REVIEW URRENT C OPINION
Immunological features of 22q11 deletion syndrome Andrew R. Gennery
Purpose of review 22q11 deletion syndrome is the most common genetic abnormality. More patients are surviving cardiac surgery, and many do not have cardiac anomalies. Adult patients are now being described. It is important for paediatricians, and increasingly adult physicians, to be aware of the optimum management of these patients. Recent findings Three main immunological patterns are recognized, namely, athymic and incomplete 22q11 deletion syndrome and autoimmunity. Newborn screening for severe combined immunodeficiency detects athymic patients, although diagnosis may be complicated, and instructive cases are described. Incomplete 22q11 deletion syndrome is the most common presentation; new findings predict which patients are likely to experience significant infection. B lymphocyte deficiencies are often overlooked. Data regarding autoimmunity in adult patients is reported, as well as newly reported immunological findings. Finally, management guidelines are now published, and these are highlighted. Summary Newborn screening detects patients with athymic 22q11 deletion syndrome, but significant illness may complicate the picture, and dual diagnoses can confound treatment. Treatment options for these patients are becoming clearer. Hypoparathyroidism is associated with more severe infection, and immunoglobulin abnormalities are more common than previously recognized. Adult patients are symptomatic and management guidelines will help general physicians in managing these patients. Keywords hypogammaglobulinemia, management guidelines, newborn screening, thymic transplantation
INTRODUCTION Chromosome 22q11 deletion (also known as DiGeorge syndrome or velocardiofacial syndrome) is a common genetic disorder affecting approximately 1 : 4000 births. Patients with Coloboma, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and urinary abnormalities and Ear abnormalities and deafness (CHARGE) syndrome due to a hemizygous deletion on CHD7 also have thymic developmental abnormalities and may have similar clinical manifestations to patients with 22q11 deletion syndrome [1]. These syndromes will be considered together in the following review, which will focus on recent findings in immunological defects found in these patients. In 22q11.2 deletion syndrome, no correlation has been found between the clinical phenotype and size of the gene deletion. The pharyngeal arches and pouches form the common embryonic precursor for the thymus, parathyroid glands and conotruncal regions of the heart – all affected in 22q11 deletion syndrome. Defects in organogenesis result from www.co-pediatrics.com
impaired migration of neural crest cells into pouch ectoderm. Disruption in the pathways of neural crest cell development in mice results in malformations similar to the 22q11.2 deletion phenotype. Classic features of 22q11 deletion syndrome have been described in patients with point mutations in TBX1, found within the 22q11.2 region, and with other chromosomal rearrangements including chromosome 10p deletion. The same deletion has also been discovered in other disorders including the velocardiofacial syndrome, conotruncal anomaly face syndrome and sporadic case of Opitz G/BBB syndrome. TBX1 belongs to a family of transcription factors containing a DNA binding domain, ‘T-box’. Mutations in TBX1 lead Institute of Cellular Medicine, Newcastle University, UK Correspondence to Andrew R. Gennery, Old Childrens’ Outpatients, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK. Tel: +44 191 282 5234; fax: +44 191 282 0497; e-mail: [email protected] Curr Opin Pediatr 2013, 25:730–735 DOI:10.1097/MOP.0000000000000027 Volume 25 Number 6 December 2013
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Immunological features of 22q11 deletion syndrome Gennery
KEY POINTS Newborn screening detects athymic 22q11 deletion syndrome, but may be confounded by dual diagnoses. The role of haematopoietic stem cell transplantation and thymic transplantation is evolving in these patients. Hypoparathyroidism is associated with poor T lymphocyte function and B lymphocyte dysfunction is part of 22q11 deletion syndrome. Adults with 22q11 deletion syndrome may be symptomatic with recurrent infection and autoimmunity. Management guidelines will help physicians, parents and patients in optimizing treatment.
to absence or reduction in the fourth pharyngeal arches. CRKL, also found within the common deleted region, encodes an adapter protein implicated in growth factor and adhesion molecular signalling, and is highly expressed in neural crest derived during tissue development. Homozygous deletion of Crkl results in gestational deaths in mice with multiple defects in neural crest derivatives including aortic arch, arteries and craniofacial structures. Compound heterozygosity in murine homologs of these genes results in a more penetrant phenotype compared with heterozygosity at either locus, suggesting that a dose sensitive interaction of these genes may be important to establish the phenotype. Some of the genes within the deleted region of chromosome 22 are critical for the development of pharyngeal, ectoderm, endoderm and mesenchyme, and disruption of these genes leads to disruption of structures of the pharyngeal arch, including the cardiac outflow track as well as parathyroid glands and thymus. CHD7, mutated in CHARGE syndrome, is a chromodomain–helicase–DNA-binding domain family of adenosine - 50 -triphosphate-dependent chromatin remodelling enzymes. CHD7 contributes to nucleosome remodelling and histone deacetylation regulating dynamic changes in chromosome structure during transcription, recombination, repair and replication and in regulating early embryonic development in cellcycle control. CHD7 is expressed throughout the neural crest-containing mesenchyme of pharyngeal arches, and thymic hypoplasia or agenesis is associated with CHARGE syndrome [2]. Thymic mesenchyme derived from pharyngeal arch neural crest cells promotes thymic epithelium development and signalling between the two cell types controlling initial thymic morphogenesis. Mesenchymal cells regulate proliferation and differentiation of immature thymic epithelial cells.
