INTRODUCTION — DiGeorge syndrome (DGS) is a constellation of signs and symptoms associated with defective development of the pharyngeal pouch system. Most cases are caused by a heterozygous chromosomal deletion at 22q11.2. The classic triad of features of DGS on presentation is conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia (resulting from parathyroid hypoplasia).
Thymic hypoplasia in DGS results in a range of T cell deficits. The majority of patients with DGS have mild defects in T cell numbers and are not clinically immunodeficient. However, there is a spectrum of T cell lymphopenia, and approximately 0.5 to 1 percent of DGS cases have a complete absence of thymic tissue and profound immunodeficiency. This congenital athymia form of DGS, called complete DGS, is a type of severe combined immunodeficiency (SCID) and is life threatening if not corrected with immune reconstitution (eg, thymic transplantation or hematopoietic cell transplantation). (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)
This topic reviews the epidemiology and pathogenesis of DGS. The clinical features, diagnosis, management, and prognosis of patients with DGS are presented separately. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis" and "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis".)
TERMINOLOGY — The clinical features of DGS were first described in 1829, and congenital absence of the thymus and parathyroid glands was reported by Dr. Angelo DiGeorge in 1965 . In the 1980s, it was discovered that heterozygous deletions in chromosome 22q11.2 were present in most patients with DGS, as well as in patients with other similar syndromes, such as velocardiofacial syndrome (VCFS, also called Shprintzen syndrome) [2-4].
Thus, these conditions can be grouped together under the term chromosome 22q11.2 deletion syndrome (22qDS). Patients with the DiGeorge phenotype and the chromosome 22q11.2 deletion are most precisely referred to as having "DGS with chromosome 22q11.2 deletion," and those with unidentifiable genetic defects are referred to as having "DGS without chromosome 22q11.2 deletion" . Other syndromes associated with deletions in chromosome 22q11.2 are mentioned briefly and reviewed in more detail elsewhere. (See "Syndromes with craniofacial abnormalities".)
EPIDEMIOLOGY — A large population-based study in the United States designed to ascertain the prevalence, phenotype, and incidence of cardiac disease revealed that heterozygous chromosome 22q11.2 deletions are relatively common in the general population, making 22qDS the most prevalent microdeletion syndrome . This study found that 1 in 5950 livebirths had a deletion in this chromosomal area, and, within this subset of infants, 83 percent had an associated cardiac defect. Another population-based study reported that the incidence of 22qDS was as high as 1 in 4000 livebirths . Two multicenter studies aimed at prenatal population-based genetic screening found that the incidence for 22qDS was considerably higher than postnatal population-based studies, with prevalences as high as approximately 1 in 400 to 1000 fetuses in low-risk pregnancies [8,9].
Only a small subset (approximately 0.5 to 1 percent) of all patient with DGS have congenital athymia that presents in infancy with a SCID-like phenotype. The advent of widespread newborn screening for SCID with the T cell receptor excision circle (TREC) test in the United States has resulted in recognition of the infants with complete DGS and partial DGS accompanied by a significant degree of T cell lymphopenia [10,11].
22qDS is probably underdiagnosed because the phenotypic findings may be mild in some patients. One report noted that African-American children with 22qDS may have a lower incidence of craniofacial dysmorphism, making diagnosis more challenging in this group . Moreover, the varied phenotype in patients with 22qDS implies factors in addition to gene deletion, such as epigenetics and other genetic modifiers, impact disease severity.
PATHOGENESIS — The signs and symptoms associated with DGS result from an abnormal development sequence in the embryonic pharyngeal system. This is a vertebrate-specific system that consists of the pharyngeal arches (comprised of mesoderm and neural crest cells), through which the pharyngeal arteries and nerves pass. The arches are separated by the pharyngeal pouches, which are internal evaginations of foregut endoderm and external invaginations of surface ectoderm (figure 1). This developmental sequence contributes to the formation and morphogenesis of the thymus, thyroid, parathyroids, maxilla, mandible, aortic arch, cardiac outflow tract, and external/middle ear. The majority of DGS cases have identifiable genetic causes. However, various teratogens have been independently associated with DGS in humans and animal models, such as maternal exposure to alcohol [13,14] and retinoic acid , and maternal diabetes [16,17].
