DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis
- Christine M Seroogy, MD
Christine M Seroogy, MD
- Associate Professor
- University of Wisconsin Medical School
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 continuous 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 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 primary immunodeficiency".)
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".)
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 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 other mutations 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".)
- Lischner HW, Dacou C, DiGeorge AM. Normal lymphocyte transfer (NLT) test: negative response in a patient with congenital absence of the thymus. Transplantation 1967; 5:555.
- Shprintzen RJ, Goldberg RB, Lewin ML, et al. A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J 1978; 15:56.
- Lim CT, Choo KE, Afzal MK. Cardiofacial syndrome--report of a case with short annoxation. J Singapore Paediatr Soc 1978; 20:232.
- de la Chapelle A, Herva R, Koivisto M, Aula P. A deletion in chromosome 22 can cause DiGeorge syndrome. Hum Genet 1981; 57:253.
- Sullivan KE. DiGeorge syndrome and chromosome 22q11.2 deletion syndrome. In: Immunologic disorders in infants and children, 5th ed, Ochs HD, Stiehm ER, Winkelstein JA (Eds), Elsevier, Philadelphia 2004. p.523.
- Botto LD, May K, Fernhoff PM, et al. A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 2003; 112:101.
- Swillen A, Devriendt K, Vantrappen G, et al. Familial deletions of chromosome 22q11: the Leuven experience. Am J Med Genet 1998; 80:531.
- McDonald-McGinn DM, Minugh-Purvis N, Kirschner RE, et al. The 22q11.2 deletion in African-American patients: an underdiagnosed population? Am J Med Genet A 2005; 134:242.
- Grati FR, Molina Gomes D, Ferreira JC, et al. Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies. Prenat Diagn 2015; 35:801.
- Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012; 367:2175.
- Ammann AJ, Wara DW, Cowan MJ, et al. The DiGeorge syndrome and the fetal alcohol syndrome. Am J Dis Child 1982; 136:906.
- Sulik KK, Johnston MC, Daft PA, et al. Fetal alcohol syndrome and DiGeorge anomaly: critical ethanol exposure periods for craniofacial malformations as illustrated in an animal model. Am J Med Genet Suppl 1986; 2:97.
- Coberly S, Lammer E, Alashari M. Retinoic acid embryopathy: case report and review of literature. Pediatr Pathol Lab Med 1996; 16:823.
- Dentici ML, Placidi S, Francalanci P, et al. Association of DiGeorge anomaly and caudal dysplasia sequence in a neonate born to a diabetic mother. Cardiol Young 2013; 23:14.
- Wilson TA, Blethen SL, Vallone A, et al. DiGeorge anomaly with renal agenesis in infants of mothers with diabetes. Am J Med Genet 1993; 47:1078.
- Saitta SC, Harris SE, Gaeth AP, et al. Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum Mol Genet 2004; 13:417.
- Digilio MC, Angioni A, De Santis M, et al. Spectrum of clinical variability in familial deletion 22q11.2: from full manifestation to extremely mild clinical anomalies. Clin Genet 2003; 63:308.
- Poirsier C, Besseau-Ayasse J, Schluth-Bolard C, et al. A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH. Eur J Hum Genet 2016; 24:844.
- Vergés L, Vidal F, Geán E, et al. An exploratory study of predisposing genetic factors for DiGeorge/velocardiofacial syndrome. Sci Rep 2017; 7:40031.
- Shaikh TH, Kurahashi H, Saitta SC, et al. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet 2000; 9:489.
- Portnoï MF, Lebas F, Gruchy N, et al. 22q11.2 duplication syndrome: two new familial cases with some overlapping features with DiGeorge/velocardiofacial syndromes. Am J Med Genet A 2005; 137:47.
- Rauch A, Zink S, Zweier C, et al. Systematic assessment of atypical deletions reveals genotype-phenotype correlation in 22q11.2. J Med Genet 2005; 42:871.
- Lindsay EA, Botta A, Jurecic V, et al. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 1999; 401:379.
- Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet 2001; 27:286.
- Lindsay EA, Vitelli F, Su H, et al. Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 2001; 410:97.
- Merscher S, Funke B, Epstein JA, et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 2001; 104:619.
- Chen J, Zhang X, Li J, et al. Identification of a Novel ENU-Induced Mutation in Mouse Tbx1 Linked to Human DiGeorge Syndrome. Neural Plast 2016; 2016:5836143.
- Yagi H, Furutani Y, Hamada H, et al. Role of TBX1 in human del22q11.2 syndrome. Lancet 2003; 362:1366.
- Piotrowski T, Ahn DG, Schilling TF, et al. The zebrafish van gogh mutation disrupts tbx1, which is involved in the DiGeorge deletion syndrome in humans. Development 2003; 130:5043.
- Choe CP, Crump JG. Tbx1 controls the morphogenesis of pharyngeal pouch epithelia through mesodermal Wnt11r and Fgf8a. Development 2014; 141:3583.
- Zhang Z, Huynh T, Baldini A. Mesodermal expression of Tbx1 is necessary and sufficient for pharyngeal arch and cardiac outflow tract development. Development 2006; 133:3587.
- Reeh KA, Cardenas KT, Bain VE, et al. Ectopic TBX1 suppresses thymic epithelial cell differentiation and proliferation during thymus organogenesis. Development 2014; 141:2950.
- Zhang L, Zhong T, Wang Y, et al. TBX1, a DiGeorge syndrome candidate gene, is inhibited by retinoic acid. Int J Dev Biol 2006; 50:55.
- Okano J, Sakai Y, Shiota K. Retinoic acid down-regulates Tbx1 expression and induces abnormal differentiation of tongue muscles in fetal mice. Dev Dyn 2008; 237:3059.
- Greenberg F. DiGeorge syndrome: an historical review of clinical and cytogenetic features. J Med Genet 1993; 30:803.
- Stalmans I, Lambrechts D, De Smet F, et al. VEGF: a modifier of the del22q11 (DiGeorge) syndrome? Nat Med 2003; 9:173.
- Guris DL, Fantes J, Tara D, et al. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nat Genet 2001; 27:293.
- Breckpot J, Thienpont B, Bauters M, et al. Congenital heart defects in a novel recurrent 22q11.2 deletion harboring the genes CRKL and MAPK1. Am J Med Genet A 2012; 158A:574.
- Ogilvie CM, Ahn JW, Mann K, et al. A novel deletion in proximal 22q associated with cardiac septal defects and microcephaly: a case report. Mol Cytogenet 2009; 2:9.
- Lopez-Rivera E, Liu YP, Verbitsky M, et al. Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. N Engl J Med 2017; 376:742.
- Sellier C, Hwang VJ, Dandekar R, et al. Decreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome. PLoS One 2014; 9:e103884.
- Daw SC, Taylor C, Kraman M, et al. A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat Genet 1996; 13:458.
- Lichtner P, König R, Hasegawa T, et al. An HDR (hypoparathyroidism, deafness, renal dysplasia) syndrome locus maps distal to the DiGeorge syndrome region on 10p13/14. J Med Genet 2000; 37:33.
- Van Esch H, Groenen P, Fryns JP, et al. The phenotypic spectrum of the 10p deletion syndrome versus the classical DiGeorge syndrome. Genet Couns 1999; 10:59.
- DeBerardinis RJ, Medne L, Spinner NB, Zackai EH. DiGeorge anomaly in a patient with isochromosome 18p born to a diabetic mother. Am J Med Genet A 2005; 138A:155.
- Greenberg F, Courtney KB, Wessels RA, et al. Prenatal diagnosis of deletion 17p13 associated with DiGeorge anomaly. Am J Med Genet 1988; 31:1.
- Inoue H, Takada H, Kusuda T, et al. Successful cord blood transplantation for a CHARGE syndrome with CHD7 mutation showing DiGeorge sequence including hypoparathyroidism. Eur J Pediatr 2010; 169:839.
