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PubMed This is a summary of 15 peer-reviewed journal articles Updated
Medical Genetics

The Science Behind the Diagnosis: Genetics and Causes

At a Glance

Lobar Holoprosencephaly (HPE) occurs when a baby's brain fails to fully divide into two halves early in pregnancy. It is often caused by genetic mutations, such as in the ZIC2 or SHH genes, or environmental factors like maternal diabetes. Unaffected parents can still pass on these genes.

The development of a baby’s brain is a highly complex process that happens very early in pregnancy. Understanding the biological and genetic reasons behind Lobar Holoprosencephaly (HPE) can help move away from feelings of guilt or “why us” and toward a clearer picture of your child’s unique biology.

The Biological “Split”: Prosencephalon Cleavage

Between weeks 5 and 6 of pregnancy (roughly 3 to 4 weeks after conception), the part of the embryonic brain called the prosencephalon (the forebrain) is supposed to divide into two separate halves [1]. This process is called cleavage.

In Lobar HPE, this cleavage process begins but does not fully complete [2]. Think of it like a zipper that gets stuck near the end; the back parts of the brain may separate correctly, but the front portions (the frontal lobes) remain fused together [2][3]. This failure to “zip” all the way through is what creates the physical structure of an HPE brain.

The Role of Genetics: SHH and ZIC2

The “zipping” of the brain is controlled by a series of chemical instructions from your child’s genes. Two of the most important genes involved in this process are SHH and ZIC2.

  • SHH (Sonic Hedgehog): This gene provides the blueprint for a protein that is essential for creating the “midline” of both the brain and the face [4][5]. When the SHH pathway is disrupted, it often results in both brain fusion and visible facial differences, such as eyes being close together [4].
  • ZIC2: This gene is frequently linked to the Lobar form of HPE [6]. Interestingly, mutations in ZIC2 often do not cause the severe facial malformations seen with other genes [6]. A child with a ZIC2 mutation might have a brain with Lobar HPE but a face that looks very typical [6][7].

Why Parents Are Often Unaffected

One of the most confusing aspects of HPE is that it can be inherited from a parent who shows no signs of the condition. This happens due to two medical concepts:

  1. Incomplete Penetrance: This means that a person can carry a genetic mutation but never develop the physical condition themselves [8].
  2. Variable Expressivity: This means the same genetic change can affect people differently [8]. A parent might have a “microform” of HPE—such as a single central front tooth (SMMCI) or a slightly narrow nose—while their child has the full Lobar HPE brain malformation [9][8].

In many cases, HPE is oligogenic, meaning it takes more than one small genetic “glitch” or a combination of genetics and environment to cause the brain to stay fused [9][10].

Environmental Risk Factors

While genetics play a major role, certain environmental factors during early pregnancy can also influence brain development. The most well-documented factor is maternal diabetes [11][12]. If a mother has pre-existing diabetes that is not perfectly controlled during those first few weeks of pregnancy, the risk of the baby developing HPE increases [11]. Other factors, such as exposure to certain pesticides or toxins, are being studied as potential contributors, though the evidence is less certain [13][14].

It is important to remember that most of the time, these factors occur long before a person even knows they are pregnant. They are not a result of anything a parent did “wrong,” but rather a complex intersection of biology and environment [15].

Common questions in this guide

What causes Lobar Holoprosencephaly?
Lobar HPE occurs when the embryonic brain fails to completely divide into two separate halves during the first few weeks of pregnancy. This incomplete separation is typically caused by genetic mutations, environmental risk factors, or a combination of both.
Can a child have Lobar HPE without facial deformities?
Yes, a child can have the brain malformations of Lobar HPE while maintaining a typical facial appearance. This is especially common when the condition is caused by a mutation in the ZIC2 gene, which typically does not cause the severe facial differences seen with other gene mutations.
How can healthy parents have a child with HPE?
Parents can carry a genetic mutation for HPE without ever developing the condition themselves due to incomplete penetrance. In other cases, a parent might only have a very mild sign, such as a single central front tooth, while passing on a more severe form of the condition to their child.
What are the environmental risk factors for holoprosencephaly?
The most well-documented environmental risk factor is pre-existing maternal diabetes that is not perfectly controlled during the first few weeks of pregnancy. Researchers are also studying other potential factors, such as early exposure to certain pesticides or toxins.
Why is genetic testing important for a Lobar HPE diagnosis?
Testing can identify if a specific genetic mutation, such as SHH or ZIC2, caused the condition. Knowing the exact gene can help explain your child's specific physical features and clarify the chances of the condition occurring again in a future pregnancy.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Can you explain which specific gene mutation, if any, was found in my child's genetic testing?
  2. 2.If a ZIC2 mutation was found, does that explain why my child's facial features appear typical?
  3. 3.Should both parents be tested for the same genetic variant found in our child, even if we have no symptoms?
  4. 4.What are the chances of this condition occurring again in a future pregnancy based on our specific genetic results?
  5. 5.Are there any 'microforms' of HPE, like a single central incisor or a narrow bridge of the nose, that you see in either parent or the child?

