Part 2: Abnormal Development of the Nervous System

INTRODUCTION

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.

NEURAL TUBE CLOSURE AND PATTERNING DEFECTS

Encephalocele

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

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 variants in HESX1 have caused a dominantly inherited disorder in siblings. This disorder can be suspected in utero, but magnetic resonance imaging (MRI) of the fetus may be necessary to assure a proper diagnosis. The prognosis for development is highly variable, with learning, intellectual, and motor impairments often described. Asymptomatic patients probably only come to medical attention if there are needs for neuroimaging. Pathogenic variants in COL11A2 and PAX6 have also been described. Since most of the genes related to this phenotype are undiscovered and no genetic panels exist, it is recommended that clinicians consider exome sequencing to delineate the recurrence risk in a family.

VENTRAL INDUCTION AND TELENCEPHALIC DIVISION

Normal Prosencephalon Division

The cerebral cortices are formed by medial division of a rostral, single, tube-like structure, the prosencephalon, and the 2 vesicles, or telencephalon, formed in this division become the 2 cerebral hemispheres. The ventral and anterior portions of this division are induced by midline facial structures and the notochord via soluble factors. Abnormalities of this induction and division lead to midline abnormalities of the brain such as holoprosencephaly. These disruptions of normal development occur before 42 days of gestation.

Sonic hedgehog, which was described first in Drosophila as a soluble factor (protein) that influences dorsoventral patterning of the developing embryo, is probably the most important of the soluble factors influencing ventral induction. It is expressed in the notochord as well as in the ventral forebrain and floor plate—future facial structures—and interacts through a well-defined signaling pathway that includes PTCH, a human homolog of patched. It then alters the expression of transcriptional factors (homeobox and other related gene products).

Other molecules of interest in this inductive process are the retinoids, which are lipids capable of crossing membranes and have been shown to exist in gradients across embryos. Retinoic acid can alter the pattern of transcriptional factors in neuroepithelial cells, and it can also downregulate sonic hedgehog, perhaps explaining some of the midfacial defects and holoprosencephaly seen in retinoid embryopathy. In addition, cholesterol and cholesterol-derived lipids serve as a cofactor for sonic hedgehog, thus perhaps explaining the occurrence of holoprosencephaly in Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency).

Holoprosencephaly

The holoprosencephaly syndromes are heterogeneous disorders of ventral induction and telencephalic cleavage that result from a failure of the prosencephalic vesicle to medially cleave normally. At least 3 forms of this disorder have been described: alobar, semilobar, and lobar. In the alobar form, the telencephalic vesicle completely fails to divide, producing a single horseshoe-shaped ventricle, sometimes with a dorsal cyst, fused thalami, and a malformed cortex. In the semilobar form, the interhemispheric fissure is present posteriorly, but the frontal and, sometimes, parietal lobes continue across the midline. In the lobar form, only minor changes may be seen: The anterior falx is absent, the frontal lobes and horns are hypoplastic, there is partial fusion of the thalamus, and the genu of the corpus callosum may be abnormal.

Holoprosencephaly is the most common human malformation leading to miscarriage (Fig. 541-1). Holoprosencephaly is associated with a spectrum of midline facial defects. These include cyclopia, in which there is a single central eye and a supraorbital proboscis; ethmocephaly, in which the nose is replaced by a proboscis located above hypoteloric eyes; cebocephaly, in which hypotelorism and a nose with a single nostril are seen; and premaxillary agenesis, with hypotelorism, a flat nose, a single frontal incisor, and a midline cleft lip.

Only children who have the semilobar and lobar forms of holoprosencephaly are known to survive for more than a few months. An infant affected with the severe form is microcephalic (unless aqueduct stenosis and hydrocephalus are present), hypotonic, and visually inattentive. In infants with the less severe forms of holoprosencephaly, myoclonic seizures frequently develop and, if the infant survives, autonomic dysfunction, failure to thrive, psychomotor retardation, and atonic or spastic cerebral palsy often are present. Some infants with the lobar form may be only mildly affected. Pituitary defects may be associated with these malformations and may result in neuroendocrine dysfunction.

Holoprosencephaly has been reported to be associated with maternal diabetes, retinoic acid exposure, cytomegalovirus, and rubella. Chromosomal abnormalities associated with this disorder include trisomies 13 and 18; duplications in 3p, 13q, and 18q; and deletions in 2p, 7q, 13q, and 18q. Autosomal dominant forms exist in which the pathogenic variant is in the sonic hedgehog gene on chromosome 7. In this form, the clinical features vary. In its mildest form, presence of a single central incisor, attention deficit disorder, or a choroid fissure coloboma may be the only clinical manifestation of autosomal dominant risk of holoprosencephaly in a family.

NEURONAL AND GLIAL PROLIFERATION

Megalencephaly and Hemimegalencephaly

The terms megalencephaly and hemimegalencephaly refer to disorders in which the brain volume is greater than normal (not due to the abnormal storage of material); usually, the enlarged brain is accompanied by macrocephaly, or a large head. Although considered by some to be a migration disorder, the increase in brain size in these disorders appears to be attributable to errors in neuroepithelial proliferation, as the microscopic appearance of the brain is that of an increase in number of cells (both neurons and glia) and in cell size.

Typically, patients are noted to have large heads at birth and may manifest accelerated head growth in the first few months of life. Children with megalencephaly or hemimegalencephaly may come to medical attention when presenting with seizures, a developmental disorder (intellectual disability), hemihypertrophy, or a hemiparesis (opposite the affected hemisphere). Seizures vary both in onset and in type and usually are the most problematic symptom, sometimes necessitating hemispherectomy.

Approximately 50% of patients with linear sebaceous nevus syndrome have hemimegalencephaly associated with HRAS or KRAS somatic-mosaic pathogenic mutations. Many patients with hypomelanosis of Ito also have hemimegalencephaly. The neuropathologic and clinical pictures in these conditions appear to be identical to the isolated hemimegalencephalies. Interestingly, the genetic aberrations suggest an upregulation of the mammalian target of rapamycin (mTOR) pathway via a disturbance of phosphoinositide 3-kinase (PI3K).

