Congenital Malformations, Perinatal Diseases, and Tumor Predisposition Syndromes

Clinical Features

The adult human brain weighs between 1200 and 1400 g, accounting for approximately 2 % of the total body mass, a considerably larger fraction than in any other primate. An expanded human brain, specifically the neocortex, likely explains many of the more complex cognitive, emotional, and social abilities in humans. Appropriate cortical development is determined by a tightly orchestrated process of neural stem cell proliferation, migration, organization, synaptogenesis, and apoptosis . Perturbation of any of these steps can lead to abnormalities of brain size, clinically manifesting as intellectual disability, autism spectrum disorders, and epilepsy typically manifesting in infancy or early childhood. The degree of neurologic or cognitive impairment generally correlates with the severity of the brain size abnormality.

Microcephaly and macrocephaly (or megalocephaly) are descriptive terms rather than specific diagnoses. Many different conditions have microcephaly or macrocephaly as a feature. The basic concept is explained here with the details left to sections on the specific underlying disorders. Clinically, the occipitofrontal circumference serves as a proxy to identify an alteration of brain size, but head circumference does not correspond with brain size in every case as the former is also influenced by head shape, normal development of which is dependent on a normal sequence of closure of the fontanelles and cranial sutures (details of which are beyond the scope of this chapter).

Microcephaly and microencephaly ( Figs. 4.1 and 4.2 ) are related terms referring to reduced head and brain size, respectively, with the cutoff being 2 standard deviations (SDs) below the mean for age and sex. Consideration must be made for intrauterine growth retardation, low birth weight, and body length. Brain growth drives cranial growth, and a small cranium and small brain occur in conjunction in most cases. We therefore discuss these conditions together under the term microcephaly. As mentioned earlier, for microcephaly and megacephaly, the degree of neurologic and intellectual deficits is directly proportional to the deviation from the mean; those having brain/head size 3 SD or more from the mean show the most severe clinical symptoms, while many with a head or brain size between 2 SD and 3 SD are clinically normal or show only subtle abnormalities.

Microcephaly can reflect an insult to the brain during intrauterine life, in which case head circumference is small at birth, or it can develop postnatally, with a normal head circumference at birth followed by failure of normal head growth thereafter. Microcephaly (or micrencephaly) (see Figs. 4.1 and 4.2 ) can be divided into (1) primary micrencephaly, which is thought to stem from decreased neuronal proliferation, or (2) secondary micrencephaly, which connotes a destructive process. Processes interfering with normal neuronal growth and proliferation (and hence causing primary microcephaly) include a variety of chromosomal disorders such as Down syndrome and other trisomies (see the section on trisomies later), malformations, and inherited factors, which may be either autosomal recessive or dominant. Secondary (destructive) microcephaly is frequently a consequence of external disruptive environmental factors such as prenatal exposure to ionizing radiation; intrauterine infections (toxoplasmosis, rubella, cytomegalovirus, and herpesvirus [TORCH]), human immunodeficiency virus, syphilis, and, most recently, ZIKA virus); maternal alcohol abuse; and maternal anticonvulsant therapy. Disruptions of synaptogenesis and myelination defects have also been implicated in secondary microcephaly. Postnatal deceleration in head growth may be a sign of metabolic (e.g., resulting from maternal phenylketonuria), nutritional, or neurodegenerative disorders, although some metabolic diseases may result in enlargement of the brain (see later). The diagnosis of the etiologies of microcephalies is under transformation with the wide availability of chromosomal microarrays (for structural chromosomal defects) and NGS-based targeted gene panels and whole exome sequencing. Metabolic or mitochondrial testing is also helpful in select cases.

Primary autosomal recessive microcephaly (microcephaly primary hereditary) has been associated with alterations in at least 60 genes/loci. A detailed list of all genes implicated is beyond the scope of this chapter, but brief organizing principles are described here.

The vastly expanded neocortex in humans is likely due to the presence of differentiation of the neural precursors into an inner and an outer radial glial population present in inner and outer subventricular germinal zones, respectively. This functional and physical differentiation is a hallmark of human brain development, with the outer radial glia either absent or highly diminutive in other mammals. Many of the implicated genes, when mutated, lead to premature displacement of radial glia to the outer subventricular zone, leading to an early exit from the cell cycle/reduced proliferative capacity of the displaced neural precursor cells, resulting in a reduction in the overall size of the brain.

Associated genes can be functionally divided into the following classes:

• 1.

  Genes involved in centrosome formation, orientation, and microtubule organization including (Abnormal Spindle Microtubule Assembly) ASPM, Microcephalin (MCPH1), WDR62, WDR73, cyclindependent kinase 5 regulatory associated protein 2 (CDK5RAP2), CASC5, CENPJ, STIL, CEP152, and KIF5C

• 2.

  Cytokinesis and cytoskeleton proteins including TUBA1A and TUBA2B

• 3.

  Mitotic chromosome structure formation including NCAPH, NCAPD2, and NCAPD3

• 4.

  Origin Recognition Complex including ORC1, ORC4, and ORC6

• 5.

  Chromosome stability and cell cycle regulation: BRCA1, BRCA2 , and CDK6

• 6.

  Kinetochore formation including CEP135

• 7.

  Cellular trafficking, fatty acid metabolism, lipid binding proteins including WDFY3

• 8.

