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22q11.2 Deletion Syndrome.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
1999 Sep 23 [updated 2013 Feb 28].

Author information

1
Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
2
Division of Human Genetics and Molecular Biology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

Excerpt

CLINICAL CHARACTERISTICS:

Individuals with 22q11.2 deletion syndrome (22q11.2DS) have a range of findings including the following: Congenital heart disease (74% of individuals), particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and truncus arteriosus). Palatal abnormalities (69%), particularly velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate. Characteristic facial features (present in the majority of individuals of northern European heritage). Learning difficulties (70%-90%). An immune deficiency (regardless of the clinical presentation) (77%). Additional findings include the following: Hypocalcemia (50%). Significant feeding and swallowing problems; constipation with or without structural gastrointestinal anomalies (intestinal malrotation, imperforate anus, and Hirschsprung disease). Renal anomalies (31%). Hearing loss (both conductive and sensorineural). Laryngotracheoesophageal anomalies. Growth hormone deficiency. Autoimmune disorders. Seizures (idiopathic or associated with hypocalcemia). CNS anomalies including tethered cord. Skeletal abnormalities (scoliosis with or without vertebral anomalies, clubbed feet, polydactyly, and craniosynostosis). Ophthalmologic abnormalities (strabismus, posterior embryotoxon, tortuous retinal vessels, scleracornea, and anophthalmia). Enamel hypoplasia. Malignancies (rare). Developmental delay (in particular delays in emergence of language), intellectual disability, and learning differences (non-verbal learning disability where the verbal IQ is significantly greater than the performance IQ) are common. Autism or autistic spectrum disorder is found in approximately 20% of children and psychiatric illness (specifically schizophrenia) is present in 25% of adults; however, attention deficit disorder, anxiety, perseveration, and difficulty with social interactions are also common.

DIAGNOSIS/TESTING:

22q11.2 deletion syndrome is diagnosed in individuals with a submicroscopic deletion of chromosome 22 detected by fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), or chromosomal microarray (CMA). At present, fewer than 5% of individuals with clinical findings of the 22q11.2 deletion syndrome have normal routine cytogenetic studies and normal results on FISH testing; however, this figure may change as individuals with atypical or nested deletions within the DGCR (DiGeorge chromosome region) but not including the area encompassing the N25 or TUPLE FISH probes are identified using array-based or MLPA technologies.

MANAGEMENT:

Treatment of manifestations: Multidisciplinary team approach (which may include any combination of the following: allergy, audiology, cardiology, cardiac surgery, child development / psychology, dental, endocrine, ENT, feeding, gastroenterology, general pediatrics, general surgery, immunology, clinical genetics, neurology, neurosurgery, ophthalmology, orthopedics, otolaryngology, plastic surgery, psychiatry, pulmonary, rheumatology, speech, and urology tailored to the affected individual’s specific needs. Calcium supplementation and referral to an endocrinologist for hypocalcemia and thyroid monitoring; specific strategies (modification of spoon placement when eating; treatment for gastroesophageal reflux and gastrointestinal dysmotility) for feeding difficulties; educational intervention and speech therapy/introduction of sign language therapy beginning at diagnosis because of risk for delays. Growth hormone deficiency is treated as in the general population. Immune deficiency requires aggressive treatment of infections; rarely, prophylactic antibiotics, IVIG therapy, or thymic transplantation are required. Early diagnosis and intervention for psychiatric illnesses improve long-term prognosis. Prevention of secondary complications: Immunization of infants who have lymphocyte abnormalities with live vaccines is not recommended; reevaluate immune status in childhood before giving live vaccines; antibody studies to assess results of immunizations are warranted; irradiated blood products are recommended until normalization of the immune system can be confirmed; serum ionized calcium concentration should be measured pre- and postoperatively to avoid hypocalcemic seizures; consider assessment of carotid arteries prior to surgical procedures involving the pharynx; consider possible effects on speech prior to adenoidectomy; consider assessment of cervical spine anomalies prior to hyperextension of the neck during surgical procedures/athletic pursuits; consider pre- and postoperative sleep studies when performing pharyngeal procedures; consider assessment of platelet volume and function prior to surgical procedures. Surveillance: Follow up as needed on a "system by system" basis, but including routine reassessment of serum ionized calcium and thyroid studies; reevaluation of immunologic status prior to live virus vaccines; annual complete blood count and differential; ophthalmologic evaluation prior to school age; evaluation of nasal speech quality; audiology evaluation prior to school enrollment; surveillance for scoliosis; routine dental care; regular speech, language and developmental assessments to provide appropriate remediation. Agents/circumstances to avoid: Carbonated drinks and alcohol consumption may exacerbate hypocalcemia. Caffeine intake may contribute to or worsen anxiety.

GENETIC COUNSELING:

22q11.2 deletion syndrome is a contiguous gene deletion syndrome inherited in an autosomal dominant manner. About 93% of probands have a de novo deletion of 22q11.2 and 7% have inherited the 22q11.2 deletion from a parent. Offspring of affected individuals have a 50% chance of inheriting the 22q11.2 deletion. Prenatal testing for pregnancies at increased risk based on family history is possible if the diagnosis has been confirmed in an affected family member and for pregnancies not known to be at increased risk in which congenital heart disease and/or other associated abnormalities (e.g., cleft palate, polydactyly, diaphragmatic hernia, renal anomalies, and polyhydramnios) have been detected by ultrasound examination.

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