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HOLOPROSENCEPHALY
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| Alobar holoprosencephaly | Facial abnormalities in the same patient |
Between the fourth to sixth week of gestation, the forebrain (prosencephalon) is divided into the two hemispheres. Absence of this cleavage results in a spectrum of malformations called holoprosencephaly (HPE). In the most severe form, alobar HPE, the brain consists of a single spherical forebrain structure with a single ventricle. A large cyst which communicates with the ventricle is present in the posterior-dorsal part of the brain. The brain in alobar HPE is small and the gyral pattern and cortical architecture are abnormal. The eyes, which evaginate from the forebrain in the fourth week, are small and malformed or there is only one eye (cyclopia).
Because the olfactory nerves which are part of the rhinencephalon are absent, the term arrhinencephaly has also been applied to this malformation. However, in alobar HPE, there is much more missing than the olfactory brain. The brain malformations are accompanied by severe midline facial anomalies. Some of these are mild such as central incisor and hypotelorism; others are severe and include a proboscis (a trunk-like structure above the single eye), a single nostril, cleft lip, and cleft palate. Alobar HPE is incompatible with survival. In milder forms (semilobar and lobar HPE), the brain is larger and there is partial separation of the hemispheres. Such cases are associated with variable psychomotor retardation depending on the pathology. Diabetes insipidus is frequent in these patients.
HPE is rare among live born infants but very common in embryogenesis. It has genetic and environmental causes. Most cases are sporadic but there are also autosomal dominant, recessive, and X-linked forms. HPE also occurs as a component of multiple malformation syndromes and in several chromosomal abnormalities. Genetic HPE is associated with four genes and has been linked to seven additional chromosomal loci. The best known HPE gene is the Sonic Hedgehog (SHH) gene on 7q36 which is important for ventral patterning of the forebrain. Mutations of this gene cause autosomal dominant HPE. Defective cholesterol synthesis inhibits SHH signaling resulting in HPE-like malformations. Retinoic acid participates in the SHH system. Excess retinoic acid during embryogenesis (from administration of Accutane for acne) inhibits SHH and causes HPE and other malformations. The HPE-associated gene TG-interacting factor (TGIF) on 18p11, regulates retinoic acid. Mutations of TGIF result in unrestrained retinoic acid activity and HPE. The multitude of genes and chromosomal loci associated with HPE underlines the complexity of genetic programs that are involved in embryonic patterning and the intricate interaction between genes and environmental factors.
The chemical messages that induce the forebrain to divide into two hemispheres, including SHH, are first expressed in the prechordal plate, an area rostral to the notochord that gives rise to the facial mesoderm. SHH is also involved in craniofacial development. The correlation between the facial anomalies and HPE was pointed out by DeMeyer in a paper titled "The face predicts the brain" (Pediatrics1964;34:256-63).
AGENESIS OF THE CORPUS CALLOSUM
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| Agenesis of the corpus callosum |
At about 10 weeks of gestation, a glial bridge (massa commisuralis) forms between the two hemispheres, at the bottom of the interhemispheric fissure. Soon after this, axons begin to cross this bridge, forming the corpus callosum (CC). This process is completed by 18 to 20 weeks gestation. Agenesis of the corpus callosum (ACC) develops either if the bridge does not form or if axons fail to cross it. HPE can be mistaken for ACC.
ACC is one of the most common and probably the most genetically diverse brain malformation. It occurs in many chromosomal abnormalities and malformation syndromes and in several inherited metabolic disorders. Among others, it is associated with mutations of the L1 cell adhesion molecule, a cell surface glycoprotein that is important for guidance of migrating neurons (see neuronal migration defects).
ACC may be complete or partial, involving only the posterior part of the CC (splenium). It may occur as an isolated defect. Many cases, however, have other associated CNS and non-CNS malformations. Most patients have psychomotor retardation. A small minority-usually patients with isolated ACC-have normal neuromotor skills. About one third of patients have seizures. When the CC is absent, the anterior horns of lateral ventricles have a bat-wing shape and the posterior horns are dilated and parallel to one another. The gap between the two hemispheres is filled sometimes by adipose tissue.