  DNA repair genes: involved in Fanconi anemia (FANC A-N), Cockayne syndrome (ERCC6/8), and Xeroderma pigmentosa (ERCC1-5)

As mentioned earlier, many of these genes play an important role in centrosome localization, organization of the mitotic spindle, and completion of cytokinesis. Others affect transmembrane or intracellular transport, Wnt signaling, autophagy, apical polarity complex, and DNA damage-response signaling, which in turn affects cell proliferation, cell division, and apoptosis. The end result is reduced production of neuronal precursors from the progenitor pool by reduced proliferation or premature differentiation and early diminution of the proliferative pool. In general, there is some overlap between genes, which, when mutated, produce microcephaly and genes that may produce pachygyria, polymicrogyria, and/or lissencephaly, the most well-known of these being the tubulin genes, including TUBA1A and TUBA2B . Many of these mutations are inherited in an autosomal recessive fashion and are, therefore, more commonly seen in geographic locations with highly consanguineous populations (primarily in the Middle East and parts of South Asia).

Apart from monogenic microcephaly syndromes, chromosomal structural abnormalities have been associated with microcephaly (chromosomal microcephaly syndromes). X-linked examples of microcephaly syndromes have also been reported.

Clinically, as a rule, microcephalic patients show intellectual disability, but they may also exhibit symptoms such as seizures or hydrocephalus, related to the underlying cause of the small brain.

Radiologic Features

On neuroimaging, the features of microcephaly and macrocephaly reflect the underlying cause and are discussed in more detail later in the corresponding sections or elsewhere in this text.

Pathologic Features

A micrencephalic brain is 2 SD less than the age- and sex-related norm. It may have a normal gyral pattern, evidence of atrophy (see Figs. 4.1 and 4.2 ), or another pattern specific to the underlying abnormality (e.g., holoprosencephaly, lissencephaly, pachygyria, polymicrogyria, callosal abnormalities, as well as abnormalities of the cerebellum, brainstem, and basal ganglia). Gross/radiologic/clinical examination is hence helpful to identify the most likely genetic alteration.

Generalized megalencephaly ( Fig. 4.3 ) refers to increased brain weight (brain weight at birth > 2.5 SD above the age- and sex-related norm) and diffuse broadening of the cerebral gyri with increased white and gray matter volume. The ventricles are normal in size. Several types of microcephalics show simplified cortical gyration with anterior-posterior gradient, with the frontal cortex being the most affected. The brain is usually microscopically normal, although some reports have suggested increased cell density and increased volume of both gray and white matter structures. Megalencephaly with nodular heterotopia or polymicrogyria has also been reported.

MACROCEPHALY/MEGALENCEPHALY—PATHOLOGIC FEATURES

Gross Findings

• n

  May have normal gyration, polymicrogyria, or lissencephaly/pachygyria, depending on the underlying cause, or may have a relatively normal gyral pattern

• n

  The cerebellum may or may not be affected as well, depending on the cause of the small or enlarged brain

Microscopic, Ultrastructural, and Immunohistochemical Features

• n

  Depend on the underlying cause

• n

  Genetically heterogenous with a large number of associated single gene mutations and chromosomal structural alterations

Clinical Features

Neural tube defects (NTDs) are caused by incomplete neurulation (fusion of the neural folds) at any point in the neuroaxis at the end of the first 4 weeks of embryonic life. NTDs are among the most common malformations and account for 0.001 % to 1 % of all human malformations, depending on the population studied.

Neural tube formation involves bending of the neuroepithelium at the midline to generate neural folds that then fuse in the dorsal midline (primary neurulation). Neural tube closure is discontinuous; rather than simultaneously rolling up along the extent of the rostro caudal axis, there are distinct sites of initiation located at characteristic axial levels. NTDs can thus be caused by failure of particular initiation events or disruption of the progression of closure between these sites. Failure of neural tube formation leads to damage to the exposed neural tissue, the ensuing deficit depending on the region affected. Although theoretically a neural tube defect can arise from reopening of a previously closed neural tube, experimental data in animals support a disruption of closure as the pathogenic mechanism in NTDs.

Failure of neural tube closure can be complete, resulting in craniospinal rachischisis ( Fig. 4.4 ), limited to the cranial region resulting in anencephaly ( Fig. 4.5 ), or caudal, resulting in myelocele or spinal meningocele ( Fig. 4.6 ). NTDs usually occur at preferred points along the neuroaxis, although they can occur anywhere.

Encephalocele, meningocele, and meningomyelocele are abnormalities of skeletal development. Encephalocele is a herniation of the brain through a defect in the skull ( Fig. 4.7 ), while a meningocele is a protrusion of meninges from the vertebral column (meningomyelocele, if the spinal cord is also included). Spina bifida occulta is a defect in the dorsal bony elements of the vertebral column not involving the cord or meninges. Encephalocele can be an indication of a syndrome such as Meckel-Gruber syndrome, a ciliopathy with multiple CNS abnormalities, the most common of which is an occipital encephalocele, present in close to 90% of the cases ( Fig. 4.8 ). Other common malformations in Meckel-Gruber syndrome include multicystic kidneys, hepatic fibrosis, and polydactyly (see Fig. 4.8 ).

