What is holoprosencephaly?

Definition: Holoprosencephaly is a neural developmental disorder where the forebrain does not successfully divide into two hemispheres.

holoprosencephaly scan ventricles

Early in embryonic development, the nervous system forms out of a small number of neurons. Through the early months of development, the neural cells start to differentiate into the precursors for the different parts of the brain that will eventually develop: The prosencephalon, or forebrain, the mesencephalon, or midbrain, and finally the rhombencephalon, or hindbrain. In typical, healthy development, the forebrain divides into two structures that eventually become the left and right hemispheres of the brain. However, in holoprosencephaly, the prosencephalon does not successfully divide.

Holoprosencephaly, or HPE, is a rare disease, occurring in an estimated 1 in 10,000 live births. It becomes noticeable around the 5th gestational week, and can be diagnosed with an ultrasound or an MRI. In an ultrasound image or an MRI scan, severe holoprosencephaly presents with a single ventricle instead of two distinct lateral ventricles, and a complete absence of the corpus callosum and the third ventricle.

Generally speaking, there are five degrees of holoprosencephaly, each with a different set of symptoms. The prognosis of a person with holoprosencephaly depends on the severity and the type of the disease. If the forebrain of the embryo does not divide at all, the outcomes are very poor.

  1. Alobar holoprosencephaly. The most severe form of the disorder. Both thalamus are completely fused together, and there is no separation between the two hemispheres of the brain. Almost all cases of alobar HPE are incompatible with life, and therefore fatal. Alobar holoprosencephaly may result in cyclopia, the rare fetal malformation resulting in a single midline orbit instead of two.

  2. Semilobar holoprosencephaly. A less severe type of HPE, this diagnosis can be made if more than 50% of the frontal lobes are fused. In semilobar holoprosencephaly, the anterior frontal lobe may be fused together.  There is some degree of facial abnormality as a result of semilobar holoprosencephaly, including cleft lip or palate. Like alobar HPE, it can be observed in an ultrasound or MRI.

  3. Lobar holoprosencephaly. Less severe form of HPE. The prognosis for lobar holoprosencephaly is not always lethal. The thalami are not usually fused. People with this form of HPE may have an absence of the olfactory bulbs, or a fused cingulate gyrus, a structure that is close along the midline. In an MRI, it can be observed that sometimes a part of the ventricles may be fused together.

  4. Syntelencephaly. A mild form of HPE which is sometimes also called middle interhemispheric variant or (MIHV). In MIHV, the posterior end of the frontal lobes or the temporal lobes may fail to separate. As with the other forms of holoprosencephaly, syntelencephaly can be detected with imaging techniques such as ultrasound or MRI. People with syntelencephaly may have unusual muscle tone, spasticity, or oromotor dysfunction.

  5. Agenesis of the corpus callosum. Agenesis is a mild form of holoprosencephaly where the corpus callosum completely fails to develop. There are many disorders that may lead to agenesis of the corpus callosum.

Causes of holoprosencephaly

In development, the neural precursor cells respond to a variety of molecular signals that cause the cells to act in certain ways. One such signal molecule is called Sonic hedgehog (Shh). Sonic hedgehog is known to be dysregulated in some cases of holoprosencephaly (Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function). Even though changes in certain developmental signals may contribute to holoprosencephaly, there are some cases where the causes are unknown.

Trisomy 13 is associated with certain types of holoprosencephaly.