Thymic epithelial differentiation becomes independent of mesenchymal cells once thymic organogenesis is able to support immature thymocytes migrating from bone marrow-derived precursors [3,4]. Molecular interaction between developing lymphoid and thymic epithelial cells is critical for further thymic development. Severely atrophic thymus development with a corticomedullary demarcation is consequent to defects in genes that promote T lymphocyte development, and complete deficiencies of thymocytes in severe combined immunodeficiency (SCID) result in a severely atrophic thymus [5]. Thymocyte development arrested at a later developmental stage leads to normal thymic cortical development but rudimentary medullary regions. Three major immunological concerns can complicate the following 22q11 deletion syndrome. (1) The most severe clinical scenario: complete absence of the thymus, alymphocytosis and SCID-like phenotype. This is rare and affects fewer than 1% of patients with 22q11 deletion [6]. (2) The most common clinical scenario: patients have small, often atopic, thymus development and present with T lymphocytopenia and recurrent sinopulmonary infection in early childhood, which usually resolves by adolescence. (3) An increasingly recognized scenario: autoimmunity, a common feature of many immunodeficiencies.
ATHYMIC 22Q11 DELETION SYNDROME The advent of newborn screening for children with SCID within some states in the United States of America has allowed rapid identification of athymic children with morphological features of 22q11 deletion syndrome [7 ]. Newborn screening detects DNA fragments, markers of T lymphocyte receptor development produced during the variable, diversity and joining gene segment recombination of T and B lymphocyte receptor development [8]. Patients with SCID and those with athymic 22q11 deletion syndrome are unable to generate T lymphocytes, and are therefore detected by newborn screening. Early diagnosis of athymic 22q11 deletion syndrome is important, particularly in those patients who may require cardiac surgery. Such patients should receive irradiated blood products to prevent transfusion-related graft-versus-host disease [9]. Definitive treatment with haematopoietic stem cell transplantation is more successful when a sibling donor is available, although survivors continue to have very low or absent naı¨ve T lymphocytes, reflecting failure of
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thymopoiesis [10 ]. There is a high risk of graftversus-host disease for these patients, and for those for whom no HLA-matched sibling donor is available thymic transplantation is the curative treatment of choice [11]. Knutsen et al. [12] have reported a patient with athymic 22q11 deletion syndrome, detected on newborn screening with associated T lymphocytopenia at 3 weeks of age prior to cardiac surgery. However, by 8 months of age the absolute lymphocyte count was normal. This patient had normal percentages of CD4þCD45RAþ naı¨ve T lymphocytes, consistent with partial rather than athymic 22q11 deletion syndrome. This case re-affirms the importance of careful immunophenotyping of these patients and early engagement of immunologists in subsequent management. For patients with athymic 22q11 deletion syndrome, thymic transplantation leads to better immunological reconstruction than haematopoietic stem cell transplantation. However, dual genetic diagnoses do need to be considered in patients who have an atypical presentation. Two unrelated infants are reported, who had consistent phenotypic features of athymic 22q11 deletion syndrome with a T-B-NKþ immune phenotype and confirmed 22q11 deletion. However, the first infant underwent thymic transplant but by 6 months following transplantation had not developed recipient naı¨ve T lymphocytes. Further, genetic analysis revealed that both patients had artemis deficiency, a rare form of SCID, for which thymic transplant alone would not be successful [13 ]. The biology of thymic transplantation in patients with 22q11 deletion is incompletely understood. Patients may receive disparate HLA-mismatched thymic stromal cells yet develop immune reconstitution. Such patients give an opportunity to explore thymic development in a unique setting. Thymic microenvironmental reconstitution following thymic transplantation was examined in seven patients who underwent thymic transplant for athymic 22q11 deletion syndrome. Findings suggest that thymic epithelium contains CK14þ progenitor thymic epithelial cells that proliferate as CK14þ CDR2þ thymic epithelial cells following transplantation, associated with cortical fibrocytes. These further differentiate into distinct cortical and medullary epithelia. There is limited information on these athymic patients; these therapies present opportunities to further our understanding of thymic development and anatomy [14]. Patients with 22q11 deletion syndrome develop hypocalcaemia due to hypoparathyroidism secondary to absence of parathyroid glands. Parathyroid transplantation offers a potential cure for this but allografts are likely to be rejected, particularly &
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when immunosuppression is withdrawn. In patients with athymic 22q11 deletion syndrome, parathyroid gland transplantation combined with allogeneic thymus transplantation offers the opportunity for induction of tolerance when there is some matching of the allogeneic thymus graft to the parathyroid donor HLA class II alleles that are not shared with the recipient [15].
