Holoprosencephaly (HPE): A Guide to Brain Development and Types
Updated: 3 days ago
Medically reviewed by Dr. Baraa Alnahhal, MD · Last reviewed: October 2026
Quick Answer
Holoprosencephaly (HPE) is a birth defect in which the brain does not split into right and left halves, occurring during the 2nd and 3rd weeks of pregnancy. Its main types range from alobar, the most severe, to lobar, the least severe. Symptoms include developmental delays, seizures and facial abnormalities. Causes include genetic and chromosomal issues, though often none is found. [1]
What the research says
HPE is rare at birth, and diabetes before pregnancy is the main non-genetic risk factor. A narrative review describes HPE as occurring in about 1 in 16,000 live births, with pregestational diabetes and periconceptional high blood sugar as the main non-genetic risk factor. Genes involved include sonic hedgehog (SHH), ZIC2 and SIX3. (Taruscio and Mantovani, Ann Ist Super Sanita, 2023)
Chromosome changes are the most commonly identified cause, but many cases stay unexplained. A clinical review found that chromosomal abnormalities account for the most commonly identified cause of HPE, while causes often cannot be identified in non-syndromic, non-chromosomal forms. The authors also noted that prevalence may be underestimated because mild forms often go undiagnosed until a more severely affected child is born. (Kauvar and Muenke, Curr Opin Pediatr, 2010)
HPE likely results from several factors acting together. A review of gene-gene and gene-environment interactions describes four ways risk factors combine: driver and modifier genes, inheritance of predisposing variants from both parents, genetic susceptibility plus environmental exposures that are insufficient alone, and multiple variants combined with multiple non-genetic factors. (Lo et al., Front Cell Dev Biol, 2021)
What is holoprosencephaly (HPE)?
Holoprosencephaly, often abbreviated as HPE, is a complex brain development disorder. In a typical pregnancy, the forebrain (prosencephalon) divides into two distinct hemispheres, the right and left sides, very early in pregnancy. In cases of HPE, this separation is incomplete or entirely absent. This failure to divide not only impacts the brain's internal structure but also frequently alters the development of the head and face. [1]
The condition is relatively common in early conception, affecting approximately 1 in 250 fetuses. However, because the structural changes are often severe, many of these pregnancies result in miscarriage. Among live births, HPE is rare, occurring in about 1 in every 16,000 babies. [1]
The three main types of HPE
The severity of holoprosencephaly is classified based on how much of the brain has failed to separate. Each type presents unique challenges and requires different levels of medical intervention.
1. Alobar holoprosencephaly
This is the most severe form, where the brain remains a single unit without any division into hemispheres. It is frequently associated with significant facial deformities, such as cyclopia (a single eye) or a proboscis (a tubular nose). Most babies with alobar HPE are stillborn or pass away shortly after birth. [1]
2. Semilobar holoprosencephaly
In this moderate form, the brain has partially divided. The separation is usually present in the back of the brain but fused in the front (frontal and parietal lobes). Children with semilobar HPE often have closely spaced eyes and a flattened nose. [1]
3. Lobar holoprosencephaly
The least severe form, lobar HPE, occurs when most of the brain has separated, but the frontal cortex remains fused. While these children face developmental challenges, children with mild cases typically live into adulthood, though they typically require ongoing medical management for complications like seizures. [1]
Causes and maternal risk factors
While many cases of HPE occur without a clear explanation, researchers have identified several genetic and environmental triggers.
Genetic and chromosomal factors
About one-third of babies born with HPE have a chromosomal abnormality, the most common being trisomy 13 (having three copies of chromosome 13). Additionally, mutations in at least 14 different genes, including the SHH and ZIC2 genes, have been linked to the condition. These mutations can be inherited or occur randomly. [1]
Maternal health and environment
Certain factors during early pregnancy can increase the risk of a fetus developing HPE:
Diabetes: Having type 1 or type 2 diabetes before becoming pregnant is a known risk factor.
Folate deficiency: A lack of vitamin B9 (folate) is critical for early brain and spine development and may increase the risk.
Teratogen exposure: Exposure to substances like alcohol (ethanol), certain medications (retinoic acid), or mold toxins can disrupt fetal growth.
Living with and managing HPE
A diagnosis of HPE is life-altering for families, but a dedicated healthcare team can help manage the symptoms and improve a child's quality of life. Because HPE affects every child differently, treatment plans are highly personalized.