NEURONAL MIGRATION DISORDERS

Near the end of the proliferative phase of normal neurodevelopment, billions of postmitotic neurons are poised along the ventricles to begin the migration to the cortical surface and to form the cerebral cortex. Many clinical entities are associated with neuronal migration disorders. In some, abnormalities are limited to the nervous system, but in others, malformations involving other organs also are present. The responsible genetic mechanism has been identified in some of these disorders, and new genetic mechanisms are being identified regularly.

Modern neuroimaging techniques, particularly MRI, have allowed the recognition of major migration disorders. Some of these disorders are associated with typical clinical features that might alert the clinician to the presence of such abnormalities even before imaging is obtained. In other disorders, the clinical features are so varied that a strong correlation between imaging and clinical presentation does not exist.

Lissencephaly

Although the term lissencephaly (smooth brain) refers to the external appearance of the cerebral cortex in those disorders in which a neuronal migration aberration leads to improper number of neurons at the surface of the cortex (Fig. 541-2), the most important observation in such cases is the thickened cortex with neurons in what should be white matter. In such deficits of migration, the gyri and sulci do not form properly because the cortical-cortical attractive forces that result from strong associations are decreased, owing to improper axon pathways (ie, the targets for synapses are malpositioned). It is important to note that the term lissencephaly is applied to cortical disorders in which there is a thickened cortex (migration deficit) and a cortical surface abnormality; rarely there is a completely smooth brain. At least 2 types of lissencephaly have been identified: type I, or classic, lissencephaly and type II, or cobblestone, lissencephaly. This classification is based on both the external appearance of the brain and the underlying histology.

Type I (Classic) Lissencephaly

Type I lissencephaly most often accompanies the Miller-Dieker syndrome. Radial migration of neurons appears to have taken place. Hallmarks on imaging are a lack of opercularization (covering of the sylvian fissure), large ventricles with colpocephaly (fetal-like configuration of the occipital horns), and agyria or pachygyria (Fig. 541-2). The corpus callosum is almost never absent, and the posterior fossa usually has a normal appearance on neuroimaging. Head size typically is in the low-normal range at birth, but most patients develop microcephaly owing to a decreased rate of brain growth over the first year of life. Nearly all patients with this disorder develop seizures within this first year, and more than 80% of them have infantile spasms. This seizure frequency is far greater than that seen in other neuronal migration disorders. Patients with this disorder typically develop seizures within this first year, and more than 80% of them have infantile spasms. This seizure frequency is far greater than that seen in other neuronal migration disorders.

In the Miller-Dieker syndrome, facial dysmorphism, cardiac abnormalities (40%), sacral abnormalities (70%), deep palmar creases, and, in male patients, genital abnormalities (70%) may be seen. The sacral abnormalities include deep sacral dimples, sacral pits, and sacral tracks. Facial abnormalities include upturned nares, a short nose, a thin “pouty” upper lip, a long philtrum, micrognathia, and bitemporal hollowing. Although the bitemporal hollowing may be the result of the underlying brain abnormality, the other facial features are difficult to explain on the basis of the brain abnormality alone. Therefore, these abnormalities are believed to result from deficits of genes near the lissencephaly gene on the 17th chromosome. Larger deletions of the distal short arm of chromosome 17 appear to result in the full Miller-Dieker phenotype, whereas microdeletions of just the lissencephaly gene LIS1 result in isolated lissencephaly. Therefore, a deletion in the lissencephaly gene appears to be sufficient for the brain abnormalities, but other genes (14-3-3) must be deleted for the full phenotypic manifestations of the Miller-Dieker syndrome to be seen.

Miller-Dieker lissencephaly is one of the migration disorders of the brain in which the responsible genetic defect has been identified. By both molecular and cytogenetic techniques, deletions in the terminal portion of 1 arm of chromosome 17 can be found in approximately 90% of Miller-Dieker lissencephaly cases. These patients typically have dysmorphic features and other congenital anomalies (see earlier discussion). The deletions of the terminal part of chromosome 17 in these cases have included microdeletions, ring 17 chromosome, pericentric inversions, and a partial monosomy of 17p13.3, the result of an inherited unbalanced translocation from a parent with a balanced translocation involving this region of chromosome 17. Multiple mechanisms of inheritance similar to this have been described for this disorder. In families that are affected in this manner, screening with amniocentesis can be performed in subsequent pregnancies because parents are at a greatly increased risk of having another child with Miller-Dieker lissencephaly.

Current chromosomal microarray testing will detect deletions of LIS1 and of the neighboring 14-3-3 gene, thus genetically distinguishing Miller-Dieker syndrome from isolated lissencephaly. Some patients with isolated lissencephaly (no facial, skeletal, or cardiac abnormalities) also have deletions (often submicroscopical) of the terminal portion of the short arm of chromosome 17.

The brain malformations in LIS1 deficiencies are usually worse posteriorly as compared with X-linked lissencephaly, which is worse anteriorly, as discussed below. However, in Miller-Dieker syndrome, the malformation may be equally severe anteriorly and posteriorly, thus making a distinction phenotypically difficult. This lesion can be detected in utero, but late and beyond the time for termination of a pregnancy. The life expectancy is dependent on the severity of the neurologic impairment.

X-linked lissencephaly appears nearly identical to the LIS1 deletion form of this disorder: Patients have classic lissencephaly, and their neurologic presentation is the same. However, the malformation is usually worse anteriorly, and the skeletal and other anomalies seen in the Miller-Dieker syndrome are not noted. In addition, X-linked lissencephaly occurs mostly in boys. Girls who are heterozygous for the same gene variants have band heterotopia. Women with band heterotopia have been noted to give birth to boys with lissencephaly.

The X-linked lissencephaly–band heterotopia syndrome has been linked to Xq22.3. In females, the less severe phenotype probably is attributable to random X inactivation, such that in a variable percentage of cells, normal gene expression is seen and, in the remaining cells, the mutated gene for X-linked lissencephaly, Doublecortin, is expressed. This is a microtubule-associated protein that appears to stabilize the cytoskeletal structure. It appears that this is a cell-autonomous disorder; in other words, the cell expressing the abnormal X chromosome manifests aberrant migration or disturbed substrate on which cells can migrate.

The band heterotopia or double-cortex syndrome is a unique form of a neuronal migration defect that almost exclusively occurs in girls and is allelic with X-linked lissencephaly in boys. Patients with band heterotopia typically present with seizures and a developmental disorder. The seizure type is variable, and the onset of epilepsy usually is between 2 months and 11 years of age. Patients may present with infantile spasms, or even though the migration abnormality is diffuse, some patients may present with focal seizures. Control of the epilepsy varies, with some patients being controlled with monotherapy and others being entirely refractory to all agents.

