Deletion 22q11 syndrome

Definition

Deletion 22q11 syndrome is a relatively common genetic disorder characterized by congenital heart defects , palate abnormalities, distinct facial features, immune problems, learning disabilities and other abnormalities. This syndrome is caused by a deletion of chromosomal material from the long arm of chromosome 22 (22q) that leads to a wide spectrum of effects.

Description

Deletion 22q11 syndrome is also known as velocardiofacial syndrome, DiGeorge syndrome, Sphrintzen syndrome, conotruncal anomaly face syndrome, and the CATCH-22 syndrome. Because of the wide variability in the features of this syndrome, medical professionals originally thought that deletion 22q11 syndrome was more than one syndrome and it was separately described by a number of physicians—Dr. DiGeorge, Dr. Sphrintzen, and others. Dr. DiGeorge described the more severe end of deletion 22q11 syndrome (infants with congenital heart defects, unusual facial features, and immune system abnormalities). The term velocardiofacial (VCF) syndrome was used for the milder end of deletion 22q11 syndrome. These individuals usually had palate anomalies, distinct facial features, and learning disabilities.

Deletion 22q11 syndrome is an extremely variable syndrome. The main features are congenital heart defects, distinctive facial features, and palate (roof of the mouth) problems. Other problems include immune system abnormalities, thyroid problems, kidney abnormalities, and learning difficulties including mild developmental delay. Very rarely do individuals have all of the problems associated with this syndrome. Most individuals with deletion 22q11 syndrome have only a few of the associated features. Some individuals with 22q11 deletion syndrome are very mildly affected and others are more severely affected. The reason for the wide variability in this syndrome is not known.

Genetic profile

Deletion 22q11 syndrome is a genetic disorder caused by a deletion of chromosomal material from the long arm of chromosome 22. A series of genes are located in this region. Individuals with deletion 22q11 syndrome may have some or all of these genes deleted. This syndrome is sometimes called a microdeletion syndrome or a contiguous gene syndrome. Contiguous refers to the fact that these genes are arranged next to each other. The size of the deletion can be large or small, which may explain why some individuals with deletion 22q11 syndrome are more severely affected than others. The exact genes responsible for this syndrome are not known.

Deletion 22q11 syndrome is an autosomal dominant disorder. Genes always come in pairs and in an autosomal dominant disorder only one gene needs too be missing or altered for an individual to have the disorder. About 10–15% of the time, the deletion on the long arm of chromosome 22 that causes this syndrome is inherited from a parent. If a parent has deletion 22q11 syndrome, then there is a 50% chance that he or she will pass the deletion on to each of his or her children who will also be affected with 22q11 syndrome. For reasons that are not understood, it is possible for a parent with mild features of deletion 22q11 syndrome to have a child with severe features of the syndrome.

Although deletion 22q11 syndrome is an autosomal dominant disorder, over 85–90% of individuals with this disorder are the only individuals in their family with this disorder. When this is the case, the chromosome deletion that causes deletion 22q11 syndrome is called de novo. A de novo deletion is one that occurs for the first time in the affected individual. The causes of de novo chromosome deletions are not known. Parents of a child with deletion 22q11 syndrome due to a de novo deletion are very unlikely to have a second child with deletion 22q11 syndrome.

Demographics

The 22q11 deletion syndrome is one of the most common chromosomal deletion syndromes. It is estimated that approximately 1 in 2000 to 1 in 6000 individuals has a deletion of chromosome 22q11. Approximately 130,000 individuals in the United States have deletion 22q11 syndrome. Because of the extreme variability of this syndrome, it is possible that individuals with milder features are under diagnosed and the exact incidence of this disorder is not known. As more physicians become familiar with this syndrome, it is likely that more individuals will be correctly diagnosed.

Individuals with deletion 22q11 syndrome are diagnosed based upon physical findings. Of infants born with congenital heart defects, 5% will be found to have a deletion of chromosome 22q11. Of infants with a cleft palate, approximately 5–8% of them will be found to a have a 22q11 deletion.