INCOMPLETE 22Q11 DELETION SYNDROME Incomplete 22q11 deletion syndrome is more common than athymic 22q11 deletion. Patients have T lymphocytopenia with a reduced number of naı¨ve T lymphocytes. The most common symptoms are sinopulmonary infection in early childhood, which usually resolves as patients reach adolescence. However, given other clinical features of 22q11 deletion syndrome, this partial immunodeficiency may have important implications for patient management. An interesting study on the impact of 22q11 deletion on the postoperative course of treatment after cardiac surgery demonstrated that, although the incidence of postoperative noncardiac complications, including re-intubation, vocal cord paralysis and diaphragmatic paralysis, was similar in a group of children with 22q11 deletion syndrome and those with no genetic abnormality, the incidence of fungal and wound infection was higher in the 22q11 deleted group. Fortunately, mortality did not differ significantly between groups, but this study emphasizes the need for multidisciplinary management of these children [16]. Predicting which patients are likely to suffer from significant T lymphocyte immunodeficiency is important. A study of 64 patients with 22q11 deletion found 48% had no significant infection history, 33% had bacterial infections and 19% had recurrent or persistent candida and/or viral enteritis and bronchiolitis, suggestive of significant T lymphocyte immunodeficiency. Those with candida or viral infections had significantly lower CD4þ and CD8þ T lymphocyte numbers and reduced phytohaemagglutinin mitogen responses than those with bacterial infections. Hypoparathyroidism was associated with T lymphocytopenia and reduced function, as well as an increased risk of infections. The authors suggest that 22q11 deletion syndrome patients with hypoparathyroidism are more likely to have clinically significant T lymphocyte immunodeficiency and lower laboratory parameters of T lymphocyte function with a greater risk of oral candida and viral bronchiolitis and enteritis. The addition of phytohaemagglutinin mitogen responses provided little or no further predictive value in most patients in terms of predicting infectious risk [17]. Volume 25 Number 6 December 2013
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Immunological features of 22q11 deletion syndrome Gennery
22q11 deletion syndrome patients demonstrate postthymic expansion of peripheral T lymphocytes over early childhood compared with normal individuals. McLean-Tooke et al. [18] demonstrated pertubations in the T cell receptor variable beta chain (TCRV beta) repertoire compared with controls, with 67% of 27 22q11 deletion patients showing TCRV-b family repertoire abnormalities. Patients with reduced thymopoiesis had more repertoire abnormalities, suggesting thymic output plays an important role in the diversity of the T lymphocyte receptor repertoire. However, no correlation was found between these immunological results and the incidence of autoimmunity or infection. Most studies of patients with partial immunity in 22q11 deletion syndrome focus on T lymphocyte abnormalities. A multicentre study of 855 patients with 22q11 deletion syndrome examined B lymphocyte function. Nineteen percent had low IgG levels, seven of 855 had undetectable IgA and 27% of patients had low IgM levels. Three percent of patients over 3 years of age required immunoglobulin replacement. Data for infectious episodes associated with hypogammaglobulinaemia were not available. However, the authors highlighted the need for greater consideration of the humoral component of immune deficiency in patients with 22q11 deletion [19 ]. ¨ rk et al. [20 ] examined antibody A study by Bjo deficiency in adults with 22q11 deletion syndrome. Twenty-six adults were studied; six had hypogammaglobulinaemia, four of whom had a pattern consistent with common variable immunodeficiency. Of these, three had reduced T lymphocyte function with a reduced response to mitogen or antigen stimulation. There was an increased incidence of severe infection or autoimmune features in those with a more profound antibody deficiency. Information on immune function in adults with 22q11 deletion syndrome is limited. This study suggests that persistent immunological dysfunction is found in adults and highlights the need for continued follow-up of these patients. A study looking at the responses of inactivated influenza vaccine showed that they were normal in young children, but there were significantly worse T lymphocyte abnormalities in adults, although antibody responses to the vaccine were normal [21]. A case report of an adult patient with sepsis due to Staphylococcus lugdunensis demonstrates that adult patients remain susceptible to unusual and opportunistic infections [22]. &&
&
MALIGNANCY IN 22Q11 DELETION SYNDROME PATIENTS Malignancy, particularly of the lymphoreticular system, is a well-recognized complication of
immunodeficiency, but rarely reported in incomplete 22q11 deletion syndrome. An interesting report of a child with a pulmonary extranodal marginal zone lymphoma of mucosa associated lymphoid tissue is described [23]. With the increased incidence of lymphoma, the occurrence of unusual lymphomas is emphasized in a case report describing an Epstein–Barr virus-positive T lymphocyteassociated lymphoma in a patient with incomplete 22q11 deletion syndrome, unusual in that these are more normally B lymphocyte-associated [24].