Most patients with the X-linked band heterotopia syndrome (double-cortex) have impaired intellectual development that ranges from severe retardation to low-normal IQ. Generally, individuals with this syndrome are less impaired than are patients with other diffuse neuronal migration defects such as lissencephaly. Patients in whom seizures are of later onset generally have less developmental impairment. Neurologic findings include mild dysarthria and mild bilateral pyramidal syndromes.

Type I lissencephaly may also be caused by mutations in tubulin genes.

Type II (Cobblestone) Lissencephaly

In type II lissencephaly, the brain may have a smooth appearance or may exhibit polymicrogyria and pachygyria. The underlying cortical histology is that of a bizarre arrangement of neurons. In addition, cells seem to penetrate the surface of the developing brain and may spill into the subarachnoid space as if part of a volcanic eruption. This deposition of neurons in the subarachnoid space imparts a cobblestone street–like appearance to the brain surface; thus, the term cobblestone lissencephaly has been used to describe the cortex in these disorders. The Walker-Warburg, muscle-eye-brain, and Fukuyama muscular dystrophy syndromes are genetically distinct. Abnormalities that may or may not be seen in these disorders include muscular dystrophy, ocular anterior chamber abnormalities, retinal dysplasias (abnormal electroretinogram and visual evoked responses), hydrocephalus (usually of an obstructive type, requiring shunting), and encephaloceles. The Walker-Warburg syndrome or muscle-eye-brain disorder might be diagnosed even if the ocular examination and muscle biopsies are normal. On MRI, an abnormal white matter signal, hypoplastic brain stem and cerebellum, and thickened falx suggest the Walker-Warburg diagnosis. Neuroimaging of the muscle-eye-brain disorders might reveal focal white matter abnormalities. This disorder and other cobblestone lissencephalies have been diagnosed in utero.

In the cobblestone lissencephaly spectrum, despite having widespread cortical abnormalities, only one-third of patients develop seizures. The typical clinical presentation is that of a child with marked hypotonia, macrocephaly (obstructive hydrocephalus), and eye abnormalities. Depending on the degree of brain and muscle involvement, this disorder may be fatal, and long-term survival is rare. Syndromes accompanying type II lissencephaly include the Walker-Warburg syndrome, HARD-1-E (hydrocephalus, agyria, retinal dysplasia, with or without eye [anterior chamber] abnormalities) syndrome, muscle-eye-brain disease, and Fukuyama muscular dystrophy. These are all the result of recessive inheritance of pathogenic variants in extracellular matrix proteins or in the cell receptors for the extracellular matrix.

Fukuyama muscular dystrophy is distinguished from the Walker-Warburg–like syndromes by the severity of the muscular dystrophy, by the cortical malformation that includes polymicrogyria, and by Japanese inheritance. This disorder is seen more often in Japan than in the Western Hemisphere, probably because it is the result of a founder pathogenic variant (a viral transposone insertion) in a gene termed FUKUTIN.

Zellweger Syndrome

Zellweger syndrome is an autosomal recessive, peroxisomal disorder characterized by neuronal migration abnormalities, hepatomegaly, renal cysts, and stippled calcification of the patella. The neuronal migration defects include pachygyria and polymicrogyria, with underlying abnormalities best characterized as a nonlayered appearance of the cortex. Migration abnormalities are also noted in the cerebellum and in the brain stem in this disorder. Children with Zellweger syndrome present in the neonatal period with severe hypotonia, characteristic facies, hepatomegaly, and seizures. More than 12 PEX genes have been implicated in Zellweger or Zellweger-like disorders; all are inherited in an autosomal recessive pattern. Zellweger syndrome results from the body’s inability to make peroxisomes owing to a deficiency of 1 of the 12 proteins encoded by the PEX genes. A number of peroxisomal enzymes are abnormal and lead to the accumulation of very-long-chain fatty acids. Therefore, testing for this disorder includes an assay of very-long-chain fatty acids.

Polymicrogyria

Polymicrogyria (many small gyri) is a disorder often considered to be a neuronal migration disorder; it is important to recognize that this malformation may result in both genetic and destructive processes. The microscopic appearance of the lesion is that of too many small abnormal gyri. The gyri may be shallow and separated by shallow sulci, which may be associated with an apparent increased cortical thickness on neuroimaging. The multiple small convolutions may not have intervening sulci, or the sulci may be bridged by fusion of overlying molecular layer, which may give a smooth appearance to the brain’s surface; alternatively, the brain may appear to have pachygyria.

Based on examination of fetuses in which the occurrence of the insult causing the malformation has been accurately timed, this pattern is believed to occur as a result of insults late in the first or early in the second trimester. Others believe that this is a postmigration insult resulting from distorted migration of cells through an injured area. Identical twin pregnancies discordant for polymicrogyria have been described, with the theory being that global insults can lead to polymicrogyria (such as twin-twin transfusion and steal syndromes). The common association of congenital cytomegalovirus infection with polymicrogyria supports the hypothesis that a destructive process can be involved in these disorders. Zika virus appears to similarly affect the brain.

Polymicrogyria has also been associated with genetic and chromosomal disorders. It is found in disorders of peroxisomal metabolism such as Zellweger syndrome (see discussion above) and neonatal adrenal leukodystrophy. It has also been associated with the Bloch-Sulzberger syndrome, Meckel-Gruber syndrome, thanatophoric dysplasia, and Fukuyama congenital muscular dystrophy. Familial bilateral frontal polymicrogyria and bilateral perisylvian polymicrogyria have been reported. Therefore, if no identifiable cause of the polymicrogyric malformation is found, the recurrence risk may be that of an autosomal recessive disorder (25%) or an X-linked disorder in boys. A bilateral parasagittal parieto-occipital polymicrogyria has also been described. Multiple chromosomal deletions and duplications, including X-linked potential inheritance, have been described. Multiple recessively inherited disorders have also been identified, including GPR56 and WDR62 pathogenic variants in families with recurrences of polymicrogyria with variable phenotypes.