For all NTDs, the clinical deficits naturally relate to the level of involvement. The most severe NTDs, such as craniorachischisis and anencephaly, are incompatible with life, and many cases are electively aborted following identification on prenatal ultrasound. Anencephalic infants who are born alive show only rudimentary brainstem reflexes and die soon after. Encephaloceles, especially those involving the frontal cortex, may be asymptomatic until adult life, when intranasal mass, pharyngeal obstruction, or recurrent meningitis develops. Facial abnormalities or hypothalamic dysfunction can be seen. Occipital region encephaloceles may include the cerebellum or calcarine cortex (or both) and may present with visual defects or cerebellar signs. Those involving the brainstem may be life-threatening. The presence of cortex within or adjacent to the displaced brain tissue may cause seizures. Spinal dysraphisms (meningocele, meningomyelocele) generally lead to paralysis and sensory deficit below the level of the lesion, as well as bladder and bowel dysfunction. Defects at or above L2 are usually accompanied by skeletal deformities, including kyphosis and scoliosis, dislocated hips, and clubfeet. Moreover, open spinal NTDs are nearly always associated with hindbrain crowding leading to displacement of the cerebellar vermis into the foramen magnum and hydrocephalus, a combination known as the Chiari II (or Arnold-Chiari) malformation ( Figs. 4.9 and 4.10 ). Pure spinal meningoceles (i.e., not involving spinal neural tissue) may be asymptomatic.

Prenatal detection of NTDs relies on screening by serum and amniotic chemistry and prenatal ultrasound. Elevated maternal serum or amniotic fluid α-fetoprotein and increased amniotic fluid acetylcholinesterase are found in almost all cases with “open” NTDs (i.e., those lacking a covering of skin over the exposed meninges or central neuroglial tissue). Even though α-fetoprotein levels are highly sensitive for open NTDs, they are not specific; if combined with acetylcholinesterase determination, however, the specificity is improved. Fetal ultrasonography as early as 14 to 16 weeks’ gestation can detect the defects themselves if large enough, as well as associated changes (see the next section). High-level fetal ultrasonography, fetal magnetic resonance imaging (MRI), and amniocentesis may be required for confirmation. Polyhydramnios is a common, although inconsistent, finding in pregnancies with NTDs.

Both genetic and environmental risk factors have been associated with neural tube closure defects. Genetic composition may also modify the teratogenic risk of environmental factors. In recent years, folic acid deficiency has been demonstrated as the major modifiable environmental risk factor for NTDs. The reduction in risk of NTDs following maternal folic acid supplementation led to public health recommendations that women who may become pregnant should consume 0.4 mg of folic acid daily or 4 mg daily following a previous affected pregnancy. Other risk factors include maternal diabetes, obesity, hyperthermia, vitamin deficiency, and anticonvulsant therapy with valproic acid and carbamazepine. Genetic risk factors for NTD cluster on genes involved in folate metabolism. Folate metabolism is important for several important cellular processes such as methylation of DNA and other macromolecules and nucleotide biosynthesis for cell division. Polymorphisms in the 5,10-methylene tetrahydrofolate reductase (MTHFR) gene are involved with increased risk of NTDs. Mitochondrial folate metabolism is likely a major contributor of substrate for cytosolic folate metabolism. Alterations in genes involved in mitochondrial folate metabolism have recently been identified in cases of NTD.

Radiologic Features

Anencephalic fetuses are easily recognized on prenatal ultrasound or fetal MRI by absence of the cranial vault, prominence of the orbits and eyes, and a flattened, downwardly sloping appearance of the skull base ( Fig. 4.11 ). Likewise, encephaloceles in the frontal, parietal, or occipital regions may be readily detected by either method (see Fig. 4.7 ). Nasal or ethmoidal (anterior) encephaloceles may be difficult to identify by prenatal ultrasound or even by computed tomography (CT) in the neonatal period because the anterior skull base is primarily cartilaginous. MRI using 2- to 3-mm sections and T1- and T2-weighted images may be useful.

Spinal defects may be identified by prenatal ultrasound as focal loss of normal echogenicity of the posterior vertebral elements; a meningocele is a hypoechoic mass of variable size and may or may not have denser material corresponding to dysraphic neural tissue. Fetal MRI easily demonstrates the spinal mass. Associated changes, such as a small posterior fossa and herniation of cerebellar tissue into the foramen magnum and cervical canal, can be clues to the Chiari II malformation, even if the spinal myelomeningocele is not well seen. (See Fig. 4.10 in section on Chiari malformations.)

On plain radiographs, spinal NTDs show absence of the dorsal spinous processes with lateral splaying of the transverse processes, findings lending an “unzipped” appearance to the spine.

Pathologic Features

Complete absence of the brain and overlying skull is known as anencephaly (see Fig. 4.5 ). The calvarium is severely hypoplastic or totally absent. There is almost complete loss of brain parenchyma with only scant supratentorial tissue. The scalp, cranium, and most of the brain is replaced by a thin film of vascular tissue referred to as area cerebrovasculosa, which consists of a jumbled mix of nervous system tissue consisting mostly of glia, thin-walled vessels, ependymal and meningeal elements, and attenuated skin (see Fig. 4.5 ). It is thought that this substance remains after degeneration of the brain tissue at the “open” edges of the defect because of direct contact between the neural epithelium and amniotic fluid. Some cases show relative sparing of the infratentorial brain. The anterior pituitary and brainstem are relatively preserved in most cases. The orbits are shallow, causing protrusion of the eyes (see Fig. 4.5 ).

