Holoprosencephaly (HPE) is a condition that occurs in the first two or three weeks of pregnancy and results in abnormal development of the brain. Typically, in the first few weeks of pregnancy, the developing embryo begins laying the structural groundwork for brain development. The front portion of this pre-brain structure is called the prosencephalon and it typically divides itself into four segments to form what will become the hemispheres of the forebrain (the front part of the brain). HPE results if the prosencephalon does not properly segment, or if it does not segment completely. When HPE occurs, it ranges in severity:
- No segmentation (alobar HPE; the most severe)
- Partial segmentation (semilobar and lobar HPE; somewhat severe)
- Almost complete segmentation (middle interhemispheric variant (MIHV); the least severe)
Prevalence and Possible Causes
HPE is the most common developmental abnormality of the forebrain in humans. It occurs in 1 of every 250 human embryos. Many of these embryos do not survive and are lost to miscarriage. By birth, the prevalence is 1 in 8,000 to 1 in 10,000 live births and stillbirths.
Sometimes HPE can be caused by environmental causes. The most common known cause of HPE in humans is maternal type 2 diabetes mellitus. In pregnancies of diabetic mothers, the chance for HPE to occur is about 1%.
Approximately 25%-50% of individuals with HPE have a chromosome error as the underlying cause of their HPE. This error can either be numeric (usually an extra chromosome) or structural (the right number, but not the right amount of genetic material due to either missing or added genetic material). Children with a chromosomal cause of their HPE often have other body systems that are affected, as well.
Approximately 18%-25% of the remaining children with HPE (those without a chromosome error) have a recognizable syndrome (HPE is one of several features). The rest have isolated HPE (HPE is the only feature). Both syndromic and isolated HPE may be heritable and caused by a change in a single gene. The syndromic forms of HPE can be inherited in a recessive or dominant manner. Those who have isolated HPE typically have a dominant gene that is responsible for their HPE. Isolated HPE has a broad range of expression that can manifest anywhere from the severe end of the spectrum (alobar HPE) to individuals who appear clinically normal or almost normal (microform HPE). This variability in clinical expression is seen even within families who have the same gene error. We don't know why any person has either severe or mild HPE when they have the same gene change. Molecular genetic testing is possible for many of the genes associated with isolated HPE. Also, approximately 10% of individuals with HPE have defects in cholesterol biosynthesis.
Common Associated Conditions
Holoprosencephaly can either manifest by itself as a single, isolated feature or as part of a syndrome. Babies born with HPE may have other clinically relevant issues as well, some of which result from the developmental error in the brain.
Below are some of the more common features that may also be diagnosed in a baby with HPE and a brief description of treatment approaches and follow up.
- Hydrocephalus - Hydrocephalus (“water on the brain”) is a condition that is seen in about one out of six babies with HPE. In hydrocephalus, the fluid that is normally in the brain and around the spinal cord (called cerebrospinal fluid) builds up in the brain and does not drain normally. When this drainage does not occur, pressure may build up in the skull cavity and damage to the brain may occur. To alleviate this pressure, a shunt is placed to allow adequate drainage. In many cases, the shunt is threaded under the skin into the abdominal cavity, where the excess cerebrospinal fluid is reabsorbed by the body. Treatment of hydrocephalus may improve developmental and functional outcomes and reduce irritability.
- Seizures/epilepsy - About 40% of children with HPE have epilepsy that requires treatment. About half of children with HPE have had at least one seizure. Seizures, if they are going to be an issue, usually begin in infancy and treatment with anti-seizure medication is usually effective. Triggers for seizures include low blood sugar (hypoglycemia) and fluctuations in electrolytes (salts and minerals normally present in body fluids).
- Motor impairment - The majority of children with HPE do not have normal muscle tone and their motor coordination is affected to at least some extent. This can usually be predicted based on the severity of HPE. Physical and occupational therapy may help to improve motor function.
- Problems with feeding, swallowing and nutrition - Most children with the more severe types of HPE have problems with swallowing. These problems often correlate with the degree of motor impairment. Speech/language therapy and possibly placing a feeding tube directly into the stomach (a gastrostomy tube) can reduce the risk of food getting sucked into the lungs instead of going down the esophagus to the stomach. If this happens, it can result in recurring respiratory problems and poor nutritional intake.
- Gastrointestinal problems - Children with HPE have a greater chance of having functional digestive system issues. These conditions can range from impaired movement of food from the stomach into the small intestine, gastroesophageal reflux, or constipation.
- Endocrine (hormonal and glandular) dysfunction - The problems with brain development may also disrupt development of the pituitary gland and the hypothalamus. The pituitary gland is the master gland of the endocrine system (the body system that produces hormones that regulate the function of other glands and many other body functions, metabolism, and growth). The hypothalamus is a region of the forebrain that coordinates the activity of the pituitary and other functions of the endocrine and nervous systems. Because of this disruption, some children with HPE may have hormonal imbalances. For example, central diabetes insipidus is the most common endocrine disorder in children with classic HPE. In addition, the function of the thyroid, adrenal glands, and other endocrine functions, including production of growth hormone, may also be altered. The degree to which the function of the endocrine system is affected should be checked in the first few days after the baby is born. Some of the unconscious functions (autonomic) of the nervous system may also be affected. These include the regulation of breathing and body temperature. Parents should be educated about the potential endocrine and nervous system problems and how to recognize when these occur to help assure the best outcomes possible.
- Eye and vision (ophthalmologic) problems - Vision problems may be due to issues with the eye itself or they can be due to neurological problems in the nerve that transmits information from the eye to the brain or problems with how this information is processed in the brain. If impaired vision is present, therapy services may be helpful.
- Craniofacial-related complications - Because the development of the brain also influences the developing structures of the skull and face, about 80% of individuals with HPE will have unusual facial features: Especially of the eyes, nose, and mouth structures. Cleft lip and/or palate is frequent feature and may be surgically repaired or accommodated by special nipples. Upper airway (nose, sinuses, and throat) obstruction may result because of a cleft or
Short-Term Treatment and Outcomes
The short-term treatment and outcome depends on the severity of HPE and any associated features. If the degree of HPE is at the severe end of the spectrum (e.g. alobar), the individual may not have a long life span. Less severe forms may have better outcomes, especially if there are no or fewer additional complications. See section on associated features above.
Long-Term Treatment and Outcomes
In any case, all individuals who have been found to have some degree of HPE do best if cared for by a team of providers who are coordinated and focus on that individual's unique needs and set of circumstances. This includes providers that address medical, developmental, and functional needs that a person with HPE typically has and potentially other clinically relevant findings.
Implications for Children's Development
The longer-term implications for a child's development depend heavily on how extensive the brain developmental error and associated features are (see above). Other central nervous system (CNS) abnormalities, not specific to HPE, may also occur. Developmental delay is present in most individuals with the HPE spectrum. Severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months and many live into adulthood.
In predicting and maximizing the prognosis for a child with HPE, sustained and attentive follow-up by a primary medical provider, whether a geneticist, neonatologist, pediatric neurologist, developmental pediatrician, or primary care pediatrician, is essential to closely follow the child in order to coordinate optimal care and to provide a balanced and realistic prognosis that allows for appropriate treatment, anticipatory guidance and optimal outcomes.