Walker-Warburg syndrome is a congenital disorder of the central nervous system involving fatal neurological lesions. Multiple malformations of the brain, eyes, and muscle tissue distinguish WWS from similar malformation syndromes. It is also known by the acronym HARD +/- E syndrome (hydroencephalus, agyri, retinal dysplasia , plus or minus "e" for encephalocele ).
Affected individuals typically show a combination of severe brain, eye, and muscle defects. Multiple malformations of the brain include type II lissencephaly ,a condition in which the brain lacks normal convolutions and is unusually smooth without folds. Eighty-four percent of the infants with WWS have macrocephaly (an enlarged head). In half of these cases, the macrocephaly is apparent at birth, and in a quarter of the cases it develops postnatally. Hydrocephalus , or excessive accumulation of cerebrospinal fluid around the brain, occurs in 95% of infants with WWS. This fluid fills abnormally large ventricles or spaces in the brain. Fifty percent of affected infants have an encephalocele, or gap in the skull that does not seal. The meninges or membranes that cover the brain may protrude through this gap. The formation of an encephalocele may be associated with the failure of the neural tube to close during development of the fetus. A malformed cerebellum characterizes the syndrome as well as distinct muscle abnormalities, including congenital muscular dystrophy .
Ocular defects occur in 100% of infants with WWS. The most common are abnormally small eyes and retinal abnormalities, which arise from the improper development of the light sensitive area at the back of the eye. Cataracts may also be present and more than three quarters of the infants born with WWS have a defect in the anterior chamber of the eye. WWS syndrome leads to severely retarded mental development and is often lethal in infancy.
WWS is inherited in an autosomal recessive pattern. Offspring of parents who have had one affected infant have a 25% chance of having WWS. The locations of the causitive genes remains unknown.
WWS is extremely rare. Cases described in the literature cite siblings with WWS born to consanguineous (closely related) parents as well as cases in families not known to be at risk.
Signs and symptoms
Clinical signs include a malformed head, small eyes, cataracts, retinal abnormalities, and muscle weakness. An encephalocele may be present as well. Microscopic examination reveals that the cells and tissues of the brain develop in a highly disorganized fashion. Seizures may occur.
Prenatal ultrasound can reveal some of the brain anomalies associated with WWS, most commonly hydrocephalus and encephalocele. Lissencephaly can not be diagnosed prenatally as normal fetal brains appear smooth. After birth, diagnosis is made on the basis of physical features and ultrasound exams. MRI may be used to confirm the smooth brain feature or type II lissencephaly typical of WWS. Genetic analysis helps distinguish WWS from Fukuyama-type congenital muscular dystrophy (FCMD), which has numerous similar features. WWS can be differentiated from other syndromes that display hydrocephalus or encephalocele by the presence of eye abnormalities including retinal defects, cataracts and anterior chamber defects. Genetic testing for Fukuyama-type congenital muscular dystrophy distinguished this from WWS.
Treatment and management
The severe malformations of the brain defy treatment and many infants with WWS die within the first year of life. Supportive care is required to provide comfort and nursing needs. Seizures may be controlled with medication. Shunting may be required to control the hydrocephalus. A shunt or short plastic tube can be placed to divert the excess cerebral spinal fluid to another area of the body where it can ultimately be absorbed by the body.
Genetic counseling is recommended for families at risk.
Patients have a very limited life expectancy and the syndrome is generally considered lethal. Most patients die before the age of two.
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