Abstract
The prosencephalon develops at the rostral end of the recently closed neural tube, starting early in the second month of gestation. Through a series of cleavages, the prosencephalon develops the optic and olfactory apparatus and divides transversely into the telencephalon (which then divides in the sagittal plane to form the cerebral hemispheres) and the diencephalon (which goes on to form the thalamus, the caudate nucleus and putamen, and the hypothalamus). Developmental disturbances of the prosecephalon result in some of the most common (agenesis of the corpus callosum) and most profound (e.g., holoprosencephaly) clinical conditions confronting the child neurologist. Advances in fetal and neonatal imaging have significantly increased our understanding of the spectrum of prosencephalic malformations and their associated conditions.
Normal Prosencephalic Development
Prosencephalic development, the major event following neurulation, results in structures most recognizable as the essential form of the central nervous system. Thus, these structures rostral to the other major vesicles of the brain, that is, the midbrain (mesencephalon) and hindbrain (rhombencephalon), will ultimately form the cerebral hemispheres and diencephalic (e.g., thalamus, hypothalamus) structures. Prosencephalic development peaks between the second and third months of gestation, with the earliest prominent phases in the fifth and sixth weeks of gestation ( Box 2.1 ). The major inductive relationship of concern is between the notochord-prechordal mesoderm and the forebrain (see Box 2.1 ). This interaction occurs ventrally at the rostral end of the embryo; thus the term ventral induction is sometimes used. The inductive interaction influences formation of much of the face as well as the forebrain ; hence severe disorders of brain development at this time also usually result in striking facial anomalies. Development of the prosencephalon is considered best in terms of three sequential events (i.e., prosencephalic formation, prosencephalic cleavage , and prosencephalic midline development ) ( Box 2.1 ). Prosencephalic formation begins at the rostral end of the neural tube at the end of the first month and the beginning of the second month, shortly after the anterior neuropore closes. Prosencephalic cleavage occurs most actively in the fifth and sixth weeks of gestation and includes three basic cleavages of the prosencephalon: (1) horizontally, to form the paired optic vesicles, olfactory bulbs, and tracts; (2) transversely, to separate the telencephalon from the diencephalon; and (3) sagittally, to form, from the telencephalon, the paired cerebral hemispheres, lateral ventricles, and basal ganglia ( Box 2.1 ). The third event, prosencephalic midline development , occurs from the latter half of the second month through the third month, when three crucial thickenings or plates of tissue become apparent ( Fig. 2.1 ); from dorsally to ventrally, these are the commissural, chiasmatic, and hypothalamic plates. These structures are important in the formation, respectively, of the corpus callosum and the septum pellucidum, the optic nerve chiasm, and the hypothalamic structures. The most prominent of these midline developments is formation of the corpus callosum, the earliest components of which appear at approximately 9 weeks ( Fig. 2.2 ). Initial development of the corpus callosum is dependent on support of the receding mesenchymal tissue of the meninx primitiva, which initially encases the entire forebrain. At 10 weeks’ gestation, glial cells begin to migrate from the subventricular zone toward the medial surface of the developing cerebral hemispheres. At 12 weeks, these glial fibers cross the midline through the meninx primitiva to form a transient glial sling across the future interhemispheric fissure. Between weeks 12 and 13, the first pioneer axons from the cingulate cortex cross through this glial sling. The early cortical axons are attracted to the midline by specialized glial cells that express chemoattractants of the Netrin family. This interhemispheric migration is orchestrated by a complex system of cellular and molecular chemoattractant and repellent signals. After crossing, these axons do not recross because of the expression of the chemorepellent protein Slit, which activates the Roundabout (Robo) receptor. By 14 weeks, all the individual components of the corpus callosum are formed. At this point there are essentially two distinct segments of the corpus callosum (anterior and posterior), which eventually fuse at the isthmus. With massive expansion of especially the frontal neocortex, the corpus callosum expands in the rostrocaudal axis with backward displacement of the splenium.
