Genetic Defects

Primary microcephaly may occur as an isolated insult to the central nervous system or may be seen in association with chromosomal abnormalities or as a part of other well-defined multiorgan genetic syndromes. Genetic forms of primary microcephaly may be autosomal recessive, autosomal dominant, or X-linked.1,41 Of the genetic forms, autosomal recessive transmission is the most common. Like other recessive disorders, this condition occurs with increased prevalence in geographic regions with high consanguinity. Investigators have been able to study consanguineous families with homozygosity mapping to localize recessive traits.⁶⁰ Since 1998, five autosomal recessive loci for microcephaly have been mapped by molecular geneticists collaborating with clinicians working in regions where consanguinity is common.⁶⁸ Autosomal dominant microcephaly has been observed in families, often associated with normal intelligence or only mild cognitive impairment.

Neurulation and Cleavage Anomalies

Anencephaly is the most devastating of all the dysraphic malformations, and occurs as a consequence of failure of the anterior neural tube to close. The insult occurs early in embryogenesis, before day 26 of gestation. Both cerebral hemispheres are absent, as is the cranial vault (Figure 64-2). Anencephaly is a lethal condition. Infants are either stillborn or live for only a few days. The incidence of anencephaly has been decreasing with the increased use of prenatal folate supplementation.

Holoprosencephaly occurs as a consequence of failure of the prosencephalon, or embryonic forebrain, to separate and form paired telencephalic hemispheres. The hemispheres are normally cleaved at 33 days’ gestation, so the insult causing holoprosencephaly must occur early. Holoprosencephaly is usually sporadic, but an autosomal dominant familial variant has been reported.33,35 Holoprosencephaly in some cases is caused by mutations in the sonic hedgehog gene (SHH) and other genes located on chromosome 7q. The cleavage defects produce a clinical picture of varying severity. In the most complete form, alobar holoprosencephaly, there is a single hemisphere of the brain and a single midline prosencephalic ventricle. Median facial defects range from a single midline eye and rudimentary nose to orbital hypotelorism, flattening of the nose, cleft lip and palate, and trigonocephaly (triangular forehead with vertical ridge along metopic suture). Neurologic findings include cognitive delay, seizures, poor temperature control, and a variety of neuroendocrine disorders related to dysfunction of the anterior and posterior pituitary gland. Less severe clinical forms of the disorder include semilobar holoprosencephaly and lobar holoprosencephaly, in order of decreasing severity (Figure 64-3).

Other genetic causes of primary microcephaly include disorders of karyotype, including trisomies, deletions, and translocation syndromes. Among the common chromosomal abnormalities are trisomies 21, 18, and 13. Primary microcephaly may be a feature of numerous somatic disorders with normal karyotypes, including Rubinstein-Taybi syndrome, Smith-Lemli-Opitz syndrome, Cornelia de Lange syndrome, and Hallermann-Streiff syndrome (see Box 64-1). In these syndromes, characteristic dysmorphic features and patterns of other organ involvement help establish the diagnosis. Additional genetic syndromes are identified each year as technical advances in genetic screening occur.

Migrational Anomalies

Neuronal migration is a radial and tangential process by which nerve cells move from their progenitor cell origin in the ventricular zone and basal forebrain to their final destination in the cerebrum. The cerebral cortex forms as the result of neuronal migration, and anomalous gyral formation is the signature finding in all migrational disorders⁶⁶ (Figure 64-4) (see Chapter 58). Because of this cortical disruption, seizures are the most common clinical manifestation of migrational disorders. The morphologic abnormality in schizencephaly is a cleft in the cerebral hemisphere, which may be unilateral or bilateral, open-lipped (walls of the cleft separated, often associated with enlargement of the lateral ventricles; Figure 64-5) or closed-lipped. In lissencephaly (agyria, or “smooth brain”), the cerebral hemispheres have few or no gyri (Figure 64-6). In polymicrogyria, the gyri are too numerous and too small, with a proliferation of secondary and tertiary sulci. The appearance of the cortical surface has been likened to that of a wrinkled chestnut kernel (Figure 64-7). Neuronal heterotopias (brain warts) are the least severe of the migrational disorders and may stand alone or occur in association with other disturbances of migration. Agenesis of the corpus callosum, partial or complete, is a relatively common accompaniment in disorders of neuronal migration (Figure 64-8). The corpus callosum is the largest of the interhemispheric commissures, and its absence may be seen in association with other midline defects, such as absence or hypoplasia of the septum pellucidum, the thin partition that divides the anterior portion of the lateral ventricles (Figure 64-9). The triad of agenesis of the septum pellucidum, optic nerve hypoplasia, and pituitary abnormalities is called septo-optic dysplasia, or De Morsier syndrome. Agenesis of the corpus callosum associated with cortical and subependymal gray matter heterotopias and chorioretinal lacunae was initially described by the French neurologist Jean Aicardi in 1965 (Aicardi syndrome).² This disorder, seen only in girls, is characterized by microcephaly, profound mental retardation, and seizures in the form of infantile spasms.

