Are You Confident of the Diagnosis?

Characteristic findings on physical examination

Deletion 22q11.2 is associated with a wide range of clinical findings. Congenital heart disease occurs in 76% of patients and primarily involves conotruncal malformations, such as tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus. Characteristic facial features include angular facies; small, posteriorly rotated ears with abnormal pinnae; and palatal abnormalities, such as a cleft of palate and submucosal cleft palate (Figure 1, Figure 2, Figure 3, Figure 4). Velopharyngeal incompetence may be the only clinical presentation. Learning difficulties occur in more than 90 percent of affected individuals. The original designation, DiGeorge syndrome, characterized individuals with developmental impairment, congenital heart disease, craniofacial and palatal abnormalities, immunodeficiency, and hypocalcemia.

Figure 1.

Neonate with facial dysmorhism, contruncal malformation, and thymic aplasia.

Figure 2.

Neonate with facial dysmorphism, contrucal malformation, and thymic aplasia.

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Figure 3.

Child with developmental delay, velopharyngealincompetance, ventricular and short stature, and septal defect.

Figure 4.

Child with developmental delay, velopharyngeal incompetance, ventricular and short stature, and septal defect.

Any child with congenital heart disease, particularly conotruncal malformation, should be considered a candidate for deletion 22q11.2 screening, regardless of other initial phenotypic findings. Frequent clinical findings in 22q11.2 are summarized in Table I.

Table I.
Feature Frequency
Developmental delay >90%
Congenital heart disease 76%
Palatal defects 76%
Immunodeficiency 77%
Hypocalcemia 49%
Renal anomalies 36%
Dysphagia 35%
Polyhydramnios 16%
Polydactyly 4%
Congenital diaphragmatic hernia 1%

Source: McDonald-McGinn, Kohut and Zackai

Diagnosis confirmation

Deletion 22q11.2 is diagnosed by fluorescent in situ hybridization (FISH) using a DNA probe from the DiGeorge chromosomal region. More than 95 percent of individuals with the deletion have a normal routine chromosomal analysis. Negative FISH testing does not rule out deletion 22q11.2 syndrome because there may be other mutations in the T-box transcription factor (TBX1) gene that are associated with multiple congenital abnormalities.

Who is at Risk for Developing this Disease?

The simplicity of FISH testing supports the screening of all newborns with complex congenital heart defects, whether they have associated craniofacial or other systemic malformations or not.

One parent of 6 percent of affected individuals has the same deletion. The parent may have no congenital malformations or other features to suggest the diagnosis of deletion 22q11.2.

Deletion 22q11.2 is inherited as a dominant trait. Each child of an individual with this deletion has a 50 percent chance of inheriting the trait. The clinical expression in individuals with this deletion in a given family may vary greatly. There is limited genotype-phenotype correlation within the family. Facial features of an affected child include a prominent frontal area,downturning of the palpebral fissures, an angular lower face, and small, cup-shaped ears with folded helices (see Figure 1, Figure 2, Figure 3, Figure 4). Patients of African descent are less likely to have typical faces than are other patients.

What is the Cause of the Disease?

The majority of individuals with phenotypic features of DiGeorge syndrome have a mirror-deletion on chromosome 22q112, which is typically detected by FISH testing. The remaining 5% have a smaller, atypical 22111.2 deletion or some other chomosomal rearrangement in this region, detectable only by microarray analysis. Mutations in the TBX1 gene are detected only by sequence analysis.


The critical chromosomal region involves a large portion of the long-arm of chromosome 22. The region contains 30-40 genes, all of which appear to have regulatory functions. These genes are responsible for DNA-binding proteins and a variety of regulatory functions that affect cell differentiation and migration. These genes appear to have a specific effect on branchial arches 2 through 4, which are regions predetermined for craniofacial development, heart structure differentiation, and thymus development. These genes also affect central nervous system development in that learning difficulties are common.

Systemic Implications and Complications

Deletion 22q11.2 affects multiple systems. Heart defects occur in 76 percent of patients. Major heart defects, including tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, truncus arteriosus, vascular rings, and other more common heart defects, may be present. Hypoplastic left heart has been reported, and bicuspid aortic valve is not uncommon. Heterotaxy, atrial ventricular canal, and interrupted aortic arch may occur in tandem.

Craniofacial findings include ear abnormalities with a hypoplastic nasal bridge and a bulbous nasal tip. Patients have been described as having a long face and malar flatness, but this condition is variable and is not considered to be diagnostic. Velopharyngeal incompetence occurs in approximately 25 percent of patients. Submucous cleft palate occurs in 15 percent of patients and should be considered with bifid uvula. Cleft palate occurs in 10-15 percent of patients.Complete cleft lip/cleft palate occurs in a smaller percentage of patients.