Peak Time Period
2–3 months
Major Events
Prechordal mesoderm → face and forebrain
Prosencephalic development
Prosencephalic formation
Prosencephalic cleavage
Paired optic and olfactory structures
Telencephalon → cerebral hemispheres
Diencephalon → thalamus, hypothalamus
Midline prosencephalic development
Corpus callosum, septum pellucidum, optic nerves (chiasm), hypothalamus
This development is followed by formation of the genu and finally, posteriorly, the splenium. The basic structure is completed by approximately 20 weeks of gestation. Subsequent thickening of this structure occurs as a result of the growth of crossing fibers during organizational events (see later).
Prosencephalic development occurs by inductive interactions primarily between the notochord-prechordal mesoderm and the forebrain ( Box 2.1 ). This inductive interaction influences formation of much of the face as well as the forebrain ; hence severe disorders of brain development at this time may result in striking facial anomalies. Major insights into the molecular genetic determinants of forebrain development have been gained in recent years. The genes involved are crucial for dorsoventral patterning in the developing forebrain. Three signaling pathways play a prominent role in forebrain development—that is, Sonic hedgehog ( Shh ), Nodal, and retinoic acid pathways. There is significant cross-regulation between these pathways, which has important implications for forebrain development. The major events are regulated through the opposing ventralizing ( Shh ) and dorsalizing ( Notch ) influences of this interaction. In addition, forebrain development and cleavage is dependent on a delicate balance between Shh and fibroblast growth factor ( Fgf ) expression.
The Shh signaling pathway is the most important molecular pathway in prosencephalic development and induces developmental events through critical ventralizing molecules. Shh is initially secreted by the notochord and prechordal mesoderm to induce ventral patterning of the developing neural tube. Before secretion, cholesterol is required to modify Shh at its C-terminus (an event relevant to causes of holoprosencephaly; see later). Secreted Shh activates the Patch receptor, which, in turn, leads to activation of several other genes (e.g., GLI2 ) and transcription factors that enter the nucleus to modify gene transcription.
A second major molecular pathway, the so-called nodal pathway , is initiated by bone morphogenetic proteins, which are key dorsalizing molecules. The transcriptional regulators induced in this pathway include TGIF , TDGFI , and FASTI . Additional genes, such as ZIC2 , may also play a role in prosencephalic formation. The clinical relevance of these insights includes the importance of performing mutation analysis of these genes in selected patients with disorders of prosencephalic development.
Disorders of Prosencephalic Development
Disorders of prosencephalic development are considered best in terms of the three major events described earlier (i.e., prosencephalic formation from the rostral end of the neural tube, prosencephalic cleavage, and midline prosencephalic development) ( Box 2.2 ). The spectrum of pathology varies from a profound derangement (e.g., aprosencephaly) to certain disturbances of midline prosencephalic development (e.g., isolated agenesis of the corpus callosum) that may be detected only incidentally by brain imaging or autopsy.
Disorders of Prosencephalic Formation
Aprosencephaly and Atelencephaly
Anatomical Abnormality.
Aprosencephaly and atelencephaly are the most severe of the disorders of prosencephalic development. In aprosencephaly , the entire process fails to occur, and the result is an absence of formation of both the telencephalon and diencephalon, with a prosencephalic remnant located at the rostral end of a rudimentary brain stem ( Fig. 2.3A ). In atelencephaly , the anomaly is less severe in that the diencephalon is relatively preserved. The findings of calcific vasculopathy and calcification in the remaining neural tissue have led to the suggestion that, in some cases, these disorders may result from an encephaloclastic event shortly after neurulation. These anomalies are distinguishable from anencephaly most readily by the presence of an intact although flattened skull and intact scalp ( Fig. 2.3B ).
Timing.
The disorders presumably have their origin no later than the onset of prosencephalic development at the beginning of the second month of gestation. A slightly later time of origin may be operative in cases that appear to be related to a destructive process.
Clinical Aspects.