Genetic abnormalities — Approximately 90 percent of patients with DGS have heterozygous deletions in chromosome 22q11.2 (designated the DGS1 locus) . The inheritance of 22qDS is autosomal dominant, but the majority of cases are the result of de novo microdeletions [18-20]. The high incidence of chromosome 22q11.2 microdeletions is attributed to the presence of several homologous enrichment of low copy repeats (LCRs) in this chromosomal region, which make it prone to homologous recombination deletion errors during meiosis , leading to copy number variants (CNVs) in the chromosome 22q11.2 region. (See "Genomic disorders: An overview", section on 'Causes of CNVs'.)
Chromosome 22q11.2 — The most common genetic deletion associated with DGS is a 1.5 to 3 Mb deletion in the chromosome 22q11.2 region (DGS1 locus) . This region of genomic DNA encodes approximately 46 protein coding genes (30 genes within the 1.5 Mb region) (figure 2). DGS is most commonly caused by heterozygous deletions in this region, although several cases of a DGS-like phenotype have been reported in association with duplications of the 22q11.2 region . Homozygous deletions in chromosome 22q11.2 have not been reported.
Several studies in humans have attempted to identify genes in the critical DGS 3 Mb region that are essential for the phenotype. An initial report studying 350 patients for defects within the DGS 3 Mb region found that patients with conotruncal heart defects and typical DGS phenotype most commonly had a nested 1.5 Mb deletion (79 percent) or the larger 3 Mb deletion (19 percent) . The size of the deletion did not correlate with the clinical phenotype. Other deletions (called atypical deletions) in the DGS critical region were found in only 5 percent of patients, and these individuals had phenotypes only mildly suggestive of DGS without conotruncal cardiac disease. None of these deletions were found in healthy individuals.
TBX1 — A region of mouse chromosome 16 is highly syntenic to the human chromosome 22q11.2 region and has been experimentally deleted . Mice heterozygous for this deletion had phenotypic abnormalities similar to DGS, namely cardiac, thymic, parathyroid, and neurobehavioral phenotypic abnormalities. Smaller deletions also resulted in a similar phenotype, leading to the question of whether DGS could result from a single gene defect. Subsequent studies in the mouse demonstrated that deletion of the gene T-box 1 (Tbx1) gene within this chromosomal region was sufficient to convey all of the exhibited phenotypic abnormalities of the larger genomic deletion [26-29]. Mice that are heterozygous for the Tbx1 deletion have aortic arch abnormalities only, whereas homozygous null mutations in Tbx1 lead to a complete DGS-like phenotype, illustrating the importance of gene dose. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'Complete DGS' and "Basic genetics concepts: DNA regulation and gene expression", section on 'Transcription'.)
A tbx1-deficient zebrafish model, historically referred to as the van gogh (vgo) mutation, has many of the features of DGS, including defects in the ear, pharyngeal arches, aortic arches, and thymus [30,31]. Complete tbx1 deficiency is required, as heterozygous zebrafish embryos do not demonstrate any DGS phenotypic features.
The zebrafish model also provided insight into the fundamental nature of interactions between endoderm, mesoderm, and neural crest cells in the development of the pharyngeal arch system . Expression analysis revealed that Tbx1 protein is found in the pharyngeal endoderm and the mesenchyme surrounding the aortic arches and the otic vesicle, although not in the neural crest cells. Transplantation of wild-type endoderm into tbx1-deficient zebrafish corrected the DGS-like phenotype. Thus, tbx1-deficient cells function autonomously in the pharyngeal arch system, and neural crest defects are secondary to this molecular defect. Studies using the zebrafish model have extended this initial work and suggest that Tbx1 protein expression in the mesoderm is necessary for development of the pharyngeal arch system, whereas Tbx1 expression in the endoderm was dispensable . Mesoderm-specific deletion of Tbx1 in mice resulted in pharyngeal and cardiac abnormalities, providing evidence in mammals that mesodermal Tbx1 protein expression is necessary for these developmental sequences . The genes regulated by Tbx1 remain poorly understood. One study in a murine model demonstrated that Tbx1 regulates the expression of the transcription factor forkhead box N1 (Foxn1) and thus the development of thymic epithelial cells and thymopoiesis .