Feeding difficulties are common occurring in over half of patients, independent of palatal anomalies. Gastroesophageal reflux and intestinal dysmotility may be sufficiently severe to require nasogastric tube feeding or, eventually, gastrostomy tube placement.

Ocular abnormalities include bilateral epicanthal folds, hooded lids, ptosis, iris cysts, posterior embryotoxin, and tortuous retinal vessels.Optic nerves may be small. Strabismus occurs in 10-15 percent of patients. Astigmatism, myopia, and hyperopia occur with the same frequency as in the general population. Cataracts and coloboma are uncommon.

Immune dysfunction occurs in 75 percent of individuals, who may also show decreased T-lymphocytes and a small to absent thymus on chest radiogragh. Immune function to assess T-cell numbers is part of the initial evaluation. Over half of patients have some degree of immunodeficiency, but there may be little clinical consequence .

Idiopathic thrombocytopenia has been reported and will be detected on routine complete blood counts, which are warranted annually.

Up to half of the affected individuals will have hypocalcemia at some point during childhood or later life. Calcium homeostasis normalizes with age, but it may recur in later childhood and adulthood.

Developmental abnormalities are common. Many infants present with generalized hypotonia and delayed milestones. There are psychological consequences with the reduction of full-scale intelligence quotient. As affected children grow into adulthood, there is an increased frequency of schizophrenia, bipolar disorder, and depression.

Seizures may occur but are not typical in the absence of hypocalcemia.

The height of about half of affected children track at or below the 5th percentile. Growth hormone deficiency presents as short stature and is screened for with assessment of bone age, insulin-like growth factor, insulin-like growth factor binding protein 3, and growth hormone stimulation study, if indicated.

Hypothyroidism is uncommon, but screening is part of the work-up for short stature.

Renal anomalies occur in a third of patients. Small kidneys, horseshoe kidney, single kidney, and duplicated collecting systems have been reported.

Musculoskeletal anomalies include pre- and post-axial polydactyly, clubbed foot, and syndactyly of toes 2 and 3. Vertebral anomalies include hemivertebra, butterfly vertebrae, and coronal clefts. Supernumerary or absent ribs occur in 20 percent of affected individuals. Atlantoaxial instability has become increasingly recognized.

Treatment Options

Treatment is directed to the specific systemic abnormalities as it would be addressed in any affected individual with similar abnormalities. Medical treatment requires calcium supplements for hypocalcemia. Infections are treated aggressively in those with immunodeficiency. Rarely, intravenous immune globulin or prophylactic antibiotics are required.

Congenital heart defects and palate malformations require surgical correction. Feeding difficulties may require gastric tube placement. In cases of complete thymus aplasia, thymus transplantation may be an option.

Developmental disabilities are common. Many children require speech, physical, and occupational therapies.

Optimal Therapeutic Approach for this Disease

Individuals with deletion 22q11.2 should be evaluated and followed by a multidisciplinary team of genetics, cardiology, child development, immunology, neurology, and other learning support systems.

Patient Management

In the neonatal period, detection of a congenital heart defect requires immediate evaluation and, if necessary, intervention. Echocardiogram is essential for all patients with deletion 22q11.2 syndrome.

Assessment of serum calcium concentration and absolute lymphocyte count establishes baseline values for ongoing evaluation. Low serum calcium concentration requires calcium supplementation.

Low absolute lymphocyte count necessitates evaluation of T and B cell subsets and referral to an immunologist. Infants and children with lymphocyte abnormalities should not be immunized with live vaccines (oral polio, MMR). The immune status should be evaluated on an ongoing basis. Those who are immunized should have antibody studies to assess the effectiveness of the immunizations .

Baseline renal ultrasound is recommended because renal anomalies occur in about a third of affected individuals.

Growth failure is not uncommon, and referral to endocrinology is indicated to evaluate the child for growth hormone deficiency and hypothyroidism.

Feeding difficulties are common in the newborn period. Gastroesophageal reflux is common, and gastric motility may affect bowel elimination. Referral to a feeding clinic is indicated.

Early intervention may be indicated at one year or sooner with referral to early intervention for developmental evaluation to provide speech, physical therapy, occupational therapy, and special instruction as needed.

Referral to a cleft lip and palate clinic for assessment of velopharyngeal incompetence is indicated.

Referral to ophthalmology is indicated because of the frequency of ocular abnormalities and to neurology to monitor for symptoms of seizures.

Gastroenterology may be required to treat constipation and to rule out malrotation, Hirschsprung disease, and the vascular ring .

Early detection of laryngotracheoesophageal malformations, congenital diaphragmatic hernia, and other airway-related abnormalities require a high level of awareness.

Atlantoaxial cervical instability has become increasingly recognized, and radiographic screening has been recommended at four years of age, to consist of six views: anterior-posterior, lateral, flexion, extension, open-mouth, and skull. The cervical spine should be evaluated before any intervention that requires hyperextension of the neck, such as intubation.