Encephaloceles (containing brain and meningeal tissue) (see Figs. 4.7 and 4.8 ) and cranial meningoceles (harboring only meninges and often filled with CSF, similar to a cyst) are associated with a defect in the skull, usually at the midline sutures or fontanelles. Occasionally, no clear bony defect or contiguity with the underlying brain can be identified. Herniation may contain fragments of disorganized CNS glia and ependyma or large portions of the cerebral hemispheres with ventricular cavities, as well as cerebellum or brainstem. Polymicrogyric cortex may be present at the edges of the displaced brain tissue and may generate seizure activity. The size of the encephalocele can vary from an inconspicuous bump to a mass larger than the infant’s head. Occipital encephaloceles are associated with Meckel-Gruber syndrome in a vast majority of cases. Parietal encephaloceles occur only rarely.

Spinal NTDs can involve the meninges alone (meningocele) or the meninges and underlying spinal cord (myelomeningocele) (see Fig. 4.6 ). Most NTDs occur in the lumbar region, followed by the lumbosacral region, but they can also be located at the cervical or thoracic level. Those arising in the lumbosacral region are often associated with other defects in the surrounding mesoderm, including vascular telangiectasis and other abnormalities of the spinal cord, such as hydromyelia (cystic dilation of the central canal) and syringomyelia (a glial-lined cavity within the parenchyma of the spinal cord). These lesions may extend rostrally to involve the brainstem (syringobulbia). It should be noted that these conditions are not specific to NTDs and can be found after trauma or in association with spinal tumors.

Iniencephaly (inien = nape of neck; encephaly = brain) represents an extreme retroflexion of the head with an intact, skin-covered cranium. Iniencephaly is caused by failure of closure of the posterior vertebral arches of the rostral cervical vertebrae. Iniencephaly is usually associated with abnormalities of the brainstem and the medulla and is often accompanied by an open defect, which can be an encephalocele or spina bifida. There is shortening of the spinal column with marked lordosis and hyperextension of the malformed cervical thoracic spine ( Fig. 4.12 ).

Diplomyelia refers to duplication of the spinal cord segments ( Fig. 4.13 ), occasionally in association with myelomeningocele; midline pegs of vertebral bone and connective tissue may result in partial duplications or splitting of the cord (diastematomyelia) (see Fig. 4.13 ).

Spinal NTDs can be occult (spina bifida occulta), defined as a defect in the dorsal bony elements of the vertebral column not involving the cord or meninges. Spina bifida occulta may be found only incidentally on radiographic studies, or it may be suspected on finding a tuft of hair, cutaneous angioma, or subcutaneous lipoma in the midline of the back overlying the occult bony defect. Occasionally, a sinus tract may communicate between the skin and underlying thecal sac.

The Chiari II (or Arnold-Chiari) malformation consists of the association of a spinal NTD with a small posterior fossa, hindbrain crowding, and secondary abnormalities of the brainstem and cerebellum (discussed later with posterior fossa malformations).

NEURAL TUBE DEFECTS—PATHOLOGIC FEATURES

Gross Findings

• n

  Anencephaly: absence of the cranium and most of the brain tissue with replacement by area cerebrovasculosa; the eyes are protuberant

• n

  Encephaloceles: vary in size from small skin-covered bumps to large masses overlying the cranial sutures/fontanelles or in the sinonasal region

• n

  Spinal defects: may be skin-covered (occult) defects in vertebral body closure or open plaquelike areas in which neural tissue and nerve roots are visible (placode), with surface covering by area medullovasculosa

• n

  Chiari II malformation: midline cerebellar tissue displaced into the foramen magnum dorsally, small posterior fossa and cerebellar hemispheres, flattened or kinked brainstem, variable expansion of the ventricular system

Microscopic Features

• n

  Area cerebrovasculosa (in anencephaly) or medullovasculosa (in spinal NTDs) is made up of ectatic, thin-walled vessels in loose connective tissue, often containing disorganized central neuroglial tissue

• n

  Spinal NTDs may contain peripheral nerve bundles

• n

  With encephaloceles, the brain, often disorganized, and the overlying meninges are in contact with dermal tissue (i.e., no intervening bone)

• n

  The cerebellum, especially the vermis, may be disorganized in Chiari II malformation

Genetics

• n

  Genetically heterogeneous, associated with various different syndromes

Differential Diagnosis

• n

  For anencephaly, amniotic band sequence with disruption of the normally closed cranial vault

• n

  For meningocele, aplasia cutis congenita (localized defect in the dermal and subcutaneous tissue of the scalp), which can show meningeal tissue, but an underlying skull defect is not found

Differential Diagnosis

The diagnosis of an NTD is usually straightforward, except in rare cases of small encephaloceles, dural sinus tracts, or aplasia cutis congenita, in which bony skull defects can occur without the protrusion of meningeal or central neuroglial tissue. Caudal lipomas, teratomas, and dermoid cysts, although often markers of an underlying spinal dysraphism, can occur in isolation.