Common management strategies
Children with HPE often require daily medications to control epilepsy and seizures. Physical, occupational, and speech therapies are essential to address developmental delays and motor issues. Regular follow-up visits with neurologists and developmental specialists are necessary to monitor progress and adjust care as the child grows. [1]
Conclusion
Holoprosencephaly is a challenging diagnosis that spans a wide spectrum of severity. While the most severe forms are often fatal, medical advancements and early intervention allow many children with milder forms to live meaningful lives into adulthood. For parents navigating this journey, genetic counseling and specialized support groups can provide both clarity and community.
Support for families. Find resources for rare neurological conditions and developmental support at Rinnit.com.
Frequently Asked Questions
Can HPE be detected during a standard ultrasound?
Yes, especially more severe cases. A prenatal ultrasound or fetal MRI can often identify the lack of brain separation before birth.
Is HPE the same as hydrocephalus?
No. While HPE is a failure of the brain to divide, hydrocephalus is the buildup of fluid in the brain. However, children with HPE may develop hydrocephalus as a complication.
Can I prevent HPE in future pregnancies?
Most cases are genetic and cannot be prevented. However, managing pre-existing diabetes and taking folate supplements can reduce environmental risks.
Does HPE always cause facial deformities?
Not always, but there is a strong correlation. The more severe the brain fusion, the more likely there are to be midline facial issues like a cleft lip or closely spaced eyes.
What is the life expectancy for a child with lobar HPE?
Many children with lobar HPE live into adulthood, though they almost always have medical complications that require lifelong care.
Is HPE an inherited condition?
HPE can be. Some cases are caused by inherited genetic mutations, while others occur randomly (de novo). Genetic testing can help determine the risk for future pregnancies.
What are the main neurological symptoms?
Developmental delays, intellectual disabilities, and seizures are the most common neurological impacts.
Can surgery fix the brain fusion?
No, surgery cannot separate the fused brain tissue. Treatment focuses on managing symptoms like fluid buildup (shunts) or seizures.
Why does HPE affect the face?
The brain and face develop from the same embryonic tissues at the same time. When the brain fails to divide, the midline of the face often fails to develop properly as well.
Are there other types besides alobar, semilobar and lobar?
Yes, there is a fourth subtype called the middle interhemispheric (MIH) variant, in which the brain is fused in the middle.
How does HPE affect feeding?
Neurological issues and facial clefts can make swallowing and sucking difficult, often requiring specialized feeding techniques or tubes.
What genes are most commonly involved?
The SHH (Sonic Hedgehog) gene is one of the most well-known genes linked to HPE.
Does HPE affect intelligence?
Yes, most children with HPE have some degree of intellectual disability, ranging from mild to profound.
Is there a cure for HPE?
There is no cure for the underlying structural brain difference; management is focused on supportive care.
Where can I find a specialist?
Neurologists specializing in pediatric brain development and geneticists are the primary specialists for HPE.
References
Cleveland Clinic. Holoprosencephaly (HPE). Cleveland Clinic. Last updated May 5, 2022. https://my.clevelandclinic.org/health/diseases/22919-holoprosencephaly-hpe
Kauvar EF, Muenke M. Holoprosencephaly: recommendations for diagnosis and management. Curr Opin Pediatr. 2010;22(6):687-95. PMID 20859208. https://doi.org/10.1097/MOP.0b013e32833f56d5
Lo HF, Hong M, Krauss RS. Concepts in Multifactorial Etiology of Developmental Disorders: Gene-Gene and Gene-Environment Interactions in Holoprosencephaly. Front Cell Dev Biol. 2021;9:795194. PMID 35004690. https://doi.org/10.3389/fcell.2021.795194
Taruscio D, Mantovani A. The rare malformation holoprosencephaly: pathogenesis, association with pregestational diabetes and the possible link with food pollutants. Ann Ist Super Sanita. 2023;59(4):295-303. PMID 38088397. https://doi.org/10.4415/ANN_23_04_09
Tekendo-Ngongang C, Muenke M, Kruszka P. Holoprosencephaly Overview. GeneReviews. Initial posting December 27, 2000; last revision June 9, 2026. https://www.ncbi.nlm.nih.gov/books/NBK1530/
Ramakrishnan S, Das JM. Holoprosencephaly. StatPearls. Last update June 7, 2024. https://www.ncbi.nlm.nih.gov/books/NBK560861/
This article is for general educational purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition.
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