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The Biology and Causes of HPE

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At a Glance

Holoprosencephaly (HPE) happens when a baby's brain fails to divide into two distinct halves early in pregnancy. It is mostly caused by genetic factors like Trisomy 13 or specific gene mutations. Genetic counseling is highly recommended to help families understand their specific risks.

Key Takeaways

  • • HPE occurs when the embryonic forebrain fails to split completely into left and right hemispheres during early development.
  • • Genetics play a central role in HPE, with Trisomy 13 and mutations in genes like SHH frequently linked to the condition.
  • • Certain broad environmental factors during early pregnancy, such as poorly controlled maternal diabetes, can slightly increase the risk of HPE.
  • • Due to variable expressivity, the severity of HPE can vary widely among family members who carry the exact same genetic mutation.
  • • Genetic counseling is an essential step for families to understand inheritance patterns and accurately estimate the risk of recurrence in future pregnancies.

Understanding the “why” behind a diagnosis of Holoprosencephaly (HPE) often begins with a look into the very first weeks of life. This condition is not the result of a single event but rather a disruption in a complex biological “blueprint” that guides the development of the brain.

The Biological Mechanism: A Failure to Divide

In the early embryo, the brain starts as a single structure called the prosencephalon (the forebrain) [1]. Between the third and fourth weeks of pregnancy, this structure is supposed to split into two distinct halves—the left and right cerebral hemispheres [2].

HPE occurs when this cleavage process is incomplete or fails entirely [1]. Think of it like a cell that begins to divide but stops halfway. Because the brain and face share the same early developmental pathways, this lack of division also often affects the development of the eyes, nose, and mouth [3].

The Genetic Blueprint

For most families, genetics play a central role. HPE can be caused by changes in chromosomes or specific genes:

  • Chromosomal Abnormalities: The most common association is Trisomy 13 (Patau Syndrome), where a child has three copies of chromosome 13 instead of two [4]. Other chromosomal deletions or duplications can also be responsible [5].
  • Specific Gene Mutations: Scientists have identified several key genes that act as “master switches” for brain division. Mutations in genes like SHH (Sonic Hedgehog), ZIC2, SIX3, and PTCH1 are frequently linked to HPE [6][7][8].

Broad Environmental Risk Factors

While genetics are a major factor, certain broad environmental conditions during the first few weeks of pregnancy can slightly increase the risk on a population-wide scale:

  • Maternal Diabetes: Poorly controlled blood sugar in the mother during the earliest stages of pregnancy is a well-documented risk factor [9][10].
  • Exposures: Some studies suggest that broad environmental or agricultural exposures to certain chemicals may play a role in disrupting early development [9][11].

Important Note: It is crucial to remember that these are large-scale risk factors being studied—no single everyday action, like occasionally using a common bug spray or having fluctuating blood sugar, “causes” HPE [9].

Why Severity Varies (Variable Expressivity)

One of the most confusing aspects of HPE is that the same genetic mutation can look very different in different people—even within the same family.

  • Variable Expressivity: This means that while two people have the same “broken” gene, one might have severe brain malformations (alobar HPE), while the other might only have a “microform” feature, such as a single central front tooth (incisor) or slightly closer-set eyes [12][13].
  • Incomplete Penetrance: Sometimes, a person can carry a genetic mutation for HPE but show no physical signs at all [12].

This happens because brain development is influenced by a “threshold.” A primary genetic mutation might push the embryo toward the threshold, but other “modifier” genes or environmental factors determine if—and how severely—the condition actually manifests [14][10].

The Role of Genetic Counseling

Because of the complex ways HPE is inherited, genetic counseling is a vital step for every family [15]. A counselor can help you:

  1. Identify if the HPE was a random “de novo” event (low risk of happening again) or part of an inherited pattern (often “autosomal dominant” meaning only one copy of the gene needs to be altered to increase risk) [16].
  2. Coordinate testing for parents to see if they are asymptomatic carriers of an HPE-related gene [17].
  3. Provide accurate information about the risk of recurrence in future pregnancies [18].

Frequently Asked Questions

What exactly causes Holoprosencephaly (HPE)?
HPE is caused by a failure of the early embryo's brain to divide into two distinct halves during the first few weeks of pregnancy. This is primarily driven by genetic changes, such as having extra chromosomes or mutations in specific genes like SHH.
Can environmental factors or maternal health cause HPE?
While genetics are the main factor, certain environmental conditions can slightly increase the risk. Poorly controlled maternal diabetes during the earliest stages of pregnancy is a well-documented risk factor for HPE.
Why do family members with the same HPE gene mutation have different symptoms?
This is due to a phenomenon called variable expressivity. The same genetic change can result in severe brain malformations in one person, but only mild features—like a single central front tooth or close-set eyes—in another family member.
What genetic tests are used to find the cause of HPE?
Doctors typically use genetic tests such as a karyotype, microarray, or gene sequencing. These tests help determine if the HPE is linked to a chromosomal condition like Trisomy 13 or a specific gene mutation.
What is the risk of HPE happening again in a future pregnancy?
The risk of recurrence depends entirely on the specific genetic cause. A genetic counselor can help determine if the HPE was a random, one-time event with a low risk of happening again, or if it follows an inherited genetic pattern.

Questions for Your Doctor

  • • Which specific genetic tests (karyotype, microarray, or gene sequencing) have been performed?
  • • Is our child's diagnosis considered 'isolated' or is it part of a syndrome like Trisomy 13?
  • • If a genetic mutation was found, does it follow an autosomal dominant pattern with reduced penetrance?
  • • Are there any 'microform' features in either parent that might suggest we carry a gene for HPE?
  • • What is the estimated recurrence risk for future pregnancies based on our specific results?

