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Holoprosencephaly (HPE)

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Related terms
Background
Signs and symptoms
Diagnosis
Treatment
Integrative therapies
Prevention
Author information
Bibliography
Causes
Types of holoprosencephaly

Related Terms
  • Alobar holoprosencephaly, arhinencephaly, brain hemispheres, cebocephaly, congenital brain disorder, cyclopia, demyer sequence, ethmocephaly, familial HPE, familial holoprosencephaly, gastroesophageal reflux disease, GERD, familial alobar holoprosencephaly, holoprosencephaly malformation complex, holoprosencephaly sequence, HPE, hydrocephalus, isolated HPE, isolated holoprosencephaly, karyotype, lobar holoprosencephaly, microcephaly, midline cleft syndrome, sleep apnea, semilobar holoprosencephaly, trisomy 13, trisomy 15, trisomy 18.

Background
  • Holoprosencephaly (HPE) occurs when an unborn baby's brain does not grow forward and divide properly during early pregnancy. Normally, the brain splits into two halves (called hemispheres) during development. The hemispheres communicate to each other through a band of 200-250 million nerve fibers, called the corpus callosum. In patients with HPE, the hemispheres are not separated properly.
  • As a result, there are abnormalities in the face and structure and function of the brain.
  • Common signs and symptoms include a small head (called microcephaly), excessive fluid in the brain (called hydrocephalus), and intellectual disabilities (formerly called mental retardation) of varying degrees.
  • The severity of HPE ranges from mild to severe. According to studies, in about 97% of cases, the malformations are so severe that the baby dies before birth. In less-severe cases, babies are born with normal or near-normal brain development and facial malformations that may affect the nose, eyes, and upper lip.
  • According to the National Institute of Neurological Disorders and Stroke (NINDS), there are three classic subtypes of HPE: alobar HPE, semilobar HPE, and lobar HPE.
  • Researchers estimate that about one baby out of 10,000-20,000 babies born in the United States has HPE. However, because so many mothers of children with HPE have miscarriages, the frequency of HPE among all pregnancies may be as high as one out of 200-250.
  • There is no cure or specific treatment for HPE. Instead, treatment is aimed at reducing the symptoms.
  • According to the NINDS, the prognosis for people with HPE is generally poor, but it depends on the severity of the brain and facial malformations and genetic abnormalities. Of the three percent of babies who are born alive, most die before the age of six months. However, patients with mild forms of HPE, such as lobar HPE, may have normal life expectancies if the brain is only mildly affected by the disorder.

Signs and symptoms
  • General: Children diagnosed with holoprosencephaly (HPE) may have a small head (called microcephaly), excessive fluid in the brain (hydrocephalus), variable degrees of intellectual disabilities (formerly called mental retardation), epilepsy (brain disorder that causes frequent seizures), craniofacial malformations, increased muscle tone that results in a tightening and shortening of muscles (called spasticity), sleeping disorders, hormonal disorders, or abnormalities of other organ systems, such as the heart, bones, genitourinary, and digestive systems.
  • Alobar HPE occurs when the brain is not divided into hemispheres at all. It is associated with severe facial abnormalities. This is the most severe type of HPE, and it causes death either before or soon after birth.
  • Semilobar HPE occurs when the brain's two hemispheres have partially divided.
  • In cases of lobar HPE, the brain has almost divided into separate brain hemispheres. Some patients with lobar HPE may have few symptoms and almost normal brains.
  • Facial malformations: Facial malformations, which range from mild to severe, are common among patients with HPE. The least severe malformations are typically seen in patients with lobar HPE, while alobar HPE is usually associated with the most severe abnormalities.
  • Mild malformations associated with HPE include a median cleft lip and eyes that are abnormally close together.
  • Another facial malformation, called cebocephaly, occurs when a small, flattened nose with only one nostril is located below incomplete or underdeveloped eyes that are abnormally close together. Some people may only develop one upper middle tooth.
  • The most severe facial malformation is called cyclopia. This occurs when a person is born with one eye that is located where the top of the nose would normally be. In addition, the nose is either missing or a tubular-shaped nose (called a proboscis) is located above the eye.
  • The least common facial malformation is called ethmocephaly. This occurs when a proboscis is located between the eyes, which are abnormally close together.
  • Sleep disorders: Multiple studies have found that people with HPE often have sleep disorders, especially sleep apnea. Sleep apnea is a serious condition that occurs when a person stops breathing for short periods of time during sleep. Patients with HPE have an increased risk of experiencing obstructive sleep apnea because of their facial malformations. Since sleep apnea causes individuals to wake up frequently throughout the night, patients are often drowsy during the day. Other patients may have difficulty falling asleep.
  • Intellectual disabilities: Most people born with HPE have intellectual disabilities (formerly called mental retardation), which range from mild to severe. Some people with lobar HPE, the mildest classic form of the disorder, have normal or near normal brain function.
  • Patients with mild intellectual disabilities have intelligence quotients (IQs) of 52-69. From birth to age six, patients are able to develop normal social and communication skills, but their motor coordination is slightly impaired. By late adolescence, patients are able to learn until about a sixth-grade level. They are generally able to learn appropriate social skills. Adults with mild intellectual disabilities are usually able to work and support themselves, although some patients may need help during times of social or financial stress.
  • Patients with moderate intellectual disabilities have IQs of 36-51. Children younger than six years old are able to talk or communicate with others, but social awareness is generally poor. Motor coordination is typically fair. Adolescents are able to learn some occupational and social skills. For instance, they may be able to learn how to travel alone in familiar places. Adults may be able to support themselves with a job. They usually require guidance and assistance during mild social or financial stress.
  • Patients with severe intellectual disabilities have IQs of 20-35. Young children can say a few words, but their speech is limited. Motor coordination is generally poor. Adolescents can usually talk or communicate with others. They are able to learn simple habits. Adults typically require lifelong assistance and guidance with daily activities.
  • Patients with profound intellectual disabilities have IQs of 19 or lower. Children younger than six years old have very little motor coordination and may require nursing care. Adolescents typically have limited motor and communication skills. Adults usually require lifelong nursing care.
  • Gastrointestinal problems: People born with HPE typically have digestive problems, such as gastroesophageal reflux disease (GERD). This condition occurs when liquid from the stomach backs up (regurgitates) into the esophagus. This liquid may contain stomach acids and bile. In some cases, the regurgitated stomach liquid can cause inflammation (esophagitis), irritation, and damage to the esophagus. GERD is common among HPE patients because they often have weak esophageal muscles.
  • Patients with HPE may have oromotor dysfunction, which occurs when the neural pathways that control the speech muscles are impaired. As a result, children may have difficulty feeding.

