Holoprosencephaly (HPE) is a brain malformation where the forebrain fails to divide into two separate hemispheres during early fetal development. It occurs in roughly 1 in 250 embryos, though most of these pregnancies end in miscarriage. Among live births, the estimated rate is 1 in 10,000 to 16,000, making it the most common forebrain malformation in humans.
The condition develops between the third and fourth weeks of pregnancy, when the front portion of the embryonic brain normally splits into left and right halves. When that midline division doesn’t happen, or only partially happens, the result is a spectrum of brain and facial abnormalities that range from mild to incompatible with life.
How the Brain Is Affected
In a typical pregnancy, cells along the midline of the developing forebrain undergo a wave of programmed cell death and slowed growth. This process allows the expanding brain tissue to split cleanly into two hemispheres, each with its own fluid-filled ventricle. In HPE, that midline patterning is disrupted, leaving the hemispheres partially or completely fused.
HPE exists on a continuum, classified into several types based on how much separation occurred:
- Alobar HPE is the most severe form. The brain has no division at all, with a single fused ventricle, fused deep brain structures (the thalami), and no separation between the hemispheres. Most pregnancies with alobar HPE end in miscarriage or stillbirth.
- Semilobar HPE involves partial separation. The back portions of the hemispheres may begin to divide, but the front remains fused. A single large ventricle is still present, though some structural distinction between left and right starts to appear.
- Lobar HPE is the mildest classic form. The hemispheres are mostly separated, but fusion persists in small areas, typically at the front of the brain. The ventricles are more normally shaped, and the deep structures may be partially or fully divided.
- Middle interhemispheric variant (syntelencephaly) is an atypical form where the front and back of the brain separate normally, but the middle portions of the hemispheres, specifically the upper frontal and parietal lobes, remain fused. The deeper brain structures are usually separated, which means the hormonal and metabolic problems common in other forms of HPE are relatively rare in this variant. Spasticity and seizures tend to be the primary concerns instead.
Facial Features Linked to HPE
Because the brain and face develop together from the same embryonic tissue, the degree of brain malformation often predicts the severity of facial differences. Clinicians sometimes summarize this as “the face predicts the brain,” though it’s not a perfect rule.
In the most severe cases, facial abnormalities can include cyclopia (a single fused eye in the center of the face, sometimes with a tube-like nose above it), ethmocephaly (closely spaced eyes with a small nose-like structure between them), or cebocephaly (closely spaced eyes with a nose that has a single nostril). These severe facial features are almost always associated with alobar HPE.
Milder forms may show closely set eyes (hypotelorism), a flat nasal bridge, cleft lip or palate, or a single central front tooth. Some children with lobar HPE or the middle interhemispheric variant have no obvious facial differences at all. The absence of facial features does not rule out HPE, but their presence is a strong diagnostic clue.
Genetic and Environmental Causes
HPE has both genetic and environmental roots, and in many cases the exact cause is never identified. Four genes account for the largest share of known genetic cases. In one Dutch study of 86 families, mutations in the genes ZIC2, SIX3, and SHH together explained about 24% of cases. A fourth gene, TGIF1, is less commonly involved. These genes all play roles in the signaling pathways that tell the embryonic brain where its midline should form.
Chromosomal abnormalities are another major cause. Trisomy 13 (an extra copy of chromosome 13) is the most frequently associated chromosomal condition. HPE also appears in other chromosomal syndromes, though less commonly.
On the environmental side, maternal diabetes diagnosed before pregnancy is one of the most consistently identified risk factors. Pregnancies involving twins and female sex of the fetus have also been associated with higher rates of HPE.
How HPE Is Diagnosed
HPE can be detected by prenatal ultrasound as early as 11 to 12 weeks of pregnancy. The key findings on imaging include a single undivided brain ventricle (instead of the normal pair), fused thalami in the center of the brain, and absence of the structure that normally connects the two hemispheres. Alobar and semilobar forms are the easiest to identify on ultrasound because the brain anatomy is so clearly abnormal. Lobar HPE and the middle interhemispheric variant can be subtler and may require MRI for a definitive diagnosis.
Facial features visible on ultrasound, such as closely set eyes or midline clefting, often prompt a closer look at the brain. When HPE is suspected, genetic testing through amniocentesis or chorionic villus sampling can check for chromosomal abnormalities or specific gene mutations.
After birth, MRI provides the most detailed picture of which type of HPE is present and how much of the brain is affected. This imaging is important for predicting what kinds of medical and developmental challenges a child is likely to face.
Medical Complications
Because HPE affects the brain’s midline structures, it frequently disrupts the hypothalamus and pituitary gland, which control hormones, body temperature, thirst, and sleep-wake cycles. Diabetes insipidus, a condition where the body can’t properly regulate water balance (unrelated to the more familiar diabetes mellitus), occurs in about 70% of children with classic HPE. Its severity tracks closely with how fused the hypothalamus is: children with alobar or semilobar HPE are most affected. Other hormonal issues like thyroid deficiency (11% of patients), cortisol deficiency (7%), and growth hormone deficiency (5%) are less common but still need monitoring.
Seizures are frequent across all types of HPE. Feeding difficulties are also common, particularly in more severe forms, where many children require a feeding tube. Children with semilobar or alobar HPE have significantly higher rates of both severe developmental disability and tube dependence compared to those with milder forms.
Survival and Long-Term Outlook
Prognosis varies enormously depending on the type and severity. Isolated alobar HPE carries the lowest survival rates, with many affected infants dying within the first year. But the picture is different for other subtypes. In a detailed study of adolescents and adults living with HPE, half had semilobar HPE, showing that even this relatively severe form is compatible with long-term survival for a meaningful number of individuals.
Factors linked to longer survival include having a subtype other than alobar, being female, and having milder or absent facial features. Mutations in the ZIC2 gene may also be associated with better survival, though data on this are still limited.
Neurodevelopmental outcomes correlate with imaging findings. Children with lobar HPE or the middle interhemispheric variant generally have less severe disabilities, though most still experience significant developmental delays, motor challenges, or learning difficulties. Those with semilobar or alobar HPE typically have profound intellectual and physical disabilities. Care focuses on managing seizures, supporting nutrition, addressing hormonal imbalances, and providing therapies to maximize each child’s functional abilities.