Questions for You

  • • Have any relatives been born with a single middle tooth, a cleft lip, or closely spaced eyes?
  • • How do I feel about the possibility of genetic testing for myself or other family members?
  • • What genetic information do I need in order to feel comfortable making decisions about future family planning?

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The Spectrum of HPE: Subtypes and Features Holoprosencephaly

References

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    Calloni SF, Caschera L, Triulzi FM

    Neuroimaging clinics of North America 2019; (29(3)):411-421 doi:10.1016/j.nic.2019.03.003.

    PMID: 31256862
  2. 2

    The wide spectrum of ultrasound diagnosis of holoprosencephaly.

    Ionescu CA, Vladareanu S, Tudorache S, et al.

    Medical ultrasonography 2019; (21(2)):163-169 doi:10.11152/mu-1614.

    PMID: 31063520
  3. 3

    Antenatal Ultrasonographic Diagnosis of a Constellation of Alobar Holoprosencephaly, Ethmocephaly, and Hydronephrosis in a Case of Early-Onset Intrauterine Growth Retardation: A Case Report.

    Ghanta PR, Phatak S, Bhansali PJ, et al.

    Cureus 2022; (14(7)):e27375 doi:10.7759/cureus.27375.

    PMID: 36046320
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    Cytogenetics and holoprosencephaly: A chromosomal microarray study of 222 individuals with holoprosencephaly.

    Hu T, Kruszka P, Martinez AF, et al.

    American journal of medical genetics. Part C, Seminars in medical genetics 2018; (178(2)):175-186 doi:10.1002/ajmg.c.31622.

    PMID: 30182442
  5. 5

    Application of quantitative fluorescent polymerase chain reaction analysis for the rapid confirmation of trisomy 13 of maternal origin in a pregnancy with fetal holoprosencephaly, cyclopia, polydactyly, omphalocele and cell culture failure.

    Chen CP, Wang LK, Chern SR, et al.

    Taiwanese journal of obstetrics & gynecology 2022; (61(1)):135-137 doi:10.1016/j.tjog.2021.11.022.

    PMID: 35181024
  6. 6

    SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization.

    Sagai T, Amano T, Maeno A, et al.

    Proceedings of the National Academy of Sciences of the United States of America 2019; (116(47)):23636-23642 doi:10.1073/pnas.1901732116.

    PMID: 31685615
  7. 7

    Reply: Another case of holoprosencephaly associated with RAD21 loss-of-function variant.

    Kruszka P

    Brain : a journal of neurology 2020; (143(8)):e65 doi:10.1093/brain/awaa177.

    PMID: 32712652
  8. 8

    Six3 dosage mediates the pathogenesis of holoprosencephaly.

    Geng X, Acosta S, Lagutin O, et al.

    Development (Cambridge, England) 2016; (143(23)):4462-4473 doi:10.1242/dev.132142.

    PMID: 27770010
  9. 9

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

    Okoye JO, Ngokere AA

    Prenatal diagnosis 2020; (40(12)):1616-1617 doi:10.1002/pd.5777.

    PMID: 32715507
  10. 10

    Identifying environmental risk factors and gene-environment interactions in holoprosencephaly.

    Addissie YA, Troia A, Wong ZC, et al.

    Birth defects research 2021; (113(1)):63-76 doi:10.1002/bdr2.1834.

    PMID: 33111505
  11. 11

    Prenatal exposure to pesticides and risk for holoprosencephaly: a case-control study.

    Addissie YA, Kruszka P, Troia A, et al.

    Environmental health : a global access science source 2020; (19(1)):65 doi:10.1186/s12940-020-00611-z.

    PMID: 32513280
  12. 12

    Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts.

    Kingdom R, Wright CF

    Frontiers in genetics 2022; (13()):920390 doi:10.3389/fgene.2022.920390.

    PMID: 35983412
  13. 13

    French Guidelines of the AchroPuce Network for the Interpretation and Reporting of Constitutional Copy Number Variants.

    Pebrel-Richard C, Kuentz P, Tabet AC, et al.

    Clinical genetics 2026; (109(1)):99-108 doi:10.1111/cge.70027.

    PMID: 40693340
  14. 14

    Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing.

    Mouden C, Dubourg C, Carré W, et al.

    Clinical genetics 2016; (89(6)):659-68 doi:10.1111/cge.12722.

    PMID: 26748417
  15. 15

    Holoprosencephaly spectrum: an up-to-date overview of classification, genetics and neuroimaging.

    Gomez GD, Corrêa DG, Trapp B, et al.

    Japanese journal of radiology 2025; (43(1)):13-31 doi:10.1007/s11604-024-01655-8.

    PMID: 39259418
  16. 16

    Semilobar Holoprosencephaly Caused by a Novel and De Novo ZIC2 Pathogenic Variant.

    Nonkulovski D, Sofijanova A, Spasovska T, et al.

    Balkan journal of medical genetics : BJMG 2023; (25(2)):71-76 doi:10.2478/bjmg-2022-0017.

    PMID: 37265970
  17. 17

    FOXI3 pathogenic variants cause one form of craniofacial microsomia.

    Mao K, Borel C, Ansar M, et al.

    Nature communications 2023; (14(1)):2026 doi:10.1038/s41467-023-37703-6.

    PMID: 37041148
  18. 18

    A Novel Heterozygous ARL3 Variant in Non-Syndromic Retinitis Pigmentosa: Clinical and Functional Characterization.

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    PMID: 41828587

This page provides educational information about the biological and genetic causes of Holoprosencephaly (HPE). It does not replace professional medical advice, and families should always consult a genetic counselor or physician to understand their specific risks.

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