AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

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

INTRODUCTION

Section 2 of 9  

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

Background

DiGeorge anomaly is one of a group of disorders that share a chromosome deletion resulting in monosomy 22q11. These disorders include cardiac defect, abnormal face, thymic hypoplasia, cleft palate, and hypocalcemia (CATCH-22) syndrome^{1, 2}; conotruncal anomaly face syndrome; and DiGeorge anomaly syndrome.

Pathophysiology

This condition is a heterogeneous genodermatosis with deletions of chromosome band 22q11, which result in monosomy 22q11. The clinical syndrome results from a congenital developmental field defect with malformation of the third and fourth pharyngeal pouches. Patients have a variable T-cell deficiency resulting from faulty embryologic development of the thymus and parathyroid glands. A combined T- and B-cell deficiency may result from lack of T-helper cell function. Other features include cardiac abnormalities; parathyroid deficiency; hypocalcemia; characteristic facies; and recurrent infections, especially oral candidiasis.

Although band 22q11.2 deletion is the most common etiology of DiGeorge anomaly, other chromosomal anomalies (namely TBX1 gene mutations³), teratogens, and maternal diabetes have also been implicated. The DiGeorge critical region 6 gene is present in 2 highly homologous copies (DGCR6⁴ and DCGR6L) on band 22q11, and deletions of this gene results in velocardiofacial syndrome/DiGeorge syndrome.

Frequency

United States

DiGeorge syndrome is rare. The 22q11 deletion is estimated to occur in approximately 1 in 4000 live births.

International

DiGeorge syndrome is rare.

Mortality/Morbidity

• Severe cases manifest with severe combined immune deficiency (SCID).
• Death is typically caused by infection during early infancy.

Race

No racial predilection is reported.

Sex

No sex predilection is recognized.

Age

DiGeorge syndrome is congenital.

CLINICAL

Section 3 of 9  

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

History

• Depending on the degree of T-cell dysfunction, infection is the primary problem and leads to early death.
• Endocrinologic problems associated with parathyroid deficiency must be addressed. These include the following:
• • Hypocalcemia (approximately 33% of patients in one study)
  • Chronic diarrhea
  • Nephrocalcinosis
  • Tetany: Neonatal tetany has been reported as a result of hypocalcemia.
• In addition, congenital defects of the heart and major vessels are common and may require early surgical intervention.
• Neuropsychological deficits include impairment in selective and executive visual attention, working memory, and sensorimotor function. Approximately 25% of children will develop schizophrenia in late adolescence or adulthood.

Physical

• Characteristic facial features
• • Short philtrum
  • Low-set malformed ears
  • Hypertelorism
• Other features
• • Micrognathia
  • Bifid uvula
  • Bowed mouth
• Cardiac features
• • Truncus arteriosus
  • Septal defects
  • Abnormal aortic arch vessels (eg, interrupted aortic arch, double aortic arch, aberrant subclavian artery)
• Neurologic features
• • Mental retardation
  • Calcification of the CNS
• Renal features - Nephrocalcinosis
• Ocular findings - Posterior embryotoxon, tortuous retinal vessels, eyelid hooding, strabismus, ptosis, and amblyopia⁵
• Pulmonary features
• • Tracheoesophageal fistula
  • Short trachea with a reduced number of tracheal rings
  • Abnormal thyroid cartilage
  • Laryngomalacia
  • Tracheomalacia
  • Bronchomalacia

Causes

The deletion of chromosomal band 22q11, which results in monosomy 22q11, produces the developmental changes of DiGeorge syndrome.

• Recent estimates suggest that the deletion of band 22q11.2 occurs in approximately 1 in 4000 live births.
• Because the 22q11.2 deletion is present in most patients with the DiGeorge anomaly and a conotruncal anomaly face syndrome, these conditions are probably phenotypic variants of the same disorder.

DIFFERENTIALS

Section 4 of 9  

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

WORKUP

Section 5 of 9  

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

Lab Studies

• Low serum calcium levels may be present. Hypocalcemia may be secondary to hypoparathyroidism.
• The white blood cell count with differential may reveal lymphopenia (ie, T-cell deficiency, not B-cell deficiency, though a combined T-cell and B-cell deficiency may result from lack of T-helper cell function).

