Walker–Warburg syndrome from Dandy–Walker syndrome.56 The corpus callosum and septum pellucidum are frequently absent or hypoplastic.255 Aqueductal stenosis and posterior encephalocele are variable findings. The white matter is severely hypomyelinated, with a paucity of oligodendrocytes and axons. Signs of congenital muscular dystrophy include pathological changes, myopathic changes on electromyography, and elevated creatinine kinase levels.255 Because most children survive only a few months, recognition of this condition may preclude surgical treatment of associated ocular malformations such as persistent hyperplastic primary vitreous, Peters anomaly, glaucoma, or retinal detachment.46,729 Approximately 20% of affected patients have mutations in the POMT gene on chromosome 9q34, suggesting that it is genetically heterogenous.77

Muscle–eye–brain disease, described primarily in patients from Finland, presents intermediate ocular and neurologic features between the previous two conditions, with some patients requiring shunting for hydrocephalus and some having callosal dygenesis.775,776 The ocular abnormalities of muscle–eye–brain disease are characterized by coarse trabecular meshwork in the anterior chamber, predisposing to glaucoma and progressive cataracts.691 It is linked to a mutation on chromosome 1p32–34.203

Fukuyama Congenital Muscular Dystrophy is an autosomal recessive condition, affecting patients primarily of Japanese ancestry and associated with mutations at chromosome 9q31–33.872 Serum creatine kinase levels are elevated, and muscle biopsy shows signs of muscular dystrophy. Ocular abnormalities are less severe (myopia, nystagmus, chorioretinal degeneration),394 as are the associated hydrocephalus and callosal abnormalities.47

Gray Matter Heterotopia

Heterotopia are masses of normal neurons in abnormal locations, presumably resulting from an arrest of normal neuronal migration along radial glial fibers. Heterotopia have been associated with a wide array of genetic, vascular, and environmental causes, and they may be subcortical, diffuse, or subependymal in location.51 MR diagnosis of heterotopia is based on the finding of heterotopic gray matter that is isointense, with orthotopic gray matter on all pulse sequences that does not enhance with contrast (Fig. 11.28).51 Children with heterotopic gray matter usually present with seizures.47,51 The degree and type of associated neurodevelopmental deficits are related to size, extent, and location of the heterotopias.

Many cases are familial, and causative mutations have been identified. Cerebral heterotopia are subclassified into subependymal heterotopia, focal subcortical heterotopia, and band heterotopia (double cortex) may reflect different

genetic causes.47,51,813 For example, mutations in the fil- amin-1 gene (FLN1) at chromosome Xq28 are now known to cause subependymal heterotopias,311 and Doublecortin mutations are the most common cause of X-linked subcortical laminar heterotopia.238 Isolated optic nerve hypoplasia is the most common neuro-ophthalmologic association,128 but multisystem disorders such as Aicardi syndrome may also be found.

Classical X-linked bilateral periventricular heterotopia, a specific disorder featuring contiguous heterotopic nodules, mega cisterna magna, cardiovascular malformations, and epilepsy, is a disorder caused by mutations causing loss of function in the human filamin A gene.669

Malformations Secondary to Abnormal Cortical Organization and Late Migration

Polymicrogyria

Polymicrogyria is a malformation of cortical development characterized by an excessive number of small gyri with abnormal lamination (Fig. 11.29).382 It is believed to result from a midcortical ischemic necrosis predominating in layer 5 of the developing cortex.56 Macroscopically, it appears as an irregular cortical surface.530 It has a range of histopathologic appearances that are all characterized by derangement of the normal six-layered lamination of the cortex.47 With the advent of MR imaging, polymicrogyria is now recognized as one of the most common malformations of cortical development­.530 Two main forms of polymicrogyria (unlayered and layered, true, or structured) have been described, but there may be considerable overlap in the same patient.530 Polymicrogyria may occur as an isolated familial condition in the setting of chromosome deletion syndromes,100,162,163,502,690,909 in metabolic disorders,530 with intrauterine ischemia,62 and cytomegalovirus infection (Fig. 1.5).47,50,530 It is a common manifestation of congenital cytomegalovirus infection.62

Polymicrogyria usually presents as an isolated malformation but may at times be accompanied by abnormalities of the corpus callosum, brain stem, and cerebellum.62,162,530 The clinical manifestations depend primarily on the location and extent of cortical involvement,47 with bilateral involvement and involvement of more than one half of a single hemisphere considered poor prognostic indicators.50 Children with focal unilateral polymicrogyria involving the frontal cortex may present with congenital unilateral hemiplegia, while focal occipital polymicrogyria may result in congenital homonymous hemianopia.891 Bilateral cases involving the occipital lobe may cause cortical visual impairment.357 Diffuse polymicrogyria is associated with microcephaly, hypotonia with subsequent appendicular spasticity, seizures (usually infantile spasms), and developmental delay.62

Fig. 11.29  Malformations secondary to abnormal cortical organization and late migration. (a) Polymicrogyria (arrows denote region of anomalous cortical migration); (b) Septo-optic dysplasia with mild holoprosencephaly. Note absence of septum pellucidum with anomalous

interdigitations of cerebral gray and white matter just above dilated lateral ventricles; (c) Agenesis of corpus callosum (arrow denotes position of normal corpus callosum)

A number of bilateral region-specific polymicrogyria syndromes of genetic origin have been documented.50 Most reported unilateral cases have been sporadic, but rare familial cases of unilateral polymicrogyria have also been noted.62,173,676,965 Unilateral polymicrogyria is a common cause of congenital hemiplegia.173,368,607 PAX6 mutations have been associated with absence of the pineal gland and unilateral polymicrogyria.607 The fact that isolated polymicrogyria so rarely accompanies optic nerve hypoplasia may reflect the selective involvement of gray matter that distinguishes it from most other forms of cortical dysgenesis.