Amniotic band sequence results when a fibrous band from the placental amniotic membrane entraps various fetal parts in utero, physically cuts through organs, and can lead to amputations and clefts by occluding the blood supply. Asymmetric clefts, body wall defects, often with extrusion of viscera, and highly variable amputations can be seen. When the amniotic membrane wraps around the skull, loss of cranial tissue and brain results, leading to striking resemblance with anencephaly. Such amniotic band disruptions can be distinguished from true NTDs by the asymmetry of involvement and the presence of facial clefts or extremity amputations ( Fig. 4.14 ).

Prognosis and Therapy

Anencephalic fetuses have a high incidence of intrauterine demise and, if liveborn, die within a few hours.

If a dysraphic disorder has been diagnosed prenatally and the pregnancy continued, an atraumatic delivery may be planned to improve the neurologic outcome in children with myelomeningoceles. Large encephaloceles may also be managed in this way, although the clinical context in which they occur (i.e., associations and syndromes) also influences decision making. Overall, surgical excision is recommended to prevent breakdown of skin over the lesion (particularly in occipital encephaloceles) and secondary infection, including meningitis, in the affected infant. The prognosis is significantly better with anterior (sinonasal) encephaloceles, which may be asymptomatic.

Spinal dysraphism is best treated by surgical closure as soon after birth as feasible, again to prevent infection and limit the extent of disability, because cognitive function in survivors of spinal NTDs has been shown to be negatively affected by meningitis or ventriculitis. The degree of ambulatory problems depends on the spinal level of the lesion. Other significant clinical issues involve recurrent upper and lower urinary tract infections and hydrocephalus, which often requires shunting. Late sequelae of myelomeningoceles include scoliosis and traction on the cord from tethering at the level of the defect, the latter occurring either as a “primary” abnormality or as a consequence of previous surgery and scarring. In either case, surgical release of the tethered cord is recommended to prevent exacerbation of deficits. Less commonly, infarction or compression of the cord by arachnoid cysts or inclusion cysts arising in the scar can be encountered.

Treatment of spinal dysraphism has historically involved surgical closure after birth; however, with advancements in prenatal diagnosis and improvement in surgical and anesthetic techniques, maternal-fetal surgery for in-utero correction of neural tube defects is increasingly being attempted.

Clinical Features

Holoprosencephaly (HPE) refers to a spectrum of primary malformations resulting from failure of the forebrain (prosencephalon) to bifurcate into two hemispheres. HPE is a defect of normal forebrain induction/patterning likely arising in the fifth week of gestation. HPE is relatively common with an estimated incidence of approximately 0.48 to 0.88 per 10,000 liveborn children with normal chromosomes. There is a high rate of fetal loss with the incidence of HPE in intrauterine demise estimated at 40 per 10,000.

In addition to variable degree of failure of midline division “holosphere” or undivided prosencephalic vesicle, patients frequently exhibit specific craniofacial anomalies ( Fig. 4.15 ) because of the interrelated development of the forebrain and underlying mesodermal structures. Midline facial clefts, cyclopia, and nasal anomalies (see Fig. 4.15 ) are commonly seen. The severity of facial malformation often predicts the degree of brain abnormalities (“the face predicts the brain”). Especially in the most severe forms, the same failure of induction of midline structures may be reflected in abnormal midline facial features. The so-called “microform” HPE shows craniofacial anomalies without accompanying structural brain defects.

HPE is likely an early malformation resulting from abnormal patterning of the prosencephalon by the mesodermal floor plate in the fifth to sixth gestational weeks. HPE is thought to result from the failure of induction of midline structural specification. Early clues to the involvement of environmental factors were provided by an outbreak of cyclopia in lambs in the early 1960s, which was linked to the teratogenic effect of the alkaloid cyclopamine in a forage plant on which the pregnant ewes were feeding. The cause of the defect was eventually discovered to be disruption of sonic hedgehog (SHH) signaling and cholesterol biosynthetic pathways by the toxin. In humans, well-established environmental/maternal factors include maternal diabetes and ethanol consumption, although the pathogenic mechanisms are still unclear.

The effect of genetic factors was hinted at by the fact that the malformation runs in families, although the degree of involvement among affected individuals can vary widely within the same family. Recently, the application of modern NGS technologies has increased our understanding of the genetic underpinnings of HPE. We now know that as many as 75 % of cases have a recognizable genetic etiology. Half of the cases have cytogenetic/chromosomal alterations, of which trisomy 13 and triploidies account for the majority of cases. Trisomy 18 and other chromosomal anomalies are less common. The second group, accounting for close to 25 % of cases, consists of syndromic patients who manifest HPE in addition to other systemic abnormalities. Some of these include Smith-Lemli-Opitz, Meckel, and velocardiofacial syndromes. The best known of the syndromes with HPE is Smith-Lemli-Opitz syndrome, a defect of cholesterol biosynthesis which is due to autosomal mutations in the DHCR7 gene. CNS abnormalities include midline malformations such as HPE and agenesis of corpus callosum. Systemic findings include severe hypocholesterolemia, craniofacial defects such as anteverted nostrils and ptosis of eyelids, skeletal anomalies such as syndactyly of second and third toes, and visceral abnormalities including hypospadias and cryptorchidism in males.

Single gene defects and small structural alterations explain most of the remaining HPE cases. Most genes implicated in HPE play a part in the SHH pathway, which regulates ventral development in both the forebrain and spinal cord. These include SHH and members of its downstream signaling pathway including Patched-1 (PTCH), SIX3, and GLI2. Other genes such as TGIF, TDGF1/crypto, and FAST1 are involved in the Nodal/TGFbeta signaling pathway, which plays a vital role in neural patterning.