Congenital Infections

The developing nervous system is susceptible to a variety of in utero infections. Implicated agents are collectively referred to by the acronym TORCH syndrome (toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes simplex virus; Figure 64-10) (see Chapters 26 and 55–57).

Biochemical Disorders

Several maternal metabolic disorders such as diabetes mellitus and uremia are associated with congenital primary microcephaly. Untreated phenylketonuria in an asymptomatic mother may be associated with microcephaly in a non-phenylketonuric infant.61,62 Maternal malnutrition and hypertension are associated with intrauterine growth restriction and microcephaly. Teratogenic agents such as nicotine, phenytoin, cortisone, cocaine, alcohol, isotretinoin, and carbon monoxide can produce microcephaly along with disorders of neuronal induction and migration. Maternal exposure to ionizing radiation has been implicated as a cause of congenital microcephaly, with earlier insults associated with more severe cases.⁶⁷

Radial Microbrain and Micrencephaly Vera

As our understanding of the timing of neuronal proliferation has improved, another scheme for classifying micrencephaly has been proposed. Two subgroups of micrencephaly have been postulated: radial microbrain and micrencephaly vera. This scheme is based on the work of Métin and colleagues,⁶⁶ who proposed a radial unit model to explain the major ontogenetic development of the cerebral cortex. They suggested that the ependymal layer of the embryonic cerebral ventricle consists of proliferative units whose cytoarchitectonic output is translated to the expanding cerebral cortex along radial glial guides. Early symmetric division of stem cells creates these proliferative units, which behave as organized cylindrical columns containing neurons. Later asymmetric division of stem cells causes the proliferative units to enlarge, with increased numbers of neurons. Subsequent migration of the proliferative units together as columns along radial glia explains the evolution of the cerebral cortex from the primitive ventricular zone.

Radial microbrain and micrencephaly vera are disorders of micrencephaly related to impaired neuronal proliferation, and would be categorized as forms of primary microcephaly in the conventional classification scheme. Radial microbrain is a rare condition described in seven cases by Evrard and colleagues,³⁸ in which the brain is extremely small with normal gyri and normal cortical lamination. The brain can be as small as 16 g at term (the normal newborn brain is 350 g), and in the reported cases, death has occurred in the first month. Radial microbrain is considered a genetic disorder, most likely with autosomal recessive inheritance. The pathologic finding is a marked reduction in the number of cortical neuronal columns (proliferative units), but a normal number of neurons per column. The reduced number of columns with preservation of columnar size suggests that the insult occurs early in the embryonic phase of neuronal proliferation.

Micrencephaly vera (true micrencephaly) describes a heterogeneous disorder in which the brain is well formed with a simple gyral pattern and small, but not as small as the radial microbrain. Pathologically, the number of cortical neuronal columns is normal, but the size of the columns is small because of a reduced number of neurons per column. The timing of the embryologic insult is later than that for radial microbrain, most likely between the 6th and 18th weeks of gestation. Micrencephaly vera is not a single entity and may be caused by genetic or environmental abnormalities. The distinction between radial microbrain and micrencephaly vera is of particular interest to investigators studying neuronal proliferation and the evolution of human cerebral neocortex from progenitor cells lining the embryologic ventricle.

