Dandy-Walker Malformation

Etiology

Historically, Dandy-Walker malformation was believed to be caused by atresia of the foramina of Luschka and Magendie, leading to enlargement of the fourth ventricle and vermian hypoplasia. However, recent evidence suggests that Dandy-Walker malformation results from developmental abnormalities of the rhombencephalic roof, leading to variable degrees of vermian hypoplasia and cystic enlargement. This complex malformation may be initiated by 2 different pathophysiological mechanisms: the arrest of vermian development and the failure of the fourth ventricle foramina fenestration, leading to an enlarged Blake pouch and causing compression of the vermis.[11] Alterations in the rhombic lip proliferation have been shown to result in disproportionate hypoplasia of the inferior vermis.[12]

Dandy-Walker malformation may be isolated or associated with chromosomal abnormalities, Mendelian disorders, syndromic malformations, congenital infections, and various other comorbidities.[11] Central nervous system (CNS) disorders associated with Dandy-Walker malformation include cortical malformations, holoprosencephaly, dysgenesis of the corpus callosum, and neural tube defects.[3]

Rare mutations have been described in some genes including FOXC1 (in locus 6p25.3), ZIC1, and ZIC4 (in locus 3q24), FGF17, LAMC1, and NID1.[6]

Epidemiology

Dandy-Walker malformation and related variants have a reported prevalence of 1 in 25,000 to 35,000 live births in the United States. These malformations account for approximately 1% to 4% of cases of hydrocephalus.[1][3] A female predominance has been reported, with a female-to-male ratio of approximately 3:1.[13][14]

Pathophysiology

The majority of cases are sporadic. However, some may result from chromosomal aneuploidy, Mendelian disorders, and environmental exposures, including congenital rubella and fetal alcohol exposure. This condition underscores the intricate interplay between genetic and environmental factors in brain development.[9]

Several conditions have been reported to be associated with Dandy-Walker malformation.

• Mendelian disorders
• Walker-Warburg syndrome
• Coffin-Siris syndrome
• Fraser syndrome
• Joubert-Boltshauser syndrome
• Meckel-Gruber syndrome
• Aicardi syndrome
• Neurofibromatosis type [15]

• Chromosomal aberrations [16]
• Duplication syndromes, including those involving 5q, 8p, 8q, and 17q
• Trisomies 9, 13, and 18
• Triploidy
• Deletion at 6(p24–p25)
• 9ph+ heteromorphism [16]

• Environmental agents
• Prenatal exposure to rubella, cytomegalovirus, toxoplasmosis, coumadin, and alcohol
• Maternal diabetes

• Sporadic syndromes
• Klippel-Feil syndrome
• Goldenhar syndrome
• Cornelia de Lange syndrome

Concept of the Midline as a Developmental Field (Opitz and Gilbert)

An insult to this field can result in pleiotropic sequelae on midline structures, including the CNS, heart, palate, midface, vertebrae, genitalia, and sacrococcygeal region. Dandy-Walker malformation should be considered a complex developmental disturbance of the midline of marked genetic and etiological heterogeneity.

Embryology

The cerebellar vermis develops from top to bottom at 17 to 18 weeks of gestation.[17] Due to vermian developmental arrest or compression of the vermis brought on by a failure of the fourth ventricle foramina fenestration and consequent growth of Blake pouch, the roof of the rhombencephalon does not form correctly.

History and Physical

The clinical presentation is nonspecific, subject to multiple factors, including the severity of hydrocephalus, intracranial hypertension, and associated comorbidities.[1] Most patients present with signs and symptoms of increased intracranial pressure in their first year of life.[6][7][18] Macrocephaly is the most common manifestation, affecting 90% to 100% of patients during their first months of life.[6] The syndromic form of Dandy-Walker malformation may also have malformations of the heart, face, limbs, and gastrointestinal or genitourinary system that can draw initial medical attention.[9] Almost 75% of cases have hydrocephalus by 3 months of age, and eventually, almost 90% of the patients have hydrocephalus. A case series of 42 patients with Dandy-Walker malformation showed hydrocephalus in all patients at the time of diagnosis, vermian hypoplasia in 88%, and cerebellar hypoplasia in 59%.[7]

Evaluation

Ultrasound is typically the first imaging modality used to assess the fetal brain. CNS structures evaluated using this modality should include head size and shape, choroid plexus, thalami, cerebellum, cavum septum pellucidum, lateral ventricles, nuchal fold, cisterna magna, and spine. Imaging may also demonstrate other CNS abnormalities that commonly correlate with Dandy-Walker malformation.