AUTOIMMUNITY IN 22Q11 DELETION SYNDROME PATIENTS Autoimmunity is a recognized feature of patients with immunodeficiency. A large study looking at the incidence of autoimmunity in a cohort of 130 paediatric patients with incomplete 22q11 deletion syndrome reported that 8.5% of patients had autoimmune disease [25]. Hypothyroidism was present in 30% and 50% had autoimmune cytopenia, similar to that described in other series. Patients with autoimmunity had lower numbers of T lymphocytes, although many with T lymphocytopenia did not have autoimmune disease. A Norwegian study examined 62 of 86 patients diagnosed with 22q11 syndrome. Fifty-nine patients took part in the study with a median age of 9 years (range 1–54). Seventy-eight percent had frequent infections before the age of 7 years and six had autoimmune disease, all of whom were female. Three had hypothyroidism diagnosed in the 30th decade of life. Of the 59 patients analysed, 48% had detectable autoantibodies against a wide range of autoantigens. Hypoparathyroidism was found in 54% of the patients aged 15 or more. The authors were unable to demonstrate auto-antiparathyroid autoimmunity but concluded that hypoparathyroidism and autoimmunity occurred frequently in the 22q11 deletion population [26].
MANAGEMENT GUIDELINES Athymic 22q11 deletion syndrome is rare, but incomplete 22q11 deletion syndrome is a common condition, with increasing numbers of patients being born to parents who also share the chromosome abnormality. Partial antibody deficiency is a common manifestation of incomplete 22q11 deletion syndrome, which may persist into adulthood, and autoimmunity is also more common than found in the normal population. Malignancy is a rare but recognized risk, particularly associated with lymphoreticular tissue. Therefore, careful follow-up of these patients is required. Guidelines for patient management have recently been published or made available on patients’ websites. Bassett et al.
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[27 ] have written practical guidelines for managing patients with 22q11 deletion syndrome, including a systemic checklist for systems affected in 22q11 deletion. Investigations into immune-related problems, including recurrent infections, impaired T lymphocyte function and autoimmunity, are recommended for infants and children, as well as teens and adults. The key immunological management decisions are as follows: (1) Irradiated, cytomegalovirus-negative blood products if immune status severely affected or unknown. (2) Urgent referral to specialist centre for further treatment if absent or very low T lymphocytes. (3) Assess vaccination status – live viral vaccines not contra-indicated unless severe immunocompromise present. (If Tetanus or Hib responses are normal and CD4 cell count more than 400, should receive Measles, Mumps and Rubella vaccination.) (4) If recurrent respiratory infection – refer to an immunologist to exclude underlying immunodeficiency. (5) Consider antibiotic prophylaxis if recurrent respiratory infection or evidence of poor specific antibody response to vaccine antigens. (6) Patients with recurrent or severe respiratory symptoms should be assessed by a respiratory paediatrician or physician. (7) Regular monitoring for autoimmunity, particularly autoimmune cytopenias and thyroid disease. Special considerations include the administration of influenza vaccination, but also recommendation of a special protocol for infants including minimization of infectious exposures, withholding live vaccines until the immune responses are investigated and use of cytomegalovirus-negative irradiated blood products until immune function has been tested. UK paediatricians have been involved in writing similar guidelines that are available on the Max Appeal website [http://www.maxappeal.org.uk/knowledge/consen sus_document; accessed 12 July 2013 (This important article details optimum multidisciplinary management and has a parent/patient friendly version)].
CONCLUSION 22q11 deletion syndrome is common and patients with complex heart disease are increasingly surviving into adulthood. Adult patients with 22q11 deletion are also being diagnosed. Predominant features include sinopulmonary infections, more 734
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common in early childhood, which may be prevented with prophylactic antibiotics. For a small but significant number of patients, immunoglobulin replacement may be indicated. Autoimmunity is more common within this cohort than in the general paediatric population. The incidence of 22q11 deletion syndrome within the adult population is as yet unknown. Adult patients do have significant immunological problems and should be investigated and followed when identified. National and international guidelines in the management of these patients should aid physicians in making appropriate age-related investigations and treatment. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. 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–e877. 2. Sanlaville D, Etchevers HC, Gonzales M, et al. Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development. J Med Genet 2006; 43:211– 217. 3. Le Lievre CS, Le Douarin NM. Mesenchymal derivatives of the neural crest: analysis of chimeric quail and chick embryos. J Embryol Exp Morphol 1975; 34:125–154. 4. Haynes BF, Heinly CS. Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment. J Exp Med 1995; 181:1445–1458. 5. Poliani PL, Facchetti F, Ravanini M, et al. Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome. Blood 2009; 114:105–108. 6. Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 1997; 34:798–804. 7. Kwan A, Church JA, Cowan MJ, et al. Newborn screening for severe && combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years. J Allergy Clin Immunol 2013; 132:140–150. This article demonstrates that a screening programme introduced to identify patients with SCID will also detect the most severely affected 22q11 deletion syndrome patients. 8. Puck JM. Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: the winner is T-cell receptor excision circles. J Allergy Clin Immunol 2012; 129:607–616. 9. Treleaven J, Gennery A, Marsh J, et al. Guidelines on the use of irradiated blood components prepared by the British Committee for Standards in Haematology blood transfusion task force. Br J Haematol 2011; 152:35–51. 10. Janda A, Sedlacek P, Ho¨nig M, et al. Multicenter survey on the outcome of && transplantation of hematopoietic cells in patients with the complete form of DiGeorge anomaly. Blood 2010; 116:2229–2236. This important article demonstrates that outcome for patients receiving haematopoietic stem cell transplantation is significantly better if they have an HLA-matched sibling donor, but if not, then thymic transplantation should be considered. 11. Markert ML, Devlin BH, Alexieff MJ, et al. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood 2007; 109:4539–4547.
