Chapter 250

## Abstract

Abstract

1. Holoprosencephaly (HPE) is a structural anomaly of the developing brain in which the forebrain fails to divide into two separate hemispheres and ventricles. HPE is the most common brain defect in humans with a prevalence of 1 in 250 during early embryogenesis and 1 in 10,000 to 1 in 20,000 at birth.

2. Our understanding of the pathogenesis of HPE derives largely from the study of animal models. Embryologically, HPE is associated with a loss or failure to develop midline structures of the ventral forebrain and of the face. The resulting apposition or fusion of structures that normally develop in lateral positions gives rise to the characteristic features of HPE. Internally, these features include the defining characteristic of HPE, an undivided forebrain. Externally, severe HPE is associated with development of a cyclopic eye, resulting in superior displacement of a fused, proboscis-like nasal structure.

3. The prechordal plate mesendoderm has emerged as a structure required for induction of ventral forebrain in the overlying neural plate, and for subdivision of the eye field. Surgical, teratologic, or genetic perturbations of the prechordal plate, particularly at or before early gastrulation, are associated with HPE.

4. Genetic studies originating in Drosophila and extending to mice and humans have identified Sonic hedgehog, a member of the Hedgehog family of secreted signaling proteins, as a critical signal produced in the prechordal plate and required for induction of ventral forebrain structures from the overlying neural plate. Mouse embryos homozygous for Sonic hedgehog mutations display the features of severe HPE, and humans with heterozygous SHH mutations have clinical findings of HPE with variable expressivity and penetrance. Loss of Shh signaling may also contribute to defects in midline facial development because Shh is also expressed in the processes that give rise to midline facial structures. Mutation of other Shh pathway components has also been associated with ventral forebrain deficits in animal models.

5. Several plant-derived and synthetic teratogens are known to specifically block the ability of cells to respond to Shh signaling. The mechanism of this effect is not known, but these agents all appear to affect cellular cholesterol homeostasis. In addition, certain mutations in mice or humans that perturb cholesterol homeostasis cause or increase the incidence of HPE.

6. Studies in the mouse and in the zebra fish have also implicated the signaling pathway headed by nodal and/or related members of the TGF-β family of secreted signaling proteins as playing a critical role in prechordal mesoderm formation, migration, and signaling to the overlying prosencephalic plate.

7. The processes of ventral forebrain and midline facial development represent a particularly sensitive target for genetic or environmental perturbations. HPE can also result from combinations of distinct insults that are mild and that alone do not cause HPE. These factors together may account for the high incidence of HPE in human embryos, and for the large number of autosomal dominant human syndromes associated with HPE. In addition, the increased severity produced by a combination of genetic and possibly environmental insults may account for the high degree of variability of HPE observed within kindreds.

8. The clinical spectrum of central nervous system anomalies ranges from alobar HPE (absent interhemispheric fissure) to semilobar (midline separation only posteriorly) and lobar HPE (complete separation of the ventricles but continuity across the cortex). Accompanying facial anomalies may include anophthalmia, cyclopia, extreme hypotelorism, a single nostril nose and/or midface hypoplasia with cleft lip and/or palate.

9. Diagnosis can be done prenatally by ultrasound examination at 16 weeks of gestation or at birth by physical exam and confirmed by brain scan (CAT or MRI).

10. Treatment is done system by system and may include anticonvulsive therapy for seizures, alternative feeding methods (e.g., tube feedings), surgical management of hydrocephaly (ventriculoperitoneal shunt) and closure of clefts of lip and palate.

11. The etiology is extremely heterogeneous with environmental (e.g., maternal diabetes) and genetic factors known to cause HPE. Familial HPE has been described with autosomal dominant, autosomal recessive, and X-linked inheritance. HPE is part of many genetic syndromes: Smith-Lemli-Opitz syndrome is one of the more common ones. Lastly, cytogenetic anomalies are present in 25 to 50 percent of newborn infants with HPE. Nonrandom structural chromosomal anomalies predict at last 12 different HPE loci. To date, cytogenetic deletions and translocations have helped to define the minimal critical regions for HPE loci on chromosomes 7q36, 13q32, 2p21, 18p11.3, 21q22.3, and others.

12. The human Sonic Hedgehog (SHH) gene in 7q36 was the first HPE gene to be identified. Heterozygous deletions, nonsense, frameshift, and missense mutations in SHH predict a loss-of-function mechanism as one cause for HPE in humans. To date, SHH mutations have been found to cause HPE in 30 to 40 percent of families with autosomal dominant transmission of HPE based on structural anomalies, whereas the detection rate in sporadic cases is low (<5 percent). Heterozygous insertions and deletions leading to frameshifts, nonsense mutations, and expansion of an alanine repeat of the human ZIC2 gene in 13q32 have been found in HPE patients. Furthermore, heterozygous deletions and missense mutations in the homeodomain of the SIX3 gene in 2p21 are associated with HPE. Lastly, heterozygous deletions and missense mutations of the gene coding for TG-interacting factor (TGIF) in 18p11.3 cause HPE.

13. The phenotype of individuals with SHH , SIX3 or TGIF mutations is extremely variable ranging from alobar HPE and cyclopia to clinically normal mutation carriers even within the same family. In contrast, preliminary data suggest that carriers of ZIC2 mutations have normal or only mildly dysmorphic facial findings despite severe central nervous system anomalies.

14. Future directions include studies to better define the milder end of the clinical spectrum in infants and older children with HPE in an attempt to design better therapies. On a molecular level, the long-term goal is to identify additional HPE genes and to analyze the interactions of multiple gene products and/or environmental factors in an attempt to elucidate the underlying mechanisms that contribute to the wide variability of the HPE spectrum.

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