Measurement of the cisterna magna forms part of the ultrasound evaluation of the fetal brain. A case series reported an upper limit of normal of 10 mm and a mean size of 5 ± 3 mm at 15 or more gestational weeks. A prominent cisterna magna during prenatal fetal ultrasound evaluation may raise concern for congenital posterior fossa abnormalities. However, as an isolated finding, a prominent cisterna magna is unlikely to be clinically significant if the patient presents no other abnormalities.[19] In addition to the enlarged cisterna magna, other ultrasound findings include varying degrees of ventriculomegaly.[14]

Radiological Criteria for Diagnosis

The classical radiological triad of Dandy-Walker malformation includes hypoplasia of the vermis, enlargement of the fourth ventricle, and elevation of the torcula.[20]

However, Klein et al modified the classification proposed by Barkovich et al in 2003 to identify the radiological criteria for the diagnosis of Dandy-Walker malformation as follows:

• Large, median posterior fossa cyst widely communicating with the fourth ventricle (see Image. Occipital Meningocele With Dandy-Walker Cyst)
• Absence of the lower portion of the vermis at different degrees (lower three-fourths, lower half, and lower one-fourth)
• Hypoplasia, anterior rotation, and upward displacement of the remnant of the vermis
• Absence or flattening of the angle of the fastigium
• Large bossing of the posterior fossa with an elevation of the torcula
• Anterolateral displacement of normal or hypoplastic cerebellar hemispheres [21]

Like ultrasound, magnetic resonance imaging (MRI) is particularly useful after the 20th week of gestation and may help identify CNS malformations that are not adequately characterized by ultrasound, as well as associated abnormalities.[3][22][23]

Prenatal diagnosis by ultrasound is possible after the 18th week of gestation when the cerebellar vermis has completely developed. Diagnosis may be confirmed by MRI.[22][24] In patients with the Dandy-Walker variant, discrepancies may be observed on prenatal and postnatal imaging due to variations in vermian development.[23] MRI also helps distinguish Dandy-Walker malformation from other posterior fossa lesions (see Image. MRI of a Child's Brain with Dandy-Walker Malformation).[3]

Karyotype and postnatal imaging should be offered to all patients with prenatal imaging findings consistent with Dandy-Walker malformation to confirm the diagnosis and screen for other possible associated abnormalities.[25][23]

Measurement of the brainstem-vermian angle and the brainstem-tentorium angle substantially aids in the differential diagnosis of patients with an enlarged cisterna magna. The brainstem-vermian angle increases with the severity of the condition. Angles less than 18° are normal, whereas angles of 18° to 30° suggest Blake pouch malformation. The brainstem-tentorium angle typically ranges between 21° and 44°. Both angles greater than 45° are strongly suggestive of Dandy-Walker malformation.[26]

In contrast to the historical definition, some authors define the Dandy-Walker malformation phenotype by inferior vermian hypoplasia, enlargement of the tegmentovermian angle, displacement of the tela choroidea or choroid plexus, an obtuse fastigial recess, and an unpaired caudal lobule. They also recommend eliminating posterior fossa size and torcular location from the diagnostic criteria.[27]

Associated CNS abnormalities include occipital encephalocele, polymicrogyria, agenesis, or dysgenesis of the corpus callosum, and heterotopia.

