Holoprosencephaly - Information for Parents

 

What is it?

In holoprosencephaly (HPE) the front part of the brain fails to develop into clearly separate right and left halves. Among children with HPE there is considerable variability in the degree of malformation of the brain and its function. One feature that all of these children have is the inability to smell, because the olfactory nerves that control smell are in the front part of the brain that does not develop. ¹

What it Isn't

Many other conditions share features with HPE and may be mistaken for HPE. Although children with those disorders often experience many of the same problems, they usually have other features that are not common in true HPE.

HPE has sometimes been considered one of the so-called neural tube defects (anencephaly, spina bifida, and encephalocele). Although both neural tube defects and HPE involve malformations of the brain, the embryologic and epidemiologic evidence indicates they are different disorders and should not be grouped together.

Types of HPE

HPE is generally classified into three types: alobar, semilobar, and lobar. The distinctions among these three types are not always clear, and gradations between the types do exist. In the alobar HPE, the most severe form, there is complete failure of brain tissue to develop into the normal right and left cerebral hemispheres, and the thalami and basal ganglia are fused. In semilobar HPE there is only partial separation into two cerebral hemispheres; the hemispheres are not separated across the midline in the front of the brain. A variety of other malformations may be mislabeled as this form of HPE because of shared features, such as absence of the corpus callosum and septum pellucidum. In lobar HPE there is virtually complete separation of the cerebral hemispheres; this form is often difficult to diagnose accurately, but if the ability to smell is present; the condition is probably not HPE.

 

¹ The sense of smell is a function of the first cranial (olfactory) nerve, while the sense of taste, which is unimpaired in HPE, is a function of the seventh (facial) nerve. To test accurately for the ability to smell, only those odors that are not detected in part by taste can be used.

Face Abnormalities

While the appearance of children with semilobar and lobar HPE is often not unusual, the more severe forms of HPE are frequently accompanied by facial malformations. In the most severe form the eyes are absent. In generally decreasing order of severity are cyclopia (ranging from a single midline eye to the fusion of two eyes in a single midline orbit), ethmocephaly (close-set eyes with a tube-like nose), cebocephaly (close-set eyes and a nose with a single nostril, but no lip cleft), and premaxillary_agenesis (or median cleft lip and palate, with close-set eyes). There may be unilateral or bilateral cleft lip (and often cleft palate), and/or close set or wide-set eyes, or the face may be normal. When the face is quite malformed, it is usually a clue that the brain is affected by the alobar type of HPE. However, some children with minimal or no unusual facial features also have alobar HPE, so the often-quoted rule that "the face predicts the brain" is not always true.

Survival

It has been stated repeatedly that HPE is a lethal abnormality and that affected infants will die soon after birth. With alobar HPE, the majority of affected infants do die very early, but there are quite a few well documeted exceptions. Of those with cyclopia, ethmocephaly and cebocephaly, virtually all die within a week of birth. Of those children with alobar HPE who are liveborn with premaxillary agenesis, unilateral or bilateral cleft lip, or more normal faces, half may die before the age of 4-5 months, 20-30% will live for at least one year, and survival to at least 8 years has been reported. For those children with the "less severe" forms of isolated HPE (semilobar and lobar), survival is generally longer, with life well into adulthood being not uncommon. The Phrase "less severe" is placed in quotation marks because the outward form of the brain does not show clearly how that brain will function, and survival usually correlates better with how well the brain works than how it looks on CT or MRI scans.

For those children with HPE and chromosomal anomalies and/or malformations in other parts of the body, the outlook is largely determined by the other malformations that are present in combination with the HPE. If the other abnormalities are not life threatening, survival and problems encountered will be very similar to those in children with isolated HPE.

 

Characteristic Problems

In the sections that follow, the descriptions are from children with alobar HPE, but it has been observed that many children with semilobar and even lobar HPE have the same sorts of problems, although often to a milder degree.

Seizures

Many of the children will have seizures. These may be full-blown siffening and shaking spells or there may be more subtle episodes of twitching or blanking out. The frequency of seizures may vary considerably over time. The response to anticonvulsant medications is often quite satisfactory. No medication is always effective, and several may need to be tried before control is established. Seizures may also occur due to low blood sugar, and this possibility should be tested for if medications do not provide satisfactory control.

Hypertonicity

Typically, the children have increased muscle tone to the point of spasticity. At the same time they have poorly developed control of their muscles and may appear to be "floppy," particularly when relaxed. Spasticity is more evident when they are stimulated, excited or in any distress. Thrusting of the legs and flexing of the arms are common in these circumstances. Unlike several other disorders with spasticity, these children have not shown a strong tendency to develop joint contractures.

