AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

The syndrome now understood to be the chromosome 22q11.2 deletion syndrome was originally described as 3 syndromes found on 2 continents. DiGeorge described the first of these, DiGeorge syndrome (DGS), in 1965. However, the description was not published until 1968, 2 years after the syndrome was named for him. The terms DGS, DiGeorge association (DGA), and DiGeorge sequence are often used interchangeably.

DiGeorge was the first to provide clinical examples in humans that demonstrated the thymus was involved in immune function, lending credence to the then new theory that the immune system was composed of 2 distinct elements: the humoral (B-cell) element and the cell-mediated (T-cell) element. He described the cases of 4 infants with thymic hypoplasia, hypoparathyroidism, and recurrent infection. Eventually, this triad of findings expanded until DGS came to include congenital cardiac anomalies, craniofacial dysmorphology, and learning dysfunction, all of which were traced to a defect in the third and fourth pharyngeal pouches during embryogenesis.

Approximately 10 years later, in Japan, Kinouchi et al described the conotruncal anomalies face (CTAF) syndrome, composed of congenital conotruncal cardiac anomalies, characteristic facies, learning dysfunction, and developmental delay.¹ Shprintzen and colleagues in 1978 described their experiences in a craniofacial clinic with a syndrome of congenital conotruncal cardiac anomalies, characteristic facies, velopharyngeal dysfunction with or without cleft palate, and learning dysfunction, which they termed the velocardiofacial syndrome (VCFS).²

Two factors prompted the discovery of a common genetic link between these supposedly distinct phenotypes. The first came from a comparison of DGS with VCFS. The children whom DiGeorge described all presented (and died) in infancy, whereas those with VCFS presented at an older age. As understanding of DGS improved, care of affected children improved as well. Many children with DGS who survived into the second decade of life, and some with partial DGS, clearly resembled older patients with VCFS. The theory arose that children with VCFS may have a form of DGS without the immune dysfunction common in the diagnosis of DGA in infancy.

Genetic support for this came in 1981, when de la Chapelle et al reported a family with carriers of a balanced chromosome translocation t(20;22)(q11;q11) and some with an unbalanced karyotype resulting in monosomy 22q11 and phenotypic features of DGA.³ Based on this finding and the phenotypic similarity between DGS and VCFS, similar genetic studies were performed on individuals with DGS, VCFS, and CTAF.

A common area of a microdeletion, known as the DGS critical region (DGCR), was found on chromosome 22 at band 22q11.2. As a result, these 3 syndromes were combined into one genetic entity with variable phenotypes. Some have used the name CATCH 22 for this group because it describes the findings of cardiac anomalies, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia on chromosome 22; however, given its literary connotation of a no-win situation, this terminology should be avoided. Chromosome 22q11.2 deletion syndrome should be the designation of these 3 overlapping conditions.

In 1955, Sedlácková described a syndrome of congenitally shortened velum accompanied by hypernasal speech, facial dysmorphisms, and further anomalies, as well as mental retardation.^{4, 5} In the following years, she also reported on cardiac malformations and submucous clefts. This report, which predated DiGeorge's report, has received little attention but is consistent with DGS.

Pathophysiology

As the name implies, this syndrome is the result of a 2-3 million base pair (Mb) deletion on the long arm of chromosome 22. This area is prone to a microdeletion because of the presence of nonallelic, flanking, low-copy repeat DNA sequences in the region, which lead to unequal crossing over between the two chromosome 22s during meiosis. Deletion of one critical gene or several contiguous genes is thought to be the basis of this syndrome. Although several genes in this area have been mapped, which genes must be deleted to cause this syndrome remains unknown. Some patients have a chromosomal rearrangement involving chromosome 22.⁶

Mutations in the TBX1 gene in individuals with the phenotype of DGS but without the 22q11.2 microdeletion have been found, indicating this is a critical gene. Several gene products from within the deleted region have been identified and are being further characterized. The result of this deletion is a developmental field defect involving the third and fourth pharyngeal pouches caused by defective migration of the neural crest cells during the fourth week of embryogenesis. Portions of the heart, head and neck, thymus, and parathyroids derive from these pouches.

Frequency

United States

Estimates of the incidence of chromosome 22q11.2 deletion syndrome range from 1 per 2000-4000 in the general population. It is a frequent cause of cleft palate and congenital heart defects.

International

The incidence of chromosome 22q11 deletion syndrome is the same internationally as it is in the United States.

Mortality/Morbidity

The cardiac aspects of the deletion syndrome lead to the greatest morbidity and mortality. Cardiac defects are observed in 74-80% of affected patients. Only a small fraction of patients experience severe recurrent infection secondary to T cell immunodeficiency due to severe thymic hypoplasia. Failure to thrive may be observed during early infancy in those with cleft palates and swallowing difficulties. Long-term complications may include learning disabilities, mild mental retardation, and psychiatric disorders.^{7, 8}

Race

No racial or ethnic predisposition has been identified.