Signs and symptoms

Deletion 22q11 syndrome is a multisystem disorder. It is also sometimes referred to as velocardiofacial syndrome. This name reflects the organ systems that are most commonly affected in deletion 22q11 syndrome. Velo is from the Latin velum which means "palate" and back of the throat, cardio refers to the heart, and facial refers to the distinctive facial features of individuals with deletion 22q11 syndrome. While it may seem unusual that these three separate areas are affected, a possible explanation lies in the early development of the embryo. Very early in development, the cells that will become the heart, face, and thyroid lie next to each other in a region called the neural crest. As the embryo continues to develop, these cells migrate, or move, to become organs (the heart, face, and palate). It is believed that the deletion of chromosomal material from chromosome 22q causes a problem in the migration of these cells leading to the variability of features or problems seen in deletion 22q11 syndrome.

In addition to the heart, palate, and face, many other organ systems can also be affected including the kidneys, the immune system, the brain, the throat, the skeletal system, the skin, the genitourinary system, and the endocrine (hormone) system. It is not possible to cover every possible feature of deletion 22q11 syndrome but the following is an overview of the most common features.

The characteristic facial features seen in individuals with deletion 22q11 syndrome include a long face with narrow palpebral fissures (the opening for the eyes), a prominent nasal bridge (the arch of the nose between the eyes), a slightly bulbous nasal tip, a long nose, small ears with thick helical folds, and a small jaw. None of these features individually is abnormal but the combination of features is characteristically seen in individuals with deletion 22q11 syndrome. These features may not be present or as easily noticeable in African-American individuals with deletion 22q11 syndrome.

Approximately 70% of individuals with deletion 22q11 syndrome have palate abnormalities. These may include complete cleft palate (an opening of the bones and skin of the roof of the mouth) or submucous cleft palate (an opening of only the bones of the roof of the mouth covered by skin). Other individuals with deletion 22q11 syndrome have more subtle palate and throat abnormalities, including velopharyngeal insufficiency, a problem in the coordination between the tongue, palate, and throat muscles. All of these problems can lead to feeding problems in infancy and speech problems such as hypernasal speech.

Cardiac defects, or congenital heart defects, are some of the more serious symptoms of deletion 22q11 syndrome and affect about 75% of individuals with the syndrome. There is a wide range of cardiac defects seen in deletion 22q11 syndrome. Some are minor and may require no treatment, some are correctable by surgery, and others are invariably fatal. The most common heart defects seen in individuals with deletion 22q11 syndrome are truncus arteriosus, interrupted aortic arch, tetralogy of Fallot, ventricular septal defects (VSDs), pulmonary stenosis, and patent ductus arteriosus . Many of these heart defects are known as conotruncal heart defects. Conotruncal refers to the type of embryonic cells that were involved in the development of these regions of the heart.

Immune problems are another of the serious problems associated with this syndrome. Because of the underdevelopment of the thymus gland, individuals with deletion 22q11 syndrome can have reduced amounts of the cells necessary to fight infections—T cells. Because of this reduction in T cells, individuals with deletion 22q11 syndrome are more prone to getting infections and less able to fight them off. The degree of immune deficiency can be variable with some individuals having life threatening infections and others having much milder problems.

Growth problems may be seen in children with deletion 22q11 syndrome. Infants with deletion 22q11 syndrome are often diagnosed as having failure to thrive. This may be due to feeding problems due to their palate abnormalities but they can also have gastroesophageal reflux and vomiting problems. It also appears that individuals with deletion 22q11 syndrome have generalized growth problems. Most adult individuals with deletion 22q11 syndrome have short stature.

Individuals with deletion 22q11 syndrome may also have specific learning disabilities and possibly mild developmental delay. The learning disabilities are specific. Most individuals with learning disabilities have a discrepancy between their performance IQ score (higher) and their verbal IQ score (lower) that indicates a nonverbal learning disability. Simple IQ testing may not reveal this learning disability and it is important to evaluate the IQ score components separately. Individuals with deletion 22q11 syndrome seem to do better at verbal learning and do well in subjects such as reading. They have more trouble with abstract concepts such as math.