Other studies in mice and zebrafish have demonstrated that retinoic acid exposure can downregulate the cellular levels of Tbx1, leading to developmental abnormalities similar to the DGS phenotype [35,36]. This finding may provide a molecular basis for the association between DGS phenotype and in utero exposure to isotretinoin .
To investigate the role of TBX1 in humans, genetic screening was undertaken in patients with the DGS phenotype but without detectable deletions in the defined 1.5 to 3 Mb region of chromosome 22q11.2 [38,39]. Several missense and truncating variants in TBX1 were demonstrated in unrelated patients and were not found in healthy persons. These patients manifested all of the major phenotypes of DGS, including facial abnormalities, cardiac abnormalities, thymic hypoplasia, palatal abnormalities, and parathyroid dysfunction. These data strongly suggest that defects in the TBX1 are responsible for the DGS phenotype in humans. TBX1 is believed to function exclusively as a transcription factor. However, increasing evidence suggests that TBX1 also functions by altering chromatin methylation and through epigenetic mechanisms [40,41].
Other affected genes in this region — Despite the strong evidence implicating TBX1 defects in the DGS phenotype, other genes or gene dosage in the critical DGS region and in other chromosome locations likely play a role in the observed phenotypic variability.
Studies in mice and zebrafish demonstrated that tbx1 and vascular endothelial growth factor (vegf) interact with and comodify pharyngeal arch vascular defects during embryogenesis, and human studies suggest that VEGF promoter polymorphisms (chromosome 6 in humans) modify cardiovascular disease in 22q11.2DS microdeletion .
Deletion of the CRK-like proto-oncogene, adaptor protein (Crkol, human ortholog: CRKL and part of the critical DGS region) gene in mice results in neurologic and cardiac defects similar to those observed in 22qDS patients . Two case reports described children with congenital cardiac defects and microcephaly who had partial deletion of the critical region of chromosome 22q11.2 leading to deletions in CRKL with unaffected or wild-type TBX1 gene [44,45]. In another study, a higher frequency of heterozygous deletions in the DGS1 locus was seen in patients with congenital kidney and urinary tract defects compared with general population controls . Next-generation sequencing of suspect DGS1 kidney defect genes in patients with congenital kidney anomalies demonstrated heterozygous missense and truncating variants in CRKL predicted to be damaging in an additional five patients. Induced loss-of-function crkl variants in zebrafish results in kidney defects, and inactivation in mice induced developmental kidney anomalies. These results suggest that haploinsufficiency of CRKL is the genetic driver of kidney defects seen in patients with DGS and may also contribute to sporadic congenital kidney and urinary tract anomalies.
Regarding gene dosage, one study showed decreased expression of several genes in DGS critical region in peripheral blood cells from patients with 22qDS . This included decreased expression of DiGeorge critical region gene 8 (DGCR8), a regulator of microribonucleic acid (miRNA) biogenesis. Variably decreased levels of numerous miRNAs seen in 22qDS patients that correlated with several phenotypic features. Thus, these data suggest a complex network of varied gene expression secondary to altered gene dosage in chromosome 22qDS and the potential for development of biomarkers for disease prognosis .
