Holoprosencephaly (HPE)

What is holoprosencephaly (HPE)?

Holoprosencephaly (HPE), pronounced “hah-low-prah-sen-SEH-fuh-lee,” is a birth defect (congenital condition) that causes a developing fetus's brain to not properly separate into the right and left hemispheres (halves). HPE can also affect the development of a fetus’s head and face.

Your brain is normally divided into the left and right hemispheres, but they remain in contact and communication with one another by the corpus callosum (a nerve fiber bundle in your brain). Each hemisphere further divides into the frontal, parietal, occipital and temporal lobes.

This division is important for several reasons, including allowing your brain to process several pieces of information and to perform several actions at once. When your brain doesn’t divide properly in development, as in HPE, it causes several physical and neurological issues.

Holoprosencephaly happens very early in fetal development in the uterus. There are several different types of holoprosencephaly with a wide range of severity and symptoms. The condition affects each child differently.

What are the types of holoprosencephaly?

There are three main types of holoprosencephaly (HPE). Ordered from most to least severe, they include:

• Alobar holoprosencephaly: This type means the fetal brain hasn’t divided into two hemispheres at all. This results in the loss of midline structures of itsbrain and face, as well as fusion of the cavities of their brain. It’s usually associated with severe facial deformities. Babies with this type of HPE are often stillborn or die shortly after birth.
• Semilobar holoprosencephaly: This type means the fetal brain has partially divided into two hemispheres. It happens when the left side of its brain is fused to the right side in the areas of their brain known as the frontal (front) and parietal lobes. Also, the dividing line between the right and left hemispheres of its brain (known as the interhemispheric fissure) is only present in the back of its brain.
• Lobar holoprosencephaly: This type means most of the fetal brain has separated into two hemispheres, but there’s an incomplete division of the two halves. There are two ventricles (right and left), but the cerebral hemispheres are fused in the frontal cortex. This is the least severe form of HPE.

There’s also a fourth subtype of HPE called middle interhemispheric (MIH) variant. It happens when the fetal brain is fused in the middle.

What is the difference between hydranencephaly and holoprosencephaly?

While hydranencephaly and holoprosencephaly are both congenital conditions (birth defects) that involve your baby’s brain, they’re different.

Hydranencephaly happens when there are missing portions of your baby’s brain. It’s a very rare form of hydrocephalus, and affected babies usually have an enlarged head.

Holoprosencephaly happens when the fetus's brain doesn’t properly separate into the right and left hemispheres during fetal development.

Who does holoprosencephaly affect?

Holoprosencephaly affects developing fetuses. It usually develops during the second and third weeks of fetal development — often before you even know you’re pregnant.

How common is holoprosencephaly?

Researchers estimate that holoprosencephaly affects 1 in 250 fetuses during early development (the second and third week of pregnancy), but most of these pregnancies result in miscarriage or stillbirths.

Holoprosencephaly is rare in live births. It’s present in approximately 1 in 16,000 live births.

What are the symptoms of holoprosencephaly (HPE)?

As there are several types of holoprosencephaly (HPE), the severity and symptoms for it vary widely.

In general, HPE is associated with the following symptoms:

• Developmental delay.
• Intellectual disability.
• Epilepsy and seizures.
• Small head (microcephaly).
• Large head (macrocephaly).
• Excessive fluid in the brain (hydrocephalus).
• Facial abnormalities.
• Tooth abnormalities (single central incisor).
• Cleft lip and/or palate.
• Problems regulating body temperature, heart rate and breathing.
• Feeding difficulties.

Signs and symptoms of alobar holoprosencephaly include:

• A single eye (cyclopia), very closely spaced eyes (ethmocephaly) or missing eyes (anophthalmia).
• Very small eyeballs (microphthalmia) with a tubular-shaped nose (proboscis).
• Closely spaced eyes (orbital hypotelorism) with a flattened nose or cleft lip that occurs in the middle of their lip (median cleft lip) or on both sides (bilateral cleft lip).

Signs and symptoms of semilobar holoprosencephaly include:

• Closely spaced eyes (orbital hypotelorism), very small eyeballs (microphthalmia) or one or no eyes (anophthalmia).
• Flattened bridge and tip of their nose.
• One nostril.
• Median cleft lip or bilateral cleft lip.
• Cleft palate.

