22q11.2 deletion syndrome overview

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Overview

Historical Perspective

Classification

Pathophysiology

Differentiating 22q11.2 deletion syndrome from other Diseases

Causes

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Ayushi Jain, M.B.B.S[3]

Overview

22q11.2 deletion syndrome is a disorder caused by the deletion of a small part of chromosome 22. It occurs in approximately 1:4000 births.[1]


The deletion occurs near the middle of the chromosome at a location designated q11.2. DiGeorge Syndrome (DGS) is a combination of signs and symptoms caused by defects in the development of structures derived from the pharyngeal arches during embryogenesis. Key findings comprises of thymic hypoplasia, hypocalcaemia, outflow tract defects of the heart, and dysmorphic facies. The manifestations of this syndrome cross all medical specialties, and care of the children and adults can be complex. Many patients have a mild to moderate immune deficiency, and the majority of patients have a cardiac anomaly. Additional features include renal anomalies, eye anomalies, hypoparathyroidism, skeletal defects, and developmental delay. Each child's needs must be tailored to his or her specific medical problems, and as the child transitions to adulthood, additional issues will arise. A holistic approach, addressing medical and behavioral needs, can be very helpful. [2]

Historical Perspective

DGS characteristics were first described in 1828 but adequately reported later in 1965 by Dr. Angelo DiGeorge, as a clinical trial that included immunodeficiency, hypoparathyroidism, and congenital heart disease.

Historically, DGS was grouped within a sphere of other syndromes such as Shprintzen-Goldberg syndrome, velocardiofacial syndrome, Cayler cardiofacial syndrome, Sedlackova syndrome, conotruncal anomaly face syndrome, and DGS, collectively called 22q11 deletion syndromes. They have the same genetic etiology but their varying phenotypes has has led to confusion in diagnosing patients with DGS, which causes potentially catastrophic delays in diagnosis.

Classification

There is no established system for the classification of DGS.

Pathophysiology

The main factor leading to DGS is the deletion of 22q11.2, which encodes over 90 genes.

The 22q11.2 deletion syndrome can be inherited in an autosomal dominant manner. Prenatal testing, such as amniocentesis, is available for pregnancies determined to be at risk. Also pregnancies who have findings of congenital heart disease and/or cleft palate detected by ultrasound examination may be offered prenatal testing. Genetic counseling may be helpful for families who may have DiGeorge syndrome. Because most of the signs of this cluster of defects can also be inherited as autosomal recessive or x-linked traits, only genetic testing of both parents can determine with any certainty the likelihood these anomalies occurring in any subsequent children.

Causes

Most cases are linked to microdeletion of chromosome 22, at the long arm (q) at the 11.2 locus.

Differentiating [Disease] from Other Diseases

DGS must be differentiated from other diseases that cause similar clinical features and have a broad spectrum of presentation. All of the clinical findings associated with 22q11.2 deletion syndrome (22q11.2DS) can also occur as an isolated anomaly in an otherwise healthy individual. Genetic disorders and teratogenic exposures that may cause a clinical phenotype similar to 22q11.2DS are discussed in this section.

Epidemiology and Demographics

22q11.2 deletion syndrome affects an estimated 25 in 100,000 live births. Microdeletion of 22q11.2 is the most common microdeletion syndrome, affecting approximately 0.1% of fetuses. The rate of 22q11.2 microdeletion in live births occurs at an estimated rate of 1 in 4000 to 6000.

Risk Factors

The only known risk factor is that of a family history of DGS.

Screening

Screening of DGS depends on known family history and then approaching with genetic studies in individual cases.

Natural History, Complications, and Prognosis

Natural History

It is important to note that the broad spectrum of disease severity makes the evaluation of DGS particularly challenging. Cases involving significant cardiac, thymic, and craniofacial deficits are more easily recognizable than those lacking severe features.

Complications

Most patients with DGS may progress to develop severe recurrent infections, autoimmune diseases, and hematologic malignancies.

Prognosis

Prognosis is very poor, if left untreated, most patients die by 12 months of age.

Diagnosis

Diagnostic Criteria

History and Symptoms

A broad spectrum of disease severity exists, and suspicion of DGS from history and physical can prompt further evaluation. Although most cases get diagnosed in the prenatal and pediatric periods, diagnosis can also occur in adulthood.

Delay in motor development is a common presenting feature first recognized by parents who notice delays in rolling over, sitting up, or other infant milestones.

Characteristic signs and symptoms include heart defects that are often present from birth, an opening in the roof of the mouth (a cleft palate or other defect in the palate), autism, other learning disabilities, mild differences in facial features, and recurrent viral or fungal infections are common due to problems with the immune system's T-cell mediated response.

Physical Examination

A complete cardiopulmonary evaluation can reveal murmurs, cyanosis, clubbing, or edema consistent with aortic arch anomalies, conotruncal defects (e.g., tetralogy of Fallot, truncus arteriosus, pulmonary atresia with ventricular septal defect, transposition of the great vessels, interrupted aortic arch), or tricuspid atresia.

Recurrent sinopulmonary infections due to T cell deficiency as a result of thymic hypoplasia

Signs of hypocalcemia, including twitching and muscle spasm, may be evident as a result of parathyroid hypoplasia. Chvostek's and Trousseau's signs may be positive.

Delayed development, unusual behavior, or signs of psychiatric disorders may be observable.

Laboratory Findings

Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Prevention

References

  1. McDonald-McGinn, Donna M. MS, CGC; Sullivan, Kathleen E. MD, PhD Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome), Medicine: January 2011 - Volume 90 - Issue 1 - p 1-18 doi: 10.1097/MD.0b013e3182060469
  2. McDonald-McGinn, Donna M. MS, CGC; Sullivan, Kathleen E. MD, PhD Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome), Medicine: January 2011 - Volume 90 - Issue 1 - p 1-18 doi: 10.1097/MD.0b013e3182060469

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