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Immunological features of 22q11 deletion syndrome Gennery 12. Knutsen AP, Baker MW, Markert ML. Interpreting low T-cell receptor excision circles in newborns with DiGeorge anomaly: importance of assessing naive T-cell markers. J Allergy Clin Immunol 2011; 128:1375–1376. 13. Heimall J, Keller M, Saltzman R, et al. Diagnosis of 22q11.2 deletion syndrome & and artemis deficiency in two children with T-B-NKþ immunodeficiency. Clin Immunol 2012; 32:1141–1144. This article highlights that 22q11 deletion syndrome may co-exist with other genetic conditions that confound treatment. 14. Li B, Li J, Devlin BH, Markert ML. Thymic microenvironment reconstitution after postnatal human thymus transplantation. Clin Immunol 2011; 140:244–259. 15. Chinn IK, Milner JD, Scheinberg P, et al. Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)(þ) and FoxP3() T cells in complete DiGeorge anomaly. Clin Exp Immunol 2013; 173:140–149. 16. McDonald R, Dodgen A, Goyal S, et al. Impact of 22q11.2 deletion on the postoperative course of children after cardiac surgery. Pediatr Cardiol 2013; 34:341–347. 17. Herwadkar A, Gennery AR, Moran AS, et al. Association between hypoparathyroidism and defective T cell immunity in 22q11.2 deletion syndrome. J Clin Pathol 2010; 63:151–155. 18. McLean-Tooke A, Barge D, Spickett GP, Gennery AR. Flow cytometric analysis of TCR Vbrepertoire in patients with 22q11.2 deletion syndrome. Scand J Immunol 2011; 73:577–578. 19. Patel K, Akhter J, Kobrynski L, et al., International DiGeorge Syndrome && Immunodeficiency Consortium. Immunoglobulin deficiencies: the B-lymphocyte side of DiGeorge Syndrome. J Pediatr 2012; 161:950–953. This important article describes, for the first time, significant defects in B lymphocyte function in a large cohort of patients with 22q11 deletion syndrome.
´ skarsdo´ttir S, Andersson BA, Friman V. Antibody deficiency in adults 20. Bjo¨rk AH, O with 22q11.2 deletion syndrome. Am J Med Genet A 2012; 158A:1934–1940. This article describes antibody deficiency in a cohort of adult patients. 21. Jawad AF, Prak EL, Boyer J, et al. A prospective study of influenza vaccination and a comparison of immunologic parameters in children and adults with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Clin Immunol 2011; 31:927–935. 22. Hirasaki S, Murakami K, Mizushima T, et al. Successful treatment of sepsis caused by Staphylococcus lugdunensis in an adult with 22q11.2 deletion syndrome. Intern Med 2012; 51:377–380. 23. Pongpruttipan T, Cook JR, Reyes-Mugica M, et al. Pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue associated with granulomatous inflammation in a child with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome). J Pediatr 2012; 161:954–958. 24. Itoh S, Ohno T, Kakizaki S, Ichinohasama R. Epstein–Barr virus-positive T-cell lymphoma cells having chromosome 22q11.2 deletion: an autopsy report of DiGeorge syndrome. Hum Pathol 2011; 42:2037–2041. 25. Tison BE, Nicholas SK, Abramson SL, et al. Autoimmunity in a cohort of 130 pediatric patients with partial DiGeorge syndrome. J Allergy Clin Immunol 2011; 128:1115–1117. 26. Lima K, Abrahamsen TG, Wolff AB, et al. Hypoparathyroidism and autoimmunity in the 22q11.2 deletion syndrome. Eur J Endocrinol 2011; 165:345–352. 27. Bassett AS, McDonald-McGinn DM, Devriendt K, et al., International 22q11.2 && Deletion Syndrome Consortium. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr 2011; 159:332–339. This important article by an international consortium details optimum multidisciplinary management. &
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Immunological features of 22q11 deletion syndrome Andrew R. Gennery
Purpose of review 22q11 deletion syndrome is the most common genetic abnormality. More patients are surviving cardiac surgery, and many do not have cardiac anomalies. Adult patients are now being described. It is important for paediatricians, and increasingly adult physicians, to be aware of the optimum management of these patients. Recent findings Three main immunological patterns are recognized, namely, athymic and incomplete 22q11 deletion syndrome and autoimmunity. Newborn screening for severe combined immunodeficiency detects athymic patients, although diagnosis may be complicated, and instructive cases are described. Incomplete 22q11 deletion syndrome is the most common presentation; new findings predict which patients are likely to experience significant infection. B lymphocyte deficiencies are often overlooked. Data regarding autoimmunity in adult patients is reported, as well as newly reported immunological findings. Finally, management guidelines are now published, and these are highlighted. Summary Newborn screening detects patients with athymic 22q11 deletion syndrome, but significant illness may complicate the picture, and dual diagnoses can confound treatment. Treatment options for these patients are becoming clearer. Hypoparathyroidism is associated with more severe infection, and immunoglobulin abnormalities are more common than previously recognized. Adult patients are symptomatic and management guidelines will help general physicians in managing these patients. Keywords hypogammaglobulinemia, management guidelines, newborn screening, thymic transplantation
