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 and Jessica C. Barry, MS, CGC, Genetic Counselor, “The 22q and You Center”, The Children’s Hospital if Phildelphia, for assistance in the preparation of this report.
Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by a small piece of chromosome 22 missing. 22q11.2DS 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.
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 a deletion on chromosome 22q was identified in individuals affected with all of these conditions.
Disorders with more than one identifying feature are called syndromes. 22q11.2DS has numerous features associated with it, not all of which will be present in every affected individual.
Some of the common features associated with this syndrome include cleft palate, abnormalities of the heart, developmental delays and learning disabilities, psychiatric disorders, and distinct physical features.
Individuals with 22q11.2DS 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.
Abnormalities of the heart associated with this syndrome often include conotruncal heart defects, or malformations of the cardiac outflow tract. These may include the following:
• Tetralogy of Fallot, 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. (For more information on this disorder choose “Tetralogy of Fallot” as your search term in the Rare Disease Database).
• Truncus arteriosus, in which there is only a single outflow vessel instead of the typical two outflow vessels (pulmonary artery and aorta)
• Interrupted aortic arch type B, a heart defect in which the aorta does not completely develop, thus resulting in an incomplete, or “interrupted” aortic arch
• Ventricular septal defect, when the wall that separates the right and left chambers of the heart which receive blood and then force it back into the arteries does not form properly
Additional heart abnormalities may include differences in the structure of the aortic arch (right aortic arch, vascular ring).
Developmental delays are common among children with 22q11.2DS. While difficulties with gross and fine motor skills are not unusual, the majority of children will demonstrate a significant delay in the development of language (70% will have minimal words by 24 months of age). Mild intellectual delay or learning disability is present in the majority of individuals with 22q11.2DS, with the average IQ around 70. The majority of individuals with 22q11.2DS will have an IQ in the range of 55-85 (general population average is 100). Problems with abstraction and comprehension in reading and math are usually apparent at school age. Severe intellectual disability is less frequent but may also be present with this syndrome.
Psychiatric disorders in individuals with 22q11.2DS include a higher prevalence of anxiety, attention-deficit disorder, and autism spectrum disorders. About one quarter of patients with 22q11.2DS are diagnosed with schizophrenia, which typically presents in late-adolescence. Clinical studies have shown that individuals with 22q11.2DS are about 25 times more likely than the general population to develop schizophrenic symptoms. However, the manifestation of schizophrenia in individuals with 22q11.2DS does not differ from that of the general population in regard to signs, symptoms, and treatment.
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 22q11.2DS:
• An absent or underdeveloped thymus causing an insufficient production of antibodies
• Deficiency of calcium in the blood (hypocalcemia)
• Problems with thyroid function and growth hormone deficiency
• Gastrointestinal difficulties including gastroesophageal reflux, chronic constipation, feeding difficulties, and dysmotility
• Curvature of the spine (scoliosis)
• Seizures and differences in the structure of the brain
• 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
• 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)
• Differences in the structure of the kidneys
• 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 22q11.2DS are missing a small part of chromosome 22. The deletion occurs at a specific location on the long arm (q arm) of chromosome 22 (region 22q11) and often includes a deletion of genes in the DiGeorge chromosomal region (DGCR). The majority of individuals (85%) have a common, standard-size deletion of approximately 3 megabases (Mb). However, 15% of individuals with 22q11.2DS have a deletion of a smaller size, often referred to as “nested” or “distal” deletions. These individuals present with nearly the same spectrum of findings as those individuals with the standard deletion.
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.
22q11.2DS 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 individual to offspring is 50% for each pregnancy. The risk is the same for males and females.
The prevalence of 22q11.2DS has been estimated to be approximately 1/3000 to 1/6,000 live births. These numbers may well be higher due to the variability of the condition, difficulty in properly diagnosing, and lack of newborn screening.
The diagnosis of 22q11.2DS is suspected when clinical symptoms are present. The diagnosis is confirmed by a blood test that can detect a microscopic chromosomal deletion 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.
A team approach is often useful and generally recommended when making decisions about the treatment of symptoms in patients with 22q11.2DS. A geneticist, pediatrician, cardiologist, immunologist, endocrinologist, gastroenterologist, otolaryngologist, plastic surgeon, speech pathologist, audiologist, orthodontist, dentist, urologist/nephrologist, orthopedist, child development specialist, neurologist and psychologist may all be called in to consult with the parents, depending on the clinical presentation of the child.
Genetic counseling is recommended for families with an affected child.
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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.
Firth HV. 22q11.2 Duplication. 2009 Feb 17 [Updated 2013 Nov 21]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK3823/ Accessed June 13, 2017.
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