Holoprosencephaly (HPE) is a primary disorder of neural induction and patterning of the rostral neural tube resulting in noncleavage of the forebrain with failure to form two separate distinct hemispheres. The spectrum of HPE is very broad and encompasses various neuropathological phenotypes of different severity. The recent literature has demonstrated that the phenotypic variability of HPE ranges from aprosencephaly-atelencephaly, at the most severe end, to milder forms such as the "middle interhemispheric variant" of HPE at the less severe end of the spectrum. Between them, different intermediate forms demonstrate a continuum in a wide phenotypic spectrum rather than well-defined categories. Although the term "HPE" suggests a disorder affecting only the prosencephalon, other brain structures are involved, underlining the complexity of the malformation. Because of close spatiotemporal interactions and common signaling pathways contributing to the development of both brain and face, concomitant facial and ocular anomalies are associated with brain malformation. In this review, the characteristic neuropathological features of the various forms of HPE are described as well as their associated brain, face, and ocular malformations, to delineate the different phenotypes.

Atelencephaly is a rare lethal congenital brain malformation characterized by underdevelopment of the prosencephalon and is often accompanied by the facial features seen in some cases of holoprosencephaly, such as cyclopia. We report a case of atelencephaly in the fetus with characteristic ultrasound findings. In addition, we report the findings on fetal MRI, which have not been previously described in the literature.

Malformations of the forebrain are characterized by abnormalities in size, shape, and arrangement of the cerebral hemispheres and ventricles. We present the morphological picture of a brain with failure of the forebrain complementary to holoprosencephaly coexisting with absence of the anterodorsal part of the prosencephalic ventricles. The anomaly can be graded within the holoprosencephalic spectrum due to the main morphological features. However, such alterations as aplasia of the forebrain ventricles and prominent leptomeningeal gliomesodermal proliferation are related to atelencephaly. The observations confirm the common pathogenic mechanism of aprosencephaly/atelencephaly and holoprosencephaly. The malformation corresponds to a wide continuous spectrum with no clear-cut boundaries of abnormal formation of the prosencephalon.

Structural malformations of the brain are an important cause of childhood mortality and morbidity, with the latter having long-term financial and psychosocial implications for the affected child and family. Holoprosencephaly (HPE) is a severe brain malformation characterized by abnormal cleavage of the prosencephalon in the 5th gestational week. Aprosencephaly and atelencephaly occur earlier because of failure in the formation of the prosencephalon and telencephalon, respectively. The HPE holoprosencephaly spectrum classically includes alobar, semilobar, and lobar forms, although there are no clear-cut defining features. The middle interhemispheric variant (MIH), also known as syntelencephaly, is classified as a variant of HPE holoprosencephaly with midline interhemispheric fusion. Other conditions sometimes included in the spectrum of HPE holoprosencephaly include septo-optic dysplasia (SOD); "minimal" HPE holoprosencephaly , which is associated with subtle craniofacial malformations and mild developmental delay; and microform HPE holoprosencephaly , which by definition excludes brain involvement. The focus of this article will be on the spectrum of findings visible in fetal manifestation of the HPE holoprosencephaly spectrum. Brain embryology; the imaging characteristics, epidemiology, and embryology of HPE; and the more common associated anomalies, particularly those of the face ("the face predicts the brain") are reviewed. Recognition of these anomalies is important for accurate parental counseling, since the prognosis is poor but not invariably lethal; children with the milder forms may live well into their teens with severe developmental delays, endocrine dysfunction, and disrupted homeostasis. Available data on outcome in surviving children are summarized. Illustrative fetal ultrasonographic and magnetic resonance images are presented with clinical, autopsy, and postnatal imaging correlation.