The clinical picture varies depending on the location, extent, and etiology of the abnormality. Microcephaly with severe developmental delay and hypertonia may result when polymicrogyria is diffuse. When polymicrogyria is unilateral, focal deficits might be seen. Epilepsy often is present, characterized by partial-complex seizures or partial seizures that secondarily generalize. The age at presentation and severity of seizures depend on the extent of the associated pathology. The lesions are most clearly recognized by MRI and are best noted on sagittal views. They often are recognized by the rough appearance of the surface of the cortex on a thin-cut T₂-weighted image. If MRI cuts are thick, these lesions may be confused with pachygyria. Because the genetic implications of pachygyria and polymicrogyria differ considerably, distinguishing between these 2 conditions is important.

When bilateral, striking clinical features include a pseudobulbar palsy with abnormal tongue movements, dysarthria, dysphasia, mental retardation, absent or hyperactive gag reflex, drooling, and pyramidal signs in more than 70% of the reported cases. These patients may be intellectually disabled, and nearly all have severe language disorders. Dysphagia can impair proper nutrition. Seizures are present in most of the affected patients. Several patients have had infantile spasms during the first year of life.

Heterotopias

Heterotopias are collections of normal-appearing neurons in an abnormal location probably secondary to a disturbance in radial migration. The exact mechanism of the migration aberration has not been established. Various hypotheses include damage to the radial glial fibers, premature transformation of radial glial cells into astrocytes, or a deficiency of specific molecules on the surface of neuroblasts or of the radial glial cells (or the receptors for those molecules) that results in disruption of the normal migration process. Heterotopias often occur as isolated defects that may result in only epilepsy. However, when they are multiple, heterotopias might also be associated with a developmental disorder and cerebral palsy (usually spastic). In addition, if other migration defects such as gyral abnormalities are present, the clinical syndrome may be more profound. Usually, no cause is apparent. Occasionally, heterotopias may be found in a variety of syndromes, including neonatal adrenal leukodystrophy, glutaric aciduria type II, GM₂ gangliosidosis, neurocutaneous syndromes, multiple congenital anomaly syndromes, chromosomal abnormalities, and fetal toxic exposures.

Heterotopias may be classified by their location: subpial, within the cerebral white matter, and in the subependymal region. Leptomeningeal heterotopias often contain astrocytes mixed with ectopic neurons and may resemble a gliotic scar. White matter heterotopias may be focal, subcortical, or diffuse.

Subependymal heterotopias often are associated only with epilepsy. Most patients will have normal intelligence and no motor deficits. These heterotopias are located just beneath and abut the ependymal lining of the lateral ventricles. They may be either bilateral or unilateral and are located most often adjacent to the occipital horns and trigones and, less commonly, within the temporal horns and frontal horns. The onset of seizures in patients with subependymal heterotopias is relatively late, often in the second decade, and more often affects women. The seizures may be partial-complex, tonic-clonic, or focal motor. Subependymal heterotopias have been identified as an X-linked dominant syndrome linked to markers in the distal Xq28 locus, and pathogenic variants in FILAMIN A have been found to be causative. FILAMIN A, a cytoskeletal protein, must be important for the initiation of migration since cells are arrested in the ventricular zone. An increased incidence of spontaneous abortions, patent ductus arteriosis, and spontaneous hemorrhage and a much higher than expected incidence of female offspring are noted in affected women, suggesting that inheritance of FILAMIN A pathogenic variants may be lethal for male embryos.

Cortical Dysgenesis

Cortical dysgenesis refers to disorders of cortical formation. In general, many of the disorders just discussed are considered to be within the spectrum of this entity. In this section, an emphasis on those focal macroscopic and microscopic lesions that do not fit into the preceding classifications will be discussed.

The terms cortical dysplasia and cortical dysgenesis often are used synonymously for the same disorders. These terms include the obvious malformations such as smooth gyri and clefts as well as lesions classified as focal cortical dysplasias and microdysgenesis. Focal cortical dysplasia may involve a major part of a lobe and may be characterized by the congregation of large, bizarre neurons and abnormal glial cells in the subadjacent white matter.

Cortical dysgenesis has also been associated with hippocampal sclerosis, leading some to believe that hippocampal sclerosis is a disorder of brain formation. Clearly, migration aberrations need not be manifested by abnormal motor function; rather, epilepsy and intellectual disability might be the only clinical symptoms in these disorders.

The severity of the migration disorder correlates with clinical symptoms. Patients with milder forms of neuronal migration defects (ie, focal cortical dysplasias, heterotopias, microdysgenesis) may appear normal. Most often, migration disorders are diagnosed in patients with epilepsy, as neuroimaging is performed for seizure. These patients generally have partial seizures and normal life expectancies. Some patients with these disorders will have developmental delays, mild intellectual deficits, or spastic or atonic cerebral palsy. Profound defects are associated with more severe symptoms.

Children presenting with intractable epilepsy, significant intellectual disability, and neurologic signs more often have diffuse migration abnormalities on MRI scanning. Therefore, not surprisingly, the degree of abnormality on MRI scans correlates well with the degree of neurologic involvement. The age of onset of seizures varies from early childhood to young adult life. Generally, the severity of the seizures and the severity of the pathology correlate positively. Severe abnormalities are associated with seizures in the first year of life, whereas microdysgenesis may be associated with adult onset of seizures. Later-onset seizures also tend to correlate with subependymal heterotopias.

Although the pathogenic mechanisms involved in focal dysgenesis remain poorly understood, the mechanisms underlying this disease are likely to resemble those involved in global or more extensive migration disorders. Therefore, it is important to define the pathogenic mechanisms causing these disorders. An important insight into the pathogenesis of focal developmental lesions may have come from the observation that the human papillomavirus (HPV) 16 RNA and its oncogenic protein E6 are present in focal cortical dysplasia type IIb resected for epilepsy. This fascinating observation potentially ties HPV with tuberous sclerosis since the E6 protein encoded by HPV exerts its oncogenic effect via depression of TSC2, thereby upregulating mTOR as occurs in tuberous sclerosis. In support of this hypothesis is the fact that cortical dysplasia type IIB also occurs in tuberous sclerosis. Indeed, other viruses could have similar effects upon the developing nervous system and could explain microdysgenesis and other lesions of the nervous system described above.