Signs and symptoms of lobar holoprosencephaly include:

• Bilateral cleft lip.
• Closely spaced eyes.
• Depressed nose.

Holoprosencephaly may be part of several different genetic syndromes. Each of these syndromes has its own characteristics and symptoms.

What causes holoprosencephaly (HPE)?

Normally, the fetal brain divides into two hemispheres (halves) during early development. Holoprosencephaly (HPE) happens when its brain doesn’t divide properly into the right and left hemispheres, specifically in its forebrain, or prosencephalon.

The forebrain is a region of the fetal brain that develops into parts of the adult brain, including their cerebral cortex. Instead of the normal complete separation of the left and right hemispheres of the forebrain, there’s an abnormal continuity between the two sides.

Specifically, causes of holoprosencephaly can include:

• Mutations (changes) in any of at least 14 different genes.
• Chromosome abnormalities.
• Certain genetic syndromes.

In many cases, healthcare providers can’t determine the exact cause.

Genetic mutations that cause holoprosencephaly

A genetic mutation is a change in a sequence of your DNA. Your DNA sequence gives your cells the information they need to perform their functions. If part of your DNA sequence isn’t complete or is damaged, you might experience symptoms of a genetic condition.

A baby can inherit a genetic mutation from either or both of their biological parents, depending on how the mutation is passed down, but some mutations occur randomly with no previous history of the mutation in your family.

Scientists have connected mutations in these specific genes to HPE:

• SHH.
• SIX3.
• TGIF1.
• ZIC2.
• PTCH1.
• FOXH1.
• NODAL.
• CDON.
• FGF8.
• GLI2.

These mutations (changes) cause the genes and their proteins to function incorrectly, and this affects the development of the fetal brain, resulting in holoprosencephaly.

Chromosome abnormalities that cause holoprosencephaly

All humans have 46 chromosomes that divide into 23 pairs. Chromosomes carry your DNA in cells, which tells your body how to form and function as its instruction manual. You receive one set of chromosomes from each of your parents.

About one-third of babies born with holoprosencephaly have an abnormality of their chromosomes. The most common chromosomal abnormality associated with HPE is when there are three copies of chromosome 13 (trisomy 13). Trisomy 18 and triploidy (having 69 chromosomes rather than the normal 46 chromosomes per cell) also cause HPE.

Genetic syndromes that involve holoprosencephaly

Holoprosencephaly can occur as a part of certain genetic syndromes in which there are other medical issues besides HPE.

Genetic syndromes that involve HPE include:

• Hartsfield syndrome.
• Kallman syndrome two.
• Steinfeld syndrome.
• Smith-Lemli-Opitz syndrome.
• Stromme syndrome.

How is holoprosencephaly (HPE) diagnosed?

Healthcare providers can often identify holoprosencephaly (HPE), especially more severe cases, before birth through a prenatal ultrasound. They can also diagnose the condition pre-birth with fetal magnetic resonance imaging (MRI).

Although healthcare providers can identify HPE with prenatal imaging, they most frequently diagnose HPE after delivery when facial abnormalities or neurologic issues are present. They then perform head imaging tests to confirm the diagnosis.

Infants with very mild forms of holoprosencephaly may not be diagnosed until they’re about one year old. In this case, developmental delays often signal a possible neurological issue, which then prompts healthcare providers to order brain imaging tests.

What tests will be done to diagnose holoprosencephaly (HPE)?

Healthcare providers use the following imaging tests to help diagnose holoprosencephaly once your baby is born:

• Head ultrasound: Ultrasound (also called sonography or ultrasonography) is a noninvasive diagnostic imaging test. It uses high-frequency sound waves to create real-time pictures or video of internal organs or other tissues, such as blood vessels.
• Magnetic resonance imaging (MRI) brain scan: An MRI brain scan is a painless test that produces very clear images of the structures and tissues in your child’s brain. MRI uses a large magnet, radio waves and a computer to produce these detailed images. It doesn’t use X-rays (radiation).
• Head computed tomography (CT) scan: A CT scan is a type of test that combines X-rays with a computer to produce many three-dimensional (3D) images of the body part being scanned — in this case, your child’s head and brain.

Healthcare providers use DNA studies, such as chromosomal analysis and cytogenetic and molecular testing, to determine the exact cause of HPE, if possible.

If genetic testing reveals any kind of chromosomal or genetic issue that’s associated with holoprosencephaly, your healthcare provider will recommend genetic counseling if you’re considering having another biological child.

