Rudolph's Pediatrics, 22nd Ed.

CHAPTER 548. Cranial Developmental Abnormalities

Omar Khwaja

The central nervous system (CNS) is the most complex organ in the human body comprising a highly organized anatomic scaffold of billions of cells and a network of trillions of connections. Structural brain development proceeds through an integrated series of often rapid developmental events from early embryogenesis through fetal life and into early adulthood. It is therefore not surprising that many common childhood neurologic and developmental disorders have their origins in genetic or environmental perturbations of embryonic or fetal brain development.

Advances in genetics and diagnostic imaging, including prenatal imaging, have led to earlier and more complete diagnosis and enhanced prognostication for CNS malformations and the ability to counsel effectively regarding recurrence. The diagnosis of malformations has been revolutionized by magnetic resonance imaging (MRI), and the challenge for the pediatrician is often to translate the imaging diagnosis to effectively counsel the family and plan further care and management for the child. Modern neonatal neurologic and neurosurgical intensive care together with progress in early intervention and pediatric rehabilitation means children with malformations of the brain or spinal cord may now survive longer and with improved quality of life.

Malformations of the CNS are among the most common problems in child neurology. Brain development is abnormal in an estimated 25% of conceptions and is responsible for a high percentage of miscarriage and stillbirth. Brain malformations are, together with congenital heart disease, the leading cause of neonatal and postneonatal mortality in the developed world. Brain malformations are after cerebral palsy, the leading cause of childhood morbidity and mortality related primarily to consequent neurologic disability and epilepsy. Brain malformations frequently coexist with other malformations of organ systems, in particular the eye, heart, kidneys, gut, and skeleton.

The neuraxis develops following the fate decision of several early embryonic cells to become neural progenitors and by the second week of embryogenesis the three primary layers of ectoderm, mesoderm, and endoderm are formed. It subsequently proceeds through the dorsal and ventral induction to form the neural tube, lower spinal cord and eventually the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). This is followed by massive cellular proliferation of both neuronal and glial precursors and later differentiation into specific neuronal and glial types. Cortical development occurs with migration of neuronal and glial precursors away from the ventricular and subventricular zone towards the pial surface to form the neocortex and major commissures such as the corpus callosum. This is followed by cortical organization that includes alignment, orientation, and layering of cortical neurons together with synaptogenesis. From the end of the second trimester into early childhood late glial differentiation and myelination, together with programmed and experience-dependent synaptic formation and pruning predominate.

The range of known malformations is almost as complex as the series of developmental events that lead to the formation of the brain. They are perhaps best understood as the effects of insults—regardless of type—at key points in the development of the brain. Although much emphasis has been placed on genetic etiologies—cytogenetic abnormalities, single gene disorders, and polygenic syndromes—environmental insults at key points in the developmental program may result in similar malformations with common clinical findings in the infant or child. As the developing brain, particularly during the first two trimesters, is not capable of generating the common glial response to injury, the etiological cause is frequently difficult to discern. For example early vascular or infectious events may cause abnormalities of cortical migration such as polymicrogyria indistinguishable from a primary genetic causation. An overview of the key developmental events in brain and spinal cord formation, together with examples of corresponding disorders related to developmental changes at these steps is given in Table 548-1.

The clinical sequelae of these malformations are broad and often location specific, but some general themes emerge. Disorders of embryonic CNS development (neurulation, prosencephalic development, and neuronal proliferation) are frequently associated with morphological findings. These include abnormal head size and shape; facial dysmorphology (in particular midline abnormalities); facial clefting; and anomalies of optic globe size, shape, and position. Intra-axial anomalies frequently lead to major variations in ventricular size and structure and consequently these lesions are diagnosed on routine obstetric fetal anomaly scans. Spinal closure abnormalities may be associated with external stigmata such as fistulae, dimples, nevi or ectopic hair, or fat. In addition fetal lower limb positioning may be abnormal with talipes and fixed flexion of the hips of extension of knees detectable prenatally. In addition to fetal miscarriage and death, other fetal manifestations of early CNS malformations include polyhydramnios, decreased fetal movement, and preterm labor. Malformations related to abnormalities in later fetal stages of CNS formation may present postnatally, often in late infancy or childhood, frequently without evident dysmorphic features or neonatal manifestation. Early symptoms may include hypotonia and motor delay, as well as feeding difficulties. Later symptoms usually encompass speech and language delay and variable degrees of cognitive impairment including mental retardation. Epilepsy is particularly associated with disorders of migration and cortical organization but may not present until late childhood or adolescence. This chapter covers developmental disorders up to and including disorders of migration. Conditions associated with aberrant organization, synaptogenesis, pruning, and myelination are covered elsewhere in detail.