Questions For You

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References

References (15)
  1. 1

    Alobar Holoprosencephaly in a Newborn: A Case Report of Prenatal Diagnosis and a Review of the Literature.

    Chafiq K, Toumi K, Khayi FE, Daoudi A

    Cureus 2024; (16(11)):e74462 doi:10.7759/cureus.74462.

    PMID: 39726469
  2. 2

    Lobar holoprosencephaly with associated meningocele: A rare case report of a 25-year-old patient with multiple seizures.

    Barman P, Mishra GV, Murugan G, et al.

    Radiology case reports 2025; (20(4)):2004-2008 doi:10.1016/j.radcr.2025.01.029.

    PMID: 39963386
  3. 3

    Disorders of Ventral Induction/Spectrum of Holoprosencephaly.

    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
  4. 4

    Unexpected diagnosis of a SHH nonsense variant causing a variable phenotype ranging from familial coloboma and Intellectual disability to isolated microcephaly.

    Bruel AL, Thevenon J, Huet F, et al.

    Clinical genetics 2018; (94(1)):182-184 doi:10.1111/cge.13211.

    PMID: 29498412
  5. 5

    Rare hypomorphic human variation in the heptahelical domain of SMO contributes to holoprosencephaly phenotypes.

    Nagai-Tanima M, Hong S, Hu P, et al.

    Human mutation 2020; (41(12)):2105-2118 doi:10.1002/humu.24103.

    PMID: 32906187
  6. 6

    ZIC2 in Holoprosencephaly.

    Barratt KS, Arkell RM

    Advances in experimental medicine and biology 2018; (1046()):269-299 doi:10.1007/978-981-10-7311-3_14.

    PMID: 29442327
  7. 7

    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
  8. 8

    A forebrain undivided: Unleashing model organisms to solve the mysteries of holoprosencephaly.

    Grinblat Y, Lipinski RJ

    Developmental dynamics : an official publication of the American Association of Anatomists 2019; (248(8)):626-633 doi:10.1002/dvdy.41.

    PMID: 30993762
  9. 9

    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
  10. 10

    Recent advances in understanding inheritance of holoprosencephaly.

    Dubourg C, Kim A, Watrin E, et al.

    American journal of medical genetics. Part C, Seminars in medical genetics 2018; (178(2)):258-269 doi:10.1002/ajmg.c.31619.

    PMID: 29785796
  11. 11

    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
  12. 12

    Response to letter from Okoye JO and Ngokere AA "Are the prevalence of Trisomy 13 and the incidence of severe holoprosencephaly increasing in Africa?"

    Abdel-Salam GMH, El-Dessouky SH, Aboulghar MM, Eid MM

    Prenatal diagnosis 2020; (40(12)):1618-1619 doi:10.1002/pd.5804.

    PMID: 32794234
  13. 13

    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
  14. 14

    Nongenetic risk factors for holoprosencephaly: An updated review of the epidemiologic literature.

    Summers AD, Reefhuis J, Taliano J, Rasmussen SA

    American journal of medical genetics. Part C, Seminars in medical genetics 2018; (178(2)):151-164 doi:10.1002/ajmg.c.31614.

    PMID: 29761639
  15. 15

    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

This page explains the genetic and biological causes of Lobar Holoprosencephaly for educational purposes. Always consult your pediatric neurologist or genetic counselor for information about your child's specific diagnosis and inheritance risks.

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