Treatment / Management

Management of Dandy-Walker malformation is primarily focused on addressing its clinical manifestations and associated comorbidities. Most patients present with signs and symptoms from increased intracranial pressure, most commonly related to hydrocephalus. For this reason, therapy generally aims to control intracranial pressure, typically through surgery.[3]

Surgical treatment options may include placement of a ventriculoperitoneal or cystoperitoneal shunt. Selected patients may be candidates for endoscopic procedures, such as endoscopic third ventriculostomy.[28] A retrospective review of patients in the Hydrocephalus Clinical Research Network (HCRN) found no difference in treatment failure between shunting and endoscopic third ventriculostomy.[29](B2)

Differential Diagnosis

The differential diagnosis of Dandy-Walker malformation includes posterior fossa abnormalities that may be associated with hydrocephalus and may present similarly to Dandy-Walker malformation. These abnormalities include retrocerebellar arachnoid cysts, cystic hygromas, Blake pouch cysts, mega cisterna magna, and vermian hypoplasia. Additionally, several syndromes are associated with Dandy-Walker malformation, including Aase-Smith syndrome, cerebro-oculo-muscular syndrome, Coffin-Siris syndrome, Cornelia de Lange syndrome, and Aicardi syndrome.[3][9]

The non-cystic malformations include Joubert syndrome, rhombencephalosynapsis, tectocerebellar dysraphia, and neocerebellar dysgenesis.[5]

• Retrocerebellar arachnoid cysts may be large enough to cause compression of cerebellar hemispheres and the fourth ventricle.[3]
• Blake pouch cyst is a retrocerebellar fluid collection with a medial line communication to the fourth ventricle.[3]
• Mega cisterna magna refers to a fluid collection located posteroinferior to a normally developed cerebellum.[3]

Several comorbidities may also correlate with Dandy-Walker malformation, including syndromic and non-syndromic, CNS and non-CNS anomalies, chromosomal abnormalities, cardiovascular conditions, mental illness, and severe intellectual disability.[9]

Prognosis

The prognosis for patients with Dandy-Walker malformation is highly variable and dependent on several factors, including the severity of the malformation, the timeliness of diagnosis and intervention, and the presence of associated complications. In milder cases, when the cerebellar vermis is less affected and intracranial pressure is minimal, individuals may experience fewer neurological deficits and lead relatively normal lives with appropriate management and support. In contrast, in more severe cases with significant cerebellar and posterior fossa abnormalities, patients are at a higher risk of experiencing developmental delays, intellectual disabilities, motor coordination issues, and hydrocephalus[30].

Without treatment, hydrocephalus has a poor prognosis: approximately 50% of affected children die before 3 years, and only 20% to 23% survive into adulthood. Among those who survive without intervention, most exhibit motor, visual, and auditory deficits.[31] 

The diameter of the fetal lateral ventricle measured by obstetric ultrasound may have substantial prognostic value. As described in a previous study, lateral ventricles measuring 11 to 15 mm are associated with a 21% risk of developmental delay. If the diameter is greater than 15 mm, the risk of developmental delay is above 50%.[32] Most case series present an overall risk for epilepsy of approximately 30%.[31] Functional outcome is subject to several factors, which include other structural brain abnormalities; extra-CNS manifestations; epilepsy; motor, visual, or hearing impairment; and other congenital abnormalities.[33][34]

Some institutions have an estimated mortality rate of 12% to 50%.[1] Treatment of hydrocephalus with shunting substantially improves mortality.[18] Fetal mortality directly correlates with the presence of extra-CNS abnormalities.[25]

Complications

Complications in Dandy-Walker malformation can encompass a broad spectrum of neurological and developmental challenges. One of the primary complications is hydrocephalus. This increased pressure can lead to symptoms such as headaches, vomiting, and cognitive impairments, making timely intervention essential. The most common complications associated with shunting include infection and shunt malfunction.[18] Patients with Dandy-Walker malformation may experience motor and coordination deficits due to cerebellar abnormalities, which can affect their daily functioning and quality of life. Cognitive and intellectual disabilities, speech and language impairments, and behavioral problems are frequently observed, adding to the complexity of managing this condition. Furthermore, the associated structural anomalies may result in additional complications, including the risk of syringomyelia or other spinal cord abnormalities.