INTRODUCTION Chromosome 22q11 deletion (also known as DiGeorge syndrome or velocardiofacial syndrome) is a common genetic disorder affecting approximately 1 : 4000 births. Patients with Coloboma, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and urinary abnormalities and Ear abnormalities and deafness (CHARGE) syndrome due to a hemizygous deletion on CHD7 also have thymic developmental abnormalities and may have similar clinical manifestations to patients with 22q11 deletion syndrome [1]. These syndromes will be considered together in the following review, which will focus on recent findings in immunological defects found in these patients. In 22q11.2 deletion syndrome, no correlation has been found between the clinical phenotype and size of the gene deletion. The pharyngeal arches and pouches form the common embryonic precursor for the thymus, parathyroid glands and conotruncal regions of the heart – all affected in 22q11 deletion syndrome. Defects in organogenesis result from www.co-pediatrics.com
impaired migration of neural crest cells into pouch ectoderm. Disruption in the pathways of neural crest cell development in mice results in malformations similar to the 22q11.2 deletion phenotype. Classic features of 22q11 deletion syndrome have been described in patients with point mutations in TBX1, found within the 22q11.2 region, and with other chromosomal rearrangements including chromosome 10p deletion. The same deletion has also been discovered in other disorders including the velocardiofacial syndrome, conotruncal anomaly face syndrome and sporadic case of Opitz G/BBB syndrome. TBX1 belongs to a family of transcription factors containing a DNA binding domain, ‘T-box’. Mutations in TBX1 lead Institute of Cellular Medicine, Newcastle University, UK Correspondence to Andrew R. Gennery, Old Childrens’ Outpatients, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK. Tel: +44 191 282 5234; fax: +44 191 282 0497; e-mail: [email protected] Curr Opin Pediatr 2013, 25:730–735 DOI:10.1097/MOP.0000000000000027 Volume 25 Number 6 December 2013
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Immunological features of 22q11 deletion syndrome Gennery
KEY POINTS Newborn screening detects athymic 22q11 deletion syndrome, but may be confounded by dual diagnoses. The role of haematopoietic stem cell transplantation and thymic transplantation is evolving in these patients. Hypoparathyroidism is associated with poor T lymphocyte function and B lymphocyte dysfunction is part of 22q11 deletion syndrome. Adults with 22q11 deletion syndrome may be symptomatic with recurrent infection and autoimmunity. Management guidelines will help physicians, parents and patients in optimizing treatment.
to absence or reduction in the fourth pharyngeal arches. CRKL, also found within the common deleted region, encodes an adapter protein implicated in growth factor and adhesion molecular signalling, and is highly expressed in neural crest derived during tissue development. Homozygous deletion of Crkl results in gestational deaths in mice with multiple defects in neural crest derivatives including aortic arch, arteries and craniofacial structures. Compound heterozygosity in murine homologs of these genes results in a more penetrant phenotype compared with heterozygosity at either locus, suggesting that a dose sensitive interaction of these genes may be important to establish the phenotype. Some of the genes within the deleted region of chromosome 22 are critical for the development of pharyngeal, ectoderm, endoderm and mesenchyme, and disruption of these genes leads to disruption of structures of the pharyngeal arch, including the cardiac outflow track as well as parathyroid glands and thymus. CHD7, mutated in CHARGE syndrome, is a chromodomain–helicase–DNA-binding domain family of adenosine - 50 -triphosphate-dependent chromatin remodelling enzymes. CHD7 contributes to nucleosome remodelling and histone deacetylation regulating dynamic changes in chromosome structure during transcription, recombination, repair and replication and in regulating early embryonic development in cellcycle control. CHD7 is expressed throughout the neural crest-containing mesenchyme of pharyngeal arches, and thymic hypoplasia or agenesis is associated with CHARGE syndrome [2]. Thymic mesenchyme derived from pharyngeal arch neural crest cells promotes thymic epithelium development and signalling between the two cell types controlling initial thymic morphogenesis. Mesenchymal cells regulate proliferation and differentiation of immature thymic epithelial cells.
