Opitz syndrome

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Opitz syndrome


Opitz syndrome is a heterogeneous genetic condition characterized by a range of midline birth defects such as hypertelorism, clefts in the lips and larynx, heart defects, hypospadias and agenesis of the corpus callosum.


Opitz syndrome or Opitz G/BBB syndrome, as it is sometimes called, includes G syndrome and BBB syndrome, which were originally thought to be two different syndromes. In 1969, Dr. John Opitz described two similar conditions that he called G syndrome and BBB syndrome. G syndrome was named after one family affected with this syndrome whose last name began with the initial G and BBB syndrome was named after the surname of three different families. Subsequent research suggested that these two conditions were one disorder but researchers could not agree on how this disorder was inherited. It wasn't until 1995 that Dr. Nathaniel Robin and his colleagues demonstrated that Opitz syndrome had both X-linked and autosomal dominant forms.

Opitz syndrome is a complex condition that has many symptoms, most of which affect organs along the midline of the body such as clefts in the lip and larynx, heart defects, hypospadias and agenesis of the corpus callosum. Opitz syndrome has variable expressivity, which means that different people with the disorder can have different symptoms. This condition also has decreased penetrance, which means that not all people who inherit this disorder will have symptoms.

Genetic profile

Opitz syndrome is a genetically heterogeneous condition. There appear to be at least two to three genes that can cause Opitz syndrome when changed (mutated) or deleted. Opitz syndrome can be caused by changes in genes found on the X chromosome (X-linked) and changes in or deletion of a gene found on chromosome 22 (autosomal dominant).

Chromosomes, genes, and proteins

Each cell of the body, except for the egg and sperm cells contain 23 pairs of chromosomes—46 chromosomes in total. The egg and sperm cells contain only one of each type of chromosome and therefore contain 23 chromosomes in total. Males and females have 22 pairs of chromosomes, called the autosomes, numbered one to twenty-two in order of decreasing size. The other pair of chromosomes, called the sex chromosomes, determines the sex of the individual. Women possess two identical chromosomes called the X chromosomes while men possess one X chromosome and one Y chromosome. Since every egg cell contains an X chromosome, women pass on the X chromosome to their daughters and sons. Some sperm cells contain an X chromosome and some sperm cells contain a Y chromosome. Men pass the X chromosome on to their daughters and the Y chromosome on to their sons. Each type of chromosome contains different genes that are found at specific locations along the chromosome. Men and women inherit two of each type of autosomal gene since they inherit two of each type of autosome. Women inherit two of each type of X-linked gene since they possess two X chromosomes. Men inherit only one of each X-linked gene since they posses only one X chromosome.

Each gene contains the instructions for the production of a particular protein. The proteins produced by genes have many functions and work together to create the traits of the human body such as hair and eye color and are involved in controlling the basic functions of the human body. Changes or deletions of genes can cause them to produce abnormal protein, less protein or no protein. This can prevent the protein from functioning normally.

Autosomal dominant Opitz syndrome

The gene responsible for the autosomal dominant form of Opitz syndrome has not been discovered yet, but it appears to result from a deletion in a segment of chromosome 22 containing the Opitz gene or a change in the gene responsible for Opitz syndrome. In some cases the deletion or gene change is inherited from either the mother or father who have the gene change or deletion in one chromosome 22 in their somatic cells. The other chromosome 22 found in each of their somatic cells is normal. Some of their egg or sperm cells contain the gene change or deletion in chromosome 22 and some contain a normal chromosome 22. In other cases the deletion has occurred spontaneously during conception or is only found in some of the egg or sperm cells of either parent but not found in the other cells of their body.

Parents who have had a child with an autosomal dominant form of Opitz syndrome may or may not be at increased risk for having other affected children. If one of the parents is diagnosed with Opitz syndrome then each of their children has a 50% chance of inheriting the condition. If neither parent has symptoms of Opitz syndrome nor possesses a deletion, then it becomes more difficult to assess their chances of having other affected children.

In many cases they would not be at increased risk since the gene alteration occurred spontaneously in the embryo during conception. It is possible, however, that one of the parents is a carrier, meaning they possess a change in the autosomal dominant Opitz gene but do not have any obvious symptoms. This parent's children would each have a 50% chance of inheriting the Opitz gene.

X-linked Opitz syndrome

Some people with the X-linked form of Opitz syndrome have a change (mutation) in a gene found on the X chromosome called the MID1 (midline1) gene. Changes in another X-linked gene called the MID2 gene may also cause Opitz syndrome in some cases. It is believed that the MID genes produce proteins involved in the development of midline organs. Changes in the MID gene prevent the production of enough normal protein for normal organ development.

