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Opitz Syndrome

What is a Syndrome?

The word syndrome is used to describe a group of medical findings or problems that occur together because they have the same underlying cause. Birth defects can often be grouped into a syndrome, even before the cause of the problems is discovered. Down syndrome is one example; people noticed years before its cause was known that some children with mental retardation had a similar physical appearance. Syndromes are often named after the first person who described them. Syndromes may be caused by a change in our genes, by something in the environment, or by a combination of the two.

What is Opitz Syndrome?

Dr. John Opitz first described families with this condition in 1965 and 1969. Findings included hypertelorism, hypospadias and swallowing problems. Hypertelorism means very wide-spaced eyes. You might notice the wide-set eyes at first glance, or it might be necessary to measure them. Hypospadias means that the opening on a boy's penis is on the underside rather than at the tip of the penis. This problem can be surgically repaired so that the child can urinate normally.

Many people with Opitz syndrome have a characteristic facial appearance, which includes wide-spaced eyes and a "widow's peak" hairline. Their ears may be low set or rotated at an unusual angle so that they seem more prominent. Individuals with Opitz syndrome may have a broad or flat nose as well as a small chin.

Opitz syndrome is relatively rare. Since 1965, there have been over 50 families reported in the literature, but there are many families that have not been reported.

What is the Cause of Opitz Syndrome?

Opitz syndrome is caused by a mutation (change) in one gene. There are at least two different genes that cause Opitz syndrome. Research on these genes and their normal function is ongoing.

We do know that mutations in Opitz syndrome genes tend to affect early development by widening the midline or center of the body. The frequency of twinning is also more common among people with Opitz syndrome than among people who do not have this condition. Most of the findings in Opitz syndrome are in the midline region of the body (see Table 1).

Other Features of Opitz Syndrome

Hypertelorism and hypospadias were the first findings that were noticed in people with Opitz syndrome. However, many other medical problems can occur in this condition. Developmental delay or mental retardation occurs in about 40% of people with the syndrome. A greater number may have learning problems. Some delays are caused by weak muscle tone (hypotonia) which usually improves with time. Congenital heart defects are seen in about 30% of people with the syndrome. This means that a baby may be born with a structural heart problem. Sometimes, these heart problems cause a heart murmur, which makes them easy to diagnose. Other tests, such as an echocardiogram, may be necessary to evaluate the heart. A heart defect can be a serious problem, but can often be fixed by surgery.

One other serious problem which is sometimes seen is called laryngotracheal esophageal (LTE) cleft. This is a malformation of the throat which may cause problems with swallowing or breathing. An LTE cleft can be very serious and can sometimes even cause death if it is not noticed and treated.
Symptoms of LTE cleft:

Thus, it is very important to see a doctor if a child has any findings of Opitz syndrome or any of the symptoms of an LTE cleft. Many babies with Opitz syndrome have trouble swallowing and spit up a lot even if they do not have a cleft in their throat. They can usually swallow better as they get older, but for a while they may have trouble with choking. Pneumonia can be causedif pieces of food get into their lungs. Even much older children can choke if they are rushed when eating. Problems with swallowing should be reported to their doctor. The frequencies of many of the common findings in Opitz syndrome are listed in Table I. Hypertelorism and hypospadias are the two most common features. The likelihood of some problems may be lower than we have estimated, since people with severe problems are more likely to be diagnosed and reported.

TABLE I ~

 Hypospadias  93%  LTE cleft/fistula  38%
 Hypertelorism  9l %  Cleft lip and palate  32%
 Swallowing problems  81%  Strabismus  28%
 Ear abnormalities  72%  Heart defects   27%
 Developmental delay  43%  Imperforate anus  21%
 Kidney anomalies  42%  Undescended Testes  20%

Occasional Features

Other problems that can be seen in Opitz syndrome are less common. These include urinary tract problems, large fontanels (the soft spot on a baby's skull), asymmetric skull, underdevelopment of the corpus callosum (located in the middle of the brain), narrow eye openings, lung abnormalities, lipomas, unusual fingerprints, and diastasis recti. Lipomas are small nodules of fat under the skin. Diastasis recti, means that the muscles of the abdomen are widely spaced causing the middle of the abdomen to bulge out slightly when the person is straining.

