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PubMed This is a summary of 20 peer-reviewed journal articles Updated
Genetics · Holoprosencephaly

Biology, Genetics, and the Spectrum of HPE

At a Glance

Holoprosencephaly (HPE) occurs when a baby's brain fails to divide into left and right hemispheres around the fifth week of pregnancy. It is primarily caused by genetic factors like Trisomy 13 or SHH gene mutations, and exists on a spectrum from alobar (most severe) to lobar.

Understanding why a child’s brain did not develop as expected is a heavy and often overwhelming task for parents. It is important to begin with a foundational truth: this condition is the result of a complex biological event that occurs extremely early in pregnancy—usually around the fifth week of gestation [1]. This is a time when most people may not even be aware they are pregnant. It is not caused by your daily activities, exercise, diet, or minor stresses [2].

The Biological Mechanism: A Failure to Divide

During early development, the embryonic brain, called the prosencephalon, is supposed to split down the middle to create two distinct halves: the right and left hemispheres [3]. This process is known as cleavage [1]. In children with holoprosencephaly (HPE), this cleavage process fails to complete [4].

Scientists believe this failure is driven by a disruption in “signaling pathways”—the biological instructions that tell cells where to go and what to become [5]. The most well-known of these is the Sonic Hedgehog (SHH) signaling pathway, which is essential for forming the midline of the brain and face [5][6]. If these signals are interrupted, the brain remains a single structure rather than two [4].

The HPE Spectrum

HPE is not a single “all-or-nothing” condition; it exists on a spectrum of severity based on how much of the brain failed to divide [1][7].

  • Alobar HPE: The most severe form. The brain has not divided at all, resulting in a single central cavity (monoventricle) and fused structures [4][8].
  • Semilobar HPE: The back of the brain (posterior) has divided into two halves, but the front (anterior) remains fused [1].
  • Lobar HPE: Most of the brain has divided, but some fusion remains in the very front and bottom portions of the brain [7].
  • Middle Interhemispheric Fusion Variant (MIHF): A rarer form where the front and back of the brain divide correctly, but the middle section stays fused [9][10].

Why It Happens: Genetics and Environment

The cause of HPE is often “multifactorial,” meaning it can be a combination of genetic “blueprints” and environmental factors [11][12].

Genetic Factors

In many cases, HPE is linked to chromosomal or single-gene changes:

  • Trisomy 13: This is the most common chromosomal cause, where a child has three copies of chromosome 13 instead of two [8][13].
  • Gene Mutations: Specific genes like SHH, ZIC2, SIX3, and TGIF1 act as the “engineers” for brain division [5][14][15]. A mutation in just one of these genes can disrupt the entire process [16].
  • Variable Expressivity: Sometimes, a parent may carry a gene mutation and have only a minor sign (like a single central front tooth), while their child has a more severe form of HPE [17].

Environmental Risk Factors

While most cases are genetic, some environmental factors are known to increase risk:

  • Maternal Diabetes: While pre-existing (pregestational) diabetes in the mother is a recognized risk factor, it is a complex biological event [2]. Because this critical window of development occurs around the fifth week of pregnancy, it happens before many women even know they are pregnant [1]. It is essential not to blame yourself for blood sugar fluctuations that may have occurred before you were aware of the pregnancy [18].
  • Medication Exposures: Certain prescription teratogenic medications taken during the first weeks of pregnancy, such as retinoic acid or statins, can increase risk [19]. However, explicitly, everyday household products and routine exposures do not cause HPE.

Summary Table of Causes

Factor Type Impact on Development
Trisomy 13 Chromosomal Disrupts overall blueprints for development [8].
SHH Gene Single Gene Fails to send the signal to “split” the forebrain [5].
Maternal Diabetes Environmental Can interfere with early embryonic signaling, prior to pregnancy awareness [2].
ZIC2 Gene Single Gene Affects the formation of the brain’s midline [14].

This diagnosis is a result of complex biology that occurred before you could have changed anything. Understanding these mechanisms is the first step in moving from “why did this happen?” toward “how do we care for our child?” [20].

Common questions in this guide

What causes holoprosencephaly (HPE)?
Holoprosencephaly is primarily caused by genetic factors, such as Trisomy 13 or mutations in specific genes like SHH and ZIC2. Sometimes environmental factors early in pregnancy, like pre-existing maternal diabetes, can increase the risk. It is a complex biological event that happens before many women even know they are pregnant.
What is the difference between alobar, semilobar, and lobar HPE?
These classifications describe how much of the brain failed to divide. Alobar HPE is the most severe form where the brain did not divide at all. Semilobar means the back of the brain divided but the front did not, and lobar means most of the brain divided successfully with only minor fusion remaining.
Did something I did during pregnancy cause my child's holoprosencephaly?
No, everyday activities, diet, exercise, or minor stresses do not cause HPE. The biological event that leads to HPE occurs very early in embryonic development, usually around the fifth week. It is important for parents to know that they did not cause this condition.
Can a parent carry a gene for HPE without having severe symptoms?
Yes, due to a genetic concept called variable expressivity. A parent might carry an HPE-related gene mutation and only show a very minor physical sign, such as a single central front tooth or eyes that are close together, while their child may develop a more severe form of the condition.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Does my child’s imaging show alobar, semilobar, or lobar HPE, and how does that specific classification affect their prognosis?
  2. 2.Was Trisomy 13 or a specific gene mutation like SHH or ZIC2 identified in the genetic testing?
  3. 3.What does the presence of a 'monoventricle' or 'fused thalami' mean in the context of my child's brain development?
  4. 4.Can you explain the 'multiple hit' theory of HPE and whether it applies to our situation?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

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    Are the prevalence of Trisomy 13 and the incidence of severe holoprosencephaly increasing in Africa?

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This page explains the biology and genetics of holoprosencephaly (HPE) for educational purposes only. Always consult your pediatric neurologist or genetic counselor for guidance specific to your child's diagnosis.

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