55 Kenosia Avenue
Danbury, CT 06810
Phone: 203.744.0100
Toll Free: 1.800.999.6673
http://rarediseases.org

Chromosome 22q11.2 Deletion Syndrome

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 1991, 1993, 1996, 1997, 1998, 2004, 2010

NORD is very grateful to Donna M. McDonald-McGinn, MS, CGC, Associate Director, Clinical Genetics; Program Director, The "22q and You" Center, The Children's Hospital of Philadelphia, for assistance in the preparation of this report.

Synonyms of Chromosome 22q11.2 Deletion Syndrome

Disorder Subdivisions

General Discussion

Chromosome 22q11.2 deletion syndrome is associated with a range of problems including: congenital heart disease, palate abnormalities, immune system dysfunction including autoimmune disease, low calcium (hypocalcemia) and other endocrine abnormalities such as thyroid problems and growth hormone deficiency, gastrointestinal problems, feeding difficulties, kidney abnormalities, hearing loss, seizures, skeletal abnormalities, minor facial differences, and learning and behavioral differences. The symptoms of this condition are extremely variable, even among members of the same family.

Chromosome 22q11.2 deletion syndrome is a disorder caused by a small piece of chromosome 22 missing. A number of separately described diagnoses including DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CTAF), autosomal dominant OpitzG/BBB syndrome and Cayler Cardiofacial syndrome were all originally thought to be separate disorders before the chromosome 22q11. 2 deletion was identified in individuals affected with all of these conditions.

Symptoms

Disorders with more than one identifying features are called syndromes. Velocardiofacial syndrome has numerous features associated with it, not all of which will be present in every affected individual.

Some of the features associated with this syndrome include cleft palate, abnormalities of the heart, learning disabilities, and distinct physical features.

Individuals with velocardiofacial syndrome typically have a mild form of cleft palate. The lobe in the middle of the back of the soft palate (uvula) is split and there is a thin union of the two halves of the palate in the middle with a mucous covering on the rear portion of the mouth. The muscles under the soft palate do not fuse together and a notch can be felt where the hard and soft palates meet. This notch replaces the back spine of the palate. (For more information on this disorder choose "Cleft Lip and Cleft Palate" as your search term in the Rare Disease Database).

Abnormalities of the heart associated with this syndrome may include the following: The wall that separates the right and left chambers of the heart which receive blood and then force it back into the arteries (ventricular septal) does not form properly; there may be right aortic arch abnormalities; and a congenital abnormality in which there is obstruction in the outflow from the right ventricle of the heart to the lungs, with an enlarged right ventricle and a displaced aorta that receives blood from both the right and left ventricles (Tetralogy of Fallot). (For more information on this disorder choose "Tetralogy of Fallot" as your search term in the Rare Disease Database).

Mild intellectual delay or learning disability is present in the majority of individuals with velocardiofacial syndrome. The average I.Q. score in high school-age children is 69-87. Problems with abstraction, comprehension in reading and math are usually apparent at school age. Mental retardation is less frequent but may also be present with this syndrome.

About one quarter of VCFS patients develop psychotic symptoms, and a diagnosis of schizophrenia is often made in adolescence. Clinical studies have shown that people with velocardiofacial syndrome are about 25 times more likely than the general population to develop schizophrenic symptoms. In addition, both schizophrenic and non-schizophrenic VCFS patients score higher on a test designed to determine schizoid personality. The schizophrenia associated with VCFS has a chronic and disabling course, and is associated with poor response to psychiatric medications.

Distinct physical features sometimes associated with the syndrome include loss of muscle tone (hypotonia), small slender stature, tapered hands and fingers, small head circumference (microcephaly), recessed jaw (retrognathia), tubular nose, flat cheeks, long upper jaw, long vertical groove in the middle of the upper lip (philtrum), blue coloring under the eyes, small outer ears, thick outer rims of the ear, two different sized ears and nasal sounding speech secondary to cleft palate.

Some (but not all) of the following additional symptoms may be present in patients with velocardiofacial syndrome:

An absent or underdeveloped thymus causing a insufficient production of antibodies; hearing loss; eye abnormalities such as clouding of the lens of the eye or its surrounding membrane obstructing the passage of light (cataract), abnormal smallness of one or both eyeballs (microphthalmia), and twisted vessels in the optic disc; curvature of the spine (scoliosis); rupture or protrusion in the groin or central abdominal region (inguinal or umbilical hernia); failure of the testes to descend into the scrotum in males (cryptorchidism); deficiency of calcium in the blood (hypocalcemia); absent or small adenoids; and absent or small tonsils. In addition, newborn children may have obstructed breathing due to the recessed jaw and loss of muscle tone in the throat area.

Causes

Individuals with chromosome 22q11.2 deletion syndrome are missing a small part of chromosome 22. The deletion occurs at a specific location on the long arm (q arm) of chromosome 22 (22q11) and includes genes in the DiGeorge chromosomal region (DGCR).

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 (from the largest to the smallest) and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 22q11" refers to band 11 on the long arm of chromosome 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The 22q11.2 deletion syndrome is considered a contiguous deletion syndrome where many genes are missing on one chromosome and where a person with the deletion can pass it on to his or her children. The deletion occurs as a new abnormality in 93% of those affected and is inherited from a parent in 7% of those affected. The risk of passing the deletion from an affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

Affected Populations

The prevalence of chromosome 22q11.2 deletion syndrome has been estimated to be approximately in 1/4,000 to 1/6,000 live births but may well be higher than this because of the variability and lack of newborn screening.

