Basics
Description
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.
- Rarely ( ≤1%), neonates have a severe T-cell immunodeficiency.
- Learning disabilities are usually borderline; rarely severe
- Treatable psychiatric illness is common.
Epidemiology
Prevalence is estimated at up to 1 in 2,000 live births.
Risk Factors
Genetics
- Associated hemizygous microdeletion of 22q11.2
- Up to 10% of newly diagnosed cases are inherited.
- 50% recurrence risk at each pregnancy for affected individuals
Pathophysiology
A developmental defect of the 3rd and 4th pharyngeal arches may be part of the mechanism.
Diagnosis
History
- The syndrome is underrecognized at all ages; thus, an index of suspicion is needed for any child with multisystem features.
- Neonatal and late-onset hypocalcemia may be present secondary to hypoparathyroidism in up to 60% of cases.
- Congenital anomalies of any organ system, classically cardiac defects, particularly 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, especially speech
- Seizures
- Anxiety, OCD and attention-deficit disorder, schizophrenia
Physical Exam
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
- Cognitive/behavioral disorders
- Hypernasal speech
- 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 & Interpretation
Lab
- Genome-wide microarray, 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)
- TSH
- Newborns
- Age 9 " 12 months (before live vaccines)
- Flow cytometry
- Immunoglobulins
- T-cell function
Imaging
- Echocardiogram
- Renal ultrasound
- Cervical spine radiographs
- Other, as indicated by history and signs
Other
- Audiology assessment
- Opthalmology assesment
Treatment
Additional Therapies
General Measures
- Cardiac monitoring for aortic root dilation
- Vitamin D supplements (those with hypocalcemia will likely need 1,25-D supplementation and calcium supplements)
- Standard treatments are generally effective for each associated feature.
- Depending on the features, the child manifests, issues may need consultation and/or follow-up:
- Neurology
- Cardiology to define aortic arch anatomy (side and branching pattern)
- Palate team, otolaryngology
- Gastroenterology/feeding team
- Endocrinology
- Infant stimulation; educational consultant
- Speech and cognitive intervention for speech and language delays
- Child psychiatry
- Dentistry
- Immunology to monitor T-cell disorder, recurrent infections, allergy, autoimmune disease
- Severe immunodeficiency may require matched sibling bone marrow transplant or thymic transplant.
- Special consideration with surgery/obstetrics/acute injury
- Risk of hypocalcemia with biologic stress
- Special consideration for infants:
- Initially withhold live vaccines.
- Cytomegalovirus-negative irradiated blood products
- Influenza vaccinations
- Respiratory syncytial virus prophylaxis.
- Avoid live viral vaccines in cases of severe T-cell dysfunction. These patients may need immunoglobulin replacement therapy to protect from infections.
- Most patients with CD4+ cell counts >500 cells/mm3 can be safely and effectively vaccinated with live viral vaccines.
- Consider varicella 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 and patient has severe T-cell defect.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Cardiac monitoring for aortic root dilation
- Monitor growth and development.
- Monitor hearing.
- Monitor for emerging endocrine, psychiatric, autoimmune, skeletal, and other disorders.
- Genetic and reproductive counseling for adolescents and at transition to adult care
Prognosis
- Most patients survive childhood. Exceptions include those with severe congenital cardiac anomalies or severe immunodeficiency.
- Associated conditions that arise through development and into adulthood include an increased risk for treatable psychiatric illness (e.g., about 1 in 4 develop schizophrenia), autoimmune phenomena, and neurologic sequelae.
- Functioning in adults is correlated most highly with the degree of intellectual deficit and to a lesser degree with severe psychiatric illness. Mortality in adults is elevated compared to unaffected siblings.
Complications
- In the newborn period, patients may present with hypocalcemic tetany/seizures, manifestation of cardiac abnormality, nasal regurgitation, GERD, dysphagia, and recurrent infections.
- Later on, patients present more commonly with speech, neurologic, developmental, and/or behavioral issues.
- Patients are at increased risk for developing multiple later onset conditions, including autoimmune disease, obesity, and psychiatric illness.
Additional Reading
- 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. [View Abstract]
- 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. [View Abstract]
- Bassett AS, McDonald-McGinn DM, Devriendt K, International 22q11.2 Deletion Syndrome Consortium. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr. 2011;159(2):332.e1 " 339.e1. [View Abstract]
- Butcher NJ, Chow EW, Costain G, et al. Functional outcomes of adults with 22q11.2 deletion syndrome. Genet Med. 2012;14(10):836 " 843. [View Abstract]
- Carotti A, Digilio MC, Piacentini G, et al. Cardiac defects and results of cardiac surgery in 22q11.2 deletion syndrome. Dev Disabil Res Rev. 2008;14(1):35 " 42. [View Abstract]
- Fung W, Butcher N, Costain G, et al. Practical guidelines for managing adults with 22q11.2 deletion syndrome [published online ahead of print January 8, 2015]. Genet Med.
- Habel A, McGinn MJ II, Zackai EH, et al. Syndrome-specific growth charts for 22q11.2 deletion syndrome in Caucasian children. Am J Med Genet A. 2012;158A(11):2665 " 2671. [View Abstract]
- McDonald R, Dodgen A, Goyal S, et al. Impact of 22q11.2 deletion on the postoperative course of children after cardiac surgery. Pediatr Cardiol. 2013;34(2):341 " 347. [View Abstract]
- McDonald-McGinn DM, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine. 2011;90(1):1 " 18. [View Abstract]
- McLean-Tooke A, Barge D, Spickett GP, et al. Immunologic defects in 22q11.2 deletion syndrome. J Allergy Clin Immunol. 2008;122(2):362 " 367. [View Abstract]
- Repetto GM, Guzm ¡n ML, Puga A, et al. Clinical features of chromosome 22q11.2 microdeletion syndrome in 208 Chilean patients. Clin Genet. 2009;76(5):465 " 470. [View Abstract]
- Adult Guidelines Paper Practical guidelines for managing adults with 22q11.2 deletion syndrome. Fung W, Butcher, Costain, Andrade, Boot E, Chow E, Chung B, Cytrynbaum, Faghfoury, Fishman L, Garc a-Mi ±a ºr, George S, Lang A, Repetto G, Shugar, Silversides, Swillen, van Amelsvoort, McDonald-McGinn D, Bassett. (2015). Genetics in Medicine.
Codes
ICD09
- 758.32 Velo-cardio-facial syndrome
- 279.11 Digeorge 's syndrome
ICD10
- Q93.81 Velo-cardio-facial syndrome
- D82.1 Di George 's syndrome
SNOMED
- 460436001 22q11 microdeletion with complete DiGeorge sequence (disorder)
- 77128003 DiGeorge sequence
- 83092002 Shprintzen syndrome (disorder)
FAQ
- Q: Can patients have severe intellectual impairments?
- A: 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, and a small minority fall in the moderate to severe intellectual deficit range. Many 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; cognitive remediation should be tailored to the individual 's relative strengths and weaknesses.