Variability

As you have probably realized by now, there is great variation in the severity of Opitz syndrome. One person with the syndrome might have many of the different features and need lots of special medical care. Rarely, these problems may be so severe that the child does not live. Someone else with Opitz syndrome not might have any medical problems and only have the characteristic facial features.

Males with Opitz syndrome tend to have severe problems more often than females. There have even been a few families where a woman with only wide-spaced eyes has had a son with severe medical problems.

Babies who survive severe problems in infancy usually have normal growth and a normal life span. Individuals with this syndrome can have very normal lives, especially those who do not have learning problems.

Other Names for Opitz

Originally there were two syndromes called BBB (or Opitz) syndrome and G (or Opitz-Frias) syndrome. They were very similar, but the G syndrome was thought to be more severe and included all the cases with LTE clefts. The BBB syndrome was characterized by developmental delay, hypospadias and the facial features. Now the two are combined under the common name of Opitz syndrome.

Genes and Chromosomes
Opitz syndrome is caused by one "misspelled" gene. Genes are the tiny bits of information that contain everything necessary to make you who you are. The way you look, the way your body grows, and even the way you break down food are all controlled by your genes. Genes are grouped together on chromosomes. Imagine a long strip of movie film, on which the separate frames are the genes arranged in a row, and you have a good idea of what a chromosome is. Humans usually have 46 chromosomes in every cell of their body. Some of these problems can be fixed by surgery. A cleft lip ("hare lip") or cleft palate can be closed and an undescended testicle can usually be corrected. A child with Opitz syndrome is more likely to develop hernias, in the groin or umbilical area, which can be surgically repaired.

FIGURE 1

Since the chromosomes are in pairs, most of our genes are in pairs as well. Sometimes, one or both of these genes are "misspelled" (have a mutation). A gene is "dominant" when a mutation in one copy is enough to cause a problem in the person who carries it. A gene is "recessive" when both copies of the gene must have a mutation for the person to have medical problems. One pair of chromosomes is different in men and women. These chromosomes, the X and Y, are called "sex chromosomes". Women have two X chromosomes, one from each of their parents. Men inherit one X chromosome from their mother and a Y chromosome from their father. Because the sex chromosome pair is different in men and women, the inheritance of gene mutations on the X chromosome is different in men and women. Inheritance of gene mutations on the other chromosomes (autosomes) is the same in men and women. _

Men have only one copy of all genes on the X chromosome. If a man has a gene mutation on his X chromosome, he will have an "X-linked condition." Women have two X chromosomes. If a woman has a gene mutation on one X chromosome, she may have no symptoms or milder symptoms.

Genetics of Opitz

What does this mean for people with Opitz syndrome? First it is important to ask your doctor or genetic counselor about the inheritance of Opitz syndrome in your family. From studying many families, we know that the syndrome is passed on in some families as an X-linked condition. In other families, it is inherited as an autosomal dominant condition. In all families, it is caused by a mutation in one gene.

Autosomal dominant Opitz syndrome:
Males and females can inherit this condition if one of their parents has it. A person with the autosomal dominant type of Opitz syndrome has one copy of a gene that does not work properly and one normal gene in that particular pair. In other words, if a person has the dominant gene for Opitz syndrome, he or she has Opitz syndrome.

When a woman makes an egg or a man makes a sperm, only one gene of each pair goes into the egg or sperm. When the egg and sperm come together at conception each provides a half set of genes so that a full set of genes is present in the first cell of the developing baby.

FIGURE 2


Which gene goes into an egg or sperm is random, like flipping a coin. Thus, a person with Opitz syndrome who has one copy of a gene that causes the syndrome and one normal copy of that gene, randomly passes either the Opitz gene or the normal gene in every sperm or egg made (Figure 2).