- Gennery AR, Slatter MA, Rice J, et al. Mutations in CHD7 in patients with CHARGE syndrome cause T-B + natural killer cell + severe combined immune deficiency and may cause Omenn-like syndrome. Clin Exp Immunol 2008; 153:75.
- Sanka M, Tangsinmankong N, Loscalzo M, et al. Complete DiGeorge syndrome associated with CHD7 mutation. J Allergy Clin Immunol 2007; 120:952.
- Jyonouchi S, McDonald-McGinn DM, Bale S, et al. CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) syndrome and chromosome 22q11.2 deletion syndrome: a comparison of immunologic and nonimmunologic phenotypic features. Pediatrics 2009; 123:e871.
- Lima K, Abrahamsen TG, Foelling I, et al. Low thymic output in the 22q11.2 deletion syndrome measured by CCR9+CD45RA+ T cell counts and T cell receptor rearrangement excision circles. Clin Exp Immunol 2010; 161:98.
- Collard HR, Boeck A, Mc Laughlin TM, et al. Possible extrathymic development of nonfunctional T cells in a patient with complete DiGeorge syndrome. Clin Immunol 1999; 91:156.
- Wilson DI, Burn J, Scambler P, Goodship J. DiGeorge syndrome: part of CATCH 22. J Med Genet 1993; 30:852.
- Bale PM, Sotelo-Avila C. Maldescent of the thymus: 34 necropsy and 10 surgical cases, including 7 thymuses medial to the mandible. Pediatr Pathol 1993; 13:181.
- Hong R. The DiGeorge anomaly. Immunodefic Rev 1991; 3:1.
- Bastian J, Law S, Vogler L, et al. Prediction of persistent immunodeficiency in the DiGeorge anomaly. J Pediatr 1989; 115:391.
- Gennery AR. Immunological aspects of 22q11.2 deletion syndrome. Cell Mol Life Sci 2012; 69:17.
- Markert ML, Sarzotti M, Ozaki DA, et al. Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients. Blood 2003; 102:1121.
- Chinen J, Rosenblatt HM, Smith EO, et al. Long-term assessment of T-cell populations in DiGeorge syndrome. J Allergy Clin Immunol 2003; 111:573.
- Piliero LM, Sanford AN, McDonald-McGinn DM, et al. T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome. Blood 2004; 103:1020.
- McLean-Tooke A, Barge D, Spickett GP, Gennery AR. Immunologic defects in 22q11.2 deletion syndrome. J Allergy Clin Immunol 2008; 122:362.
- Sullivan KE, McDonald-McGinn D, Driscoll DA, et al. Longitudinal analysis of lymphocyte function and numbers in the first year of life in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Diagn Lab Immunol 1999; 6:906.
- Davis CM, Kancherla VS, Reddy A, et al. Development of specific T-cell responses to Candida and tetanus antigens in partial DiGeorge syndrome. J Allergy Clin Immunol 2008; 122:1194.
- Ye P, Kirschner DE. Measuring emigration of human thymocytes by T-cell receptor excision circles. Crit Rev Immunol 2002; 22:483.
- Finocchi A, Di Cesare S, Romiti ML, et al. Humoral immune responses and CD27+ B cells in children with DiGeorge syndrome (22q11.2 deletion syndrome). Pediatr Allergy Immunol 2006; 17:382.
- Derfalvi B, Maurer K, McDonald McGinn DM, et al. B cell development in chromosome 22q11.2 deletion syndrome. Clin Immunol 2016; 163:1.
- Patel K, Akhter J, Kobrynski L, et al. Immunoglobulin deficiencies: the B-lymphocyte side of DiGeorge Syndrome. J Pediatr 2012; 161:950.
- Müller W, Peter HH, Kallfelz HC, et al. The DiGeorge sequence. II. Immunologic findings in partial and complete forms of the disorder. Eur J Pediatr 1989; 149:96.