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This chapter will summarize abnormal human central nervous system (CNS) formation and will describe the genetic aberrations that cause congenital malformations of the CNS. Without being exhaustive, the proteins believed to be involved in the individual components of CNS development and those involved in pathologic alterations of normal development will be listed.



Encephaloceles (brain substance outside of the skull) and meningoceles (meninges and cerebrospinal fluid [CSF] outside of the skull) vary in location, in the amount of brain involved, and therefore, in the clinical manifestations of the lesions. In most cases, the neural tube is closed, and the gyral pattern of the protruding brain appears normal. In the Western Hemisphere, most encephaloceles are occipital and midline. In the Eastern Hemisphere, anterior encephaloceles (nasal and frontal) surpass posterior lesions. One should avoid nasogastric tube placement in the situation of a nasal mass in a newborn due to the possibility of a nasal encephalocele; it is possible in this situation to place the tube in the brain substance.

Meckel syndrome, a genetic disorder that involves an occipital encephalocele, cerebellar malformations (molar tooth anomaly; see discussion below under Joubert syndrome), microcephaly, renal dysplasia (polycystic kidneys), polydactyly, retinal dystrophy, and other malformations, appears to be caused by pathogenic variants in genes involved in ciliary function. Meckel syndrome is allelic with Joubert syndrome, and the same genetic aberrations are present in both disorders. Most of these disorders are inherited in an autosomal recessive fashion, although can be inherited in an autosomal dominant, or X-linked dominant fashion. The genes involved are part of a ciliary complex that determines cell polarity and are important for the migration of early neurons in the posterior fossa.


Schizencephaly, a cleft in the brain, may extend from the pia to the ventricle and is lined with polymicrogyric gray matter. The defect is termed open-lipped if the cleft walls are separated by CSF and closed-lipped if the walls appose. These clefts may be unilateral or bilateral, and the prognosis appears to be dependent on location, bilateral occurrence, or extent of the lesion. Bilateral schizencephaly is associated with intellectual disability and spastic cerebral palsy; affected patients often are microcephalic. Seizures almost always accompany severe lesions, especially the open-lipped and bilateral schizencephalic clefts.

Septo-Optic Dysplasia

Septo-optic dysplasia (de Morsier syndrome) is a disorder characterized by absence of the septum pellucidum, optic nerve hypoplasia, and hypothalamic dysfunction. This disorder should be considered in any patient who exhibits at least 2 of these, and all such patients should have hypothalamic function screening. Fifty percent of patients with septo-optic dysplasia have schizencephaly. Although this is a rare disorder, genetic syndromes with this phenotype and with some risk of recurrence have been described. For instance, pathogenic ...

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