Sex

Males and females appear to be equally affected.

Age

This is a congenital condition, but age at diagnosis largely depends on the severity and nature of the defect. Thus, those with more serious cardiac defects, hypocalcemia, or both observed in classic DGS are diagnosed in the neonatal period. Recurrent infections usually present in patients older than 3-6 months. Some individuals without hypocalcemia who have normal immune function, mild cardiac defects, and minimal facial anomalies may not be diagnosed until late childhood. Late diagnosis into adulthood continues to be reported. Diagnosis in fetuses with a congenital heart anomaly should be offered to the pregnant woman.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

The most common reason to suspect chromosome 22q11.2 deletion syndrome is a cardiac anomaly, especially a conotruncal one. Neonatal hypocalcemia should also raise suspicion for this syndrome, especially if the hypocalcemia or heart defect is coupled with cleft palate, which is frequently observed in affected individuals. The characteristic facies of this syndrome are often subtle in infancy and not fully manifested until the child is older; therefore, they are not common causes of genetic investigation. The same is true of developmental delays, which often go unnoticed until the child reaches school age. The facial features are often absent in people of African or other nonwhite descent. Abnormalities of every organ system have been reported, although, individually are rare. These abnormalities may include the following:

• Cardiac defects are observed in 74-80% of patients. A higher incidence is noted in cases diagnosed during infancy because of the symptomatic nature of the heart lesion.
• • Any conotruncal heart defect can occur. In infancy, tetralogy of Fallot, truncus arteriosus, and interrupted aortic arch are more common; ventricular septal defect (VSD), pulmonary atresia plus VSD, and other conotruncal defects are seen in cases diagnosed after age 2 years.
  • Rare cardiac anomalies include vascular ring anomaly, transposition of great arteries with VSD, coarctation of the aorta, atrial septal defect (ASD), pulmonary stenosis, hypoplastic left heart, and patent ductus arteriosus.
  • Some patients have vascular anomalies, and those who need pharyngeal surgery should be specifically checked for anomalies of the carotid arteries.
• Patients usually have characteristic facies, which become more pronounced as the children grow into the second decade. These are often recognized in white children and consist of a high and broad nasal bridge, long face, narrow palpebral fissures, and micrognathia. Microcephaly and asymmetric crying face may be present.
• • The most common malformation in this region is cleft of secondary palate. Submucous cleft palate or velopharyngeal incompetence (VPI) without a cleft may be present. Approximately 70% of patients have VPI.
  • Poor sucking and nasal regurgitation due to VPI may be present.
  • The swallowing problem usually resolves by the end of the first year, leaving the child with hypernasal speech as the major remaining manifestation.
  • Recurrent episodes of otitis media may be observed. Conductive or sensorineural hearing loss (or both) may be present.
• Recurrent infections secondary to immune deficiency may be observed.
• • The characteristic immunodeficiency is a mild-to-moderate defect in T-cell lineage as a consequence of thymic hypoplasia. Naïve T-cell production is usually reduced. Only a small fraction of patients present with marked impairment of T-cell function associated with complete absence of thymus and T cells and severe systemic infections consistent with severe combined immunodeficiency (SCID) phenotype. T-cell functions and numbers that improve with age may be attributed to homeostatic T-cell proliferation secondary to limited T-cell production.
  • Variable secondary humoral defects, including hypogammaglobulinemia and selective antibody deficiency, may be present.
  • Impaired T-cell production may predispose patients with 22q11.2 deletion to autoimmune diseases. In a cohort of 195 patients with chromosome 22q11.2 deletion syndrome, various autoimmune diseases, including juvenile rheumatoid arthritis (JRA), idiopathic thrombocytopenic purpura (ITP), and autoimmune hemolytic anemia (AHA), were each more prevalent than in the age-matched general population.⁹ No specific pattern of autoimmune diseases appears to be associated with 22q11.2 deletion.
• Hypocalcemia due to hypoparathyroidism can cause seizures. The incidence of hypocalcemia varies widely, from 17-60%. This is frequently a self-limiting problem, and approximately one half of these children are no longer receiving calcium supplementation by age 1 year.
• Developmental delay and learning difficulties are observed in 70-90% of patients.
• • In infancy, developmental milestones are achieved later than expected for age. Delayed language acquisition is often seen in older children.
  • A frequent pattern of disability is observed in these children, consisting of a low performance intelligence quotient (IQ) compared with verbal IQ, which creates problems with nonverbal learning, abstract reasoning, and math. In school-aged children, full-scale IQ scores can range from average to low average to mild mental retardation. The incidence of mild mental retardation is approximately 30%.
• Various behavioral abnormalities, including attention deficit disorder, shyness, disinhibition, and autism spectrum disorders, have been reported. The incidence of psychoses such as depression, bipolar disorders, schizophrenia, and anxiety is increased, and some report their prevalence to be about 10%.
• kidney and renal pelvis duplications can occur.