The X-linked form of Opitz syndrome is inherited differently by men and woman. A woman with an X-linked form of Opitz syndrome has typically inherited a changed MID gene from her mother and a changed MID gene from her father. This occurs very infrequently. All of this woman's sons will have Opitz syndrome and all of her daughters will be carriers for Opitz syndrome. Only women can be carriers for Opitz syndrome since carriers possess one changed MID gene and one unchanged MID gene. Most carriers for the X-linked form of Opitz syndrome do not have symptoms since one normal MID gene is usually sufficient to promote normal development. Some carriers do have symptoms but they tend to be very mild. Daughters of carriers for Opitz syndrome have a 50% chance of being carriers and sons have a 50% chance of being affected with Opitz syndrome. A man with an X-linked form of Opitz syndrome will have normal sons but all of his daughters will be carriers.


Opitz syndrome is a rare disorder that appears to affect all ethnic groups. The frequency of this disorder is unknown since people with this disorder exhibit a wide range of symptoms, making it difficult to diagnose and many possess mild or non-detectable symptoms.

Signs and symptoms

People with Opitz syndrome exhibit a wide range of medical problems and in some cases may not exhibit any detectable symptoms. This may be due in part to the genetic heterogeneity of this condition. Even people with Opitz syndrome who are from the same family can have different problems. This may mean there are other genetic and non-genetic factors that influence the development of symptoms in individuals who have inherited a changed or deleted Opitz gene. Most individuals with Opitz syndrome only have a few symptoms of the disorder such as wide set eyes and a broad prominent forehead. Opitz syndrome can, however, affect many of the organs and structures of the body and primarily affects the development of midline organs. The most common symptoms are: hypertelorism (wide-spaced eyes), broad prominent forehead, heart defects, hypospadias (urinary opening of the penis present on the underside of the penis instead of its normal location at the tip), undescended testicles, an abnormality of the anal opening, agenesis of the corpus callosum (absence of the tissue which connects the two sides of the brain), cleft lip, and clefts and abnormalities of the pharynx (throat) and larynx (voice-box), trachea(wind-pipe) and esophagus.

People with Opitz syndrome usually have a distinctive look to the face such as a broad prominent forehead, cleft lip, wide set eyes that may be crossed, wide noses with upturned nostrils, small chins or jaws, malformed ears, crowded, absent or misplaced teeth and hair that may form a 'widow's peak'. In many cases the head may appear large or small and out of proportion to the rest of the body.

Often people with Opitz syndrome have difficulties swallowing because of abnormalities in the pharynx, larynx, trachea, or esophagus. This can sometimes result in food entering the trachea instead of the esophagus, which can cause damage to the lungs and pneumonia, and can sometimes be fatal in small infants. Abnormalities in the trachea can sometimes make breathing difficult and may result in a hoarse or weak voice and wheezing.

Both males and females may have abnormal genitals and abnormalities in the anal opening. Males can have hypospadias and undescended testicles and girls may have minor malformation of their external genitalia. Heart defects are also often present and abnormalities of the kidney can be present as well. Intelligence is usually normal but mild mental retardation can sometimes be present. Twins appear more common in families affected with Opitz syndrome.

Males and females with the dominant form of Opitz syndrome are equally likely to have symptoms whereas carrier females with the X-linked form of Opitz syndrome are less likely to have symptoms then males with the condition. In general, males with the X-linked form of Opitz syndrome tend to be more severely affected than females and males with the autosomal dominant form of Opitz syndrome. People with X-linked Opitz syndrome and dominant Opitz syndrome generally appear to exhibit the same range of symptoms. The only known exceptions are upturned nostrils and clefts at the back of throat, which appear to only occur in people with X-linked Opitz syndrome.

Frequencies of common conditions associated with Opitz syndrome
Hypospadias93%LTE cleft/fistula38%
Hypertelorism91%Cleft lip and palate32%
Swallowing problems81%Strabismus28%
Ear abnormalities72%Heart defects27%
Developmental delay43%Imperforate anus21%
Kidney anomalies42%Undescended testes20%


Diagnostic testing

The diagnosis and cause of Opitz syndrome is often difficult to establish. In most cases, Opitz syndrome is diagnosed through a clinical evaluation and not through a blood test. This means a genetic specialist (geneticist) has examined the patient and found enough symptoms of Opitz syndrome to make a diagnosis. Since not all patients have obvious symptoms or even any symptoms at all, this can be a difficult task. It can also be difficult to establish whether an individual has an X-linked form or an autosomal dominant form, and whether it has been inherited or occurred spontaneously. In many cases, the geneticist has to rely on physical examinations or pictures of multiple family members and a description of the family's medical history to establish the cause of Opitz syndrome. In some cases the cause cannot be established.

