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Key Points

  • A complex brain malformation characterized by the forebrain failing to cleave into two hemispheres, a process that is usually completed by 5 weeks.

  • Four subtypes exist, listed in order of decreasing severity: alobar, semilobar, lobar, and middle hemispheric variant.

  • Incidence is approximately 1 in 8000 second trimester pregnancies.

  • Approximately 40% of cases have a chromosome abnormality. Of these 75% are due to trisomy 13.

  • Maternal diabetes increases the risk of holoprosencephaly by 200-fold.

  • Management of pregnancy should include fetal karyotype, DNA mutation testing, and consideration of fetal MRI. A detailed family history should be obtained.

  • Mutations in eight different genes are associated with holoprosencephaly (SHH, PTCH, SIX3, SL12, ZIC2, TGIF, TDGF1, and FAST1).

  • If chromosome abnormalities and craniofacial anomalies are absent, long-term survival is possible.


The term holoprosencephaly describes a spectrum of cerebral and facial malformations that result from absent or incomplete division of the embryonic forebrain, the prosencephalon. The abnormality occurs during the 3rd week of gestation (Müller and O’Rahilly, 1989). Two separate sets of terms are used to describe the facial and brain anomalies. DeMyer (1964) proposed a subclassification of holoprosencephaly based on the extent of sagittal division of the cerebral cortex, thalamus, and hypothalamus. In the most severe form, alobar holoprosencephaly, midline structures are absent and there is no division of the hemispheres. A single common ventricle is present and the thalami are fused. In semilobar holoprosencephaly, incomplete division of the forebrain results in partial separation of the hemispheres. In lobar holoprosencephaly, there is normal cortical division and two thalami, but abnormalities exist in the corpus callosum, septum pellucidum, or olfactory tract or bulbs. More recently, a fourth subtype of holoprosencephaly was described, known as the middle interhemispheric variant (MIH) (Simon et al., 2002; Pulitzer et al., 2004). In MIH, the posterior frontal and parietal lobes fail to separate, but the poles of the frontal and occipital lobes are well separated.

The facial abnormalities accompanying holoprosencephaly range from subtle to grotesque (Figure 14-1). In general, the more severe facial malformations are associated with alobar holoprosencephaly, but exceptions do occur (Table 14-1). The most severe facial malformation is cyclopia, a single or fused double eye and absent nasal structures (Figures 14-1A and 14-1B). A proboscis, a cylindrical protuberance, may also be present (Figure 14-1C). In ethmocephaly, the eyes are separate but closely placed (hypotelorism); a proboscis is present (Figure 14-1D). Ethmocephaly is the rarest of the facial malformations seen in holoprosencephaly. In cebocephaly, ocular hypotelorism is present along with a nasal structure that has a single nostril (Figure 14-1E). In the milder forms of holoprosencephaly, ocular hypotelorism, flat nose, and a median cleft lip occur (Figure 14-1F). Arrhinencephaly refers to the absence of the olfactory tracts ...

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