POSTERIOR FOSSA FORMATION AND MALFORMATION

For the purposes of this chapter, posterior fossa malformations are divided into predominantly neuronal structural malformations and malformations of the foramina, ventricular, and transient cyst structures of the developing brain. This division is in all likelihood further defined by the genetic abnormalities that are involved in neuronal genesis, migration, and patterning (predominantly neuronal structural malformations) and those of mesenchymal support structures that are important in the formation of the transient cyst of the developing posterior fossa.

Joubert, Meckel-Gruber, and Other Ciliopathies

In the classic form, Joubert syndrome is a disorder with a recessive mode of inheritance, and with clinical features of variable intellectual impairment, respiratory rate dysregulation, oculomotor movement abnormalities (classically oculomotor apraxia), hypotonia, and ataxia. Kidney, liver, renal, and retinal abnormalities may accompany these symptoms and signs. Radiologically, Joubert syndrome is recognized by the molar tooth anomaly and accompanying vermian hypoplasia or aplasia. The molar tooth malformation results from thin cerebellar peduncles that extend dorsally at right angles to the brain stem and absence or hypoplasia of the vermis, giving the appearance of roots of a molar tooth on axial imaging of the posterior fossa. Absence of the cerebellar peduncle decussation and disturbance of the cortical spinal tract decussation combined with brain stem nuclei abnormalities result in a thinning of the brain stem with a prominent isthmus, giving the ventral brain stem the appearance of the crown of a molar tooth. Cerebellar foliation defects may be noted along with other brain stem abnormalities.

The Meckel-Gruber syndrome may include the brain stem and cerebellar abnormalities seen in patients with Joubert syndrome, but is distinguished by the presence of an occipital encephalocele that is usually located near the level of the torcula and may contain supratentorial contents or infratentorial contents or both. This may accompanied by syndactyly and renal, liver, retinal, or kidney problems, and the developmental outcomes are more severe than those of Joubert syndrome.

Genetically, Joubert and Meckel-Gruber syndromes are caused by recessive loss-of-function pathogenic variants in primary ciliary genes. The primary cilia are the polarity antenna of many cells do not have motility functions other than to determine directionality in development.

Rhombencephalosynapsis

Rhombencephalosynapsis refers to the fusion of the cerebellar hemispheres with absence of the vermis. Its precise mode of development is poorly understood, but apparently results from a dorsal lack of division of the developing cerebellum. Clinical manifestations may be developmental in some cases, but it may also be asymptomatic. To date, the genetics of this lesion are undetermined with the exception of an implication of ZIC2 in a combination of holoprosencephaly and rhombencephalosynapsis noted in 2 half-sisters concordant for a pathogenic variant in this gene.

Dandy-Walker

The Dandy-Walker malformation possibly arises from failure to form the foramina of Magendie or failure to involute the anterior membranous area results in an enlargement of the fourth ventricle, thereby lifting, externally rotating, and compressing the vermis. The cerebellar hemispheres are splayed outward, and the torcula may be elevated. The posterior fossa is enlarged, and in 80% of cases, there is obstructive hydrocephalus requiring postnatal shunting from either failure to form the foramina and therefore outflow from the fourth ventricle or from compression of the aqueduct of Silvius. Surprisingly, this lesion is associated with good neurologic outcomes if there are no accompanying distinct malformations of the brain or if not accompanying trisomy 9, 13, 18, or 21 or other chromosomal aberrations. Some of the genes associated with this disorder are expressed in meninges and developing skull (FOXC1) and others in the dorsal cerebellum during development (ZIC1, ZIC4). The single-gene defects thus far associated with this brain lesion are heterozygote deletions or loss-of-function mutations.

PROCESS OUTGROWTH AND SYNAPSE FORMATION

Corpus Callosum

Callosal formation begins surprisingly early in human development, with the first axons crossing from 1 developing hemisphere to the other becoming apparent at 6 weeks of gestation. By 11 to 12 weeks, there is an identifiable corpus callosum, and by 18 to 20 weeks, all of the structures of the corpus callosum are present (rostrum, body, splenium). Errant formation of this structure can result in complete agenesis, so-called partial agenesis or dysgenesis. The corpus callosum continues to form, and differences in appearance may be seen through adolescence owing to myelination and pruning of crossing fibers.

The outcome depends on the genetic disorder, and outcome data are heavily biased toward poor outcomes. There is an ascertainment bias in many brain developmental disorders, but perhaps none more than in callosal disorders. Most patients with callosal agenesis/dysgenesis have neuroimaging because they have presented to a neurologist owing to developmental or neurologic issues. Asymptomatic people with callosal agenesis or dysgenesis are therefore not recognized. However, with common fetal imaging, it is possible that more accurate data regarding outcomes in these disorders may be noted. In fact, in a French cohort of 20 patients with agenesis or dysgenesis of the corpus callosum identified in utero (without prejudice), 80% have had normal outcomes up to 10 years later.

Multiple etiologies of agenesis/dysgenesis of the corpus callosum have been described, and the potential etiologies are many and could deserve their own chapter. For the clinician, the division into accompanying other brain malformations, isolated, and symptomatic seems the most useful. Examples of accompanying other brain malformations include Walker-Warburg and other muscle-eye-brain disorders, ciliopathies (see posterior fossa malformations), X-linked lissencephaly with ambiguous genitalia (ARX pathogenic variants), and Aicardi syndrome.

Aicardi syndrome occurs mostly in females (and in XXY males), is accompanied by other brain anomalies (polymicrogyria, intracranial cysts, nodular heterotopia), and is defined by chorioretinal lacunae; the genetic basis of this disorder is unknown. The prognosis is poor, and epilepsy is nearly a certainty.

It is important for the clinician to recognize that structural brain disease can result from metabolic disorders. Nonketotic hyperglycinemia may result in agenesis/dysgenesis of the corpus callosum. With the structural brain disease and lack of acidosis, the neurologist and neonatologist may easily assume that the seizures, hypotonia, and depressed mental status at birth are the result of the brain malformation. Similarly, pyruvate dehydrogenase complex deficiency may result in callosal agenesis/dysgenesis with or without lactic acidosis.

A reasonable evaluation of a patient symptomatic from a callosal dysgenesis would include an ophthalmologic exam if female to rule out Aicardi syndrome, metabolic studies to include CSF glycine–to–serum glycine ratios, urine organic acids, and chromosomal microarray, and if these are negative, consideration for whole-exome sequencing should be made.

