22Q11.2 Deletion Syndrome (Digeorge Syndrome, Velocardiofacial Syndrome)
22q11.2 deletion syndrome, formerly known as DiGeorge or velocardiofacial syndrome, is a multisystem disorder with variable severity and number of associated features, classically including developmental delay, learning difficulties, congenital cardiac anomalies, palatal abnormalities, especially velopharyngeal insufficiency, hypocalcemia, and subtle facial dysmorphism.
- Intellectual disabilities are usually borderline to mild; rarely severe
- Treatable psychiatric illness is common.
- Rarely (≤1%), neonates have a severe T-cell immunodeficiency.
Prevalence is estimated at up to 1 in 2,000 live births.
- Associated hemizygous microdeletion of 22q11.2
- Up to 10% of newly diagnosed cases are inherited.
- 50% recurrence risk at each pregnancy for affected individuals
A developmental defect of the 3rd and 4th pharyngeal arches may be part of the mechanism; molecular disturbances of neurodevelopment are yet to be identified.
- This syndrome is underrecognized at all ages; thus, an index of suspicion is needed for any child with multisystem features.
- Neonatal and more commonly later onset hypocalcemia may be present secondary to hypoparathyroidism in up to 60% of cases.
- Congenital anomalies of any organ system
- Cardiac defects include interrupted aortic arch type B, septal defects, tetralogy of Fallot ± pulmonary atresia, truncus arteriosus, and vascular ring.
- Failure to thrive/dysphagia/gastroesophageal reflux disease (GERD), occasional growth hormone deficiency
- Recurrent infections/autoimmune disease
- Developmental delays, any, including speech
- Anxiety, attention-deficit disorder, OCD, autism spectrum, and schizophrenia
Subtle facial dysmorphism (e.g., malar flatness, hooded eyelids, auricular anomalies, small mouth, micrognathia; tubular nose, bulbous nasal tip with hypoplastic alae nasi), not as recognizable in non-Caucasians
- Developmental/cognitive/behavioral disorders
- Hypernasal speech; disarticulation
- Heart murmur
- Hypothyroidism; hyperthyroidism
- Renal/urogenital abnormalities
- Scoliosis; other skeletal abnormalities, for example, polydactyly and butterfly vertebrae
- Recurrent otitis media; hearing deficits
- Thrombocytopenia; splenomegaly
- Juvenile rheumatoid arthritis
- Enamel hypoplasia; chronic caries
Diagnostic Tests and Interpretation
- Genome-wide microarray, multiplex ligation-dependent probe amplification (MLPA), or fluorescence in situ hybridization (FISH) using specific probe (may miss smaller deletions)
- Most common microdeletion in humans
- Parents also require testing for the deletion.
- CBC with differential
- Calcium and parathyroid hormone (PTH)
- Flow cytometry
- Age 9 to 12 months (before live vaccines)
- Flow cytometry
- T-cell function
- Renal ultrasound
- Cervical spine radiographs
- Other, as indicated by history and signs
- Audiology assessment
- Ophthalmology assessment
- Standard treatments are generally effective for each associated feature.
- Vitamin D supplements (those with hypocalcemia may need 1,25-D calcitriol supplementation and calcium supplements)
- Special consideration for infants:
- Initially withhold live vaccines.
- Irradiated blood products
- Influenza vaccinations
- Respiratory syncytial virus prophylaxis
- If severe T-cell dysfunction: Avoid live viral vaccines; consider immunoglobulin replacement therapy.
- Consider varicella zoster immune globulin in a patient with either unknown humoral immunity status or definitive humoral abnormalities and a history of exposure. IV acyclovir may be necessary if varicella develops with severe T-cell defect.
- Most patients with CD4+ cell counts >500 cells/mm3 can be safely and effectively vaccinated with live viral vaccines.
