NORD gratefully acknowledges 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.
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.
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.
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.
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.
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 hav. a chromosome rearrangement involving chromosome 22q which may change the recurrence risk counseling for the parents.
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.
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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.
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