DiGeorge Syndrome 

DiGeorge syndrome (DGS), now understood to be the chromosome 22q11.2 deletion syndrome, was originally described as 3 separate syndromes from 2 different 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.

In 1955, Sedlacková described a syndrome of congenitally shortened velum accompanied by hypernasal speech, facial dysmorphisms, and further anomalies, as well as mental retardation.^{[1, 2]} 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.

Dr. DiGeorge was the first to provide clinical examples in humans that demonstrated that 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 reported on 4 infants with thymic hypoplasia, hypoparathyroidism, and recurrent infections. 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.^[3] Shprintzen and colleagues in 1978 described patients from their craniofacial clinic with features of congenital conotruncal cardiac anomalies, characteristic facies, velopharyngeal dysfunction with or without cleft palate, and learning dysfunction, which they termed the velocardiofacial syndrome (VCFS).^[4]

Two factors prompted the discovery of a common genetic link between these presumed distinct phenotypes. The first came from a clinical 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. However, with improved understanding and medical care, many children with DGS and those with partial DGS survived into the second decade of life, allowing comparison between the two. Many older DGS patients clearly resembled those with VCFS, which began a speculation that VCFS may be a form of DGS without the immune dysfunction.

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 of band 22q11 and phenotypic features of DGA.^[5] 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 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 the acronym 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.

As the name chromosome 22q11.2 deletion syndrome implies, the cause of the syndromeis a deletion on the long arm of chromosome 22, typically 2-3 million base pair (Mb) in size. This region is prone to microdeletion because of the presence of nonallelic, flanking, low-copy repeat DNA sequences, which lead to unequal crossing over between the 2 chromosome 22s during meiosis. Deletion of one critical gene or several contiguous genes is thought to be the basis of this syndrome. Some patients have a chromosomal rearrangement involving chromosome 22.^[6]

Disease mechanism

Although more than 35 genes in this area have been identified, except the TBX1, which other genes must be deleted to cause this syndrome remains unknown. The TBX1 gene appears to play a major role in many features of the syndrome. Mutations and deletions in the TBX1 gene have been detected with the phenotype of DGS but without the 22q11.2 microdeletion, indicating this is one critical gene. Inactivation of the TBX1 gene in mice resulted in incomplete cleft palate, suggesting the gene regulates oral epithelial adhesion and palatal development.^[7] TBX1 gene abnormalities do not account for the CNS manifestations of this syndrome; therefore, other critical genes are suspected to be causative. No genotype-phenotype correlations can be made.

The result of common 22q11.2 deletion is a developmental field defect involving the third and fourth pharyngeal pouches leading to 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

Congenital heart defects, which are observed in 74-80% of affected patients, cause the greatest morbidity and mortality in infancy. However, the infant mortality rate has gone down to approximately to 4% owing to improvements in medical care. 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.^{[8, 9]}

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 or hypocalcemia 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 remain undiagnosed until late childhood. Late diagnosis into adulthood continues to be reported, especially in those with isolated mild symptoms. Prenatal diagnosis in fetuses with a congenital heart anomaly has been made frequently and should be offered to a pregnant woman at risk of carrying a fetus with this syndrome.