Fetal recognition of isolated agenesis of the corpus callosum may carry a different prognosis from that discussed earlier; 80% of the fetuses so identified will be normal in follow-up. It is important to recognize that Aicardi syndrome, with its poor prognosis, needs to be considered as a possibility for females.

CONCLUSION

New insights into the genetic and molecular aspects of nervous system development and disturbances in that development have led to this attempt to give the clinician the framework to understand malformations of the human CNS and to evaluate patients afflicted by these disorders. Obtaining an etiology in such situations is of value to the patient, the family, and potentially society. With new technologies such as exome sequencing, the potential for obtaining an etiology is vastly enhanced.

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INTRODUCTION

Neural tube defects are the most common congenital defect of the central nervous system. The term spina bifida was first used by Nicholas Tulpius in 1652 and described failure of the posterior arch of the vertebrae to close. Prior to the 1940s, the vast majority of newborns with open neural tube defects did not survive, dying from infection, hydrocephalus, or complications of surgery. The 1940s ushered in new neurosurgical techniques to repair open neural tube defects, but it was not until the 1950s that the first one-way valve cerebrospinal fluid (CSF) shunts were introduced to manage hydrocephalus. Armed with an effective treatment for hydrocephalus, this resulted in earlier surgical repairs of open lesions and lower mortality. Introduction of clean intermittent catheterization in the 1960s allowed infants with spina bifida to survive into childhood, and today, 75% of all aggressively treated individuals with open neural tube defects are surviving into adulthood. Long-term prognosis is related to the severity of the Chiari II malformation, the presence of hydrocephalus, and the level of the defect, with higher lesions generally having worse outcomes.

PATHOGENESIS AND ETIOLOGY OF NEURAL TUBE DEFECTS

Disorders of neural tube formation can involve defects in primary neurulation, closure of the anterior or posterior neuropore, or failure in the development of the lower spinal cord, which may be present before 28 days’ gestation. This leads to defects in the spinal cord, dura, meninges, cranium, and vertebrae as well as the dermal coverings. Open neural tube defects, the most common being the myelomeningocele, are characterized by failure of the surface ectoderm to close over the neural elements leaving meninges and spinal cord exposed. However, disorders in neural tube formation include a wide array of disorders including cranioschisis (total failure of neurulation), anencephaly (defects in cranial neural tissue development), and encephalocele (herniation of brain or meninges through a cranial defect), as well as occult spinal dysraphisms (skin-covered defects of vertebrae and dermal structures with subtle or absent neural abnormalities).

The incidence of spina bifida is 2 in 10,000 worldwide, but this varies widely based on geography and ethnicity. The incidence in northern China (Shanxi Province) is reported to be 100 per 10,000, with the incidence in Mexico being 5 per 10,000 and that in Northern Ireland being 3 per 10,000. The incidence in the United States is similar to the worldwide average of 2 in 10,000. Rates in African Americans are about one-third those of Caucasians, and rates in Hispanics are 2 to 3 times those of Caucasians. The incidence of spina bifida in the United States has steadily been declining, with a peak incidence of 14 to 15 per 10,000 during the Great Depression of the 1930s.

Neural tube defects result from a combination of environmental risk factors in addition to genetic causes. Seventy to eighty percent of all cases are the result of environmental/gene interactions, with the rest being related to aneuploidies, duplications, or deletions. The most common risk factors include folic acid deficiency, fetal exposure to drugs such as valproic acid, and gestational diabetes. Based on the known association of spina bifida and folic acid deficiency, the US Food and Drug Administration mandated supplementation of folic acid into US grain sources in 1998. Exposure to environmental chemicals may also play a role. Many genes are involved in the closure of the neural tube, but defects in the methylenetetrahydrofolate reductase gene (MTHFR) are known to be associated with spina bifida. Commercial prenatal testing for this gene is now available.

Recurrence risks within families are estimated to be 2% to 3% overall. If a woman has spina bifida, her risk of having an affected child is 5%, and siblings of individuals with spina bifida have a 1% risk of having an affected child. Folic acid supplementation has been shown to decrease this recurrence risk.

DIAGNOSIS

Diagnosis of open neural tube defects is suspected early in the second trimester of pregnancy if elevated serum levels of α-fetoprotein are detected. Open neural tube defects are also diagnosed prenatally through the routine use of fetal ultrasonography. Changes in the head shape (lemon sign) and cerebellum (banana sign) are often the presenting findings on fetal ultrasound. Early prenatal diagnosis is crucial in order to allow families the opportunity to plan the pregnancy, including considering the option of fetal surgery, which can be performed between 19 and 26 weeks of gestation. Prenatal diagnosis is also beneficial in order to plan for delivery at an institution that provides level 3 neonatal intensive care, pediatric neurosurgical services, and other subspecialists knowledgeable in the care of infants with spina bifida.

MANIFESTATIONS AND TREATMENT OF NEURAL TUBE DEFECTS

Initial Management

Clinical manifestations vary depending on the type of defect. Open defects of the spinal cord can affect a child’s motor, autonomic, and sensory functioning caudally from the level of the spinal cord lesion. Treatment of spina bifida is best delivered in a multidisciplinary setting given the complexity of medical and developmental complications.

Prenatal diagnosis prior to 26 weeks of gestation of an open neural tube defect allows for the option of fetal surgery, which has been shown to decrease the risk of hydrocephalus by approximately 50% and to increase the lower extremity motor function. However, like other fetal interventions, this can be associated with preterm delivery, uterine dehiscence at delivery, and perinatal death (3%). Candidates for fetal surgery must be a singleton pregnancy, have a myelomeningocele lesion between T1 and S1, and have evidence of hindbrain herniation. Fetal surgery patients should also have no other major fetal anomalies or maternal risk factors for preterm delivery. Because fetal surgery is not always effective in preventing hydrocephalus and because of the significant risks to both fetus and mother, this treatment should not be considered the ideal or “gold standard” of therapy, but rather, as a treatment option. Extensive counseling of families by a multidisciplinary team is necessary to aid in the decision making.

Postnatal treatment remains the safest treatment option for both mother and child with open neural tube defects. Infants are usually delivered at term by cesarean section to prevent potential injury to the exposed neural elements during a vaginal birth. Broad-spectrum antibiotics are started after delivery, a moist sterile dressing is applied to the back, and baseline neurologic assessment and head ultrasound are performed. Surgical closure of the defect occurs 24 to 72 hours after delivery with the goals of a multilayered closure that protects the functioning neural elements and prevents meningitis. The surgical repair does not improve neurologic function.