Related Disorders

Symptoms of the following disorders can be similar to those of chromosome 22q11.2 deletion syndrome. Comparisons may be useful for a differential diagnosis:

Smith-Lemli-Opitz syndrome (SLOS) is a variable genetic disorder that is characterized by slow growth before and after birth, small head (microcephaly), mild to moderate mental retardation and multiple birth defects including cleft palate, heart defects, fused second and third toes, extra fingers and toes and underdeveloped external genitals in males. The severity of SLOS varies greatly in affected individuals, even in the same family, and some have normal development and only minor birth defects. SLOS is caused by a deficiency in the enzyme 7-dehydrocholesterol reductase that results in an abnormality in cholesterol metabolism. SLOS is inherited as an autosomal recessive genetic disorder. (For more information on this disorder choose "Smith" as your search term in the Rare Disease Database.)

Alagille syndrome is a genetic liver disorder usually present at birth. It is characterized by insufficient passage of bile due to a lower than normal number of bile ducts inside the liver. In some cases, the child may be born with no bile ducts. Major symptoms include prolonged yellow skin discoloration (jaundice), eye and heart structure anomalies, abnormally shaped vertebrae of the spine, compression of nerve space inside the lower spine, an absence of deep tendon reflexes, mental deficiency, kidney (renal) abnormalities, and pancreatic insufficiency. (For more information on this disorder choose "Alagille" as your search term in the Rare Disease Database.)

VACTERL association is a nonrandom association of birth defects that affects multiple organ systems. The term VACTERL is an acronym with each letter representing the first letter of one of the more common findings seen in affected children: (V) = vertebral abnormalities; (A) = anal atresia; (C) = cardiac (heart) defects; (T) = tracheoesophageal fistula; (E) = esophageal atresia; (R) = renal (kidney) abnormalities; (L) = limb abnormalities. In addition, affected children may also exhibit growth deficiencies and failure to gain weight and grow at the expected rate (failure to thrive). In some cases, the acronym VATER association is used. Some researchers have added an (S) to the VACTERL or VATER acronym to represent a single umbilical artery instead of the normal two. Intelligence is usually normal. The cause of VACTERL association is unknown. (For more information on this disorder choose "VACTERL" as your search term in the Rare Disease Database.)

Oculo-auriculo-vertebral spectrum (OAVS) refers to three rare disorders that many clinicians believe to be intimately related to one another and which represent the range of severity of the same disorder. Oculo-auriculo-vertebral disorder (OAVD) is the mildest form of the disorder, while Goldenhar syndrome is the most severe form. Hemifacial microsomia appears to be an intermediate form. The disorder is characterized by a wide spectrum of symptoms and physical features that may vary greatly in severity from case to case. However, such abnormalities tend to involve the cheekbones, jaw, mouth, ears, eyes, and/or bones of the spinal column (vertebrae). In most cases OAVS appears to occur randomly, with no apparent cause (sporadic). However, in some cases, family histories suggest autosomal dominant or recessive inheritance. In addition, some researchers suggest that the disorder may be caused by the interaction of many genes, possibly in combination with environmental factors (multifactorial inheritance). (For more information on this disorder choose "oculo-auriculo-vertebral" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
The diagnosis of chromosome 22q11.2 deletion syndrome is suspected when clinical symptoms are present. The diagnosis is confirmed by a blood test that can detect a small chromosomal deletion in the DiGeorge chromosomal region (DGCR) on chromosome 22. There are many new tests to detect this deletion including whole genome array, SNP array, comparative genomic hybridization, and MLPA. FISH studies have also been useful in finding the deletion in most patients. Furthermore, routine chromosome (cytogenetic) testing is also performed because a small number of affected individuals have a chromosome rearrangement involving chromosome 22q which may change the recurrence risk counseling for the parents.

Treatment
A team approach is often useful and generally recommended when making decisions about the treatment of symptoms in patients with chromosome 22q11.2 deletion syndrome. A pediatrician, speech pathologist, orthodontist, plastic surgeon, otolaryngologist, audiologist, dentist, cardiologist, immunologist, endocrinologist, gastroenterologist, urologist/nephrologist, orthopedist, child development specialist, neurologist and psychologist may all be called in to consult with the parents.

Genetic counseling is recommended for families with an affected child.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Chromosome 22q11.2 Deletion Syndrome Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

JOURNAL ARTICLES
Antshel KM, Kates WR, Roizen N, et al. 22q11.2 deletion syndrome: genetics, neuroanatomy and cognitive/behavioral features keywords. Neuropsychol Dev Cogn C Child Neuropsychol. 2005;11(1):5-19.

Robin NH, Shprintzen RJ. Defining the clinical spectrum of deletion 22q11.2. J Pediatr. 2005;147(1):90-6.

Sullivan KE. The clinical, immunological, and molecular spectrum of chromosome 22q11.2 deletion syndrome and DiGeorge syndrome. Curr Opin Allergy Clin Immunol. 2004;4(6):505-12.

McDonald-McGinn DM, Tonnesen MK, Laufer-Cahana A, et al. Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net! Genet Med. 2001;3(1):23-9.

McDonald-McGinn DM, Driscoll DA, Bason L, et al. Autosomal dominant "Opitz" GBBB syndrome due to a 22q11.2 deletion. Am J Med Genet. 1995;59(1):103-13.

Matsuoka R, Takao A, Kimura M, et al. Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2. Am J Med Genet. 1994;53(3):285-9.

FROM THE INTERNET
McDonald-McGinn DM, Emmanuel BS and Zackai EH. (Last Updated 12/16/05). 22q11.2 Deletion Syndrome. In GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2009. Available at http://www.genetests.org. Accessed 2/09.

Report last updated: 2010/04/28 00:00:00 GMT+0