Introduction

This section of the book reviews a large and growing number of complex developmental disorders of the brain, often associated with malformations of the spinal cord and skull and recognizable on clinical examination or imaging studies, encompassing a field of knowledge that has expanded dramatically over the past several decades. But the field has not expanded in isolation. From our collective experience over several decades, we have observed that brain malformations:

largely (but not exclusively) represent defects during the earliest stages of brain development, and thus reflect the underlying embryology and developmental genetics of the nervous system

provide an important window into normal brain development and into the genetic regulation of brain development and function

frequently co-occur with other diverse developmental brain disorders both with and without recognized structural defects

are often associated with a wide spectrum of functional deficits, including intellectual disability, developmental language disorders, epilepsy, social and behavioral disabilities, numerous other specific learning disabilities, attention deficits, motor deficits connected with abnormal motor tone and posture or dyskinesias, and a host of problems associated with sleep, feeding, mood, and hormonal and autonomic dysregulation.

Thus, an understanding of brain malformations is important in assessing almost all types of neurological disorders in children. On a practical basis, we have separated brain malformations into disorders involving development of the neural tube (Chapter 22), forebrain (Chapter 23), and mid-hindbrain (Chapter 24); disorders of cortical development, separated into those of brain size (Chapter 25) and those of migration and later cortical development (Chapter 26); disorders predisposing to hydrocephalus (Chapter 27); and disorders of skull development (Chapter 28). We end with an overview of prenatal diagnosis for all brain malformations (Chapter 29). Here, we will address a few topics relevant to brain malformations generally, including epidemiology, classification, clinical recognition, relationship to other neurological disorders and selected environmental factors, and genetic counseling.

Epidemiology

The incidence of brain malformations has been estimated to be approximately 3.32 per 1000 and the prevalence approximately 2.21 per 1000 at age 14 years from studies of a 1-year birth cohort from northern Finland [Von Wendt and Rantakallio, 1986]. These are much higher rates than were recognized in the era before magnetic resonance imaging (MRI) and recent increases in surgical treatment of hydrocephalus and epilepsy [Kuzniecky et al., 1993; Massimi et al., 2009; Warkany et al., 1981]. Not surprisingly, the incidence is much higher (i.e., approximately 88 per 1000) in studies of children with cerebral palsy [Rankin et al., 2010]. This is an important point. To emphasize this, a boy was recently evaluated with apparent cerebral palsy attributed to prematurity at approximately 29 weeks’ gestation. But his brain MRI revealed mild callosal and cerebellar vermis hypoplasia, and chromosome microarray revealed a small deletion in 22q11.2, which implies either a genetic or a mixed pathogenesis.

Classification

While the chapters that follow review many different malformations, they are not complete, as the number of recognized malformations continues to grow steadily. Presenting these data is also complicated by the tendency for malformations to co-occur in some patients. For example, Figure 21-1 shows a striking example of a boy with malformations of the forebrain (agenesis of the corpus callosum), mid-hindbrain (severe cerebellar hypoplasia and mega-cisterna magna), brain size (megalencephaly), neuronal migration (periventricular nodular heterotopia), and cortical organization (polymicrogyria overlying the heterotopia).

Fig. 21-1 Brain images from a single patient showing multiple malformations.

A and B, T1-weighted sagittal images demonstrate severe callosal hypogenesis with a small anterior remnant (angled arrow in A), very small cerebellar vermis (horizontal arrow in A) in an enlarged posterior fossa, extended sylvian fissure with cortex connecting the perisylvian and superior parietal regions (angled arrow in B), and periventricular nodular heterotopia in the trigone (horizontal arrow in B). C and D, T2- and T1-weighted axial images show periventricular nodular heterotopia adjacent to the posterior portion of the lateral ventricles (horizontal arrows in C and D), and infolded gyri with mildly thick cortex overlying the heterotopia (angled arrows in C and D).

(Courtesy of WB Dobyns, research subject LR00-086.)

From time to time, flexible classification schemes have been constructed for many of these malformations that primarily rely on traditional concepts such as embryology and anatomy, with a contribution from genetic discoveries. While recent discoveries are leading us to think more of genes and gene pathways than of embryology and anatomy, a more traditional classification scheme is presented in this and the following chapters. The most current outline for brainstem and cerebellar (mid-hindbrain) malformations is shown in Box 21-1, and an outline for cortical malformations in Box 21-2. Further details regarding most subgroups of malformations and the basis for the classification are given in the primary references [Barkovich et al., 2005, 2009]. These schemes were constructed relying on – in decreasing order of priority – the underlying genetic basis when known, the relevant embryology, brain imaging features, and miscellaneous other clinical features.

