Holoprosencephaly

Holoprosencephaly is an abnormality of brain development in which the brain doesn’t properly divide into the right and left hemispheres. The condition can also affect development of the head and face. There are four types of Holoprosencephaly, distinguished by severity. From most to least severe, the four types are:

• Alobar holoprosencephaly, when a baby’s brain is not divided into two hemispheres, and is missing the midline structures
• Semilobar,when the forebrain is not completely divided, only partially.
• Lobar, when the brain has separated into two hemispheres, but the division is incomplete
• Middle interhemispheric variant (MIHV), the incomplete separation of midline cerebral hemispheres with the absence of the callosal body, or the bundle of nerves that connect the two brain hemispheres 

Causes of holoprosencephaly are diverse and include environmental exposure to teratogens (factors that cause malformations in embryos) in early pregnancy, chromosomal abnormalities (most often trisomy 13) and gene mutations. Most mutations do not have a recognized genetic cause.

The following risk factors are present in parents more likely to have a biological child diagnosed with holoprosencephaly:

• Teratogen exposure: Commonly found in ethanol, retinoic acid and food-borne mold toxins, teratogens can cause birth defects and problems with fetal development.
• Diabetes: Links have been shown between holoprosencephaly and parents with type 1 or type 2 diabetes prior to pregnancy.
• Folate deficiency: Most pregnant women are encouraged to increase their intake in folate (or folic acid) to aid healthy fetal development. This natural form of vitamin B9 is especially important for spine and brain development in the fetus.

Because genetic issues—which are typically the cause of holoprosencephaly—are inherited, little can be done to prevent this abnormality. It may be helpful to discuss genetic testing with your provider in advance of pregnancy and to identify risk factors that may be present.

Holoprosencephaly malformations result from incomplete cleavage of the prosencephalon affecting both the forebrain and the face. Three ranges of increasing severity are described: lobar, semilobar and alobar HPE. Another milder subtype of HPE called middle interhemispheric variant (MIHF) or syntelencephaly is also reported. In most of the cases, facial anomalies are observed in HPE, like cyclopia, proboscis, median or bilateral cleft lip/palate in severe forms, ocular hypotelorism or solitary median maxillary central incisor in minor forms. These latter midline defects can occur without the cerebral malformations and then are called microforms. Children with HPE have many medical problems: developmental delay and feeding difficulties, epilepsy, and instability of temperature, heart rate and respiration. Endocrine disorders like diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia and growth hormone deficiency are frequent.

Holoprosencephaly is the most common congenital malformation to affect the forebrain and face in liveborn infants that typically forms between the 18th and 28th day of gestation. Holoprosencephaly is typically diagnosed on a newborn infant using imaging tests like a head ultrasound (a test that takes pictures and/or video of internal organs), an MRI (a painless, radiation-free brain scan that takes images of structures and tissues of the child’s brain) or a head CT scan (3D images are produced using X-rays).

In early stages of pregnancy, parents may choose to work with their providers to conduct genetic (chromosomal analysis, cytogenetic and molecular) testing to detect any chromosomal or genetic issues.

In its most severe forms, holoprosencephaly is lethal; in milder forms, prolonged survival is possible but may require specialized, long-term care. While there is no standard treatment protocol or cure for holoprosencephaly, symptoms may be treated individually. Options may include plastic/reconstructive surgery (commonly for facial features or a cleft lip or palate), occupational or physical therapy, medications (to treat conditions like seizures and pituitary gland hormone imbalances) or placing a ventriculoperitoneal shunt to treat the buildup of fluid in the brain.

Life expectancy depends on the type of holoprosencephaly (HPE) diagnosis. Some babies with severe forms are stillborn or only live for up to six months. Around half of those diagnosed with semilobar or lobar HPE who have healthy organs may live up to one year. Those with mild cases may live into adulthood. Caring for a child with holoprosencephaly requires diligence in working with a team of medical professionals, including primary care physicians, surgeons, and physical and occupational therapists. Additionally, care may include regular assessments and prescription management.

To further your understanding of your diagnosis and to contribute to cutting-edge research, consider participating in a clinical trial so clinicians and scientists can learn more about causes, symptoms, treatment and prevention. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat or prevent disease.

All types of volunteers are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.

For information about participating in clinical research, visit NIH Clinical Research Trials and You. Learn about clinical trials currently looking for participants at Clinicaltrials.gov.