How is holoprosencephaly treated?

There isn’t a cure or main treatment for holoprosencephaly (HPE). Instead, healthcare providers target treatment toward the specific symptoms that each child with HPE has.

Treatment may require the coordinated efforts of a team of specialists, including:

• Pediatricians.
• Neurologists.
• Endocrinologists.
• Plastic surgeons.
• Occupational and physical therapists.
• Palliative care
• Complex care team.

Common treatments for HPE include:

• Anti-seizure medications to help prevent, reduce or control seizures.
• Placing a ventriculoperitoneal (VP) shunt to treat hydrocephalus (a buildup of fluid in your child’s brain).
• Medications and occupational and physical therapy to help with movement issues, like spasticity and dystonia.
• Plastic reconstructive surgery of cleft lip and palate or other facial features.
• Medications to treat pituitary gland hormone imbalances.
• Measures to improve the intake of nutrients for children with feeding difficulties, such as a gastrostomy tube (G-tube).

Can holoprosencephaly be prevented?

Unfortunately, most cases of holoprosencephaly (HPE) can’t be prevented, as “hidden” inherited genetic issues often cause HPE. If you plan on having a biological child, talk with your healthcare provider about genetic testing to understand your risk of having a child with a genetic condition or a condition that can be caused by an inherited genetic mutation, such as HPE.

Scientists have identified some risk factors that might make it more likely for a fetus to develop holoprosencephaly, including:

• Having diabetes: Having Type 1 or Type 2 diabetes before you become pregnant might increase your risk of having a baby with HPE. This isn’t to be confused with gestational diabetes.
• Folate (folic acid) deficiency: Folate, the natural form of vitamin B9, is important for healthy fetal development, especially for the brain and spine. A folate deficiency before and during pregnancy may increase the risk of having a baby with HPE.
• Exposure to teratogens: Teratogens are substances or factors that cause issues with fetal development that lead to birth defects. Exposure to teratogens — like ethanol, retinoic acid and food-borne mycotoxins (mold toxins) — may increase your risk of having a baby with holoprosencephaly.

What is the prognosis (outlook) for holoprosencephaly (HPE)?

The prognosis (outlook) for holoprosencephaly (HPE) varies depending on the severity of the condition and the specific cause of the condition.

Moderate to severe cases of HPE generally have a poor prognosis. A very small number of children with moderate to severe cases live into adulthood. Children with mild to moderate cases of HPE typically live into adulthood, but they almost always have medical complications related to HPE.

Most children with holoprosencephaly need daily medications and therapies to prevent seizures and treat other complications.

What is the life expectancy of someone with holoprosencephaly?

The life expectancy of someone with holoprosencephaly (HPE) depends on the type of HPE they have and the underlying cause of the condition.

Babies with alobar HPE (the most severe form of HPE) are usually stillborn or die shortly after birth or during the first six months of life.

More than 50% of children with semilobar or lobar HPE without malformations of other organs live to at least 12 months of age.

Children with mild cases of HPE typically live into adulthood.

What can I expect if my baby has holoprosencephaly?

It’s important to remember that no two children with holoprosencephaly are affected in the same way. It’s impossible to predict with certainty how your child will be affected. The best way you can prepare for the future is to talk to healthcare providers who specialize in researching and treating holoprosencephaly.

How can I take care of my baby with holoprosencephaly (HPE)?

To help take care of your child with holoprosencephaly (HPE), follow their healthcare providers’ instructions for:

• Giving any medications as prescribed.
• Getting developmental assessments and therapies.
• Going to all follow-up medical visits.

Holoprosencephaly can cause cognitive (intellectual), neurologic and/or motor (muscle) issues. Most children with HPE will have problems with their development and may need help with daily tasks throughout their lives.

Your child’s healthcare team can answer questions and offer support. They also might be able to recommend a local or online support group.

When should I see my child’s healthcare provider about holoprosencephaly?

If your child has been diagnosed with holoprosencephaly, they’ll need to see their healthcare team regularly to make sure their treatment is working and to assess their developmental progress.

A note from Cleveland Clinic

Learning that you're carrying a fetus with holoprosencephaly can be overwhelming. Know that you're not alone — many resources are available to help you and your family. It’s important that you speak with a healthcare provider who’s very familiar with the condition so you can learn more about how your baby will be affected and how to prepare.