Brain Imaging Recognition

The improved quality of brain imaging studies, especially advances in MRI technology, has led directly to increased recognition and more accurate classification of brain malformations. Still, several recurrent types of classification errors continue to occur, based on studies sent to the authors for review. First, pachygyria appears to be the best known of the severe cortical malformations, and accordingly all types of severe cortical malformations are often interpreted as “pachygyria.” The prime examples of malformations mistaken for pachygyria include severe congenital microcephaly (but here the cortex is thin rather than thick), polymicrogyria, and cobblestone malformations (for these, the cortex is moderately thick but the surface and cortex–white matter interface are irregular rather than smooth). This unfortunately often leads to testing of the “lissencephaly” genes in patients with these other cortical malformations, with uniformly negative results. Second, a thin corpus callosum may result from reduced volume of white matter due to abnormal development of white matter, progressive white-matter dysgenesis, or white-matter injury. However, this appearance is sometimes interpreted as agenesis of the corpus callosum. Next, diverse causes of cerebellar hypoplasia are often interpreted as Dandy–Walker malformation (when associated with a large posterior fossa and an enlarged fourth ventricle) or the so-called “Dandy–Walker variant” (equated with isolated cerebellar vermis hypoplasia). The latter is so overused and misapplied that the authors have abandoned the term. Finally, enlarged fluid collections below and especially behind the cerebellum are interpreted as arachnoid cysts or as “mega-cisterna magna,” considering the latter a nonpathogenic variant. In the authors’ experience, mega-cisterna magna with fluid both below and behind the cerebellum sometimes represents a developmental disorder that belongs in the Dandy–Walker spectrum [Aldinger et al., 2009], and may be incorrectly interpreted as an arachnoid cyst.

Relationships to Other Neurologic Disorders

The close connection between brain malformations and other classes of developmental disorders is conceptually important. A few examples include agenesis of the corpus callosum associated with nonketotic hyperglycinemia [Dobyns, 1989], cerebellar vermis hypoplasia or heterotopia with multiple acyl-CoA dehydrogenase deficiency, also known as glutaric aciduria type 2 [Bohm et al., 1982; Lehnert et al., 1982], cobblestone malformations and cerebellar hypoplasia with congenital disorders of glycosylation [Aronica et al., 2005; Morava et al., 2009; Van Maldergem et al., 2008], pachygyria variants with severe peroxisomal disorders such as Zellweger’s syndrome [Barkovich and Peck, 1997; Van Der Knaap and Valk, 1991], and cerebellar hypoplasia or agenesis of the corpus callosum with either autism or infantile spasms [Chugani and Conti, 1996; Courchesne et al., 1988; Kato et al., 2004; Manes et al., 1999; Schiffmann et al., 1993]. Further, most malformations of cortical development are associated with epilepsy, which may be severe [Guerrini, 2005; Leventer et al., 2008]. Observations in these and many other disorders collectively lead us to hypothesize that brain malformations represent the most severe expression or “tip of the iceberg” of a host of developmental brain disorders. Of course, this is much more than a hypothesis, as it has already been proven for disorders reviewed in chapters throughout this text.

Relationship to Environmental Factors

The genetic basis for many brain malformations has been known for years, and new genes are constantly being discovered. The question arises: are all brain malformations genetic? While easy to overlook, substantial data exist to support environmental (extrinsic) causes for several brain malformations. Both microcephaly and hydrocephalus can result from numerous prenatal and early-life diseases, such as intraventricular hemorrhage in premature infants, other causes of intracranial bleeding, hypoxic-ischemic injury, central nervous system infections, and a host of other disorders reviewed throughout this text. Holoprosencephaly has been associated with pregestational diabetes and with structural analogs of cholesterol that interfere with cholesterol metabolism or uptake in humans and animals [Edison and Muenke, 2004; Haas and Muenke, 2010; Johnson and Rasmussen, 2010; Lipinski et al., 2010]. Periventricular nodular heterotopia has been seen in mice and rats following prenatal exposure to high-dose ionizing radiation, and possibly in humans as well [Barth, 1987; Dekaban, 1968; Ferrer et al., 1993]. Schizencephaly and polymicrogyria have been associated with second trimester (13–21 weeks’ gestation) prenatal vascular disruption and with intrauterine cytomegalovirus infections [Barth and Van Der Harten, 1985; Curry et al., 2005; Marques Dias et al., 1984; Mcbride and Kemper, 1982; Pati and Helmbrecht, 1994; Sherer and Salafia, 1996; Suchet, 1994].

Genetic Counseling

While the genetic basis for more and more brain malformations and malformation syndromes is being uncovered, few studies examining the overall contribution of genetic disorders to brain malformations have been reported. Accordingly, only partial and selective information about the genetic recurrence risk for different brain malformations is available. While the authors have conducted only a few formal studies of recurrence risk, we collectively have several decades of experience with these disorders and can provide some general guidelines, which are listed in Table 21-1.

For example, the recurrence risk for holoprosencephaly reported in the literature is approximately 6 percent [Roach et al., 1975]. This report dates from more than 35 years ago, and we are now aware of frequent mild expression or “formes frustes” of this malformation, and accordingly we suggest using a higher recurrence risk of 13 percent for isolated holoprosencephaly without known chromosome imbalances [Mercier et al., 2010]. For several malformations such as agenesis of the corpus callosum and polymicrogyria, single-gene inheritance has been reported, but only rarely, and no formal studies are available. We therefore suggest a “generally low” risk, and counseling for some uncertainty, given that the experience is limited and exceptions occur. For some other malformations, such as rhombencephalosynapsis, hemimegalencephaly, and focal cortical dysplasia, no examples of familial recurrence have ever been reported, despite clinical recognition for decades. We therefore suggest that the recurrence risk is very low. The most difficult malformations are those with significantly different recurrence risks for different subtypes and syndromes, such as diffuse and vermis-predominant cerebellar hypoplasia. These estimates are largely anecdotal in origin, so treating physicians and genetic counselors are encouraged to review information on the specific disorder at hand when counseling families.

References

The complete list of references for this chapter is available online at www.expertconsult.com.

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