Holoprosencephaly is a disorder in which there is a failure of the front part of the brain to properly separate into what is commonly know as the right and left halves of the brain. This lack of separation is often accompanied by abnormalities of the face and skull. Holoprosencephaly may occur individually or as a component of a larger disorder.
Types of holoprosencephaly
Holoprosencephaly comes in three different types: alobar, semilobar, and lobar. Each of these classifications is based on the amount of separation between what is commonly known as the left and right halves of the brain. Alobar holoprosencephaly is considered to be the most severe form of the disease, in which the separation between the two halves, or hemispheres, completely fails to develop. Semilobar holoprosencephaly represents holoprosencephaly of the moderate type, where some separation between the hemispheres has occurred. Lobar holoprosencephaly represents the least severe type of holoprosencephaly in which the hemispheres are almost, but not completely, divided.
The severity of the effect of the disease on the brain is often reflected in craniofacial abnormalities (abnormalities of the face and skull). This has led to many health care professionals utilizing the phrase "the face predicts the brain." This phrase is generally but not always accurate. Children may have severe craniofacial abnormalities with mild (lobar) holoprosencephaly, or children may have severe (alobar) holoprosencephaly with mild facial changes. Since the development of the face, skull, and the front of the brain are interconnected, the changes in the face often, but do not always, correspond with changes in the brain. Finally, the designation of these disorders from least severe to most severe can be mildly misleading, since the best predictor of the severity of the disease, according to Barr and Cohen, is how well the brain functions, not its appearance. However, the alobar, semilobar, and lobar categories are universally utilized and give an indication of the severity of the disease, so knowledge of these categories and what they represent is useful.
Other brain abnormalities in holoprosencephaly
All patients with holoprosencephaly lack a sense of smell through the first cranial nerve (the olfactory nerve). Interestingly enough, one has a partial sense of smell through the sense of taste, which is governed by the seventh cranial nerve. The term "smell" and what it means in a conventional and strictly neurological sense differ, so it may be useful to think of persons with holoprosencephaly as lacking a portion of what is in common usage referred to as smell. This deficiency in smell can be detected by testing. One other important structural abnormality should be mentioned. The corpus callosum, which is the part of the brain that connects the right and left hemispheres with each other, is absent or deficient in persons with holoprosencephaly.
Synonyms for holoprosencephaly
Arrhinencephaly and familial alobar holoprosencephaly are synonyms for this disorder.
Genetic causes of holoprosencephaly
Holoprosencephaly is a feature frequently found in many different syndromes including, but not limited to: trisomy 13, trisomy 18 , tripoloidy, pseudotrisomy 13, Smith-Lemli-Opitz syndrome , Pallister-Hall syndrome , Fryns syndrome , CHARGE association , Goldenhar syndrome , frontonasal dysplasia , Meckel-Gruber syndrome , velocardiofacial syndrome, Genoa syndrome, Lambotte syndrome, Martin syndrome, and Steinfeld syndrome, as well as several teratogenic syndromes such as diabetic embryopathy, accutane embryopathy , and fetal alcohol syndrome . Holoprosencephaly has been linked to at least 12 different loci on 11 different chromosomes . Some candidate genes are Sonic hedgehog (abbreviated Shh, and located at 7q36), SIX3 (located at 2p21), and the ZIC2 gene (located on chromosome 13). The gene causing Smith-Lemli-Opitz syndrome, which affects cholesterol synthesis, also is interesting, since it is also obviously a candidate to cause holoprosencephaly.
Shh, cholesterol, the prechordal plate, and the cause of holoprosencephaly
Holoprosencephaly probably arises in one of two ways (suggested by experiments in animal models). Early in the life of an embryo, an area called the prechordal plate forms. The prechordal plate is an area of the embryo which is important for the formation of the brain. The prechordal plate is said to induce brain formation. One can think of the induction process in the following way. If you take a sponge, wet it, and then place a paper towel on top of it, the paper towel will absorb some of the water. In the same way, a signal (the water) goes from the sponge (prechordal plate) to the paper towel (future brain tissue). If the water doesn't hit the paper towel, brain tissue will not form. This is an extremely simplified version of how the process works, for many reasons. One is that the prechordal plate is not the only "sponge." The notochord is another sponge, which sends out the signal (water) of Shh to form brain and spinal cord and other nervous tissue. Of course, Shh has already been mentioned as a candidate for a gene which causes holoprosencephaly. It turns out it is better than a candidate, because mutations in Shh have been found in some familial forms of holoprosencephaly. Further evidence that Shh plays a role in holoprosencephaly comes from Shh in mice and fish, which both result in holoprosencephaly. Thus, it would be a nice, clear-cut picture if mutations in Shh and Shh alone led to holoprosencephaly, because Shh mutations lead to holoprosencephaly in other animals and Shh is already known to be involved in the formation of neural tissue.
However, Shh is not the only answer. Many persons with holoprosencephaly have perfectly normal Shh genes, and, as previously mentioned, a number of genes have been linked to holoprosencephaly, including genes involved in cholesterol synthesis. So why are so many genes involved?
One possible answer stems from the connection between cholesterol and the Shh signaling pathway. When Shh travels from one tissue to another tissue, there are a number of other genes involved before Shh has its final effect. This process is called signal transduction, and the genes that make it up are part of a signaling pathway. Signal transduction can be compared to a shot in the game of pool. When shooting pool, one must take the cue (Shh), hit the cue ball (another gene; for Shh this would be the gene Patched), and the cue ball goes on to hit the ball that one is interested in sinking (in this case sinking the ball means making a normal brain). Thus, each step depends on the last step and the next step. If one doesn't have the stick or the cue ball one cannot sink the ball in the pocket. Thus, a number of mutations in genes in the Shh signaling pathway, and not just Shh, could cause holoprosencephaly. Not just that, but other genes involved in cholesterol biosynthesis can have effects on genes in the Shh signaling pathway. Cholesterol appears to affect the function of the gene Patched. In the pool example, a lack of cholesterol would not mean the cue ball is gone, but maybe that the cue ball has a big lump on one side, so the shot is likely to miss.
