of the genetic conditions associated with DWM can present with developmental delay and other brain anomalies. Agenesis of the corpus callosum has been found in between 5% and 17% of those with DWM. This does not seem to result in intellectual disability on its own, however. Other brain abnormalities known to be sometimes associated with DWM include grey matter heterotopia, pachygyria (fewer ridges in the brain), lissencephaly (shallower ridges), polymicrogyria, holoprosencephaly and schizencephaly. Individuals with these features tend to have developmental delay or seizures. Those without any other central nervous system abnormalities tend to have normal or close-to-normal intellectual development. A 2003 review found that moderate-to-severe intellectual disability and non-DWM brain abnormalities were only present in those with the most severe cerebellar vermis malformations (less than two fissures/three lobules in the vermis), and these comprised 16% of their sample. Hydrocephalus also affected all of these patients.
In Dandy–Walker variant (DWV) and mega cisterna magna specifically, which are less severe malformations, there appears to be an increased rate of psychotic spectrum disorders such as schizophrenia, bipolar disorder, mania or catatonia.
Associated anomalies A 2017 review found the following associations in patients with DWS (usually from an associated genetic condition or abnormality): 27% of patients had a congenital heart defect. These included patent ductus arteriosus, coarctation of the aorta, ventricular septal defect and atrial septal defect. In 2.7% of patients, heart failure was reported. 24% of patients had at least one ocular abnormality. These included cataracts, small eyes (microphthalmia), chorioretinal dysplasia/atrophy, optic nerve dysplasia/atrophy, a small cornea (microcornea) or corneal opacity (leukoma), short-sightedness (myopia) and coloboma (a hole in an eye structure). 16% of patients were diagnosed with a mental or behavioural disorder, with 6.4% also having a learning disability. 5.3% had either bipolar disorder or a psychotic spectrum disorder, and 2.1% had ADHD. Slightly more of these were found in Dandy–Walker variant (DWV) than in classic DWM, despite DWV being less common, at only around 20% of DWS diagnoses. Around 12% of patients had cancers or tumours arising from congenital genetic abnormalities. The most common were neurocutaneous melanosis (5.9%), hemangiomas (4.8%, including those with PHACE syndrome) and Wilms' tumour (4.4%). 3.2% of patients had congenital melanocytic nevi, and 2.1% had tongue hamartoma. The melanocytic tumours in these cases are thought to relate to the same genetic errors in the development of the embryonic neural tube that lead to the DWM, since the subsequent embryonic neural crest gives rise to melanocytes, among other cells. 10% of patients had endocrine or metabolic disorders, and 2.7% had excessive hair growth (hypertrichosis). 9% of patients (almost all with classic DWM) had musculoskeletal abnormalities, which included scoliosis or kyphoscoliosis and arthrogryposis. 5.9% of patients had underdeveloped reproductive organs, such as hypoplastic genitalia or undescended testicles (cryptorchidism). 5.3% of patients had underdeveloped or polycystic kidneys.
Occipital encephalocele may occur in DWM. This has generally been found at rates of 6–8%. It has been suggested to occur to compensate for the increased pressure in the posterior fossa during foetal life.
Syringomyelia occasionally occurs with DWM, though it is not certain how often. One review reported an occurrence of 4.3% in a sample. This may be due to herniation of the bottom of the cyst through the foramen magnum (a similar mechanism to Chiari malformation). Alternatively, it may be a result of hydrocephalus, in which it forms as a "fifth ventricle" due to an enlarged central canal.
Rarely, spina bifida has been found with DWM. When it is present, it is usually spina bifida occulta.
Cause
DWM is caused by any disruption to embryonic development that affects the formation of the cerebellar vermis. This is usually a genetic mutation that results in impaired cell migration and division. A large number of genetic conditions can result in the anomaly. In a large portion of DWM cases, the condition is identified in the person affected, however in most cases the cause is not identified. At least 21% of those with DWM have a sibling with the malformation, and at least 16% have a parent with the malformation.
Ciliopathic genetic conditions
A genetic condition is identified in around 33% of those diagnosed with DWM after birth. In a 2017 review, 4.3% were found to have PHACE syndrome, a condition involving brain, cardiovascular and eye abnormalities, while 2.3% had Joubert syndrome, a condition involving neurological and sometimes eye and kidney abnormalities. Anywhere from 21% to 81% of those with PHACE syndrome have DWM. Other comorbid genetic conditions that were found included oculocerebrocutaneous syndrome, oral-facial-digital syndrome, Coffin–Siris syndrome, Meckel–Gruber syndrome type 7 and Kallmann syndrome, among many others. DWM has also been associated with 3C syndrome, Rubinstein–Taybi syndrome, Marden–Walker syndrome, Sheldon–Hall syndrome, Shah–Waardenburg syndrome, Fryns syndrome, Walker–Warburg syndrome, Fukuyama congenital muscular dystrophy, Ellis–Van Creveld syndrome, Fraser syndrome, Aicardi syndrome, Cornelia de Lange syndrome, Klippel–Feil syndrome and acrocallosal syndrome, among others. Craniosynostosis-Dandy-Walker malformation-hydrocephalus syndrome has also been described in a handful of cases. Many of these disorders are classified as ciliopathies, genetic disorders that affect the cellular primary cilia, thin cell projections made from microtubules that are believed to be crucial in signalling embryonic cell division and migration. DWM is one of the single largest predictors of a ciliopathic genetic disease.
Other genes that have been linked to DWM include ZIC1, ZIC4, FOXC1, FGF17, LAMC1 and NID1.
Chromosomal abnormalities In those who are diagnosed with DWM before birth on ultrasound, up to half are found to have a chromosomal abnormality, with the most common being Edwards syndrome (trisomy 18), at roughly 26% of prenatal DWM cases. 6.5% of those diagnosed with DWM after birth also have Edwards syndrome. Other chromosomal abnormalities that can lead to DWM include triploidy, Patau syndrome (trisomy 13), trisomy 9 and partial 3q deletion or duplication. The 3q24 region contains the ZIC1 and ZIC4 genes, known to be associated with DWM.
External toxins Warfarin use during pregnancy has been known to lead to systemic defects in the fetus, including ocular dysgenesis, microcephaly, agenesis of the corpus callosum, skeletal abnormalities and heart defects. In 1985, it was also linked to DWM.
Pathophysiology
The cerebellum begins forming at the fifth week of embryonic development. It differentiates at the top of the metencephalon, while the pons (in the brainstem) differentiates at the bottom, separated by the fourth ventricle. The cerebellar hemispheres form from the rhombic lips on the forward surface of the fourth ventricle, which expand and roll over to fuse in the midline to form the cerebellar vermis by the 15th week. If this process does not complete, the cerebellar vermis will not form fully. This long period of development of the cerebellar vermis makes it particularly vulnerable to disruptions.
In DWM, the fourth ventricle opens up into and is continuous with almost the entire posterior fossa subarachnoid space.
Pathophysiology of hydrocephalus