Unusual Clinical Scenarios to Consider in Patient Management

Before surgery for palatal defect or velopharyngeal incompetence, MRA of the neck is indicated because of the high risk of ectopic internal carotid arteries that would pose a risk for surgery.

What is the Evidence?

McDonald, DM, Kohut, Y, Zackai, EH, Cassidy, B, Allnson, JE. “Deletion 22q11.2 (Velo-Cardio-Facial Syndrome/DiGeorge Syndrome)”. Management of genetic syndromes. 2010. pp. 263-84. (This is the most current comprehensiveover review of deletion 22q11.2 with emphasis on diagnosis, treatment and long-term management. This is a comprehensive summary of the diagnostic criteria, etiology, pathogenesis, and genetics of deletion 22q11 2 syndrome with detailed summaries of the broad spectrum of manifestations associated with this syndrome and the challenges in management of the neonate and the infant, as well as in late childhood and in transition to adult care.)

McDonald-McGinn, DM, Emanual, BS, Zachai, EH, Pagon, RA, Bird, TC, Dolan, CR, Stephens, K. “22q11.2 Deletion Syndrome”. Gene Reviews. (The authors extend their personal experience with deletion 22q11.2 in this seminal summary of their experience with over 200 patients with this deletion and extend information about the molecular genetics of the syndrome.)

Emanuel, BS. “Molecular mechanisms and diagnosis of chromosome 22Q11.2 rearrangements”. Dev Disabil Rev. vol. 14. 2008. pp. 11-18. (Chromosome 22 is involved in a wide range of rearrangements associated with DiGeorge and velocardiofacial syndrome. The author describes the mechanisms responsible for these changes and provides insight into the role of genomicroarrangements in the development of human disease.)

Shprintzen, RJE. “Velo-Cardio-Facial Syndrome: 30 years of study”. Dev Disabil Rev.. vol. 14. 2008. pp. 3-10. (This article provides a historical perspective of deletion 22q11.2, including the evolution of the recognition of the broad range of phenotypic features included in this syndrome and the more recent awareness of the increased risk of psychiatric illness in this condition.)

ODriscoll, MO. “Haploinsufficiency of DNA damage response genes and their potential influence in human genomic disorders”. Current Genomics. vol. 9. 2008. pp. 137-46. (The author reviews heterozygous contiguous gene deletion syndromes, including 22q11.2, from the perspective of the effect of the gain, loss or reorientation of genomic regions in the expression of human genomic disorders, emphasizing the interaction of multiple genes in these regions.)

John, AS, McDonald-McGinn, DM, Zachai, EH, Goldmuntz, E. “Aortic root dilation in patients with 22q11.2 Deletion Syndrome”. Am J Med Genet. Part A. vol. 149A. 2009. pp. 939-42. (Cardiac anomalies are common in deletion 22q11.2 syndrome, and most heart malformations are detected in infancy by echocardiogram. However, cardiovascular abnormalities are not limited to malformations in infancy and childhood, and there is a risk of aortic root dilatation in adults with this syndrome, suggesting the need for continuous healthcare surveillance in the syndrome.)

Kiehl, TR, Chow, EWC, Mikulis, DJ, George, SR, Bassett, AS. “Neuropathologic features in adults with 22q11.2 Deletion Syndrome”. Cerebr Cort. vol. 19. 2009. pp. 153-64. (This article emphasizes the multisystem manifestations of deletion 22 q. 11.2 syndrome, which indicates that microvascular pathology may have a role in the pathogenesis of the neuropsychiatric phenotype of deletion 22q11.2, including white matter abnormalities and schizophrenia.)

Simon, TJ. “A new account of the neurocognitive foundations of impairments in space, time and number processing in children with chromosome 22q11.2 Deletion Syndrome”. Dev Disabil. vol. 14. 2008. pp. 52-58. (Neurocognitive abnormalities in deletion 22q11.2 syndrome are common, and this thoughtful overview attempts to explain the basis for the cognitive processing and nonverbal intellectual impairments experienced by most children with the syndrome.)

Jatana, V, Gillis, J, Webster, BH, Ades, LC. “Deletion 22q11.2 syndrome: Implications for the intensive care physician”. Pediatr Crit Care Med. vol. 8. 2007. pp. 459-63. (The current status of thymus transplantationfor those individuals born without a thymus is summarized by authors experienced in this therapy.)

Markert, ML, Devlin, BH, McCarthy, EA. “Thymus transplantation”. Clin Immunol. vol. 135. 2010. pp. 236-46. (Deletion 22q11.2 presents many challenges for the intensivist, including treating hypocalcemia and associated seizures, recognizing the immune status of the patient, and providing appropriate blood products, such as a radiated red blood cell preparations. The authors summarize their experience with 40 patients admitted to the intensive care unit with the diagnosis of deletion 22q11.2.)