Individuals with deletion 22q11 syndrome are also at risk to develop psychological problems and mental illness. Deletion 22q11 syndrome has been associated with higher rates of bipolar affective disorder, manic-depressive illness, and schizoaffective disorder when compared to individuals who do not have deletion 22q11 syndrome. Other mood disorders, such as depression , also occur at a higher incidence in individuals with deletion 22q11 syndrome. Most of these disorders appear during adolescence or adulthood. Some individuals with deletion 22q11 syndrome are mildly mentally retarded. Others have learning disabilities and some are diagnosed as having attention deficit hyperactivity disorder.

Endocrine problems are also commonly seen. The endocrine system is the hormone-producing system of the body and is composed of glands such as the thyroid and parathyroid. Individuals with deletion 22q11 syndrome may be missing one or more of these glands or they have underactive glands. An underactive thyroid is called hypothyroidism and an underactive parathyroid is called hypoparathyroidism. Because the parathyroids help to regulate the level of calcium in the body, individuals with deletion 22q11 syndrome can also have problems with their calcium levels. Low levels of calcium can lead to seizures.

Individuals with deletion 22q11 syndrome may also have kidney problems such as a cystic kidney, missing (aplastic) kidney, or malformed kidney. They may also have limb differences such as such as extra fingers or ribs and problems with the vertebrae in the back that might lead to scoliosis .

Diagnosis

The diagnosis of deletion 22q11 syndrome is usually made by a physician familiar with the syndrome and based upon a physical examination of the individual and a review of his or her medical history. It is often made in infants after a heart problem is diagnosed. In children without significant heart problems, the possibility of a diagnosis may first be raised by preschool teachers or by other medical professionals such as plastic surgeons and speech therapists. These medical professionals may be seeing the child for one of the features of deletion 22q11 syndrome and may be the first ones to become suspicious about the diagnosis. In rare cases, the diagnosis is made in a parent after they have had an affected child.

While a diagnosis may be made based upon physical examination and medical history, the diagnosis can now be confirmed by a DNA test.

Sometimes the 22q11 deletion is large enough that it can be seen during a karyotype analysis. A karyotype is a microscopic analysis of an individual's chromosomes . However, many 22q11 deletions are too small to be seen by microscopic examination and another specific technique called fluorescent in situ hybridization testing, or FISH testing, can determine whether genetic material is missing. A FISH test will be positive (detect a deletion) in over 95% of individuals with deletion 22q11 syndrome. A negative FISH test for deletion 22q11 syndrome means that no genetic material is missing from the critical region on chromosome 22. Research testing on these individuals usually reveals that up to 5% of individuals with deletion 22q11 syndrome will have a smaller deletion that is not picked up by the routine FISH test.

Prenatal testing (testing during pregnancy) for deletion 22q11 syndrome is possible using the FISH test on a DNA sample obtained by chorionic villus sampling (CVS) or by amniocentesis . Chorionic villus sampling is a prenatal test that is usually done at 10–12 weeks of pregnancy and involves removing a small amount of tissue from the placenta. Amniocentesis is a prenatal test that is usually performed at 16–18 weeks of pregnancy and involves removing a small amount of the amniotic fluid that surrounds the fetus. DNA is obtained from these samples and tested to see if the deletion responsible for deletion 22q11 syndrome is present. While prenatal testing is possible, it is not routinely performed. Typically, the test is done only if there is a family history of deletion 22q11 syndrome or if a congenital heart defect has been seen on a sonogram (ultrasound).

A sonogram uses sound waves to provide an image of a fetus. During the second trimester of pregnancy, it becomes possible to evaluate the fetal heart. If a heart defect is detected, DNA testing may be offered to the parents (along with other tests) to determine the cause of the heart defect. Unfortunately, congenital heart defects are common and there are many other syndromes that also cause congenital heart defects.

Treatment and management

Because of the incredible variability seen in deletion 22q11 syndrome, there is no one plan of treatment for all affected individuals. The treatment and management of an individual with deletion 22q11 syndrome depends on his or her age and symptoms. Because deletion 22q11 syndrome is a multisystem disorder, it is important to have multiple evaluations. Individuals with deletion 22q11 syndrome may see geneticists, plastic surgeons, immunologists, cardiologists, rheumatologists, endocrinologists, ophthalmologists, neurosurgeons, pediatricians, audiologists, and specialists in feeding, speech, and child development.