Imaging Studies

• Radiography of the head may reveal calcifications in the CNS.
• Radiography of the abdomen depicts nephrocalcinosis.
• CT of the thorax and angiography may show malformations of the heart and great vessels, an interrupted aortic arch, tetralogy of Fallot, and truncus arteriosus.
• An absent thymus or one in an aberrant location may be noted on chest radiographs and CT scans.
• • Despite the emphasis on thymus defects in the literature about DiGeorge anomaly, clinically significant thymus defects are found in less than 5% of the cases.
  • Maldescent of the thymus is extremely common.

Other Tests

• Prenatal diagnostic testing can be offered to couples at risk.⁶
• Indications for testing include a previous child or an affected parent with a 22q11.2 deletion, or the in utero detection of a conotruncal cardiac defect.
• • Fluorescent in situ hybridization (FISH) using commercial probes is the most common technique used to detect the 22q11.2 deletion.⁷
  • Chromosomal breakpoints and deletion size are determined by short tandem repeat tests or further FISH probes.⁷
  • A newer technique, multiplex ligation-dependent probe amplification (MLPA) single-tube assay has been developed to detect the 22q11.2 region and other chromosomal regions associated with DiGeorge syndrome. The advantage of MLPA is that it is a rapid, reliable economical high throughput method for diagnosis.⁷
  • A high-resolution, single-nucleotide polymorphism (SNP) genotyping assay has been developed to detect 22q11 deletions.⁸
  • Array comparative genomic hybridization (array CGH) is a high-resolution genome scanning procedure for DNA dosage aberrations. It can detect single copy number aberrations.
  • FastFISH is a rapid FISH method that allows release of accurate results the same day the amniocentesis is performed.⁹

TREATMENT

Section 6 of 9  

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

Medical Care

• Hypoparathyroidism is controlled with vitamin D and calcium supplementation. Vitamin D 1-5 mcg/d and calcium 2-3 g/d are required.
• Recurrent infection is treated with antibiotics appropriate for the cultured organism.
• The use of bone marrow transplantation and fetal thymic transplantation to correct immune defects has been reported in a small number of patients.
• The disorder remains difficult to treat.

Surgical Care

• Cardiac and great vessel defects should be corrected.
• Thymus transplantation can help reconstitute immune function in infancy.^{10, 11}

Consultations

• A pediatric cardiothoracic surgeon may help in the evaluation and correction of cardiac and great vessel defects.
• An endocrinologist may be consulted regarding the management of hypoparathyroidism.
• An infectious disease specialist may assist in the management of recurrent infections.
• An ear, nose, and throat specialist may be needed to manage structural abnormalities in the airway.

FOLLOW-UP

Section 7 of 9  

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

Further Outpatient Care

• Management of infection early in the course of illness is important.
• Endocrinologic follow-up care for hypocalcemia is indicated.

In/Out Patient Meds

• For hypocalcemia
• • Vitamin D 3-5 mcg/d
  • Calcium 2-3 g/d

Complications

• Sepsis is a risk in athymic patients.
• Early treatment of infections is important.
• Avoid live vaccines. Use caution when administering live viral vaccines to severely immunodeficient patients.¹²

Prognosis

• The prognosis is poor and depends on the degree of T-cell deficiency.
• Infants with severe immunodeficiency typically die of sepsis, which is usually due to bacterial or fungal infections.

Patient Education

• Patients must be aware that early intervention of infections improves the prognosis.

MISCELLANEOUS

Section 8 of 9  

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

Medical/Legal Pitfalls

• Failure to diagnose the condition is a pitfall.
• Failure to treat the infection is a pitfall.
• Failure to offer prenatal testing is a pitfall.

Special Concerns

• Prenatal diagnostic testing can be offered to couples at risk (see Other Tests).⁶

REFERENCES

Section 9 of 9

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

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Article Last Updated: Nov 1, 2007