Holoprosencephaly

The term holoprosencephaly refers to a failure of differentiation and cleavage of the prosencephalon so that the cerebrum fails to cleave laterally into distinct cerebral hemispheres and transversely into a diencephalon and telencephalon (Fig. 11.29). Severe cases are associated with facial dysmorphism, particularly hypotelorism and midline facial clefts.47 Affected areas of brain show no definable interhemispheric fissure and no falx cerebri. Holoprosencephaly is the only nondestructive condition in which one may see the presence

of the splenium of the corpus callosum and absence of the rostrum, body, and genu.47 The holoprosencephalies represent a continuum of forebrain malformation, with the anterior portions of the brain most severely affected and the posterior portions least severely affected. Although the terms alobar, semilobar, and lobar are often applied to describe the extent of involvement, no clear distinction between these categories exists.47

Holoprosencephaly is caused by both teratogens and genetic factors.748 The most common teratogen is maternal diabetes. Holoprosencephaly may be seen in children with trisomy 13 (Patau syndrome) and trisomy 18 (Edward’s syndrome).47 Mutations in at least five genetic loci have been implicated in the development of familial holoprosencephaly.47,137,748 Mutations of the sonic hedgehog gene (SHH) at the HPE3 locus, which cause an autosomal dominant form of holoprosencephaly, have been studied extensively.75 The gene product, sonic hedgehog, is a protein that is essential for the production of prechordal mesenchyme and induction of the ventral forebrain. Barkovich49 questioned whether some forms of septo-optic dysplasia with a central holoventricle and no hemispheric malformations fall within the mildest end of the spectrum of holoprosencephaly. Occasionally, cases of optic nerve hypoplasia are associated with midfacial malformations or other systemic malformations.693 Mutations in the HESX1 gene (a human homeobox gene whose mouse homologue plays a role in forebrain, midline, and pituitary development) have been demonstrated in patients with septo-optic dysplasia224,869 but are absent in most cases.693

Absence of the Septum Pellucidum

Absence of the septum pellucidum may accompany a variety of cerebral malformations5,60,616; however, its frequent association with optic nerve hypoplasia has given it widespread attention in neuro-ophthalmologic circles (Fig. 11.29). Despite its numerous neuroanatomical connections with subcortical regions,779 congenital absence of the septum pellucidum in humans appears to be of no neurodevelopmental or endocrinological consequence unless concurrent abnormalities of the cerebral hemispheres (e.g., schizencephaly, periventricular leukomalacia) or pituitary infundibulum (i.e., posterior pituitary ectopia) are present.119,941 The ability of MR imaging to detect the presence or absence of these other clinically relevant anomalies now enables the neuro-ophthal- mologist to predict the likelihood that hormone supplementation will be required, or that additional neurodevelopmental deficits will complicate the clinical course in the infant with optic nerve hypoplasia.119

Hypoplasia, Agenesis, or Partial Agenesis of the Corpus Callosum

The corpus callosum is the major white matter tract concerned with interhemispheric transfer and integration of information.61 Dysgenesis of the corpus callosum may occur as part of a midline malformation syndrome (e.g., in association with Dandy–Walker syndrome or transsphenoidal encephalocele). More commonly, however, it results from a wide variety of gestational or perinatal insults to the cerebral hemispheres, which secondarily affect early formation or myelination of the corpus callosum.61 Because the corpus callosum forms in an anterior-to-posterior direction with the rostrum forming last, a partially formed corpus callosum always has a genu and, less commonly, a body, while the splenium and rostrum are frequently absent.58,61 This concept is useful in distinguishing a dysgenetic corpus callosum from secondary callosal destruction that may result in a small or absent genu or body in the presence of a normal splenium or rostrum.58

Although primary agenesis of the corpus callosum has been documented, high-resolution MR imaging has demonstrated that callosal anomalies (Fig. 11.29) almost always occur in the setting of additional CNS anomalies, such as migration anomalies (schizencephaly, lissencephaly, cortical heterotopia), transsphenoidal encephalocele, holoprosencephaly, or the Dandy–Walker malformation.61 In the child with optic nerve hypoplasia, thinning of the corpus callosum is commonly seen, but complete callosal agenesis is rare.119 In this context, thinning of the corpus callosum is predictive of neurodevelopmental problems only by virtue of its frequent association with cerebral hemispheric abnormalities. The finding of callosal anomalies on MR imaging therefore necessitates a careful search for cerebral hemispheric abnormalities, which appear to be the most direct neuroimaging correlate of neurodevelopmental impairment.128 The complete callosal agenesis in Aicardi syndrome and in some of the coloboma syndromes may also reflect the severity of the associated CNS anomalies.163 An association between PAX6 mutations and callosal agenesis is now recognized.1 Agenesis of the corpus callosum can be associated with cataracts and microcephaly in the MICRO syndrome,177a and with albinism, immunodeficiency, and cardiomyopathy in the Vici syndrome.925a There seems to be a strong associate between copy number variation on chromosome 8p and agenesis of the corpus callosum, particularly for duplication at 8p.295a,421a

Focal Cortical Dysplasia

Focal cortical dysplasia describes a focal disruption in the architectural lamination of the cerebral cortex, with or without