The pathogenesis of the HPE sequence has been shown to be related to failure of induction of the ectoderm overlying the ventral neural tube by the notochord. The notochord secretes the signaling molecule SHH, which mediates ventral patterning of the midbrain and forebrain. SHH also appears to directly participate in craniofacial and eye development.

Radiologic Features

While prenatal ultrasound remains the most commonly used imaging modality, it is unable to diagnose less severe cases on the HPE spectrum. MRI is more sensitive. In alobar HPE, prenatal and transfontanelle sonograms and fetal MRI may demonstrate absence of the falx cerebri and interhemispheric fissure, as well as a crescent-shaped holoventricle and fused diencephalon ( Fig. 4.16 ). By ultrasound, semilobar HPE may show disordered cerebral cortical gyration and thalamic midline fusion, with or without a dorsal cyst. In semilobar HPE, the posterior portion (splenium) of the corpus callosum forms normally, whereas the anterior (body and genu) is absent, best seen on sagittal T1-weighted MRI; this pattern is opposite the situation in partial callosal agenesis ( Fig. 4.17 ; see the section later on midline/commissural defects). The septum pellucidum is absent on MRI in both the alobar and semilobar forms. Arhinencephaly is detectable on MRI as absence of the olfactory sulcus and tracts; CT may demonstrate absence or hypoplasia of the nasal bones.

Pathologic Features

The essential feature of all forms of HPE is incomplete separation of midline structures, which can range from isolated absence of the olfactory bulbs and tracts (arhinencephaly) to total absence of the interhemispheric fissure in alobar HPE. Virtually all except the mildest forms of HPE show a smaller brain size (micrencephaly) with brain weight averaging about 100 g at term in alobar HPE (normal, 380–410 g). The olfactory bulbs and tracts, as well as the straight sulci, are absent in virtually all cases (arhinencephaly). The optic nerves may be hypoplastic, or fused in the case of cyclopia, whereas the remaining cranial nerves are usually normally formed. The middle and anterior cerebral arteries may be disorganized. A single anterior cerebral artery may course over the rostral midline of the cerebral hemispheres. There is a tendency for sparing of the temporal lobes in some of the milder variants.

Classification into alobar, semilobar, and lobar forms is based on the presence and extent of the midline interhemispheric fissure. In alobar HPE, the interhemispheric fissure separating the two cerebral hemispheres is absent, as are the Sylvian fissures. There is generally no delineation of the lobes of the cerebral hemisphere ( Fig. 4.18 ). In infants and older individuals, the gyri are usually distinct; however, their patterns are abnormal. Viewed posteriorly, the cerebrum is shaped like a horseshoe, with the rim contiguous with the cystlike membrane representing the roof of the single midline ventricle. The basal ganglia and thalamus lie beneath the membrane and vary from distinct paired structures to poorly defined masses that are fused along the midline. Rarely, the basal ganglia cannot be identified. The corpus callosum and anterior commissure are generally absent; however, rudimentary crossing fiber bundles may occasionally be seen. The brainstem and cerebellum are relatively normal, except for hypoplastic or absent corticospinal tracts.

Semilobar HPE represents a lesser degree of the same CNS malformation. Usually, a partial interhemispheric fissure separates the parieto-occipital lobes, whereas the cerebral cortex crosses the midline in continuity over the frontal lobes ( Fig. 4.19 ). Variable degrees of midline fusion of diencephalic structures may be demonstrable. Occasionally, the separated parieto-occipital lobes may have an intervening dorsal midline cyst.

Lobar HPE is characterized by an interhemispheric fissure that divides virtually the entire brain with the exception of the most rostral and ventral regions of the frontal lobes. Beneath the apparent interhemispheric fissure, however, cerebral cortex may still cross the midline ( Fig. 4.20 ). There may be a segment of well-developed corpus callosum posteriorly where the cerebral hemispheres are truly separated. The lobes of the cerebral hemispheres may have a nearly normal pattern. Cross sections of the brain continue to show abnormal communication between the lateral ventricles with fusion of the basal ganglia rostrally. The thalami may have an enlarged massa intermedia or be completely fused.

A relatively newly described variant is the middle interhemispheric variant or syntelencephaly, which shows failure of separation at the posterior frontal and parietal lobes, while the poles of the frontal and occipital lobes are well separated. The caudate nuclei and thalami are often incompletely separated.

Microscopically, the cytoarchitecture of the cerebral cortex may be normal, although displaced from its usual location. For example, the inferomedial aspect of the lip of the holosphere may contain hippocampal structures and entorhinal cortex. Some cases, however, may have significant disorganization of the cerebral cortex, possibly representing abnormal cell migration, secondary injury to the cerebral cortex, or an abnormality in connections into and out of the cerebral cortex. In alobar HPE, the basal ganglia may be microscopically unidentifiable or recognized only as a fused midline mass with disorganized cytoarchitecture. In less severe forms of HPE, the basal ganglia are present, although the head of the caudate may be fused and the septal region indistinct. The septum pellucidum is generally absent in all forms. Microscopically, the cerebellum may have focal cortical disorganization or heterotopia. Abnormalities of the brainstem are limited to hypoplastic or absent corticobulbar and corticospinal tracts or fused colliculi or peduncles at the midbrain level. Presumably in some instances, the implicated patterning molecules are shared between the forebrain and more caudal diencephalic and even midbrain structures. Depletion of certain GABAergic interneuron populations (those expressing nitric oxide synthase 1 (NOS1), neuropeptide Y (NPY), and somatostatin (SST) has been reported in HPE, which can be explained by abnormal development of the ganglionic eminences, part of the germinal matrix that produces GABAergic neurons.