Hydrocephalus

Open neural tube defects are one of the most common causes of pediatric hydrocephalus in the world. Prior to the introduction of fetal surgery, approximately 80% of patients with a myelomingocele required treatment for hydrocephalus, and the most common treatment is the implantation of a CSF ventriculoperitoneal shunt. Shunts are an effective treatment; however, they have a very high failure rate, especially in infants, in whom the failure rate is 30% to 40% in the first year. Endoscopic third ventriculostomy with choroid plexus coagulation is a reemerging alternative treatment for hydrocephalus that does not rely on an implant and has a moderate success rate in the myelomeningocele population (50–66% success). Long-term cognitive effects of this intervention are being studied, but early results are encouraging. If this has been successful for 6 months, there is a very low subsequent failure rate; this is in contrast to a shunt that is an implant and will eventually fail over time.

Chiari II Malformations

Open neural tube defects almost always result in Chiari II malformations. This condition is named after Hans Chiari, an Austrian pathologist working in Prague, who described it in the late 19th century. It is defined by the caudal herniation of the cerebellar vermis, brain stem, and fourth ventricle into the spinal canal, and it is associated with a variety of other changes in the brain and skull due to the persistent leak of CSF through the open neural tube defect. Fortunately, most Chiari II malformations are asymptomatic or mildly symptomatic and respond to treatment with a CSF shunt. Occasionally Chiari II malformations (3–8%) are associated with severe brain stem dysplasia resulting in stridor, apnea, dysphagia, and aspiration during infancy or the first 2 years of life. This is the leading cause of death in patients following treatment for a myelodysplastic syndrome. Treatment for this condition includes tracheostomy, gastric tube, and cervical decompressive laminectomies for palliation.

Cognitive Development

The brain development of children with myelomeningocele is affected by the presence of the Chiari II malformation. Cognition can be further affected by complications of hydrocephalus and by shunt infections, especially those that occur during infancy. Most individuals with myelomeningoceles have cognition in the normal range but with averages of 1 standard deviation below the general population. However, many experience learning disabilities characterized by deficits in nonverbal skills. This manifests primarily as difficulty learning mathematics in school. Reading skills are often better, but reading comprehension can become more difficult as children progress in school. Poor executive functioning, delayed fine motor skills, and attentional deficits are also commonly seen. Early intervention is crucial in the first years of life. Therapeutic goals are best integrated into the family routine. Preschool is also important to help the child develop independence and prepare for entry into elementary school. Early recognition and intervention of learning disabilities is crucial in order to help individuals reach their highest potential and optimize independence.

Lower Extremity Paraparesis

Lower extremity weakness occurs in varying degrees with neural tube defects, and is much more common with open defects. The anatomic level of the spinous process defect should be used as a guide prenatally for predicting motor function, but the anatomic level does not always correlate with the motor level. Infants with the ability to flex their hips and extend their knees have the best prognosis for ambulation with or without orthotics. Early evaluation and intervention by a physical medicine and rehabilitation specialist maximizes the potential for ambulation.

Neurogenic Bowel and Bladder

Neurogenic bowel and bladder leads to incontinence in nearly all individuals with open neural tube defects. Bowel and bladder dysfunction is related to the lack of communication of the lower sacral nerves with the central nervous system. Bladder pressures are often high secondary to bladder sphincter dysfunction, and poor drainage leads to stasis and risk of infection. Lack of proper bladder care can lead to the deterioration of the upper urinary tract and the development of renal disease. Management of the neurogenic bladder involves routine clean intermittent catheterization to drain the bladder and the use of anticholinergic drugs to decrease bladder irritability and pressures. Antibiotic prophylaxis is also helpful for those with vesicoureteral reflux. These treatment modalities also help with the achievement of continence.

The neurogenic bowel presents with poor motility and sphincter control, leading to incontinence. Constipation and fecal impaction are common. Fecal impaction can lead to encopresis, with the passage of liquid stools, which is often misinterpreted by patients and their families as diarrhea. Management of the bowel involves the use of laxatives and a high-fiber diet to prevent constipation. Continence is best achieved through the use of suppositories or enemas daily.

Achieving continence is crucial for social development and self-esteem. Management of this problem needs to be a goal for the entire family and will likely limit independence if not achieved.

Orthopedic Issues

Joint and spine complications are common such as scoliosis, talipes equinovarus, hip dislocation, and contractures. Paralysis with resulting unbalanced muscle strength around joints leads to various deformities. Management involves maximizing the potential for ambulation and independence. Scoliosis is common in higher level lesions, but rapidly progressing curves warrant an evaluation for a tethered cord. Surgical intervention is also directed at maintenance of proper positioning in braces and wheelchairs to prevent skin breakdown and pressure ulcer development. Individualized lower extremity bracing support and equipment are crucial for maximal physical independence. Physical therapy plays an important role in the early years to encourage gross motor development and, for older children, in the prevention of contractures, maintenance of strength and endurance, and encouragement of independence.

Tethered Cord

Deterioration of motor function and bowel and bladder function, progressive scoliosis, and pain are symptoms of a tethered cord. This is a rare clinical syndrome occurring in approximately 10% of patients. When the syndrome results in loss of existing bladder or lower extremity function, it is treated surgically with a tethered cord release. Most cases of a tethered cord occur between the ages of 5 and 17 when the spine is still growing.

PREVENTION OF NEURAL TUBE DEFECTS

Although there have been many advancements in the care for patients with spina bifida over the years, none are as effective as prevention. Neural tube defects are not completely preventable; however, the addition of folic acid to the food supply has lowered the incidence of spina bifida significantly. Women of childbearing age should take folic acid supplementation to prevent open neural tube defects; mothers of children with spina bifida should take high doses of folic acid if they plan on becoming pregnant again. Current recommendations are 400 μg of folic acid daily for all women of childbearing ages and 4 mg daily for women who have had a previously affected pregnancy.

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INTRODUCTION

Human head size is largely determined by the size of the brain, cerebrospinal fluid (CSF) volume, and blood vessels and their content. Destructive processes or errors in proliferation of cells can lead to small heads that are less than the second percentile, a condition known as microcephaly. An increase in the volume of any 1 of these contents can lead to a head circumference greater than the 98th percentile, a condition known as macrocephaly. The development of a child can be affected depending on the processes that are involved in these disorders.