Aprosencephaly-atelencephaly is characterized by a strikingly small cranium with little volume apparent above the supraorbital ridges ( Fig. 2.3B ). However, as noted earlier, distinction from anencephaly is based easily on the intact skull and dermal covering. Facial anomalies (including cyclopia or absence of eyes) that bear similarities to those associated with holoprosencephaly (see later) are associated much more commonly with aprosencephaly than with atelencephaly. Similarly, anomalies of external genitalia and limbs are more common with aprosencephaly than with atelencephaly.
Prognosis.
Aprosencephaly is a lethal condition; most examples have been fetal specimens or involved patients who died in the neonatal period. Survival for approximately a year with little neurological function except breathing has been observed with atelencephaly.
Disorders of Prosencephalic Cleavage
Holoprosencephalies
Anatomical Abnormality.
The holoprosencephalic spectrum of disorders comprises the next most severe derangements of prosencephalic development and specifically involves prosencephalic cleavage ( Box 2.2 ). In this category of disorders, the forebrain malformation may be so severe that there is marked disturbance of formation of both the telencephalon and diencephalon, in which case the term holoprosencephaly is most appropriate. However, in general, the term holoprosencephaly is used for the entire spectrum of cleavage disorders. The essential abnormality is failure of horizontal, transverse, and sagittal cleavage of the prosencephalon.
In the original neuropathological classification of the holoprosencephaly spectrum, De Myer described three entities, based principally on the severity of the cleavage abnormality in the cerebral hemispheres and deep nuclear structures. The major neuropathological features of the most severe disturbance, appropriately characterized as alobar holoprosencephaly , include a single-sphered cerebral structure with a common ventricle, fusion of basal ganglia and thalamus, a membranous roof over the third ventricle that is often distended into a large cyst posteriorly ( Fig. 2.4 ), absence of the corpus callosum as well as of the olfactory bulbs and tracts, and hypoplasia of the optic nerves or the presence of only a single optic nerve ( Figs. 2.5 and 2.6 ). a
a .
The cerebral cortex surrounding the single ventricle exhibits the cytoarchitecture of the hippocampus and other limbic structures, and the most striking abnormality is the essentially total failure of development of the supralimbic cortex, the hallmark of the human cerebrum ( Fig. 2.5 ). The cortical mantle often shows heterotopias and other signs of subsequently disordered neuronal migration. In semilobar holoprosencephaly , there is failure of separation of the anterior hemispheres with presence of a posterior portion of the interhemispheric fissure and less severe fusion of deep nuclear structures ( Fig. 2.7 ). In this form, the anterior portion of the corpus callosum is absent, a finding that differs from all other types of callosal hypoplasia, in which the posterior callosum is absent or deficient (see later). In lobar holoprosencephaly , the cerebral hemispheres are nearly fully separated, deep nuclear structures are nearly or totally separated (by brain imaging), and the posterior callosum is well developed, although the anterior callosum may be somewhat underdeveloped ( Fig. 2.8 ). Microcephaly is present in the majority of infants with semilobar and lobar holoprosencephaly. Hydrocephalus is present in the majority of infants with alobar holoprosencephaly, usually in association with a large dorsal cyst of the third ventricle secondary to marked fusion of thalamus and impaired egress of cerebrospinal fluid (CSF) through the aqueduct ( Figs. 2.4 and 2.15 ). Dorsal cysts are seen in 92% of alobar, 28% of semilobar, and 9% of lobar holoprosencephaly cases.