Isolated Macrencephaly

Isolated macrencephaly can be familial or sporadic. Familial macrencephaly is an inherited disorder in which the head size of an otherwise normal infant is excessively enlarged.⁸⁷ A clue to the diagnosis is the finding of an abnormally enlarged head in one or both parents. The child is born with an enlarged head that tends to remain enlarged and can sometimes grow at a rapid rate. Most children are neurologically normal or near-normal. In true familial macrencephaly, the only finding on neuroimaging studies is enlargement of the brain. Familial macrencephaly is thought to be related to another condition, so-called benign external hydrocephalus of infancy, in which there is enlargement of the extracerebral subarachnoid space (see External Hydrocephalus), and one wonders whether these are really variants of the same condition. Most cases of familial macrencephaly are characterized by autosomal dominant inheritance. Infants with the rare autosomal recessive variant are more likely to be neurologically impaired, with cognitive delay, seizures, and motor delay. Sporadic macrencephaly is used to describe isolated macrencephaly in an infant whose parents have normal head circumferences and for whom there is no other demonstrable etiology for brain enlargement. Macrocephaly has been described in children with autism.⁹

Macrencephaly and Growth Disorders

Macrencephaly is sometimes associated with generalized disorders of growth. The syndrome of cerebral gigantism was described by Sotos and colleagues in 1964.⁹⁰ Sotos syndrome is characterized by macrencephaly along with macrosomia, enlargement of the hands and feet, and poor coordination.³² Macrencephaly begins prenatally in 50% of cases and is manifest by 1 year in all affected children. Cognitive impairment is variable, but behavioral problems are significant, and there is often delay in motor milestones. Midline intracranial anomalies have been described on MRI, including agenesis of the corpus callosum and septum pellucidum, as well as hypoplasia of the cerebellar vermis. Ventriculomegaly is common, with prominence of the trigone and occipital horns.⁸⁶

Macrencephaly may be seen in association with macroglossia, macrosomia, visceromegaly, omphalocele, exophthalmos, and neonatal hypoglycemia. This condition, the Beckwith-Wiedemann syndrome, was described independently by John Bruce Beckwith, an American pathologist, and Hans-Rudolf Wiedemann, a German pediatrician. The syndrome is an imprinting disorder in chromosome 11p15.5.⁸⁹ Craniofacial features include a prominent occiput, large anterior fontanelle, and a ridge along the metopic suture.⁵⁰ Cognitive delay, if present, is thought to be more likely a consequence of uncontrolled neonatal hypoglycemia than of malformation of the brain. Children with Beckwith-Wiedemann syndrome have an increased incidence of Wilms tumor, adrenal cortical carcinoma, and hepatoblastoma.

Achondroplasia, the most common form of dwarfism, results from exaggerated signaling of the fibroblast growth factor receptor 3.⁵⁸ Head enlargement in achondroplasia is sometimes a consequence of hydrocephalus and sometimes a consequence of true macrencephaly. Head circumference charts are available for infants and young children with achondroplasia. Affected children have frontal bossing with a flattened nasal bridge, mild midface hypoplasia, as well as a short cranial base and small foramen magnum. True compression of the brainstem and cervical spinal cord are infrequent but potentially devastating. Achondroplastic children usually have normal intelligence.

Neurocutaneous Syndromes

The neurocutaneous syndromes, or phakomatoses, are each characterized in part by abnormal cellular proliferation in the central nervous system. Several of the neurocutaneous syndromes are associated with macrencephaly. Neurofibromatosis type 1 (NF-1) is an overgrowth syndrome that can be associated with neonatal or infantile macrencephaly. Distortion of cortical architecture has been reported, along with spongiform hamartomatous changes in the white matter, basal ganglia, brainstem, and cerebellum. Glial neoplasms are common, and optic glioma can be seen in neonates. Using quantitative MRI, Cutting and associates²⁶ found that brains of patients with NF-1 are significantly larger than normal, with a prevalence of macrencephaly in NF-1 of approximately 50%.

Macrencephaly may be a part of other neurocutaneous disorders, but is seen with less frequency. The Sturge-Weber syndrome (encephalotrigeminal angiomatosis) is a sporadic phakomatosis characterized by a facial port wine stain (nevus flammeus) and leptomeningeal vascular proliferation with cerebral cortical calcification, usually in the parietal and occipital regions. Ocular manifestations include glaucoma and buphthalmos (Greek “ox eye,” also called hydrophthalmia: enlargement of the eye because of congenital glaucoma). Neurologic manifestations include seizures (which may be medically refractory), focal deficits of visual, language, or motor function, and developmental delay with learning disorders and cognitive delay.