Another possible answer comes from studies on bone morphogenetic proteins (BMPs) in chickens. Up until now, the problem of holoprosencephaly has been addressed as if it occurs when neural tissue is formed. However, the presence of too much BMP in a chick embryo after the time neural tissue is formed can cause holoprosencephaly. It appears there are two stages that can be interfered with: one that occurs at the time of neural tissue formation involving Shh, and another that occurs later involving BMPs. Increased levels of BMPs may cause important neural cells to die. It has been speculated that holoprosencephaly is either a failure to grow neural cells due to failure in Shh pathway, or an excess of neural cells dying possibly due to increased levels of BMPs. Both may end up being true, with some Shh signaling defects early, and BMP mutations later.
Teratogens also cause holoprosencephaly
A teratogen is any environmental influence that adversely affects the normal development of the fetus. Teratogens can be skin creams, drugs, or alcohol. Alcohol, when ingested in sufficient amounts during the second week of pregnancy, is thought to lead to some cases of holoprosencephaly. Cytomegalovirus infections in the mother during pregnancy have also been associated with holoprosencephaly. Additionally, in animals, drugs inhibiting cholesterol synthesis have been shown to cause cases of holoprosencephaly. Finally, the drug cyclopamine, which affects the Shh pathway, also causes holoprosencephaly in animals. Cyclopamine was discovered when an abnormally large number of sheep were found to have holoprosencephaly. A local shepherd and scientists determined the drug was found in a fungus called Veratrum californicum.
Holoprosencephaly affects males and females at the same rate. Estimates vary on the frequency of the disorder in children with normal chromosomes. The estimates range from one case in every 11,363 births to one case in 53,394 births. It is important to note that this rate of incidence excludes those cases which are caused by chromosomal abnormalities , like trisomy 13.
Signs and symptoms
In holoprosencephaly alone, symptoms involve the brain and/or the face and bones of the face and skull. Facial abnormalities exhibit a wide range. In the most severe cases, persons with holoprosencephaly lack eyes and may lack a nose. Less severe is cyclopia, or the presence of a single eye in the middle of the face above the possibly deformed or absent nose. Even less severe are ethmocephaly and cebocephaly, in which the eyes are set close together and the nose is abnormal. In premaxillary agenesis the patient has a midline cleft lip and cleft palate and close-set eyes. If the face is very abnormal, the patient is likely to have alobar holoprosencephaly, the most severe type. In addition to abnormalities of the face, children with alobar holoprosencephaly also have small brains (less than 100g). These children also have small heads unless they have excess cerebrospinal fluid. Excess cerebrospinal fluid can cause the head to be abnormally large.
Persons with holoprosencephaly experience many problems due to brain malformations including in utero or neonatal death. Survivors may experience seizures, problems with muscle control and muscle tone, a delay in growth, problems feeding (choking and gagging or slowness, pauses, and a lack of interest), intestinal gas, constipation, hormone deficiencies from the pituitary, breathing irregularities, and heart rhythm and heart rate abnormalities. These problems are usually least severe in lobar holoprosencephaly and most severe in alobar. Children with holoprosencephaly also experience severe deficiencies in their ability to speak and in their motor skills. An ominous sign that children with holoprosencephaly may exhibit is a sustained (lasting many hours or days) period of irregular breathing and heart rate. This may precede death. However, episodes lasting only minutes are usually followed by a full recovery.
Prenatal ultrasound and computerized tomography can be used to determine whether the fetus has holoprosencephaly and its severity. After birth, physical appearance and/or imaging of the brain can determine a diagnosis of holoprosencephaly. Once a diagnosis of holoprosencephaly has been made, syndromes of which holoprosencephaly is a part must be considered. Forty-one percent of holoprosencephaly cases are thought to have a chromosomal abnormality as the primary cause. Holoprosencephaly is estimated to be found in the context of a larger syndrome in 25% of the remaining cases.
Treatment and management
Although no treatment exists for the underlying disease, symptomatic treatment can reduce the amount of fluid surrounding the brain and assist in feeding. Medical intervention can reduce or eliminate seizures and hormonal deficiencies. However, few treatments exist for the most serious aspects of the disease—breathing and heart arrhythmias (irregular heart rate)—or for the problems associated with developmental delay and poor muscle control. One important aspect of treatment is to help parents understand the effects of the disease and what may be expected from the child. Support groups, like the one listed at the end of this entry, may be important for this purpose. Parents should also be prepared to deal with a large number of health care professionals based on their child's particular needs.
About half of the children born with alobar holoprosencephaly die before the age of four to five months, but a much longer survival time is possible, up to at least 11 years. Children with semilobar and lobar holoprosencephaly may live for any length of time. Depending on the severity of the holoprosencephaly, however, parents should be prepared for differences in their child. For example, children with alobar holoprosencephaly and semilobar holoprosencephaly learn to speak very little, if at all, and children with alobar holoprosencephaly have difficulty even mastering the simple task of reaching and grasping an object. On the other end of the spectrum, children may develop much more normally. It is very important to understand the severity of the disorder to understand the child's abilities and possibilities.
Sadler, T. W. Langman's Medical Embryology. Baltimore: Williams and Williams, 1995, pp. 53-60.
Barr, M., and M. Cohen. "Holoprosencephaly survival and performance." American Journal of Medical Genetics 89 (1999): 116-120.
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
Michael V. Zuck, PhD