Thymic epithelial differentiation becomes independent of mesenchymal cells once thymic organogenesis is able to support immature thymocytes migrating from bone marrow-derived precursors [3,4]. Molecular interaction between developing lymphoid and thymic epithelial cells is critical for further thymic development. Severely atrophic thymus development with a corticomedullary demarcation is consequent to defects in genes that promote T lymphocyte development, and complete deficiencies of thymocytes in severe combined immunodeficiency (SCID) result in a severely atrophic thymus [5]. Thymocyte development arrested at a later developmental stage leads to normal thymic cortical development but rudimentary medullary regions. Three major immunological concerns can complicate the following 22q11 deletion syndrome. (1) The most severe clinical scenario: complete absence of the thymus, alymphocytosis and SCID-like phenotype. This is rare and affects fewer than 1% of patients with 22q11 deletion [6]. (2) The most common clinical scenario: patients have small, often atopic, thymus development and present with T lymphocytopenia and recurrent sinopulmonary infection in early childhood, which usually resolves by adolescence. (3) An increasingly recognized scenario: autoimmunity, a common feature of many immunodeficiencies.
ATHYMIC 22Q11 DELETION SYNDROME The advent of newborn screening for children with SCID within some states in the United States of America has allowed rapid identification of athymic children with morphological features of 22q11 deletion syndrome [7 ]. Newborn screening detects DNA fragments, markers of T lymphocyte receptor development produced during the variable, diversity and joining gene segment recombination of T and B lymphocyte receptor development [8]. Patients with SCID and those with athymic 22q11 deletion syndrome are unable to generate T lymphocytes, and are therefore detected by newborn screening. Early diagnosis of athymic 22q11 deletion syndrome is important, particularly in those patients who may require cardiac surgery. Such patients should receive irradiated blood products to prevent transfusion-related graft-versus-host disease [9]. Definitive treatment with haematopoietic stem cell transplantation is more successful when a sibling donor is available, although survivors continue to have very low or absent naı¨ve T lymphocytes, reflecting failure of
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Allergy, immunology and related disorders &&
thymopoiesis [10 ]. There is a high risk of graftversus-host disease for these patients, and for those for whom no HLA-matched sibling donor is available thymic transplantation is the curative treatment of choice [11]. Knutsen et al. [12] have reported a patient with athymic 22q11 deletion syndrome, detected on newborn screening with associated T lymphocytopenia at 3 weeks of age prior to cardiac surgery. However, by 8 months of age the absolute lymphocyte count was normal. This patient had normal percentages of CD4þCD45RAþ naı¨ve T lymphocytes, consistent with partial rather than athymic 22q11 deletion syndrome. This case re-affirms the importance of careful immunophenotyping of these patients and early engagement of immunologists in subsequent management. For patients with athymic 22q11 deletion syndrome, thymic transplantation leads to better immunological reconstruction than haematopoietic stem cell transplantation. However, dual genetic diagnoses do need to be considered in patients who have an atypical presentation. Two unrelated infants are reported, who had consistent phenotypic features of athymic 22q11 deletion syndrome with a T-B-NKþ immune phenotype and confirmed 22q11 deletion. However, the first infant underwent thymic transplant but by 6 months following transplantation had not developed recipient naı¨ve T lymphocytes. Further, genetic analysis revealed that both patients had artemis deficiency, a rare form of SCID, for which thymic transplant alone would not be successful [13 ]. The biology of thymic transplantation in patients with 22q11 deletion is incompletely understood. Patients may receive disparate HLA-mismatched thymic stromal cells yet develop immune reconstitution. Such patients give an opportunity to explore thymic development in a unique setting. Thymic microenvironmental reconstitution following thymic transplantation was examined in seven patients who underwent thymic transplant for athymic 22q11 deletion syndrome. Findings suggest that thymic epithelium contains CK14þ progenitor thymic epithelial cells that proliferate as CK14þ CDR2þ thymic epithelial cells following transplantation, associated with cortical fibrocytes. These further differentiate into distinct cortical and medullary epithelia. There is limited information on these athymic patients; these therapies present opportunities to further our understanding of thymic development and anatomy [14]. Patients with 22q11 deletion syndrome develop hypocalcaemia due to hypoparathyroidism secondary to absence of parathyroid glands. Parathyroid transplantation offers a potential cure for this but allografts are likely to be rejected, particularly &
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when immunosuppression is withdrawn. In patients with athymic 22q11 deletion syndrome, parathyroid gland transplantation combined with allogeneic thymus transplantation offers the opportunity for induction of tolerance when there is some matching of the allogeneic thymus graft to the parathyroid donor HLA class II alleles that are not shared with the recipient [15].