Tuberous sclerosis (Bourneville syndrome) is an autosomal dominant disorder affecting skin (facial angiofibromas, subungual fibromas, ash leaf spots, shagreen patches), eye (retinal hamartomas, astrocytomas), viscera (cardiac rhabdomyomas, renal angiomyolipomas, and cysts), and brain. Neurologic manifestations are characterized by the abnormal proliferation of neurons and glia. Neuropathologic findings include cortical tubers, subependymal nodules, and, occasionally, subependymal giant cell astrocytomas that can obstruct the cerebral ventricles at the foramina of Monro (Figure 64-12). The neurologic presentation is one of seizures, cognitive impairment, and behavioral disorders.

Chromosomal Disorders

Fragile X syndrome is second to Down syndrome as a genetic cause of mental retardation. The genetic mutation is thought to involve unstable trinucleotide repeats, with a fragile site at the tip of the long arm of the X chromosome. The disorder predominantly affects boys. Craniofacial manifestations include macrocephaly with a prominent jaw, a long, narrow face with a prominent forehead, and prominent ears. Klinefelter syndrome (genotype 47 XXY) has been reported in association with macrencephaly.¹⁷ Boys with Klinefelter syndrome may have normal intelligence, although behavioral disorders are common, along with minor disturbances in learning and development.

Degenerative Disorders

Canavan disease is named for Myrtelle Canavan, an American neurologist who first described the disorder in 1931. It is an autosomal recessive leukodystrophy caused by mutation in the gene for the enzyme aspartoacylase, leading to accumulations of N-acetylaspartate and deterioration of the white matter, predominantly affecting individuals of eastern European (Ashkenazi) Jewish descent. Canavan disease is a progressive cerebral spongiform degenerative disorder characterized by vacuolization of the deep layers of the cortex and the subcortical white matter. The infantile form presents in the first few months of life with hypotonia and macrencephaly. The natural history is one of cognitive delay, loss of acquired motor skills, hypotonia, and acquired blindness, with death usually occurring by 3 to 4 years of age. The diagnosis can be confirmed on urine organic acid analysis by the finding of elevated levels of N-acetylaspartate. Treatment is supportive.

Alexander disease is a sporadic progressive leukodystrophy described by W. Stewart Alexander, a 20th-century English pathologist. Three clinical syndromes have been described: the infantile, juvenile, and adult forms. The infantile form of the disease is the most common and is characterized by macrocephaly, developmental delay, spasticity, and seizures. Onset is at age 6 months on the average, but clinical manifestations may be seen shortly after birth. The predominant feature on cranial MRI is impaired development of the white matter anteriorly, with the posterior white matter affected later. The disorder is progressive, usually leading to death within the first decade, and treatment is supportive. The pathologic finding is macrencephaly with Rosenthal fibers—spherical eosinophilic intracytoplasmic inclusion bodies in the astrocytes. Alexander disease results from a mutation in the gene for glial fibrillary acidic protein, an intermediate filament protein found in the Rosenthal fibers.¹³

Metabolic Disorders

Gangliosidoses are marked by the accumulation of gangliosides (glycosphingolipids) in cellular lysosomes secondary to enzymatic deficiency states. The hallmark of the gangliosidoses is Tay-Sachs disease (infantile GM2 gangliosidosis), a fatal autosomal recessive disorder. Like Canavan disease, it predominantly affects individuals of Ashkenazi Jewish descent. It is caused by a deficiency of the enzyme hexosaminidase A, which leads to accumulation of the lipid GM2 ganglioside in the central nervous system. Clinical features include macrencephaly, cherry-red spots on the retinal maculae, weakness, developmental delay, seizures, and blindness, leading to death in early childhood. The macular findings were described by British ophthalmologist Warren Tay in 1881 and the clinical and pathologic findings were described by American neurologist Bernard Sachs in 1887.

Macrencephaly may also be seen with other GM1 and GM2 gangliosidoses. Sandhoff disease is a variant of Tay-Sachs disease in which GM2 ganglioside accumulates because of deficiency of both hexosaminidase A and B. The clinical manifestations are similar to those of Tay-Sachs disease, with the addition of visceromegaly.