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Pathogenesis of holoprosencephaly
Xin Geng, Guillermo Oliver
Xin Geng, Guillermo Oliver
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Science in Medicine

Pathogenesis of holoprosencephaly

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Abstract

Holoprosencephaly (HPE), the most common human forebrain malformation, occurs in 1 in 250 fetuses and 1 in 16,000 live births. HPE is etiologically heterogeneous, and its pathology is variable. Several mouse models of HPE have been generated, and some of the molecular causes of different forms of HPE and the mechanisms underlying its variable pathology have been revealed by these models. Herein, we summarize the current knowledge on the genetic alterations that cause HPE and discuss some important questions about this disease that remain to be answered.

Authors

Xin Geng, Guillermo Oliver

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Figure 2

Clinical manifestations of HPE.

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Clinical manifestations of HPE.
(A–I) Coronal images of control and HPE ...
(A–I) Coronal images of control and HPE brains from anterior (A, D, and G) to posterior (C, F, and I). (A–C) In the control brain, the two hemispheres are separated completely (arrow in A) and the septum (arrow in B) and the corpus callosum (arrowhead in B) are present. (D–F) In alobar HPE, a single cerebral ventricle is present and the interhemispheric fissure is completely absent. (G–I) In semilobar HPE, the two hemispheres are incompletely separated (arrow in G) and the septum and corpus callosum are absent (arrow and arrowhead in H, respectively). (J and K) Horizontal images of control (J) and lobar HPE (K). The septum is present in the control brain (arrow in J); however, it is partially absent in the lobar HPE brain (arrow in K). (L) Sagittal image of a MIH brain. The genu and splenium of the corpus callosum are present (arrows in L); however, the corpus callosum is absent at the region lacking the interhemispheric fissure (arrowhead in L). (M–O) Craniofacial defects associated with HPE. (M) Alobar HPE with cyclopia and proboscis. (N) Semilobar HPE with microcephaly and cleft lip and palate. (O) Semilobar HPE with ocular hypotelorism and midface hypoplasia. (P and Q) Microforms of HPE. (P) Absence of nasal bones and cartilage with a narrow nasal bridge. (Q) Single central maxillary incisor. (R) MIH patient with normal facial appearance. A–C and G–I are reprinted with permission from Cerebral cortex (17); D–F are reprinted with permission from American Journal of Medical Genetics (18); J is reprinted with permission from Brain Maps (111); K is reprinted with permission from MedPix (112); L is reprinted with permission from American Journal of Neuroradiology (23); M and O are reprinted with permission from Human Molecular Genetics (19); N and P are reprinted with permission from Human Molecular Genetics (20); Q is reprinted with permission from Nature Genetics (21); and R is reprinted with permission from Human Molecular Genetics (24).

Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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