As mentioned earlier, in most cases, the severity of facial abnormalities predicts the severity of underlying brain abnormalities. For example, the mildest craniofacial abnormality, such as a single midline maxillary incisor, might be associated with arhinencephaly, whereas at the other end of the spectrum, complete alobar HPE may be associated with cyclopia—a single orbit with one or partially divided eyes and a proboscis, an abnormally formed and placed nose, above the eye (see Fig. 4.15A ). In the semilobar forms, the facial abnormalities may include cebocephaly (elongated nose with a single nostril) and hypotelorism (abnormally close-together eyes) (see Fig. 4.15B ). Cases with less severe facial abnormalities that have no visible brain alterations are termed “HPE microforms” and are generally associated with normal or near normal cognitive development.

HOLOPROSENCEPHALY SEQUENCE—PATHOLOGIC FEATURES

Gross Findings

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  Absence of the olfactory bulbs and tracts and straight sulci of the orbitofrontal cortex in arhinencephaly, as well as in the more severe forms

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  Fusion of the inferior frontal cortex and occasionally the basal ganglia across the midline in lobar holoprosencephaly

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  Absence of the anterior interhemispheric fissure with continuity of the cerebral convolutions across the midline and thalamic or more extensive diencephalic fusion in semilobar holoprosencephaly

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  Complete absence of the interhemispheric fissure, septum pellucidum, and corpus callosum (holosphere) with fusion of the diencephalon and absence of the third ventricle; occasional fusion of the optic nerves (in cyclopia)

Microscopic Features

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  The inferomedial aspect of the lip of the holosphere may contain hippocampal structures and entorhinal cortex

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  Some cases have abnormalities in cerebral neocortical cytoarchitecture, as well as pia/subarachnoid glioneuronal heterotopia

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  Certain subpopulations of GABAergic interneurons may be depleted/reduced owing to hypoplastic germinal matrix

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  Fused diencephalic structures have disorganized neuronal cytoarchitecture

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  The brainstem and cerebellum are usually spared

Genetics

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  Associated with cytogenetic/chromosomal alterations including trisomies 13 (up to 35% of all cases), less commonly trisomy 18 and triploidy

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  Can be a feature of a variety of different syndromes (25% of all holoprosencephaly cases)

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  Inherited or de-novo mutations in SHH or nodal/TGFbeta pathway genes

Prognosis and Therapy

Surviving liveborn infants with the most severe variants (alobar HPC) generally have profound mental retardation and often suffer from seizures, which may be difficult to treat. They may have apneic spells and hypothalamic dysfunction with diabetes insipidus, poikilothermy, and inappropriate secretion of antidiuretic hormone. Their life span can be reduced. Patients with intermediate forms of HPC and pure arhinencephaly may have a normal life span and limited clinical deficits, such as cognitive delay and seizures.

Radiologic Features

Because the corpus callosum develops rostral to caudally after the telencephalic commissural fibers cross over between the 11th and 20th weeks of gestation, agenesis of the corpus callosum can be seen even in early prenatal ultrasonograms as a “bat wing” configuration of the ventricles. Prenatal MRI can readily illustrate the ventricular configuration ( Fig. 4.25 ) and, often, any associated structural brain and facial anomalies. In neonates and adults, MRI in the sagittal and coronal planes best demonstrates the abnormalities. An interhemispheric cyst, when present, has imaging qualities similar to those of CSF, along with a wall that may cause a mass effect on the adjacent cerebral hemispheres.

In septo-optic dysplasia, the optic canals may be small on CT or plain radiographs, although hypoplasia of the optic system may be difficult to resolve. The septum pellucidum is absent on CT or MRI, and the third ventricle and foramen of Monro may be markedly enlarged.

Prognosis And Therapy

Since isolated callosal agenesis may be asymptomatic and only incidentally discovered, the other neuropathologic abnormalities associated with the lesion determine the clinical course.

Radiologic Features

In FCD type I, the dyslamination and disrupted architecture do not significantly alter cellular density. Consequently, MRI may show no visible changes in the cortex. Blurring of the gray-white matter junction can be seen due to neuronal dispersion into the U-fiber layer. FCD type II shows more prominent imaging abnormalities including cortical thickness abnormalities, hyperintensities of the cortex and subcortical white matter, blurring of the gray or white matter, and sulcal hypoplasia. A characteristic finding in FCD II is the transmantle sign, which is more often seen in FCD type IIb (see Fig. 4.43 ).