Physical

Physical examination findings vary depending on the organ systems involved.

• Patients usually have characteristic facies, which become more pronounced as the child grows into the second decade. These are more commonly and easily recognized in white children. Retrognathia or micrognathia, long face, high and broad nasal bridge, and narrow palpebral fissures are common features.
• • The most common malformation in this region is cleft of the secondary palate. VPI without a cleft palate can occur. Cleft lip, cleft palate, or both may be present.
  • Other frequent facial features include small teeth, asymmetric crying face, and down-turned mouth.
• Cardiac findings may be present, depending on the nature of the cardiac lesion.
• Long tapering fingers may be present.

Causes

Occurrence is sporadic in 85% of cases. Approximately 7% of cases are inherited as dominant, and less than 1% of cases are due to chromosomal rearrangements. The hereditary cases show no predilection in inheritance from the mother or the father. An affected person has a 50% chance of transmitting the condition to his or her child. Wide intrafamily and interfamily variations in clinical manifestations are seen

Remember that not all patients with DiGeorge syndrome (DGS) have the 21q11.2 deletion. Patients with other chromosomal anomalies, such as those with deletion of chromosome 10p or 17p, infants of mothers with diabetes, and patients with fetal alcohol syndrome, may show signs of DGS. Chromosome 10p13-p14 deletion is often referred to as DGS2.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

CTAF syndrome
Caylor syndrome
Alagille syndrome
Vertebral anomalies, anal atresia, cardiac defect, tracheoesophageal fistula, renal abnormalities, limb abnormalities (VACTERL) association
Goldenhar syndrome
CHARGE syndrome

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Perform fluorescent in situ hybridization (FISH) to detect the 22q11.2 deletion. Standard chromosome analysis should be performed concurrently to look for rearrangements and other chromosomal abnormalities.
• A few individuals with findings of the 22q11.2 deletion syndrome have normal routine cytogenetic study findings and no deletion on FISH testing findings using the commercially available probes. In these patients, array comparative genomic hybridization (aCGH) and TBX1 gene sequencing should be considered in consultation with a clinical geneticist.
• Perform an absolute lymphocyte count in the peripheral blood. If lymphopenia is present, consult an immunologist and obtain T-cell and B-cell counts.
• Measure ionized serum calcium levels to evaluate parathyroid function. If the levels are low, obtain simultaneous ionized serum calcium and parathyroid hormone levels. Consult an endocrinologist as well.

Imaging Studies

• Cardiac: Perform chest radiography and other imaging studies based on the cardiologist's recommendations.
• Thymus: Chest radiography can reveal a decreased thymic silhouette but are unreliable. MRI is slightly better; however, thymic size evaluation is not recommended because it is a poor predictor of immune function.
• Head and neck: Magnetic resonance angiography (MRA) or conventional angiography is necessary before performing neck surgery to identify abnormalities of the internal carotid arteries.

Procedures

• Cardiac catheterization studies are performed as needed to assess cardiac anatomy.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

A multidisciplinary team best cares for these individuals; however, one physician (usually the primary physician) needs to take the lead. The primary physician must monitor growth and development. A system-by-system approach gives the best results.

• Cardiac: Consult cardiologist as needed.
• Immunologist: Consult an immunologist if absolute lymphopenia is present. Follow the immunologist's recommendations for immunizations. Recent reports indicate that patients with DiGeorge syndrome (DGS) who are clinically stable can safely tolerate live vaccines, including the measles, mumps, and rubella (MMR) and varicella vaccine.
• Endocrine: If the patient is found to be hypocalcemic, begin calcium supplementation after proper tests (simultaneous serum calcium and serum parathyroid hormone levels) are obtained. Vitamin D supplementation may become necessary.
• Failure to thrive: Feeding difficulties and failure to thrive are common in these patients, especially in those with significant cleft palates. Occasionally, placement of a nasogastric or gastrostomy tube is necessary for feeding during the first 6-12 months of life. The tube provides adequate nutrition to prevent serious growth failure.
• Other problems: Patients with other conditions, including developmental delay and psychosis, should receive appropriate care.

