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PubMed This is a summary of 17 peer-reviewed journal articles Updated
Maternal-Fetal Medicine

Does the Face Predict the Brain in Holoprosencephaly?

At a Glance

In holoprosencephaly, the severity of facial differences typically mirrors the severity of the brain malformation. However, doctors cannot rely on the face alone because mutations in genes like ZIC2 can cause severe brain fusion alongside relatively typical facial features.

In this answer

3 sections

01

The Rule: “The Face Predicts the Brain”

02

The Major Exception: The ZIC2 Gene

03

Getting the Full Picture

In most cases, yes. Doctors who specialize in holoprosencephaly (HPE) often use a guiding rule: “the face predicts the brain” [1]. This means that the severity of a baby’s facial differences typically mirrors the severity of their brain malformation [2]. However, this is only a general rule. Because of certain genetic exceptions, doctors cannot rely on facial features alone to determine how severe the brain fusion is [3].

The Rule: “The Face Predicts the Brain”

During early pregnancy, the tissues that form a baby’s face and the front of their brain develop together at the exact same time [4]. Because they are so closely linked, a disruption in one usually means a disruption in the other.

In general, more profound facial differences on an ultrasound suggest a more severe type of HPE. Note: Reading about severe facial differences can be emotionally difficult, but understanding these terms can help you navigate conversations with your medical team.

  • Severe facial features: Features such as cyclopia (a single eye in the center of the face) or a proboscis (a tube-like nasal structure above the eye) almost always indicate alobar HPE [5][6]. This is the most severe form, where the brain has not divided into right and left halves at all [7].
  • Moderate to milder facial features: Features like close-set eyes (hypotelorism), a flattened nose, or a single central front tooth are often associated with milder brain malformations, such as semilobar or lobar HPE [8][9].

Understanding Cleft Lip in HPE

If your ultrasound shows a cleft lip, doctors will look closely at its location, as this can offer clues about the brain:

  • Median cleft lip: A cleft located perfectly in the center (midline) of the lip, often with missing tissue beneath the nose, is generally linked to more severe brain fusion [10][11].
  • Lateral cleft lip: A cleft on one or both sides (unilateral or bilateral) is considered a less extreme facial difference and may point toward a milder form of HPE [12].

The Major Exception: The ZIC2 Gene

While the “face predicts the brain” rule is helpful, it has a massive exception. Changes (mutations) in a gene called ZIC2 can cause a baby to have a very severe brain malformation (like alobar or semilobar HPE) while having a relatively typical-looking face [3][13].

Babies with a ZIC2 mutation rarely have the severe facial features normally expected with profound brain fusion [14]. This means that if a baby has this specific genetic type of HPE, finding a milder facial feature (like a cleft lip) on an ultrasound does not guarantee the brain malformation is less severe [3].

Getting the Full Picture

Because of exceptions like the ZIC2 gene, your medical team—which may include maternal-fetal medicine (MFM) specialists, pediatric neurologists, and genetic counselors—will never use the face alone to predict your baby’s future [15].

To get a complete understanding of how the brain has formed, they will recommend a combination of detailed imaging and testing:

  • Fetal MRI: This imaging provides a much clearer, more detailed picture of your baby’s brain structure than a standard ultrasound [16].
  • Genetic Testing: They will likely recommend testing for genes like ZIC2 (using a microarray or an HPE gene panel). During pregnancy, this is typically done through an amniocentesis (testing the amniotic fluid) or chorionic villus sampling (CVS, testing the placenta) to gather the baby’s DNA [17].

Common questions in this guide

Do facial features always predict the severity of holoprosencephaly?
Usually, the severity of facial differences seen on an ultrasound mirrors the severity of the brain malformation. However, doctors cannot rely on facial features alone because specific genetic mutations can cause a severe brain malformation with a relatively typical face.
What facial features indicate alobar holoprosencephaly?
Profound facial differences almost always indicate alobar holoprosencephaly, the most severe form of the condition. These features can include cyclopia, which is a single eye in the center of the face, or a proboscis, a tube-like nasal structure above the eye.
What does a cleft lip mean for a baby with holoprosencephaly?
The location of a cleft lip can offer clues about the brain. A median cleft lip, located perfectly in the center, is generally linked to more severe brain fusion, while a lateral cleft on the sides usually points to a milder form of the condition.
How does the ZIC2 gene affect facial features in holoprosencephaly?
A mutation in the ZIC2 gene causes a baby to have very severe brain fusion, such as alobar or semilobar holoprosencephaly, but with a relatively typical-looking face. Because of this exception, finding a mild facial feature on an ultrasound does not guarantee the brain malformation is also mild.
How do doctors confirm the severity of the brain malformation?
Because the face does not always predict the brain, specialists will use advanced imaging and testing. A fetal MRI provides a much clearer picture of the brain's structure, and genetic testing like an amniocentesis can check for specific gene mutations.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Is the cleft lip you see on the ultrasound in the middle (a median cleft) or on the side (a lateral cleft)?
  2. 2.Based on the ultrasound, what specific type of holoprosencephaly (alobar, semilobar, or lobar) do you suspect my baby has?
  3. 3.Should we consider an amniocentesis or chorionic villus sampling (CVS) to test for HPE-related genes like ZIC2?
  4. 4.What are the risks and benefits of getting a fetal MRI to get a clearer picture of the brain?
  5. 5.Can you refer me to a maternal-fetal medicine specialist or a genetic counselor to discuss these findings in more detail?

Questions For You

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References

References (17)
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    Ventriculoperitoneal Shunting in Alobar Holoprosencephaly: Does it Work Even When Patient Has No Sign of Raised Intracranial Pressure?

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This page provides general information about holoprosencephaly facial features and brain development. It does not replace a professional evaluation by a maternal-fetal medicine specialist or genetic counselor.

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