The Presentation, Testing, and Diagnoses of 22Q11 deletion

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Presentation

The features of this syndrome vary widely, even among members of the same family, and affect many parts of the body. 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. DiGeorge syndrome is often first spotted when the affected newborn begins convulsing from hypocalcemia due to an absence of parathyroid and parathyroid hormone. Affected individuals may also have kidney abnormalities, significant feeding difficulties, autoimmune disorders such as rheumatoid arthritis, and an increased risk of developing mental illnesses.^[2] Microdeletions in chromosomal region 22q11 are associated with a roughly 30-fold increased risk of schizophrenia, ^[3] and are frequently detected in schizophrenic patients. Different studies provide different occurrence rates, ranging from 0.5 to 3%, compared with the overall 0.025% risk of the 22q11 deletion syndrome in the general population.^[4]

Nomenclature

Because the signs and symptoms of 22q11.2 deletion syndrome are so varied, different groupings of features were once described as separate conditions. These included the velo-cardio-facial syndrome (also called Shprintzen's syndrome), DiGeorge syndrome, hearing loss with craniofacial syndromes and conotruncal anomaly face syndrome, thymic hypoplasia, cleft palate, psychiatric disorders, and hypocalcaemia. The acronym CATCH-22 (C = cardiac defects, A = abnormal facies, T = thymic hypoplasia, C = cleft palate, H = hypocalcemia from parathyroid aplasia, 22 = microdeletions in chromosome 22) is sometimes used, although it is widely rejected because of the negative connotations with catch 22 meaning a 'no-win' situation.

In addition, some children with the 22q11.2 deletion were diagnosed with Opitz G/BBB syndrome and Cayler cardiofacial syndrome. Once the genetic basis for these disorders was identified, doctors determined that they were all part of a single syndrome with many possible signs and symptoms. To avoid confusion, this condition is usually called 22q11.2 deletion syndrome, a description based on its underlying genetic cause.

Symptoms

Individuals with a 22q11 deletion can suffer from a range of over 180 possible symptoms, ranging from the mild to the very serious. Possible symptoms are:

• Congenital heart disease (74% of individuals), particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and persistent truncus arteriosus)
• palatal abnormalities (69%), particularly velopharyngeal incompetence (VPI), submucosal cleft palate, and cleft palate; characteristic facial features (present in the majority of Caucasian individuals) including hypertelorism.
• learning difficulties (70-90%)
• an immune deficiency regardless of their clinical presentation (77%)
• hypocalcemia (50%)(due to hypoparathyroidism)
• significant feeding problems (30%)
• renal anomalies (37%)
• hearing loss (both conductive and sensorineural) (Hearing loss with craniofacial syndromes)
• laryngotracheoesophageal anomalies
• growth hormone deficiency
• autoimmune disorders
• seizures (without hypocalcemia)
• skeletal abnormalities
• Autism and Autism spectrum disorders

Thymus, parathyroid glands and heart derive from the same primitive embryonic structure and that is why these three organs are dysfunctioned together in this disease. Affected patients (usually children) are prone to yeast infections.

Cause

The syndrome is caused by genetic deletions (loss of a small part of the genetic material) found on the long arm of the 22nd chromosome. Some patients with similar clinical features may have deletions on the short arm of chromosome 10.

DiGeorge syndrome causes migration defects of neural crest-derived tissues, particularly affecting development of the third and fourth Branchial pouches (pharyngeal pouches). Also affected is the thymus gland; a mediastinal organ largely responsible for differentiation and induction of tolerance in T-cells. Impaired immune function results principally from this aetiology.

Treatment

Although genetic transplantation methods are currently being developed by researchers, there is yet no genetic treatment of this disease.

It is important that the immune problems are identified early as special precautions are required regarding blood transfusion and immunisation with live vaccines.

Treatment is largely symptomatic, infections are treated with antibiotics, and these patients may undergo cardiac surgery for their heart abnormalities. Hypoparathyroidism causing hypocalcaemia is often transient, but may require lifelong vitamin D treatment.

Thymus transplantation can be used to address absence of the thymus in complete DiGeorge syndrome.^[5]

Diagnosis/testing

The 22q11.2 deletion syndrome is diagnosed in individuals with a submicroscopic deletion of chromosome 22 detected by fluorescence in situ hybridization (FISH) using DNA probes from the DiGeorge chromosomal region (DGCR). Such genetic testing is widely available for the clinical and prenatal testing of the 22q11.2 deletion syndrome. Fewer than 5% of individuals with clinical symptoms of the 22q11.2 deletion syndrome have normal routine cytogenetic studies and negative FISH testing. They may have variant deletions of DiGeorge syndrome that may be detectable on a research basis only.