Diagnosis
  • Holoprosencephaly (HPE) may be suspected during a routine ultrasound examination if the unborn baby's head is smaller than normal.
  • After birth, severe cases of HPE may be diagnosed based on the child's signs and symptoms. In severe cases, characteristic features, such as a small head and facial malformations, are apparent.
  • In less severe cases, such as lobar HPE, a magnetic resonance imaging (MRI) scan or computerized tomography (CT) scan is performed to confirm a diagnosis. During this non-invasive procedure, a machine takes a picture of the child's brain. This allows the doctor to see if the brain's hemispheres have divided properly. If the hemispheres have not completely divided, HPE may be diagnosed.
  • Molecular testing is also available to detect genetic abnormalities associated with HPE.

Treatment
  • General: There is no cure or specific treatment for holoprosencephaly (HPE). Instead, treatment focuses on reducing the symptoms. The prognosis for individuals with the disorder depends on the severity of the brain and facial deformities and genetic abnormalities. The prognosis for most people is poor. Out of the three percent of babies with HPE who are born alive, most die before the age of six months. However, patients with lobar HPE may have normal life expectancies if the brain is only mildly affected by the disorder.
  • Heartburn medications: If a baby with HPE has gastroesophageal reflux disease (GERD), a doctor may prescribe infant doses of medications commonly used to treat heartburn in adults. Commonly prescribed medications include H-2 blockers, such as cimetidine (Tagamet®) or ranitidine (Zantac®), or proton pump inhibitors, such as esomeprazole (Nexium®) or omeprazole (Prilosec®). Although these drugs are considered safe for use in infants and children with GERD, a 2006 study suggests that they may increase the risk of intestinal and respiratory infections in otherwise healthy children.
  • Esophageal surgery: In some cases, the muscles in the esophagus that prevent food in the stomach from being regurgitated may need to be surgically tightened. This is typically only performed if GERD interferes with breathing or prevents growth in the baby. Complications of this surgery are serious and may include persistent gagging during feedings.
  • Anticonvulsants: Medications, called anticonvulsants, may be used to treat epilepsy (a condition that causes seizures) in children with HPE. These drugs are typically taken once daily to help prevent seizures from occurring. Phenobarbital (Luminal® Sodium) is one of the oldest and safest anticonvulsants for children. Valproic acid (Depakene® or Depakote®) has also been shown to be a safe and effective treatment for seizures in children.
  • Botulinum toxin (Botox®): Children with HPE who experience increased muscle tone that results in a tightening and shortening of muscles (called spasticity) may benefit from botulinum toxin (Botox®) injections. This drug is injected directly into spastic muscles in order to stop muscles from twitching. The effects of Botox® last several months. Some patients may have a severe allergic reaction to Botox. All over body swelling, difficulty swallowing and/or difficulty breathing are the most likely symptoms that an allergic reaction is occurring. Patients who experience any or all of these symptoms after a Botox® injection should have a person nearby call 911 immediately. Patients should not wait to see if the symptoms resolve or try to take themselves to the hospital.

Integrative therapies
  • Currently, there is a lack of scientific data on the use of integrative therapies for the treatment or prevention of holoprosencephaly (HPE).