Following de Myer’s earlier classification, several increasingly milder variants of holoprosencephaly have been described ( Table 2.1 ). In syntelencephaly , or the middle interhemispheric variant, only the posterior frontal and parietal regions fail to separate, leaving only the body of the corpus callosum deficient, with the genu, rostrum, and splenium preserved ( Fig. 2.9 ). More recently, a mild holoprosencephaly subtype has been described in which nonseparation is confined to the septal (subcallosal) and/or preoptic regions. This septopreoptic form is associated with mild midline craniofacial anomalies (single midline maxillary incisor, nasal piriform aperture stenosis); as a result, severe endocrine disturbances may develop ( Fig. 2.10 ). In addition, the corpus callosum may be thickened, possibly due to heterotopic cingulate fibers. The classic forms of holoprosephaly uniformly have some degree of failed hypothalamic separation. On this basis, the interhypothalamic adhesion (IHA) lesion described recently has been proposed as an even milder forme fruste variant of holoprosencephaly, especially since it is often accompanied by other midline defects, including agenesis of the corpus callosum ( Fig. 2.11 ). The IHA variant is also commonly associated with hippocampal dysgenesis and white matter lesions. Unlike the classic forms of holoprosencephaly, the septum pellucidum may be intact in both the septopreoptic and IHA variants.
| ALOBAR | SEMILOBAR | LOBAR | MIH | |
|---|---|---|---|---|
| Cerebral non-separation | Diffuse (holosphere) | Frontal | Rostroventral frontal | Posterior frontal and parietal |
| Corpus callosum | Absent | Splenium present Rostrum, genu, and body absent | Splenium present Rostrum and genu absent Anterior body variably present | Splenium present Body absent Genu variably present |
| IHF and falx | Completely absent | Absent anteriorly Present posteriorly | Hypoplastic anteriorly Present posteriorly | Absent in posterior frontal and parietal region |
| Ventricles | Monoventricle communicating widely with dorsal cyst | Anterior horns absent Posterior horns present Small third ventricle | Anterior horns rudimentary Third ventricle formed | Anterior horns normal or hypoplastic Third ventricle formed |
| Dorsal cyst | Usually present | Variably present | Absent | Present in 25% |
| Septum pellucidum | Absent | Absent | Absent or dysplastic | Absent |
| Thalamus | Often fused | Partial fusion | Usually fully separated | Fused in 30%–50% |
| Basal ganglia | Often fused (may be single mass with thalami) | Partial fusion (especially head of caudate) | Variable degree of fusion | Separated |
| Hypothalamus | Fused always | Fused very often | Fused often | Separated |
| Sylvian fissure | Often absent | Anteromedially displaced (wide sylvian fissure) Fused frontal lobe | Anteromedially displaced (wide sylvian fissure) Small frontal lobes | Often connect across the midline over the vertex |
| Dysplastic/heterotopic gray matter | Diffuse broad gyri with too few sulci | Occasional broad gyri with too few sulci | Rare midline subcortical heterotopias in frontal regions | Very common |
| Cerebral vasculature | Vascular rete branching from internal cerebral arteries | Azygos anterior cerebral artery | Azygos anterior cerebral artery | Azygos anterior cerebral artery |
| SEPTOPREOPTIC VARIANT | INTERHYPOTHALAMIC ADHESION | |
|---|---|---|
| Cerebral nonseparation | Fusion of septal cortex | Separated |
| Corpus callosum | Rostrum absent/hypoplastic Genu hypoplastic Body/splenium present May be thickened | Formed in most (may be absent as an associated midline defect) ( Fig. 2.11 ) |
| IHF and falx | Present anteriorly/posteriorly | Present anteriorly/posteriorly |
| Ventricles | Frontal horns normal or small Third ventricle formed | Normal lateral and third ventricles |
| Dorsal cyst | Absent | Absent |
| Septum pellucidum | Present/dysplastic | Present |
| Thalamus | Fused in some | Separated |
| Basal ganglia | Separated | Separated |
| Hypothalamus | Anterior often fused | Fused across anteroinferior third ventricle |
| Sylvian fissure | Present/normal | Present/normal |
| Dysplastic/heterotopic gray matter | Rare | Hippocampal dysgenesis common Periventricular heterotopias occasional |
| Cerebral vasculature | Azygos anterior cerebral artery | Normal |
Not surprisingly, a range of ventricular anomalies have been described in the holoprosencephaly spectrum, from the striking monoventricle of alobar holoprosencephaly to the relatively normal ventricular configuration of milder lobar holoprosencephaly and the septopreoptic and IHA variants. Several reports have described absence of lateral and third ventricles or of the entire ventricular system associated with abnormal midline fusion (fused hemispheres and thalami, rhombencephalosynapsis) and agenesis of the corpus callosum. Some have proposed that aventriculi is a distinct variant of holoprosencephaly.