Table 548-1. Major Events in Human Brain and Spinal Cord Formation and Corresponding Disorders in Development

ABNORMALITIES OF CRANIAL DEVELOPMENT

ANOMALIES OF PROSENCEPHALIC DEVELOPMENT

The developing forebrain and face is contingent on the ventral induction by the prechordal mesoderm at the rostral end of the neural tube. The sonic hedgehog signaling pathway is critical to the development of the prosencephalon, with sonic hedgehog protein (Shh) secreted from the prechordal mesoderm to activate the Patch receptor and downstream genes.

The major events are formation of the prosencephalon at the end of the first month; cleavage in three planes to give the basic structure of paired cerebral hemispheres, basal ganglia, and ventricles; separation from the midbrain; and development of paired optic and olfactory structures. These events are followed by midline prosencephalic development with thickening of the commissural, chiasmatic, and hypothalamic plates necessary for formation of the corpus callosum, septum pellucidum, optic nerve chiasm, and the hypothalamus. The corpus callosum forms as developing cortical axons cross the midline under the influence of chemoattractants and repellents.

HOLOPROSENCEPHALY

This group of disorders is the result of different degrees of failure of prosencephalic cleavage and distinguished by the severity of failed cleavage of the cerebral hemispheres and deep nuclear structures. The most severe form is alobar holoprosencephaly where there is a single sphere cerebral structure and monoventricle with fusion of the thalami and deep nuclei together with absence of the corpus callosum and olfactory bulbs. Neuronal migration and cortical organization is severely disordered. In semi-lobar holoprosencephaly there is failure of separation of the anterior cerebral cortex and absence of the anterior corpus callosum. The least severe forms are lobar holoprosencephaly, in which the cerebral hemispheres are fully separated and the deep nuclei partially separated, and the middle interhemispheric variant, in which only the posterior frontal and parietal regions fail to separate. Hydrocephalus is present in most infants with alobar holoprosencephaly due to fusion of the thalami and impaired drainage of cerebrospinal fluid (CSF) through the aqueduct. Infants with semilobar and lobar forms are usually microcephalic. Facial anomalies are usual and range from severe cyclopia with proboscis through to ocular hypotelorism with a flat single nostril nose (cebocephaly) to mild hypotelorism with or without cleft palate. Malformations of other organ systems are present in 75% of patients.

Alobar holoprosencephaly occurs in 1/10,000 live births but is 100 times more common in conceptuses examined after miscarriage or abortion. Causes include both genetic and cytogenetic etiologies as well as teratogens. Over two thirds are related to full or partial chromosomal aneuploidies, in particular trisomy 13. A list of known etiologic factors is given in Table 548-2.

The clinical features relate to the severity of failure of cleavage of the cerebral hemispheres, basal ganglia, and abnormal hypothalamic function. Most patients with alobar holoprosencephaly do not survive infancy. Children with less severe forms do have prolonged survival. Seizures are common as is profound visuomotor and cognitive impairment. The failure of basal ganglia and thalamic cleavage leads to dystonia and motor impairment, as well as early apnea. Hypothalamic dysfunction leads to often life-threatening endocrinopathies such as diabetes insipidus, as well as poikilothermia. Management is primarily supportive. Although shunting is performed, the development of hydrocephalus is often a sign of unrecognized severe failure of cleavage.

AGENESIS OF THE CORPUS CALLOSUM AND ABSENT SEPTUM PELLUCIDUM

This group of disorders is characterized by varying degrees of failure of midline prosencephalic development. Agenesis of the corpus callosum (ACC) may be complete or partial and is associated with deformation of the lateral ventricles to give a parallel ventricular arrangement known as colpocephaly. This is usually accompanied by longitudinal fibers coursing along the medial aspect of the hemispheres known as Probst bundles. Partial ACC usually comprises absence of the posterior callosum. Agenesis of the corpus callosum (ACC) may be isolated or in up to 40% to 50% of cases associated with other cerebral abnormalities, specifically cerebellar malformation and cortical migration anomalies. Agenesis of the corpus callosum is one of the most common anomalies occurring in up to 7 in 1000 live births and 3% of children with developmental delay. It is increasingly diagnosed in fetal life. Agenesis of the corpus callosum may be completely asymptomatic or have symptoms only detected on very refined testing of interhemispheric transfer. In association with other anomalies however there is a strong risk of cognitive and neuromotor impairment. Agenesis of the corpus callosum is associated with well over 65 known genetic syndromes and the presence of extra-axial abnormalities or cytogenetic abnormalities is a risk factor for impaired neurologic development (Table 548-3). A notable condition is Aicardi syndrome, an X-linked dominant condition affecting females associated with neuronal heterotopias, chorioretinal lacunes, early onset infantile spasms and subsequent refractory epilepsy and profound developmental delay.