Fluid Balance

The pituitary gland, located at the base of the brain may not function properly in children with HPE. This gland secretes various hormones involved in growth and regulation of fluid and chemical balance of the body. Several children have had a condition called diabetes insipidus, which is characterized by irritability and dehydration due to excessive water loss through urination. In these cases hormone replacement therapy has been successful in controlling the problem. Yet other children, without diabetes insipidus, have shown no signs of dehydration despite episodes of very limited fluid intake over several days. The reason for this resistance to dehydration is not well understood, but may relate to an excessive volume of cerebrospinal fluid acting as a reservoir of fluid. The pituitary gland secretes other hormones that control growth and the thyroid and adrenal glands, and in HPE these may also be deficient and need replacement therapy.

Behavior

Behavior often fluctuates between calmness and irritability. Sudden changes in mood may occur for no particular reason, which can be quite confusing for the parent. Most often holding, cuddling, or walking the child will calm the irritable behavior; at other times, nothing seems to work. Often they overreact to sussen or loud noises by crying. Many parents have noted that having a radio or TV going all the time provides enough background noise so that the child no longer overreacts to additional or sudden noises. This type of background noise can be continued day and night and does not interfere with the child's sleep.

Feeding

Feeding is usually a major problem. Some children have choking spells and gag during feedings. More common are marked slowness in eating, frequent pauses, and rapid loss of interest. Spitting up or frank vomiting may occur after feeds, and there is a risk of aspiration of feeds into the lungs. Alternate feeding methods may be very helpful (see Gastrostomy, below). It has been observed repeatedly that the caloric needs of children with HPE may be considerably less than those of children with normal brains. Growth, particularly weight gain, can be monitored to determine what intake is sufficient for the particular child (see Growth, below).

Intestinal Gas

Problems handling intestinal gas, or colic, are common. Excessive air swallowing requires careful burping during and after feeds. For the child in acute discomfort, many parents have found that a gentle stomach massage offers some relief. A variety of medications that decrease the force of intestinal contractions and/or promote stomach emptying may be helpful.

Elimination

Constipation is a common problem, particularly in those children with high muscle tone (spasticity). For many, the problem can be dealt with satisfactorily by altering the diet. Others will need periodic or regular use of rectal suppositories or other more rigorous bowel emptying programs. Because retention of stool may cause considerable abdominal discomfort, and thereby increase agitation, early attention to regulation of stool consistency and bowel emptying is important.

Growth

Growth delay is a common feature in children with HPE. Some grow normally early but then slow down in later months. As mentioned above, appropriate growth may occur even on a caloric intake that is lower than normal. When growth delay is evident at the time of birth, "catch-up" growth usually does not occur despite optimal feeding. It seems that to achieve the best results for the child with HPE the quality of the feeds is more important than the quantity required to achieve "normal" growth.

 

Developmental Progress

The statement has been made in the medical literature that children with HPE fail to show any developmental progress. While profound developmental delay is the rule, many of the children with alobar HPE do acquire new skills. These are discussed below.

Hearing

Virtually all children with HPE demonstrate that they can hear. They react to noises, learn to turn their heads to sound, and in time develop the ability to recognize certain voices and noises and react to those sounds in predictable ways.

Vision

Children whose eyes are not involved by malformations usually demonstrate the ability to see. They can focus on faces and nearby objects, they develop the ability to track moving objects, and they respond to facial expressions. The time at which these abilities appear is often delayed from the normal schedule of development.

Memory

The majority of those children who have lived beyond a few months show evidence that they can learn and remember. They can anticipate games that involve touching or tickling and can recognize familiar voices and sounds.

Language

Full development of expressive language (speaking words) has not been observed in children with alobar HPE. However, among those children with longer survival, several have been noted to use particular sounds to indicate particular reactions or needs. Also several children have shown some ability to respond in predictable ways to words or phrases that are spoken to them (receptive language). Perhaps more common is their ability to respond to particular tones of voice, such as those used to soothe them or to express irritation.

Voice

The voice of the child with HPE is frequently not normal. The voice may be hoarse or "barking," but more commonly it is high pitched, particularly during crying, making the child's distress appear worse than it actually is.

Motor Skills

Development of motor skills is typically minimal. Several children have shown ability to wave at or even hit objects dangled in front of them. A few have brought their hands to the midline to put them in the mouth or support a feeding bottle. Reaching for and grasping an object have not been reliably and consistently observed. Head control is usually quite deficient: the children can roll the head from side to side when lying down, but they have a great deal of difficulty controlling their heads when sitting up or when being pulled to a sitting position. In general, most motor activity in the arms and legs is seen as random waving or wiggling; short repetitive motions are sometimes seen but these are usually seizures.