Radiologic Features

In type I lissencephaly, the normal gyral and sulcal pattern is effaced by a smooth agyric surface on imaging (see Fig. 4.34 ). Overall volume of cortical gray matter and white mater is reduced, and the cerebral cortex is markedly thickened. Cases with DCX mutation show a layer of white matter separating a thin cortical layer from a deeper swath of gray matter representing arrested neurons. A diffuse pattern of such gray matter duplication (“double cortex”) corresponds to the pathologic finding of subcortical band heterotopia (see Fig. 4.31 ). In so-called incomplete lissencephalies (with or without 17p mutations), pachygyric and agyric areas may coexist along with shallow, vertical Sylvian fissures. In X-linked lissencephaly, the posterior cerebral lobes are relatively spared, in contrast to the agyria and pachygyria anteriorly. Of course, care must be taken when reviewing prenatal MRI and ultrasonography because the cortex is normally free of convolutions until 18 to 20 gestational weeks.

In WWS and MEB disease (type II lissencephalies), hydrocephalus is seen frequently, as well as patchy white matter hyperintensity on T2-weighted MRI. The irregular, fine nodularity of the cortex at the gray-white junction corresponds to the cobblestone pattern seen on pathologic evaluation. In FCMD, MRI of the brain demonstrates areas of pachygyria and polymicrogyria, as well as regions of abnormal T2 signal in white matter. The white matter is hypodense on CT.

Periventricular nodular heterotopia appears as irregular nodules of gray matter signal intensity along the ventricular surfaces (see Figs. 4.28 , 4.29 ).

Differential Diagnosis

As mentioned earlier, the Miller-Dieker phenotype is distinguished from isolated lissencephaly sequence by the lack of distinctive facial features in the latter, although bitemporal hollowing and a small chin may be seen in some patients with isolated lissencephaly sequence. The distinction between these two entities is not entirely straightforward, inasmuch as microdeletions detected by fluorescent in situ hybridization have been seen in a significant number of patients with isolated lissencephaly sequence, thus suggesting a relationship to Miller-Dieker syndrome.

The differential diagnosis of the lissencephaly type II syndromes is complex, as reflected in the many essentially synonymous designations of these entities, including the MEB, HARD ± E (hydrocephalus, agyria, retinal dysplasia, with or without encephalocele), and CODM (congenital ocular dysplasia/muscular dystrophy) syndromes, which share phenotypic features. FCMD, despite many similar features, does not usually include the severe eye and brain anomalies found in WWS. If clinically important, distinction among these entities can be assisted by genetic studies.

Cortical anomalies recapitulating the syndromic features of lissencephaly, pachygyria, and polymicrogyria can be seen as components of several other entities. Specifically, Zellweger syndrome, a disorder of peroxisomal biogenesis characterized by neonatal hypotonia, facial dysmorphism, open fontanelles, and renal and hepatic abnormalities, has both lissencephalic/pachygyric and polymicrogyric cortical changes ( Fig. 4.45 ). The related peroxisomal disorders, neonatal adrenoleukodystrophy, rhizomelic chondrodysplasia punctata, and bifunctional enzyme deficiency may show migrational abnormalities. The metabolic abnormalities, glutaric aciduria type II, pyruvate dehydrogenase deficiency, nonketotic hyperglycemia, and sulfite oxidase deficiency/molybdenum cofactor deficiency, are examples of other metabolic disorders that occasionally demonstrate cortical dysplasia. Assays for long chain fatty acids are diagnostic of the peroxisomal disorders; complementation studies, although not widely available, may be confirmatory and allow precise biochemical characterization.

Polymicrogyria may also occur in various settings, including lissencephaly type II conditions and the Aicardi, Neu Laxova, and Smith-Lemli-Opitz syndromes (see the earlier section on holoprosencephaly sequence), thus reflecting the nonspecific nature of the malformation. In addition, polymicrogyria can occur in a variety of chromosomal abnormalities and in disruptions (see the corresponding sections). Likewise, neuronal heterotopia and focal cortical dysplasia may accompany many of these same syndromes.

Both periventricular and subcortical band heterotopia can occur as X-linked inherited conditions, although they map to different regions on the X chromosome. In familial band heterotopia, affected females are found to have heterotopia and often seizures, whereas affected males show more severe brain malformations, including lissencephaly. This sex difference is thought to result from random X chromosome inactivation in females, in which full expression of the defect is prevented and a spectrum of developmental disturbances from focal heterotopia to lissencephaly can occur.

Prognosis and Therapy

Feeding problems, respiratory infections, and status epilepticus are thought to contribute to the high mortality rate of approximately 50 % up to the age of 10 years in LIS1-associated lissencephaly.

As mentioned earlier, eye involvement (myopia, infantile glaucoma, retinal and optic nerve hypoplasia, coloboma, and cataracts) is commonly seen, along with mental retardation and seizures in patients with lissencephaly type II. In FCMD, like other congenital dystrophies, the onset of marked diffuse weakness and hypotonia, facial weakness, and joint contractures is noted in the neonatal period, with mortality approaching 50 % in infancy. In WWS and MEB disease, mortality is also quite high in the first months of life. There are no specific therapies for any of the neuronal migration defects, although surgery to remove the localized malformation may be effective for seizure control in cases of focal cortical dysplasia.

Clinical Features

Hindbrain malformations account for a significant proportion of all CNS anomalies. The use of second-trimester ultrasonography for dating and monitoring of asymptomatic pregnancies has led to prenatal detection of posterior fossa abnormalities, primarily Dandy-Walker malformations, and an increased incidence of these findings among abortuses.