Head shape also determines head circumference. For a given volume, a perfect sphere is the structure with the least surface area. Any deviation from such a spherical shape can lead to larger circumferences.

MICROCEPHALY

In the evaluation of a child with a head circumference less than the second percentile, one must first consider body size and gestational age if the child is a newborn. Head circumference percentiles can be corrected for gestational age if a child is born prematurely; symmetric less than second percentile body size and head size may not be as concerning as isolated microcephaly. In some families, a head circumference less than the second percentile may be normal and can be associated with normal developmental outcomes, although this is unusual. When presented with a child with a head circumference that measures less than the second percentile, one must consider whether this is an acquired lesion or a genetic one. Acquired microcephaly is often accompanied by hypertonia, whereas genetic disorders often present with hypotonia.

Acquired Microcephaly

In Utero Infection

Acquired microcephaly may be present in infants with TORCH (toxoplasmosis, other [syphilis, varicella-zoster, parvovirus B19], rubella, cytomegalovirus [CMV], and herpes) or other in utero infections. Typically, neuroimaging demonstrates calcifications in this form of acquired microcephaly, and the pattern of these calcifications may help to determine the etiology. Scattered parenchymal calcifications would suggest in utero CMV infection, whereas periventricular calcifications may suggest toxoplasmosis infection. Although CMV is ubiquitous and may cause a mononucleosis-like illness in the mother, very little is done to educate expectant mothers regarding the risks for acquiring this virus in pregnancy, and typically, preconception titers are not assessed. It is estimated that 50% of pregnant women have not had exposure to CMV, and unfortunately, in the 1% to 4% of pregnant women in which the virus is acquired, the outcome can be devastating (Fig. 543-1). Classically, having young children in daycare or working in a school or daycare center increases risk of acquiring CMV while pregnant; according to the Centers for Disease Control and Prevention, hand washing after contact with bodily fluids from young children may prevent infection with the virus.

Calcifications may also be seen in Zika virus infection, which is also associated with microcephaly. However, Zika has also been associated with microcephaly in the absence of calcifications. Presently, a travel history to endemic areas for Zika might suggest the diagnosis, but certainly this virus is likely to spread and affect many regions of the United States and beyond.

Other Prenatal Insults

Acquired microcephaly may be associated with other in utero insults, such as stroke and hypoxic damage. If the damage to the brain occurs near parturition, head size may be normal. Over time, the head size may fall to less than the second percentile, by plateauing, by involution, or by growing less than the rest of the body. Therefore, the pattern of head growth on a circumference chart can give important clues regarding an acquired microcephaly. Other acquired microcephalies may relate to genetic disorders that are neurodegenerative, such as Rett syndrome. Microcephaly may also develop after traumatic brain injury in which large volumes of brain tissue are lost.

Microcephaly Vera

The term microcephaly vera refers to presumed genetic causes of small head size and ultimately small brain size; the contemporary term for these disorders is primary microcephaly. Typically, this is an autosomal recessive disorder, and most of the genes have encoded cyclins and related proteins, suggesting a primary cell proliferation deficit. Why the brain is most affected by the global deficit in a cell proliferation mechanism is unclear, but probably has to do with symmetric and asymmetric cell divisions. Symmetric divisions in the neuroepithelium result in undifferentiated clones of cells available for further divisions. Asymmetric divisions lead to differentiation of cells and, in the case of neurons, loss of further division capabilities. Since these are recessive disorders, families affected by these must be advised accordingly. Whole-exome sequencing can be useful in delineating the genes involved and prevention of future pregnancies affected by these disorders.

Brain malformations may also result in small heads and typically do so. These are discussed elsewhere (see Chapter 541). Brain imaging can delineate these and point to the proper genetic workup.

Craniosynostosis may result in misshaped, small heads and may fall into the category of microcephaly. The head should be palpated for the presence of ridges in place of open sutures. Three-dimensional computed tomography imaging should be considered depending on the sutures involved. Most of the genetic syndromes associated with craniosynostosis are dominantly inherited.

MACROCEPHALY

Macrocephaly can result from enlargement of any of the intracranial contents. Brain enlargement occurs via pathologic processes or via normal physiologic and familial mechanisms. Theoretically, blood vessel enlargements or large vascular malformations may enlarge the head. Finally, increase in ventricular size may lead to macrocephaly.

Familial Macrocephaly

In some families, macrocephaly may be the norm. Therefore, it is reassuring when encountering a child with macrocephaly to measure the parents’ heads and find one has macrocephaly and is normal. Macrocephaly in such families is dominantly inherited, and if imaging is obtained (in familial macrocephaly, this is probably not necessary), benign subdural CSF collections may be noted (in infancy termed benign subdural collections of infancy). These findings are normal, expected, and not pathologic.

Hydrocephalus

CSF is produced in the choroid plexus, flows from the lateral ventricles into the third ventricle, then flows through the aqueduct of Silvius to the fourth ventricle, and exits through the foramina of Magendie and Luschka. Absorption of CSF is via the arachnoid villi near the superior sagittal sinus. The flow of CSF may be obstructed at almost any level, resulting in hydrocephalus and macrocephaly. If male, one has to consider hydrocephalus owing to aqueduct of Silvius stenosis, so-called X-linked aqueductal stenosis, due to mutations in the L1 cell adhesion molecule (L1CAM). Other central nervous system anomalies may accompany this genetic disorder, and classically, adducted thumbs may suggest the diagnosis. Intellectual disability is common in this disorder.

Genetic Disorders

Macrocephaly may be seen in some forms of autism and intellectual disabilities. Classically, fragile X syndrome is associated with macrocephaly. Other genetic syndromes may be associated with macrocephaly and may be accompanied by developmental aberrations. One particular disorder to be aware of is glutaric aciduria, which may be associated with macrocephaly, underopercularization (a widening of the Sylvian fissures on imaging studies), and rarely, spontaneous subdural hematomas. This condition is often mistaken for nonaccidental trauma (child abuse). Enlarged head size may be seen in neurofibromatosis 1, Beckwith-Wiedemann syndrome, Soto syndrome, Alexander disease, Canavan disease, mucopolysaccharidoses, and Tay-Sachs and other storage diseases.

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