Day-Night Confusion

Children with HPE frequently do not settle into the expected sleep-at-night/awake-during-the-day routine. In fact, the opposite routine may develop. This can be particularly difficult to deal with, and no universally effective method has been found to cope with it. Some families have found that having a radio or TV playing in the child's room serves to keep the child quiet so the parents can sleep. Bedtime sedatives do the trick for some children; in others, sedatives may have the opposite effect of stirring them up.

 

Brainstem Dysfunction

The brainstem is the part of the brain that controls some vital functions, such as breathing, heart rate and swallowing. Virtually all children with alobar HPE show at least periodic evidence of brainstem dysfunction.

Respiration

The pattern of breathing is often quite irregular. There may be alternating periods of rapid and slow breathing, long pauses between breath's, or complete irregularity. At other times breathing is at a perfectly normal rate and rhythm. With respiratory infections the pattern of breathing is often quite unusual and may be life-threatening.

Heart rate

Like the breathing pattern, the heart rate and rhythm are often quite irregular. The pulse rate may change abruptly, within a second or two, from fast to slow or slow to fast. Sometimes the pulse is fast when it would be expected to be slow (as when the child is calm and relaxed). Marked and persistent irregularity of pulse is an ominous sign that may presage impending death.

Swallowing

A number of children experience periodic difficulty with swallowing. They may choke and gag on feedings, or even on their own saliva. When this happens repeatedly, feeding may be particularly difficult and consideration may be given to tube or gastrostomy feeding. A related problem is gastroesophageal reflux (spitting up or vomiting). In some children the reflux of stomach contents back up the esophagus may be so severe that there is a risk of aspiration of food into the lungs (aspiration pneumonia).

Temperature

Temperature control is often erratic. Elevated temperatures (usually not above 101.5°F / 38.6°C) may occur in the absence of infection or other definable cause. At other times the body temperature may be subnormal (below 96.8°F / 36.0°C) for no apparent reason. "Fevers" not due to infection usually do not respond well to treatment with acetaminophen (Tylenol) or other medications. However, there is no evidence that such mildly elevated temperatures cause any harm to the child. As long as an infection has been excluded as the cause, no treatment needs to be given.

 

Surgery

Although most of the care of children with HPE involves special handling techniques and medicines, surgical procedures may sometimes be advised. There are some risks associated with anesthesia and surgery, but these risks are fairly low when procedures are performed by experienced surgeons and anesthesiologists. There are no universal answers about whether surgery should be done or not; it must be decided on a case-by-case basis.

Cleft Repair

Because some children with alobar HPE are born with cleft lip (unilateral, bilateral, or median with cleft palate) consideration may be given to surgical repair of the lip and palate, particularly to make feeding easier. Such repairs have been done a number of times without ill effects from the surgery or anesthesia. It should be remembered, however, that feeding problems may not be eliminated, because much of the difficulty in feeding stems from the brain abnormality not the configuration of the child's mouth.

Hydrocephaly Shunt

The brain in alobar HPE is quite small. If here is no excess of cerebrospinal fluid around the brain, the head is also small (microcephaly). About half of the children with HPE have excess cerebrospinal fluid. If the excess is only moderate, the head size will be close to normal. However, sometimes the amount of fluid is markedly excessive and the head can be massively enlarged. Despite the common perception, such head enlargement does not kill the child, but it can make caring for the child quite difficult. For that reason, an operation may be recommended to shunt the fluid by way of fine tubing from the head to another part of the body, such as the abdomen, where it can be absorbed back into the blood stream.

Gastrostomy

When feeding becomes too difficult, either because of difficulty swallowing or because it simply takes too long, consideration may be given to performing a gastrostomy. In this procedure a tube is placed directly into the stomach through the abdominal wall so the feeds may be put directly into the stomach. If the child has vomiting or gastroesophageal reflux, tightening up the inlet if the stomach (fundoplication) may be recommended at the same time as gastrostomy. These operations have been done successfully on a number of children with HPE and can make their care much easier.

Causes

HPE is not a single disorder but a spectrum of related brain abnormalities, and it has a number of different causes. Approximately half of the children with HPE will also have malformations in other areas of the body caused by abnormalities of the chromosomes or other multiple malformation syndromes. The other half will have isolated HPE, with or without associated facial malformation.