Defects on other chromosomes — Approximately 2 to 5 percent of patients have heterozygous deletions in chromosome 10p13-14 (the DGS2 locus) [48,49]. Comparison of patients with DGS1 and DGS2 locus deletions demonstrate many similarities, although there is an increased incidence of sensorineural hearing loss in patients with the DGS2 locus deletion . There also have been isolated case reports of patients with phenotypic features of DGS and a microdeletion in chromosome 17 or an isochromosome 18q [51,52].
Pathogenic variants in the chromodomain helicase DNA-binding protein 7 gene (CHD7), located at chromosome 8q12.2, are found in approximately 70 percent of patients with CHARGE (coloboma of the eye, heart anomalies, choanal atresia, retardation, genital and ear anomalies) syndrome association. Several groups have described patients with CHD7 pathogenic variants who have the DGS phenotype along with the other unique features of CHARGE [53-56].
Thymic hypoplasia — A spectrum of thymic abnormalities is possible in DGS. In one study, 39 of 43 patients with DGS who had a detectable thymus on ultrasound had decreased thymic tissue volume compared with age-matched healthy controls . The majority of patients have sufficient thymic tissue for the development of functional T cells. Congenital absence of thymic tissue, which defines complete DGS, is rare in patients with DGS . (See 'Immune function' below.)
The precise nature of the thymic abnormalities in DGS patients is not entirely clear. One theory is that the T cell defects observed are secondary to an insufficient amount of thymic tissue that is otherwise functioning normally and is located in the normal anatomic location. However, undescended, morphologically small thymi were found on autopsies of patients with DGS in whom the cause of death was not immunologically related [59,60].
A second theory proposes that the T cell defects in DGS are due to an abnormal anatomic location of the thymus . This theory is better substantiated by clinical studies. One study of 14 patients with DGS undergoing cardiac surgery revealed ectopic thymic tissue, most commonly in the neck, in 11 patients . However, only two patients were immunodeficient. Another study found no difference in the correlation between recent thymic emigrant T cells and T cell receptor excision circle (TREC) values in patients with ectopic thymic tissue compared with those patients whose thymus was in the expected anatomic location . Findings from another study suggest that there are fundamental defects in thymic epithelial cells, which, in turn, affect thymopoiesis . (See "Newborn screening for inborn errors of immunity", section on 'Formation of TRECs'.)
Immune function — Patients with DGS are divided into two subtypes, partial or complete DGS, based upon the level of immunologic function and degree of thymic hypoplasia. Partial DGS describes the majority of patients, who have variable and non-life-threatening immunologic defects. In contrast, complete DGS is fatal within the first few years of life, unless detected promptly and treated with immunologic reconstitution. It is believed that a total absence of thymic tissue is responsible for the complete DGS phenotype . The identified genetic defects underlying complete DGS are similar to partial DGS suggesting that additional epigenetic, genetic modifiers, or environmental factors are responsible for the more severe immunologic manifestations. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'Complete DGS'.)
Complete DGS — Both T cell numbers and function are highly abnormal in infants with complete DGS . Peripheral blood CD3+ T cells typically comprise <1 to 2 percent of the circulating lymphocytes (or absolute values <50 CD3+ T cells/mm3). Response to mitogens is absent or severely diminished. . Development of some T cells over weeks or months has been reported in a subset of athymic patients. The circulating T cells in these patients have abnormal T cell receptors (specifically, a restricted variable beta T cell receptor [V beta TCR] repertoire) and are functionally defective in vitro, demonstrating extrathymic outgrowth of an oligoclonal abnormal T cell population [58,65]. These patients are classified as atypical complete DGS and have associated rash and lymphadenopathy. (See "Normal B and T lymphocyte development".)
Partial DGS — Patients with partial DGS or other chromosome 22q11.2 deletions display a range of T cell numbers and function, ranging from normal to immunodeficient. In normal neonates, T cell counts decline rapidly in the first year of life and then decline further at a slower rate until reaching normal adult range. In contrast, in infants with partial DGS, T cell numbers may initially fall below the lower limit of normal for age and then may rise slightly during the first year. Several prospective studies have demonstrated that the normal attrition of T cell numbers that occurs with age is blunted in DGS patients and may result in normal T cell numbers by adulthood [66-70]. Normalization appears to result from homeostatic proliferation of existing T cells, rather than from thymus recovery [67,71].