It is important that all individuals with deletion 22q11 syndrome have a cardiac evaluation by a cardiologist. An evaluation may include special tests such as a chest x ray, electrocardiogram, and echocardiogram (ultrasound of the heart). Some cardiac defects do not require treatment and others may require surgery.

Because of the wide variety of cleft palate and velopharyngeal problems, all individuals with deletion 22q11 syndrome should be evaluated by a cleft palate team. Cleft palate teams may include a plastic surgeon, ENT (ear, nose, and throat) specialist, genetic counselor, and other staff. Because of the effect of cleft palate abnormalities on speech, all children with deletion 22q11 should have a speech evaluation and speech therapy if necessary. A referral to a feeding specialist may also be helpful if there is a cleft problem or other medical problem that interferes with feeding.

Because of the possibility and serious nature of immune problems, individuals with deletion 22q11 syndrome should have an immune evaluation. This can be done by an immunologist and usually requires blood tests to check immune function.

Individuals with deletion 22q11 syndrome should also have an endocrinology examination to check the function of their thyroid, parathyroid, and pituitary glands. They may also see an endocrinologist if they are having growth problems.

Neurologists can help with issues such as seizures and other neurology problems. Psychiatrists can help with psychiatric illness and problems arising from having a chronic illness.

Individuals with deletion 22q11 syndrome should be seen by a geneticist to confirm the diagnosis and to discuss issues such as the inheritance of deletion 22q11 syndrome, the recurrence risks and the availability of prenatal diagnosis. Geneticists can also help arrange the necessary medical consults.

Prognosis

The prognosis for individuals with deletion 22q11 syndrome is highly dependant on the medical complications of the specific individual. Because this is such a variable syndrome, it is impossible to give one prognosis. The cardiac defects associated with deletion 22q11 syndrome are a major variable in determining prognosis. Those with serious heart defects have a guarded prognosis. Individuals with deletion 22q11 syndrome with minor or treatable cardiac defects have a good prognosis. Good medical care and treatment of problems allows most individuals with deletion 22q11 syndrome to have a normal life span.

While the physical features and medical complications of deletion 22q11 syndrome can affect prognosis, the degree of intellectual and psychological can also have an effect. Those individuals with normal IQ and no mental illness have a good prognosis. Those with learning disabilities can benefit from specific educational interventions. Individuals with developmental delay need more help but can do well in sheltered environments. Individuals with mental illness may or may not do well. Some individuals benefit from psychiatric counseling and medication.

The range of abilities among individuals with deletion 22q11 syndrome is very wide and the ultimate functioning of an individual is dependent on his or her abilities.

Resources

ORGANIZATIONS

National Institute on Deafness and Other Communication Disorders. 31 Center Dr., MSC 2320, Bethesda, MD 20814. <http://www.nidcd.nih.gov>.

Velo-Cardio-Facial Syndrome Educational Foundation. VCFS Educational Foundation, Inc., Upstate Medical University Hospital, 708 Jacobsen Hall (C.D.U.), 750 East Adams St., Syracuse, NY 13210.

Velo-Cardio-Facial Syndrome Research Institute. Albert Einstein College of Medicine, 3311 Bainbridge Ave., Bronx, NY 10467. (718) 430-2568. Fax: (718) 430-8778. rgoldber@aecom.yu.edu. <http://www.kumc.edu/gec/vcfhome.html>.

WEBSITES

McDonald-McGinn, Donna M., Beverly S. Emanuel, and Elaine H Zackai. "22q11 deletion syndrome." Gene Clinics. (Updated 15 Sept. 1999). <http://www.geneclinics.org/profiles/22q11deletion/index.html>.

National Institute on Deafness and Other Communication Disorders. <http://www.nidcd.nih.gov/health/pubs_vsl/velocario.htm>.

The VCFS Educational Foundation. <http://www.vcfsef.org/>.

Kathleen Fergus, MS, CGC