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Holoprosencephaly is a relatively rare malformation of the central nervous system (CNS) that is frequently associated with specific craniofacial anomalies including midline facial clefts, cyclopia, and nasal anomalies. The incidence in live born children with normal chromosomes has been estimated to be 0.48-0.88 per 10,000 (1-3). In contrast, the rate among human abortuses was estimated at 40 per 10,000 indicating a high rate of fetal loss (4). Until recently, the pathogenesis of this disorder remained speculative, however, advances over the past 10 years have provided a clearer picture of the development of this anomaly in at least some cases. This review provides an update of the current data regarding predisposing factors, genetics, and pathology of holoprosencephaly. Finally, the cellular and molecular basis underlying the development of holoprosencephaly will be considered. These data support the hypothesis that early induction and patterning of the neural tube is essential for normal development, and disruptions in this patterning result in CNS malformations.
CLASSIFICATION AND ASSOCIATED ANOMALIES
Holoprosencephaly represents a major malformation of the brain. The cardinal features of which are a single telencephalic ventricle and continuity of the cerebral hemisphere across the midline. Several methods of grading or classifying the CNS anomalies have been developed (reviewed in 5). The most frequently used divides the brain anomaly into 3 categories based on the extent of the malformation (see Neuropathology section below). The alobar form of holoprosencephaly is the most severe, the semilobar intermediate, and the lobar form the least severe. However, these 3 categories probably represent a spectrum rather than clearly distinguishable forms of the same disorder. In fact, it has been observed that individuals within I family can have CNS findings that fit into any 1 of the 3 categories or even no structural brain abnormality (6). In addition to the CNS anomalies, specific craniofacial abnormalities are associated with holoprosencephaly and together represent the holoprosencephaly sequence or syndrome (reviewed in 7). Similar to the brain, the craniofacial anomalies vary in extent from the most severe being cyclopia with a single proboscis located above the midline eye, to the mildest facial abnormality consisting of a single midline maxillary incisor. In 1964, William DeMyer (8) studied a group of patients with holoprosencephaly and concluded that the "face predicts the brain."...