Holoprosencephaly (HPE) is a birth defect in which the forebrain (prosencephalon) fails to develop normally.
The forebrain is a part of the brain in a fetus that develops into parts of the adult brain, including the cerebral cortex. Normally, the left and right halves of the forebrain are completely separated during fetal development but with HPE there is an abnormal continuity between the two sides.
There are several different types of holoprosencephaly and they range in severity. The life expectancy varies widely depending on the severity of the condition.
- Very mild HPE (microform HPE)
- Microform HPE often has no observable symptoms and has little to no effect on life expectancy
- Mild HPE (middle interhemispheric variant HPE)
- Mortality rates vary but long-term survival is possible in this mild form
- Moderate to severe HPE (lobar HPE, semilobar HPE)
- About half of all of infants diagnosed with this form of HPE will survive beyond one year
- Severe HPE (alobar HPE)
- Infants with the most severe forms of alobar HPE, including cyclopia or ethmocephaly, usually do not survive beyond one week after birth
- About 50% of children with alobar HPE die between four to five months of age, and only 20% survive beyond the first year of life
What Are Symptoms of Holoprosencephaly?
Symptoms of holoprosencephaly vary widely and may include:
- Small head (microcephaly)
- Excessive fluid in the brain (hydrocephalus)
- Intellectual disability
- Developmental delays
- Facial abnormalities
- Closely spaced eyes
- Depressed or narrow nasal bridge
- Cleft lip and/or palate
- Tooth abnormalities (single central incisor)
- Epilepsy (seizures)
- Endocrine abnormalities
- Defects in the pituitary gland that cause abnormally low blood sugar levels (hypoglycemia), low blood sodium levels, or genital abnormalities
- In severe and very rare cases, a single central eye (cyclopia)
What Causes Holoprosencephaly?
Holoprosencephaly is a birth defect that occurs during the first few weeks of pregnancy. The exact cause is unknown in many cases.
Risk factors for developing holoprosencephaly include:
- Maternal diabetes in during pregnancy
- Trisomy 13 and other chromosomal abnormalities
- Genetic changes in the genes SHH, SIX3, TGIF1, ZIC2, PTCH1, FOXH1, NODAL, CDON, FGF8, and GLI2
- Certain genetic syndromes in which there are other medical issues that affect organs in addition to the brain and face (e.g., Smith-Lemli-Opitz syndrome)
How Is Holoprosencephaly Diagnosed?
Imaging tests are often used to diagnose holoprosencephaly, which depend on the severity of the condition and whether it is suspected prenatally or in the neonatal period.
Testing may include:
- Prenatal ultrasound
- May be able to detect facial abnormalities in severe HPE, especially the alobar subtype, within the first trimester
- Milder forms of the condition may not be able to be detected
- Fetal magnetic resonance imaging (MRI)
- High-resolution MRI scans, which include thin-section image sequences in three orthogonal planes (axial, sagittal, and coronal) for infants suspected of HPE
- Computerized tomography (CT) scan
Children with mild holoprosencephaly may not be diagnosed until they are older. The average age at diagnosis is four years, with about 15% of patients diagnosed at 10 and 19 years of age.
What Is the Treatment for Holoprosencephaly?
Treatment for holoprosencephaly involves supportive care based on the specific medical issues each individual child has. Children may need to see a variety of different medical specialists.
- Endocrinology evaluation to check for pituitary abnormalities
- Neurologist involvement to guide treatment for seizures, if present
- Plastic reconstructive surgery of cleft lip and palate or other facial features
- A developmental pediatrician to help direct developmental therapies
- Clinical genetics evaluation and genetic counseling for patients and families once the diagnosis is made
- Chromosome analysis and gene testing is often performed
- Relatives of a child with holoprosencephaly may have an increased risk of having a child with holoprosencephaly
- Some specific features suggest an increased risk for having another child with holoprosencephaly
- Other specialists involved with care may include: pediatricians, dentists, special education teachers, therapists, and psychologists