Issue for Referral
- Depending on the features the child manifests, issues may need consultation and/or follow-up:
- Infant stimulation; educational consultant
- Speech and cognitive intervention for speech and language delays
- Palate team, otolaryngology
- Developmental pediatrics
- Child psychiatry
- Cardiology to define aortic arch anatomy (side and branching pattern); monitoring for aortic root dilation
- Gastroenterology/feeding team
- Immunology to monitor T-cell disorder, recurrent infections, allergy, autoimmune disease
- Severe immunodeficiency may require bone marrow transplant or thymic transplant.
- Special consideration with surgery/obstetrics/acute injury
- Risk of hypocalcemia with biologic stress
- Increased risk of any complication
- Monitor growth and development.
- Monitor hearing.
- Monitor for emerging endocrine, psychiatric, autoimmune, skeletal, obesity, and other disorders.
- Cardiac monitoring for aortic root dilation
- Genetic and reproductive counseling for adolescents and at transition to adult care
- Most patients survive childhood. Exceptions include those with severe congenital cardiac anomalies, severe immunodeficiency, other major anomalies.
- Associated conditions that arise through development and into adulthood include an increased risk for treatable psychiatric illness (anxiety disorders and psychotic disorders; ~1 in 4 develop schizophrenia).
- Other later onset conditions include autoimmune diseases and neurologic sequelae, including seizure disorder, movement disorders, early-onset Parkinson disease.
- Functioning in adults is correlated most highly with the degree of intellectual deficit and to a lesser degree with severe psychiatric illness.
- Age at death of adults is on average several decades younger than population expectations.
- In the newborn period, patients may present with hypocalcemic tetany/seizures, manifestation of cardiac abnormality, nasal regurgitation, GERD, dysphagia, and/or recurrent infections.
- In childhood and adolescence, patients present more commonly with speech, neurologic, developmental and/or behavioral issues, endocrine disorders, and/or psychiatric illness.
- Patients are at increased risk for developing multiple later onset conditions, including autoimmune disease, obesity, and psychiatric illness.
- Al-Sukaiti N, Reid B, Lavi S, et al. Safety and efficacy of measles, mumps, and rubella vaccine in patients with DiGeorge syndrome. J Allergy Clin Immunol. 2010;126(4):868–869. [PMID:20810153]
- Bassett AS, Chow EW, Husted J, et al. Premature death in adults with 22q11.2 deletion syndrome. J Med Genet. 2009;46(5):324–330. [PMID:19246480]
- Bassett AS, McDonald-McGinn DM, Devriendt K, et al; and International 22q11.2 Deletion Syndrome Consortium. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr. 2011;159(2):332–339.e1. [PMID:21570089]
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- Repetto GM, Guzmán ML, Delgado I, et al. Case fatality rate and associated factors in patients with 22q11 microdeletion syndrome: a retrospective cohort study. BMJ Open. 2014;4(11):e005041. [PMID:25377008]
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- 758.32 Velo-cardio-facial syndrome
- 279.11 Digeorge’s syndrome
- Q93.81 Velo-cardio-facial syndrome
- D82.1 Di George’s syndrome
- 460436001 22q11 microdeletion with complete DiGeorge sequence (disorder)
- 77128003 DiGeorge sequence
- 83092002 Shprintzen syndrome (disorder)
- Q: Can patients have severe intellectual impairments?
- A: They can but relatively rarely. Most patients with 22q11.2 deletion syndrome have IQs in the borderline range, about 30% fall in the mild intellectual deficit range; a minority are in the average range. A minority fall in the moderate to severe intellectual deficit range. Some children have a >10 point split between their verbal and performance IQ, and thus, the full-scale IQ may not reflect the true functional potential. Over development in childhood, the IQ tends to decline. Most patients have particular difficulties in the areas of arithmetic, auditory working memory, and executive functioning such as social judgment. Cognitive remediation should be tailored to the individual’s relative strengths and weaknesses.
- Q: How often are 22q11.2 deletions found in the general (unaffected) population?
- A: The penetrance of any individual associated clinical feature, when considering the multisystem nature of 22q11.2DS, is very high, approaching 100%. The typical 22q11.2 deletion is almost never found in control populations.
Anne S. Bassett, MD, FRCPC
Donna M. McDonald-McGinn, MS, LCGC
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