Chromosomal

About 40% of the time, HPE is caused by an abnormality of the chromosomes. Chromosomes are structures in the cells of the body that contain the genes controlling development and cell function. The most common chromosomal abnormality in HPE is an extra copy of Chromosome 13 (trisomy 13 or Patau syndrome), but a wide variety of other chromosome anomalies have been recorded.

Multiple Malformation Syndromes

In about 10% of affected children HPE is part of a more extensive malformation syndrome (or recognized pattern of anomalies). There are at least 25 different conditions, most caused by genetic mutations, in which some form of HPE has been an occasional feature. The majority of these disorders are quite rare.

Genetic Basis of Isolated HPE

In isolated HPE, the child's chromosomes will usually be normal, but there may be a genetic basis for the defect. In some families HPE occurs because of the presence of a single copy of an abnormal gene (autosomal dominant). There are several different genes that cause HPE. One of these (named sonic hedgehog) has been identified, but it accounts for only some of the affected families. In families with mutations of this gene, some members have HPE (in any of its forms), others have minor anomalies such as close-set eyes, small heads, or a single incisor tooth, and yet others have no detectable abnormalities. The risk for any child in these families to inherit the mutated gene is 50%, but serious HPE only occurs in about half of these.

In a few families, HPE is caused by the presence of two copies of an abnormal gene (autosomal recessive). Each of the parents, who are normal themselves, contributes one copy of the abnormal gene to the baby who has HPE. For such parents, the risk of having a baby with HPE is 1 in 4 for each and every pregnancy. The gene involved has not been identified. The only way to detect which parents are at such risk is by the birth (or diagnosis by ultrasound exam before birth) of a second affected baby.

Teratogenic

There are two known exposures during pregnancy that can cause HPE. Maternal insulin-dependent diabetes mellitus has been associated with alobar HPE in more cases than would be expected by chance alone, but HPE is nonetheless a rare outcome. Very few children with HPE have been born to mothers with major abuse of alcohol during pregnancy. Other reports of a fetal exposure to a drug or chemical during pregnancy have been recorded, but from their rarity it is not all certain that there is a cause-and-effect relation between the exposure and the HPE.

Prenatal Detection

Targeted ultrasound examination can detect the presence of alobar HPE quite reliably by the 15-16th week of gestation. Some cases of semilobar HPE can be recognized by the prenatal ultrasound study, but few cases of lobar HPE can be detected by this method. If HPE is found prenatally, an amniocentesis is usually recommended to examine the fetal chromosomes, particularly if other malformations of the fetus are evident. With such information, informed decisions can be made about the management of the pregnancy, labor, delivery and postnatal care of the baby.

Cause of Death

As stated in the beginning, HPE is a group of brain malformations that are generally lethal early in life. From the information we have been able to collect, half of the children liveborn with alobar HPE will have died by 4-5 months of age. However, for many children with alobar HPE, and for most of those with semilobar or lobar HPE, no one can make an accurate prediction of when death will occur. The best we can really do is to recognize impending death within days or hours of its occurrence. Certain problems that occur in these children can lead to their deaths, and these are discussed below.

Brainstem Malfunction

Some degree of brainstem malfunction is present in virtually all children with alobar HPE, and may be worse when they have infections or other stressful conditions. Abnormal brainstem functions, particularly control of respiration and heart rate, can be a primary cause of death. A particularly worrisome sign is a very irregular pattern of breathing and heart rate, particularly when one is fast and the other slow. The children may have brief (minutes to hours) episodes like this with full recovery, but more sustained episodes (many hours to days) usually precede death.

Infection

Infections, particularly of the lungs (pneumonia and bronchiolitis), are also a leading cause of death. Ordinary bacterial infections usually respond to appropriate antibiotics. However, repeated infections carry more and more risk of a fatal outcome because of accumulated damage to the lungs. Viral infections and aspiration pneumonia do not respond to antibiotics, and the child with a malfunctioning brain and brainstem may have a very difficult time recovering from such conditions.

Other

Children with diabetes insipidus are at risk of severe dehydration and death if they are unable to replace water lost through urination.

Acknowledgment

We are grateful to the many parents and colleagues who have provided information about their experiences in caring for their children with HPE. As always, we are eager to learn more about these children so that we can pass accurate and realistic information on to other parents and caregivers. We can be reached at the addresses below.

Mason Barr, Jr., M.D.

Department of Pediatrics

TC 1924 - 0318

University of Michigan Hospitals

Ann Arbor, Michigan 48109, USA

E-mail: barr@umich.edu

M. Michael Cohen, Jr., D.M.D., Ph.D.

Department of Pediatrics

Dalhousie University

Halifax, Nova Scotia B3H 3J5, Canada

E-mail: remaclea@is.dal.ca

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