Surgical Care

• Cardiac: Surgical repair is often necessary to correct the frequently observed cardiac defects.
• Head and neck: As patients with chromosome 22q11.2 deletion syndrome grow older, correction of hypernasal speech becomes important; this can be performed initially with speech therapy but surgery may be required. Consult a plastic surgeon experienced in treating velopharyngeal incompetence (VPI). Adenoidectomy may worsen the VPI.

Consultations

Multidisciplinary follow-up care is usually necessary to ensure that these patients receive optimal medical care; the following specialists can be consulted:

• Geneticist for initial evaluation and genetic counseling: Periodic follow-up consultations are recommended to apprise the family of new developments, to reinforce the counseling and recurrence risk assessment, and to direct the family to resources in the community.
• Pediatric cardiologist for evaluation and management of cardiac disease
• Pediatric cardiothoracic surgeons when patient requires cardiac surgery
• Craniofacial specialist for treatment of patients with cleft palate and feeding difficulties
• Otolaryngologist when recurrent otitis media occurs
• Immunologist for evaluation of immune function
• Pediatric endocrinologist for evaluation and management of hypocalcemia
• Psychologist and other specialists based on the organ system involved

Diet

No special diet is indicated. Tube feeding may be indicated when feeding problems are severe.

Activity

Activity restrictions depend on the nature and severity of the cardiac defect.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medications are useful only when hypocalcemia or immune deficiency is present. Treat patients with severely impaired T-cell function or profound lymphopenia prophylactically with trimethoprim/sulfamethoxazole, as directed by the immunologist. Calcium supplementation is necessary in those with hypocalcemia. In rare cases in which calcium supplementation may not suffice, vitamin D may also be administered. In patients with primary immune deficiencies, an immunologist should decide whether to initiate replacement therapy with intravenous immunoglobulin.

Drug Category: Antibiotics

These agents are used prophylactically in patients with immunodeficiency.

Drug Category: Vitamin and mineral supplements

Hypocalcemia may occur, requiring supplementation with calcium. In patients with symptoms refractory to calcium, supplementation with a vitamin D analog may also be necessary.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Deterrence/Prevention

• Evaluation by a clinical geneticist and genetic counseling is recommended prior to making family-planning decisions.

Prognosis

• Prognosis in DiGeorge syndrome (DGS) widely varies. It largely depends on the nature and degree of involvement of different organs. Many adults live long, productive lives.

Patient Education

• Given the frequent learning disabilities observed in these children, they should undergo early developmental assessment and be enrolled in an early education program to help offset the expected educational delays. Such interventions have proven effective both academically and socially.
• The families of patients with clinically significant immunodeficiency should be educated regarding the potential complication from exposure to live attenuated poliovirus vaccine, MMR vaccine, and chicken pox vaccine.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Failure to recognize the chromosome 22q11.2 deletion syndrome may lead to lack of or delayed care for people with many organ system involvement and, occasionally, permanent sequelae.
• Failure to provide genetic counseling may lead to the family/patient remaining uninformed regarding recurrence risks and reproductive options.

Special Concerns

Patients' families often feel alone when this diagnosis is made. Because of its rarity, most parents have not heard of the syndrome, nor do they know anyone who has it to whom they can turn for comfort. Support groups and other resources are an invaluable help in this regard. The following are examples of support groups and resources that are available:

• The International 22q11.2 Deletion Syndrome Foundation, Inc.
  1874 E. Route 70, Suite 3
  Cherry Hill, NJ 08003
  Phone: 877-739-1849
  Email: mabissi@22q.org
• International DiGeorge/VCF Support Networkc/o Family Voices of New York
  46 1/2 Clinton Avenue
  Cortland, NY 13045
  Phone: 607-753-1621 (day); 607-753-1250 (night)
  Fax: 607-758-7420
• Max Appeal
  Lansdowne House
  13 Meriden Avenue
  Wollaston, Stourbridge
  West Midlands
  DY8 4QN
  UK phone: 0800-389-1049
  Email: info@maxappeal.org.uk
• National Library of Medicine Genetics Home Reference, 22q11.2 deletion syndrome
• NCBI Genes and Disease, DiGeorge syndrome
• Velo-Cardio-Facial Syndrome Education Foundation
  PO Box 874
  Milltown, NJ 08850
  Phone: 866-VCFSEF5 (866-823-7335); 732-238-8803
  Email: info@vcfsed.org
• Chromosome 22 Central
  237 Kent Avenue
  Timmins, ON
  Canada P4N 3C2
  Phone: 705-268-3099
  Email: a815@c22c.org
• Chromosome Deletion Outreach, Inc
  PO Box 724
  Boca Raton, FL 33429-0724
  Phone: 888-CDO-6880 (888-236-6680); 561-395-4252 (family helpline)
  Email: info@chromodisorder.org

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Daniel AC Frattarelli, MD, FAAP, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Oct 29, 2008