Prevention
  • Because the cause of holoprosencephaly (HPE) is poorly understood, there is no known method of prevention for the disorder.
  • Infants born to diabetic mothers may have an increased risk of having HPE. Diabetic mothers can help reduce their risks of having children with birth defects and congenital disorders, such as HPE, by strictly controlling their blood sugar levels. Therefore, expectant mothers with diabetes are encouraged to choose doctors with expertise in diabetes care. This helps ensure that the pregnant mother and the fetus obtain the best possible care before and during pregnancy.
  • Infants born to mothers who have infections, such as herpes, syphilis, cytomegalovirus, rubella, and toxoplasmosis, may have an increased risk of developing HPE. Therefore, pregnant mothers who have symptoms of infections should seek prompt medical treatment.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography
  1. American Academy of Pediatrics (AAP). . Accessed December 4, 2007.
  2. Dubourg C, Bendavid C, Pasquier L, et al. Holoprosencephaly. Orphanet J Rare Dis. 2007 Feb 2;2:8.
  3. Krauss RS. Holoprosencephaly: new models, new insights. Expert Rev Mol Med. 2007 Sep 24;9(26):1-17.
  4. Nanni L, Schelper RL, Muenke MT. Molecular genetics of holoprosencephaly. Front Biosci. 2000 Mar 1;5:D334-42.
  5. National Human Genome Research Institute (NHGRI). . Accessed December 4, 2007.
  6. National Institute of Neurological Disorders and Stroke (NINDS).
  7. National Institutes of Health (NIH). . Accessed December 4, 2007.
  8. Natural Standard: The Authority on Integrative Medicine. . Copyright © 2008. Accessed December 4, 2007.
  9. Roesler CP, Paterson SJ, Flax J, et al. Links between abnormal brain structure and cognition in holoprosencephaly. Pediatr Neurol. 2006 Dec;35(6):387-94.
  10. Shiota K, Yamada S, Komada M, et al. Embryogenesis of holoprosencephaly. Am J Med Genet A. 2007 Oct 26.
  11. The Carter Centers for Brain Research in Holoprosencephaly and Related Malformation. . Accessed December 4, 2007.
  12. Wallis DE, Muenke M. Molecular mechanisms of holoprosencephaly. Mol Genet Metab. 1999 Oct;68(2):126-38.
  13. Wallis D, Muenke M. Mutations in holoprosencephaly. Hum Mutat. 2000;16(2):99-108.

Causes
  • General: The cause of holoprosencephaly is not fully understood. According to scientific studies, about 25-50% of all cases are associated with genetic abnormalities. Several other factors, including the use of certain medications during pregnancy, having diabetes during pregnancy, a history of miscarriage, and certain infections during pregnancy, may contribute to HPE.
  • Genetic abnormalities: About 25-50% of HPE cases are associated with structural or numerical chromosomal abnormalities. Many patients have karyotypes, or abnormal numbers of chromosomes. Chromosomes contain a person's genetic makeup. Each person has 23 pairs of chromosomes. HPE is most commonly associated with an extra copy of chromosome 13 (called trisomy 13), an extra copy of chromosome 18 (called trisomy 18), and an extra copy of chromosome 15 (called trisomy 15). Researchers believe that HPE might be linked to as many as 12 chromosomal regions on 11 different chromosomes. Genetic abnormalities associated with HPE may occur randomly or they may be passed down among families.
  • Diabetic mother: According to the National Institute of Neurological Disorders and Stroke (NINDS), children of diabetic mothers appear to have an increased risk of having HPE.
  • History of miscarriage: It has been suggested that mothers who have had previous miscarriages and bleeding during the first trimester of pregnancy may have an increased risk of having children with HPE.
  • Infections during pregnancy: Certain infections, including herpes, syphilis, cytomegalovirus, rubella, and toxoplasmosis, have been associated with HPE. However, it is unclear if these infections actually cause HPE.
  • Medications during pregnancy: Certain medications, including alcohol, aspirin, lithium, thorazine, anticonvulsants, hormones, retinoic acid, and nicotine, have been suggested as possible risk factors for HPE.

Types of holoprosencephaly
  • According to the National Institute of Neurological Disorders and Stroke (NINDS), there are three classic subtypes of HPE: alobar HPE, semilobar HPE, and lobar HPE.
  • Alobar HPE: Alobar HPE is the most severe type of HPE. This type of HPE occurs when the brain is not divided into hemispheres at all. It is usually associated with severe facial malformations. Almost two-thirds of infants with HPE have alobar HPE. Research has shown that about half of patients with alobar HPE die before the age of 4-5 months, and 20% live past the first year of life.
  • Semilobar HPE: Semilobar HPE occurs when the brain's two hemispheres have partially divided. Semilobar HPE occurs when the left and right frontal and parietal lobes are fused and the interhemispheric fissure is only present posteriorly. It is considered a moderate form of HPE. About 25% of people with HPE have semilobar HPE.
  • Lobar HPE: Lobar HPE is the mildest classic form of HPE. It occurs when the brain has almost divided into separate brain hemispheres. In some cases, a patient's brain may be near normal.
  • Middle interhemispheric fusion variant (MIHV): Middle interhemispheric fusion variant is a very rare and unusual condition that occurs when the anterior parts of the frontal lobes and the occipital lobes are separated. It is unclear if MIHV is a subtype of HPE or a separate medical condition.

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