Sometimes a clinical diagnosis is confirmed through fluorescence in situ hybridization (FISH). FISH testing can detect whether a person has a deletion of the region of chromosome 22 that is associated with Opitz syndrome. Fluorescent (glowing) pieces of DNA containing the region that is deleted in Opitz syndrome are mixed with a sample of cells obtained from a blood sample. If there is a deletion in one of the chromosomes, the DNA will only stick to one chromosome and not the other and only one glowing section of a chromosome will be visible instead of two. Most patients with the autosomal dominant form of Opitz syndrome cannot be diagnosed through FISH testing since they possess a tiny change in the gene that cannot be detected with this procedure. As of 2001, researchers are still trying to discover the specific gene and gene changes that cause autosomal dominant Opitz syndrome.

FISH testing is unable to detect individuals with the X-linked form of Opitz syndrome. As of 2001, DNA testing for the X-linked form of Opitz disease is not available through clinical laboratories. Some research laboratories are looking for changes in the MID1 gene and the MID2 gene as part of their research and may occasionally confirm a clinical diagnosis of X-linked Opitz syndrome.

Prenatal testing

It is difficult to diagnose Opitz syndrome in a baby prior to its birth. Sometimes doctors and technicians (ultrasonographers) who specialize in performing ultrasound evaluations are able to see physical features of Opitz syndrome in the fetus. Some of the features they may look for in the ultrasound evaluation are heart defects, wide spacing between the eyes, clefts in the lip, hypospadias, and agenesis of the corpus callosum. It is very difficult, however, even for experts to diagnose or rule-out Opitz syndrome through an ultrasound evaluation.

Opitz syndrome can be definitively diagnosed in a baby prior to its birth if a MID gene change is detected in the mother or if a deletion in chromosome 22 is detected in the mother or father. Cells from the baby are obtained through an amniocentesis or chorionic villus sampling. These cells are analyzed for the particular MID gene change or chromosome 22 deletion found in one of the parents.

Treatment and management

As of 2001 there is no cure for Opitz syndrome and no treatment for the underlying condition. Management of the condition involves diagnosing and managing the symptoms. Clefts, heart defects, and genital abnormalities can often be repaired by surgery. Feeding difficulties can sometimes be managed using feeding tubes through the nose, stomach, or small intestine. Early recognition and intervention with special education may help individuals with mental retardation.


For most patients, the prognosis and quality of life of Opitz syndrome is good, with individuals typically living a normal lifespan. The prognosis, however, is very dependent on the type of organ abnormalities and the quality of medical care. Patients with severe heart defects and major abnormalities in the trachea and esophagus may have a poorer prognosis.



Buchner, G., et al. "MID2, a homologue of the Opitz syndrome gene MID1: Similarities in subcellular localization and differences in expression during development." Human Molecular Genetics 8 (August 1998): 1397-407.

Jacobson, Z., et al. "Further delineation of the Opitz G/BBB syndrome: Report of an infant with congenital heart disease and bladder extrophy, and review of the literature." American Journal of Medical Genetics (July 7, 1998): 294-299.

Macdonald, M. R., A. H. Olney, and P. Kolodziej. "Opitz syndrome (G/BBB Syndrome)." Ear Nose & Throat Journal 77, no. 7 (July 1998): 528-529.

Schweiger, S., et al. "The Opitz syndrome gene product, MID1, associates with microtubules." Proceedings of the National Academy of Sciences of the United States of America 96, no. 6 (March 16, 1999): 2794-2799.


Canadian Opitz Family Network. Box 892, Errington, BC V0R 1V0. Canada (250) 954-1434. Fax: (250) 954-1465. [email protected] <http://www.apollos.net/arena/opitz/start.html>.

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. [email protected] <http://www.modimes.org>.

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>.

Opitz G/BBB Family Network. PO Box 515, Grand Lake, CO 80447. [email protected] <http://www.gle.egsd.k12.co.us/opitz/index.html>.

Smith-Lemli-Opitz Advocacy and Exchange (RSH/SLO). 2650 Valley Forge Dr., Boothwyn, PA 19061. (610) 485-9663. <http://members.aol.com/slo97/index.html>.


McKusick, Victor A. "Hypertelorism with Esophageal Abnormality and Hypospadias." OMIM—Online Mendelian Inheritance in Man.<http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?145410>. (March 28, 2000)

McKusick, Victor A. "Opitz syndrome." OMIM—Online Mendelian Inheritance in Man.<http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300000>. (February 6, 2001).

Lisa Maria Andres, MS, CGC