Defects of Organogenesis



Holoprosencephaly (HPE) is a malformation characterized by continuity of the right and left cerebral hemispheres across all or part of the midline. The phenotype is quite variable, secondary to incomplete penetrance, and comprises a continuous spectrum from severe brain, face and eye anomalies to clinically normal individuals. Three subtypes are recognized based on the extent of right-left continuity and are known as alobar, semilobar and lobar HPE. In alobar HPE, the embryonic forebrain completely fails to divide into right and left hemispheres, resulting in an absent interhemispheric fissure, single ventricle and undivided thalamus and basal ganglia. In semilobar HPE, the interhemispheric fissure is present posteriorly with continuity of the left and right frontal and parietal lobes, as well as the thalamus and basal ganglia. In lobar HPE, most of the hemispheres are separate with an area of continuity present usually in the posterior frontal region and sometimes in the thalamus and basal ganglia (Fig. 1). All forms of HPE may be associated with congenital hydrocephalus, which may obscure recognition of HPE and the correct subtype of HPE.

In classic HPE, a continuous series of facial anomalies are seen, with more severe anomalies being associated with a more severe form of HPE, and all are associated with hypotelorism or decreased distance between the orbits. The specific anomalies include cyclopia, ethmocephaly (severe hypotelorism with a proboscis located just above the eyes), cebocephaly (severe hypotelorism with a single central nasal cavity), midline and bilateral cleft lip and palate, and a single central upper incisor. In families with autosomal dominant HPE, some individuals have a forme fruste of HPE, which includes mild microcephaly, no obvious structural abnormalities of the brain, hypotelorism and sometimes a single central incisor.

Pediatric Neurosurgery, edited by David Frim and Nalin Gupta. ©2006 Landes Bioscience.

Table 1. Making sense of human brain development and malformations

Development of the neural tube Neural tube closure Neural tube structure and integrity

Development of basic brain structure (organogenesis) Forebrain (prosencephalon) Midbrain (mesencephalon) Hindbrain (rhombencephalon)

Development of the cortex

Neuronal and glial proliferation Neuronal migration Cortical organization

Table 2. Organization of congenital CNS abnormalities by proposed developmental abnormality

Neural Tube Defects i. Defects of neural tube closure

Anencephaly Craniorachischisis Myelomeningocele Chiari II malformation Tethered spinal cord Spina bifida occulta ii. Structural defects of the neural tube

Chiari I malformation

Encephaloceles (anterior, posterior and basal) Iniencephaly split cord malformations (diplomyelia and diastamatomyelia)

Organogenesis Defects i. Forebrain malformations

Holoprosencephaly (alobar, semilobar and lobar) Middle interhemispheric fusion (syntelencephaly) Arhinencephaly

Agenesis of the corpus callosum Lipoma of the corpus callosum Absent septum pellucidum Septo-optic dysplasia Pituitary agenesis ii. Midbrain-hindbrain malformations

Brainstem-vermis decussation malformation (molar tooth sign)


Dandy-Walker malformation

Cerebellar hypoplasia (hemispheres ± vermis)

Cerebellar vermis hypoplasia

Brainstem hypoplasia

_Pontocerebellar hypoplasia_

Table 2. Continued

Malformations of Cortical Development i. Malformations with abnormal proliferation

Malformations with decreased proliferation

Microcephaly (primary microcephaly or microcephalia vera) Microcephaly with simplified gyral pattern Microlissencephaly Malformations with increased and dysplastic proliferation Megalencephaly Hemimegalencephaly

Focal cortical dysplasia with balloon cells (focal transmantle dysplasia)

ii. Malformations with defective neuronal migration


Classic lissencephaly and subcortical band heterotopia Lissencephaly with agenesis of the corpus callosum Lissencephaly with cerebellar hypoplasia Cobblestone dysplasia (lissencephaly) Heterotopia

Focal subependymal heterotopia Bilateral periventricular nodular heterotopia Bilateral periventricular laminar heterotopia Focal subcortical heterotopia iii. Malformations of cortical organization

Polymicrogyria Bilateral diffuse polymicrogyria Bilateral frontal polymicrogyria Bilateral perisylvian polymicrogyria Bilateral parietooccipital polymicrogyria Bilateral mesial-occipital polymicrogyria Schizencephaly

Clinical Course and Management

The severity of clinical features is in proportion to the severity of the HPE. Children with alobar HPE are profoundly affected and usually die early in life. Patients with semilobar HPE are also severely handicapped, although not quite as severely as those with the alobar form, so survival may be longer. Patients with lobar HPE often have moderate to severe mental retardation and typically learn to walk and use limited language. Individuals with a forme fruste of HPE may have normal intelligence or borderline to mild mental retardation. Other complications include feeding problems with an aspiration risk, spastic diplegia or quadriplegia, blindness or poor vision, epilepsy and pituitary insufficiency including diabetes insipidus, such that all patients with HPE should have an endocrine evaluation.

Perhaps the most difficult and important part of management is providing accurate counseling regarding the prognosis. Correct identification of the degree of severity of HPE is required for accurate prognostic information. In the presence of hydrocephalus, it is usually best to defer diagnosis of the subtype of HPE until after a shunt has been placed and a repeat magnetic resonance imaging (MRI) scan has been done.

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