Table 548-2. Etiologic Factors in Holoprosencephaly

Table 548-3. Associations with Agenesis of the Corpus Callosum (AgCC)

Absence of the septum pellucidum is another common anomaly and frequently associated with more diffuse cerebral malformations such as schizencephaly, septo-optic dysplasia, ACC, holoprosencephaly, and hydrocephalus. Failure of fusion of the septal leaflets is known as cavum septum pellucidum. This is a normal finding in fetal life and in premature infants, but, after the neonatal period, has a weak association with later cognitive deficits. As with ACC, the outcome of absent septum pellucidum is related to associated brain malformations. The most common and important of these is septo-optic dysplasia (SOD, de Morsier syndrome) where absent septal leaflets are associated with optic nerve hypoplasia and disturbances of the hypothalamic-pituitary axis. Children with SOD may have profound panhypopituitarism. Identification of absent septal leaflets on prenatal imaging should be accompanied by postnatal magnetic resonance imaging (MRI), ophthalmic examination, and complete endocrinology evaluation.

Table 548-4. Common Cerebellar Malformations

CEREBELLAR MALFORMATIONS

Cerebellar development varies considerably and coincides with prosencephalic development. As the cerebellum is intimately related to development of the aqueduct of Sylvius and foramina outflow of the fourth ventricle, hydrocephalus and posterior fossa fluid collections are frequent accompaniments. Common malformations are listed in Table 548-4.

Of these the Dandy-Walker malformation (DWM) is the most frequently encountered and together with stenosis or atresia of the aqueduct of Sylvius accounts for over 40% of cases of congenital hydrocephalus. DWM comprises agenesis of the cerebellar vermis, enlargement of the posterior fossa with rostral displacement of the torcula, and cystic dilatation of the fourth ventricle. Hydrocephalus and supratentorial migrational abnormalities are common accompaniments (70–90%). It is associated with a range of genetic syndromes including Smith-Lemli-Opitz, Meckel-Gruber, and Rubinstein-Taybi syndrome. The hydrocephalus may be striking at birth and the majority of children require shunting. Outcome is related to the onset of hydrocephalus (early fetal onset being associated with a high mortality and severely impaired neurologic outcomes) and the associated cerebral malformations.

Joubert syndrome is another important pediatric cerebellar malformation. Characterized by vermian dysplasia, neuronal heterotopias, absent decussation of the cerebellar peduncles, and multiple brainstem abnormalities. This group of disorders is identifiable by the “molar tooth” conformation of the superior cerebellar peduncles on magnetic resonance imaging (MRI). At least 5 gene loci have been identified. The disorder is characterized by hypotonia, craniofacial dysmorphisms, nystagmus, and respiratory dysrhythmia. Associated anomalies include retinal colobomata, renal malformations, and hepatic fibrosis. Cognitive impairment may be mild and not apparent until later in schooling.

ABNORMALITIES OF NEURONAL PROLIFERATION AND MIGRATION

Following establishment of the basic pattern of the developing neuraxis, brain growth proceeds by rapid proliferation of progenitor neurons and glia and migration from the ventricular surface to the developing fetal cortex. Neuronal and glial progenitors are formed by symmetric and asymmetric division of pluripotent stem cells in the ventricular and subventricular zones. These cells exit the cell cycle and migrate into the intermediate zone and thence to the cortical plate at the pial surface.

Abnormalities of proliferation give rise to disorders of brain size (primary micrencephaly and megalencephaly) that are covered in more detail in Chapter 550. These include the autosomal recessive disorders of micrencephaly vera (primary micrencephaly or microcephaly with simplified gyri) and radial microbrain (where, despite the extremely small brain size, gyration, and cortical lamination are normal). Children with micrencephaly vera often do not have major neurologic findings and cognitive impairment may be mild. There is often associate migrational abnormality, in particular simplification of the gyri, which is usually associated with more profound mental retardation. By contrast, infants with radial microbrain usually die in the neonatal period.

Macrencephaly/megalencephaly is a highly heterogeneous group of disorders that includes macrocosmic syndromes such as Soto, fragile X, and Beckwith-Tiedemann syndromes. It is a common finding in neurocutaneous syndromes such as neurofibromatosis and Sturge-Weber syndrome. Of interest is autosomal dominant and recessive isolated familial macrencephaly where the head size is large at birth and continues to grow rapidly postnatally. Neurologic and cognitive development is usually normal.

FIGURE 548-1. Patterns of migration in the developing cerebral cortex. CP, cortical plate; IZ, intermediate zone; MZ, marginal zone; SVZ, subventricular zone; VZ, germinal ventricular zone. (Source: Courtesy of Drs Kringstein and Noctor.)