Thymically derived CD25+ T regulatory (Treg) cells are an important T cell subset in suppressing autoimmune diseases and dysregulated immune responses. Diminished numbers of these cells are found in patients with 22qDS after two years of age compared with controls in a small cohort study of children with 22q11.2 deletion . A separate study showed that Treg cell suppressor function is diminished in patients with DGS compared with age-matched controls . These findings may be a factor in the increased incidence of autoimmune and atopic disease seen in patients with DGS. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'Other immune-related problems'.)
T cell function is variable, with the majority of patients having relatively intact function. The response to mitogens is normal for the majority of patients with partial DGS . Mitogen response in patients with low T cell numbers (below the 10th percentile of normal range) can be abnormal by standard methods, although this probably represents a quantitative defect as opposed to intrinsic T cell dysfunction . In one study, the T cell proliferative response to mitogens was comparable with controls, but the response to specific antigens was variable . In another study, proliferative responses to Candida and tetanus were significantly lower in a subset of patients with partial DGS compared with controls . The majority of these patients with partial DGS also had T cell numbers below the 10th percentile of normal range.
B cells are usually normal or increased in number and mildly abnormal in function, consistent with defective T cell help . Although total B cell numbers are normal, the proportion of memory B cells is lower in patients with 22q11.2 deletions, particularly in older patients [68,73]. A DGS registry reported use of immune globulin replacement therapy in 3 percent of patients with DGS . More in-depth studies are necessary to understand the significance of memory B cell abnormalities and indications for immune globulin replacement therapy in patients with partial DGS.
Natural killer cells are typically normal in number and function in patients with 22qDS .
●Epidemiology – Chromosome 22q11.2 deletion syndrome (22qDS), which includes DiGeorge syndrome (DGS), is the most prevalent microdeletion syndrome. Estimated prevalence of 22qDS ranges from 1 in 4000 to 1 in 6000 livebirths, although only a small subset (approximately 0.5 to 1 percent) of all patient with DGS have the complete form that presents in infancy as a severe combined immunodeficiency (SCID) phenotype. 22qDS is probably underdiagnosed because the phenotypic findings may be mild in some patients. (See 'Epidemiology' above.)
●Embryology – DGS is a constellation of signs and symptoms associated with defective development of the pharyngeal pouches (figure 1). These embryologic structures give rise to the thymus, thyroid, parathyroids, maxilla, mandible, aortic arch, cardiac outflow tract, and external/middle ear. (See 'Pathogenesis' above.)
●Genetics – Approximately 90 percent of patients with DGS have spontaneously arising heterozygous deletions in chromosome 22q11.2 (termed DGS1) (figure 2). Defects in the T-box transcription factor 1 gene (TBX1) are central to the phenotype. (See 'Genetic abnormalities' above.)
●Immune defects – Clinically, patients with DGS are divided into two subtypes, partial or complete DGS, based upon the level of immunologic function and degree of thymic hypoplasia. Partial DGS refers to the majority of patients, who have variable and non-life-threatening immunologic defects. Complete DGS is a form of congenital athymia with a SCID-like phenotype, in which there is no thymic tissue and profound immunodeficiency. (See 'Thymic hypoplasia' above and 'Immune function' above.)
•Complete DGS – The thymus is completely absent, and peripheral blood CD3+ T cells typically comprise <1 to 2 percent of the circulating lymphocytes in patients with complete DGS. These patients are profoundly immunosuppressed, and the condition is fatal if not recognized and treated with thymic or bone marrow transplant. (See 'Complete DGS' above.)
•Partial DGS – Infants with partial DGS demonstrate variable T cell counts and function. B cells are usually normal or increased in number and mildly abnormal in function, consistent with defective T cell help. (See 'Partial DGS' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.
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