Timing.
Onset of the holoprosencephalies is no later than the fifth and sixth weeks of gestation. A particularly critical impaired event (i.e., the evagination of the cerebral hemispheres through sagittal cleavage of the prosencephalon) occurs at approximately 35 days of gestation. The olfactory bulbs and tracts are not discernible until approximately 42 days of gestation; thus the frequent absence of olfactory structures is understandable.
Clinical Aspects.
The frequency of holoprosencephaly is approximately 1 in 10,000 live births. The incidence is more than 60-fold greater (i.e., 1/250) in studies of aborted human embryos, a finding indicating that most cases are eliminated prenatally.
Facial anomalies are present in up to 80% to 90% of holoprosencephaly cases, although the severity is variable. In the most severe cases the facial anomaly is represented by a single median eye ( cyclops ) or even no eye at all and a rudimentary nasal structure, the proboscis, often located above the midline orbit. a
a .
There may be no nasal structure at all. Less severe facial deformities include marked ocular hypotelorism with or without a proboscis (ethmocephaly) and ocular hypotelorism with a flat, single-nostril nose (cebocephaly [i.e., facial appearance of the Cebus monkey]) ( Figs. 2.12 and 2.13 ). Still less severe deformities include mild to moderate ocular hypotelorism (less commonly, ocular hypertelorism), a flat but double-nostril nose, and median cleft lip and palate, often with an absent philtrum and similar features with bilateral cleft lip and palate. In the least affected cases, the facial deformity may be difficult to detect or there may be no facial deformity at all. Cases with severe facial malformations are consistently associated with severe holoprosencephaly, but the converse is not true; alobar holoprosencephaly is unassociated with a significant facial abnormality in approximately 10% of cases. Abnormalities of other organ systems occur in approximately 75% of cases of holoprosencephaly and consist primarily of disturbances of cardiac, skeletal, genitourinary, and gastrointestinal development, understandable in view of the similar time periods of rapid development.
Neurological features in the most severe cases are obvious from the neonatal period. Infants exhibit frequent apneic spells, stimulus-sensitive tonic spasms, various abnormalities of hypothalamic function (e.g., poikilothermia, diabetes insipidus, or inappropriate antidiuretic hormone secretion), and virtually total failure of neurological development. Seizures occur in a large minority; especially in infants with cytogenetic abnormalities, the most severe forms of holoprosencephaly result in death in the first year. However, prolonged survival is common with the less severe forms of holoprosencephaly. Subsequent neurological deficits relate to the nature of the neuropathological features. The degree of failure of cerebral cleavage correlates with the cognitive deficits, hypothalamic cleavage with the endocrinopathies, and basal ganglia and thalamic cleavage with dystonia and impaired motor function. Still less severely affected children may escape clinical detection until later in infancy or childhood. a
a .
Etiology.
Chromosomal, genetic, and environmental factors have been implicated in the pathogenesis of holoprosencephaly. Some have proposed that the majority of holoprosencephalies are multifactorial (the “multiple-hit” hypothesis), resulting from a combination of genetic and environmental factors.
Chromosomal causes of holoprosencephaly account for 60% of cases, of which trisomy 13 accounts for approximately half ( Box 2.3 ). The relative distribution of these causes varies considerably with the method of case ascertainment. The following discussion represents a general consensus of available data. Additional chromosomal abnormalities have involved chromosome 18 in particular. These data may provide additional prognostic data; in one study, only 2% of cases with cytogenetic abnormalities survived to 1 year of age, compared to 30% to 54% of those without cytogenetic abnormalities.
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