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22q11.2 Deletion Syndrome (Digeorge Syndrome, Velocardiofacial Syndrome), Pediatric

Basics

Description

- 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.

- 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 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.

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 humansParents also require testing for the deletion.
  • CBC with differential
  • Calcium and parathyroid hormone (PTH)
  • TSH
  • Newborns
  • Age 9 " 12 months (before live vaccines)Flow cytometryImmunoglobulinsT-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:NeurologyCardiology to define aortic arch anatomy (side and branching pattern)Palate team, otolaryngologyGastroenterology/feeding teamEndocrinologyInfant stimulation; educational consultantSpeech and cognitive intervention for speech and language delaysChild psychiatryDentistryImmunology to monitor T-cell disorder, recurrent infections, allergy, autoimmune diseaseSevere immunodeficiency may require matched sibling bone marrow transplant or thymic transplant.
  • Special consideration with surgery/obstetrics/acute injuryRisk of hypocalcemia with biologic stress
  • Special consideration for infants:Initially withhold live vaccines.Cytomegalovirus-negative irradiated blood productsInfluenza vaccinationsRespiratory 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.