DiGeorge Syndrome 

DiGeorge syndrome (DGS) now understood to be the chromosome 22q11.2 deletion syndrome was originally described as 3 syndromes found on 2 continents. Dr. DiGeorge described the first of these, 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.

Dr. 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 Dr. 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.

As the name chromosome 22q11.2 deletion syndrome implies, the 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 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. The TBX1 gene may be one important gene in the deleted region. 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 infections 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 the types of birth defects. 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, especially in those with isolated mild symptoms. Diagnosis in fetuses with a congenital heart anomaly should be offered to the pregnant woman.