Table 548-5. Lissencephaly Syndromes

Migrational disorders are a large and complex group of conditions characterized by relative impairments in the radial migration of neurons into the cerebral cortex and tangential migration of interneurons into the cortex (Fig. 548-1). This process requires the presence of radial glial guides, a series of fetal transient zones, and a complex panoply of molecular determinants including guidance molecules, signaling pathways, surface ligands, cytoskeletal elements, ion channels, and neurotransmitters, in particular glutamate. Clinically these disorders are manifested by neonatal hypotonia, early onset of often refractory seizures, and developmental delay. MRI is the most useful initial investigational tool when a migrational disorder is suspected, with the hallmark finding of gyral abnormalities and occasionally abnormalities of the corpus callosum.

Lissencephaly-pachygyria represents a spectrum of disorders marked by underdevelopment or absence of normal gyrification. In type 1 lissencephaly there are absent gyri and an immature cerebral mantle with disorganized and heterotopic neuronal layering. Type II lissencephaly is characterized by clustered, whorled arrays of neurons separated by glia and large heterotopic formations of neurons, often migrating into the pia giving a characteristic “cobblestone” appearance. Pachygyria is demonstrated by thickened simple gyri that are underdeveloped and is a continuum of lissencephaly. Radiologic features are shown in Chapter 550, Figure 550-1. The known causes of these types of lissencephalies are listed in Table 548-5 together with salient clinical features and diagnostic indicators.

Clinically type I lissencephaly are characterized by postnatal deceleration of head growth, profound neonatal hypotonia evolving to a spastic quadriparesis, severe dysphagia, poor movement, early seizures often evolving to infantile spasms, and eventually Lennox-Gastaut syndrome. Mental retardation is prominent. Type II lissencephalies in addition to those clinical features seen in type I lissencephaly, differ by the presence of microcephaly, retinal and anterior chamber malformations, congenital muscular dystrophy, and cerebellar malformations. Epilepsy and hypotonia predominant and death in infancy are common.

Polymicrogyria is characterized by numerous small folds of gyri that may have a basic four-layered anatomy, or unlayered with a poorly laminated heterotopic collection of neurons below the cerebral mantle. Polymicrogyria is associated with a number of primary genetic conditions, as well as metabolic conditions, in particular disorders of peroxisomal biogenesis, such as Zellweger syndrome. It frequently accompanies other dysgenetic brain malformations as well as in utero encephaloclastic events such as vascular insults or congenital infection (congenital infection in particular). The neurologic sequelae are very variable and range from severe mental retardation and refractory epilepsy to milder disorders of neuromotor function or mild learning disability. A special note is made of perisylvian polymicrogyria syndromes, particularly the bilateral form, which is associated with specific deficits in orolingual impairment and pseudobulbar palsy, with expressive language delay and feeding problems prominent.

Neuronal heterotopias and focal cortical dysplasias represent arrest of migration of neurons. These may be located close to the ventricular surface in the subependyma following arrest in early radial migration. These are usually nodular and multiple. Other heterotopias are seen in the subcortical white matter and may be small nests of cells or more commonly bands. A list of conditions associated with heterotopias is given in Table 548-6. The clinical manifestation is usually epilepsy, often presenting in early adolescence or adulthood. Although heterotopias may be clinically occult, they elevate the lifetime seizure risk to 40% to 50%. Focal cortical dysplasias represent abnormalities of the later stages of migration and are a cause of intractable epilepsy, which may respond to epilepsy surgery. They may comprise collections of abnormally laminated normal neurons or large dysplastic multipotent cells known as balloon cells.

Schizencephaly is a severe restricted disorder of cortical formation characterized by failure of development of a portion of the cerebral wall leaving a cleft extending from the ependymal surface to the pial surface. The cleft is usually lined by dysplastic heterotopic gray matter in particular polymicrogyria. The lesion may be unilateral or bilateral, usually frontal or perirolandic. The edges of the pial surface may be opposed (“closed-lip”) or more commonly, widely separated (“open-lipped”). Like polymicrogyria the disorder may have a primarily genetic etiology (eg, mutation in the EMX2 gene) but vascular disruption and congenital infection such as congenital infection (CMV) is also associated with this abnormality.

Table 548-6. Diseases and Syndromes Associated with Neuronal Heterotopias

Clinically the condition is associated with cognitive deficits (particular in bilateral clefts), late-onset seizures and motor deficits (particular in frontal open-lipped lesions). Agenesis of the corpus callosum or absent septum pellucidum may be frequent accompaniments. Hydrocephalus of unclear mechanism, complicates up to half of cases.^1-8