There is a 50/50 chance that each sperm or egg will contain the gene that causes Opitz syndrome. If an egg or sperm with the Opitz gene goes on to make a baby, that baby will have one gene for Opitz syndrome paired with a normal gene. Since Opitz syndrome is a dominant condition, having one copy of the non-working gene means that the child will have Opitz syndrome. That is why a person with the dominant form of Opitz syndrome has a 50% risk for each child to inherit the syndrome.

FIGURE 3

X-linked Opitz syndrome

This form of Opitz syndrome usually occurs only in males. Women who have one gene on the X chromosome for Opitz syndrome and one normal gene may have mild features of the condition such as wide-spaced eyes, or may have no symptoms. Men with Xlinked Opitz syndrome cannot pass the condition to their sons, but all their daughters will inherit the gene mutation. Women who have one misspelled gene for X-linked Opitz syndrome have a 50% chance for each child to inherit this gene. Their chance to haYe a son with Opitz syndrome is 25% in each pregnancy (Figure 3).

Spontaneous Mutations

What about a child who is diagnosed with Opitz syndrome when no one else in the family has it? Sometimes a spontaneous (or new) mutation occurs. This means that a change or mutation happened in the gene around the time of conception. Thus, even though neither parent has the gene for Opitz syndrome, the child still has the condition. Spontaneous mutations rarely happen with Opitz syndrome. If you do have a child with Opitz syndrome, and no one else in the family has it, the chance that you will have another child with the syndrome may be very low. Yet it is difficult to be certain that no one else has it, because some people with Opitz syndrome have very subtle findings.

Even if Opitz syndrome occurs as a result of a spontaneous mutation, the individual with the condition still has a 50% chance of passing the gene on to any children he or she might have. Anyone with Opitz syndrome should therefore have genetic counseling before planning to have children.

Is There a Test for Opitz?

There is ongoing research to develop a test for Opitz syndrome. At the time this pamphlet was published, at least 2 genes in different families had been associated with clinical findings of Opitz syndrome. These genes appear to be located on chromosomes 22 and X. Mutations have been identified in some families with Xlinked Opitz syndrome. If a mutation is identified in your family, other at-risk relatives and pregnancies can be tested for Opitz syndrome.

For now, physical examination by a geneticist is the most reliable way to make the diagnosis in most families. Boys with Opitz syndrome who have no affected relatives should be tested for mutations in the X-linked Opitz gene. We do not have a test to tell if an unborn child will have dominant Opitz syndrome. However, if you are concerned about the risk for Opitz syndrome in your pregnancy, there are some clues which might be useful. Polyhydramnios (excess amniotic fluid) is sometimes seen if a fetus has Opitz syndrome. Also, it may be possible to see some features of the condition after 22 weeks gestation, with a high-resolution ultrasound.

We hope that this brief summary has helped you understand more about Opitz syndrome. As with any genetic condition, it is important to keep in touch with your doctor or genetic counselor, because new discoveries are being made all the time.

You may wish to contact the Opitz Family Network at P.O. Box 515, Grand Lake Colorado 80447 (telephone: 970-627-8935, email: opitznet@mac.com) for additional information and support. The following web sites may also be useful. _

Opitz Family Network: http://gle.egsd.k12.co.us/opitz/index.html
National Organization for Rare Disorders (NORD): (800) 999-6673
http://www.nord-rdb.com/~orphan


References:

 Authors:

 Reviewers:
 Vickie Hannig, M.S.  John Opitz, M.D.
 Melinda Cohen, M.S.  Jaime Frias, M.D.
 Jean Pfotenhauer, M.S.  John A.Phillips, III, M.D.
 Alexis Poss, MS
   Barbara Ramsey, PhD
   Carol Kirshner, MA

For free copies of the original pamphlet contact:


Vanderbilt University Medical Center
DD-2205, MCN, Division of Medical Genetics
Nashville, TN 37232-2578

Telephone 615 322-7601

 

 

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