INCOMPLETE 22Q11 DELETION SYNDROME Incomplete 22q11 deletion syndrome is more common than athymic 22q11 deletion. Patients have T lymphocytopenia with a reduced number of naı¨ve T lymphocytes. The most common symptoms are sinopulmonary infection in early childhood, which usually resolves as patients reach adolescence. However, given other clinical features of 22q11 deletion syndrome, this partial immunodeficiency may have important implications for patient management. An interesting study on the impact of 22q11 deletion on the postoperative course of treatment after cardiac surgery demonstrated that, although the incidence of postoperative noncardiac complications, including re-intubation, vocal cord paralysis and diaphragmatic paralysis, was similar in a group of children with 22q11 deletion syndrome and those with no genetic abnormality, the incidence of fungal and wound infection was higher in the 22q11 deleted group. Fortunately, mortality did not differ significantly between groups, but this study emphasizes the need for multidisciplinary management of these children [16]. Predicting which patients are likely to suffer from significant T lymphocyte immunodeficiency is important. A study of 64 patients with 22q11 deletion found 48% had no significant infection history, 33% had bacterial infections and 19% had recurrent or persistent candida and/or viral enteritis and bronchiolitis, suggestive of significant T lymphocyte immunodeficiency. Those with candida or viral infections had significantly lower CD4þ and CD8þ T lymphocyte numbers and reduced phytohaemagglutinin mitogen responses than those with bacterial infections. Hypoparathyroidism was associated with T lymphocytopenia and reduced function, as well as an increased risk of infections. The authors suggest that 22q11 deletion syndrome patients with hypoparathyroidism are more likely to have clinically significant T lymphocyte immunodeficiency and lower laboratory parameters of T lymphocyte function with a greater risk of oral candida and viral bronchiolitis and enteritis. The addition of phytohaemagglutinin mitogen responses provided little or no further predictive value in most patients in terms of predicting infectious risk [17]. Volume 25 Number 6 December 2013
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Immunological features of 22q11 deletion syndrome Gennery
22q11 deletion syndrome patients demonstrate postthymic expansion of peripheral T lymphocytes over early childhood compared with normal individuals. McLean-Tooke et al. [18] demonstrated pertubations in the T cell receptor variable beta chain (TCRV beta) repertoire compared with controls, with 67% of 27 22q11 deletion patients showing TCRV-b family repertoire abnormalities. Patients with reduced thymopoiesis had more repertoire abnormalities, suggesting thymic output plays an important role in the diversity of the T lymphocyte receptor repertoire. However, no correlation was found between these immunological results and the incidence of autoimmunity or infection. Most studies of patients with partial immunity in 22q11 deletion syndrome focus on T lymphocyte abnormalities. A multicentre study of 855 patients with 22q11 deletion syndrome examined B lymphocyte function. Nineteen percent had low IgG levels, seven of 855 had undetectable IgA and 27% of patients had low IgM levels. Three percent of patients over 3 years of age required immunoglobulin replacement. Data for infectious episodes associated with hypogammaglobulinaemia were not available. However, the authors highlighted the need for greater consideration of the humoral component of immune deficiency in patients with 22q11 deletion [19 ]. ¨ rk et al. [20 ] examined antibody A study by Bjo deficiency in adults with 22q11 deletion syndrome. Twenty-six adults were studied; six had hypogammaglobulinaemia, four of whom had a pattern consistent with common variable immunodeficiency. Of these, three had reduced T lymphocyte function with a reduced response to mitogen or antigen stimulation. There was an increased incidence of severe infection or autoimmune features in those with a more profound antibody deficiency. Information on immune function in adults with 22q11 deletion syndrome is limited. This study suggests that persistent immunological dysfunction is found in adults and highlights the need for continued follow-up of these patients. A study looking at the responses of inactivated influenza vaccine showed that they were normal in young children, but there were significantly worse T lymphocyte abnormalities in adults, although antibody responses to the vaccine were normal [21]. A case report of an adult patient with sepsis due to Staphylococcus lugdunensis demonstrates that adult patients remain susceptible to unusual and opportunistic infections [22]. &&
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MALIGNANCY IN 22Q11 DELETION SYNDROME PATIENTS Malignancy, particularly of the lymphoreticular system, is a well-recognized complication of
immunodeficiency, but rarely reported in incomplete 22q11 deletion syndrome. An interesting report of a child with a pulmonary extranodal marginal zone lymphoma of mucosa associated lymphoid tissue is described [23]. With the increased incidence of lymphoma, the occurrence of unusual lymphomas is emphasized in a case report describing an Epstein–Barr virus-positive T lymphocyteassociated lymphoma in a patient with incomplete 22q11 deletion syndrome, unusual in that these are more normally B lymphocyte-associated [24].
AUTOIMMUNITY IN 22Q11 DELETION SYNDROME PATIENTS Autoimmunity is a recognized feature of patients with immunodeficiency. A large study looking at the incidence of autoimmunity in a cohort of 130 paediatric patients with incomplete 22q11 deletion syndrome reported that 8.5% of patients had autoimmune disease [25]. Hypothyroidism was present in 30% and 50% had autoimmune cytopenia, similar to that described in other series. Patients with autoimmunity had lower numbers of T lymphocytes, although many with T lymphocytopenia did not have autoimmune disease. A Norwegian study examined 62 of 86 patients diagnosed with 22q11 syndrome. Fifty-nine patients took part in the study with a median age of 9 years (range 1–54). Seventy-eight percent had frequent infections before the age of 7 years and six had autoimmune disease, all of whom were female. Three had hypothyroidism diagnosed in the 30th decade of life. Of the 59 patients analysed, 48% had detectable autoantibodies against a wide range of autoantigens. Hypoparathyroidism was found in 54% of the patients aged 15 or more. The authors were unable to demonstrate auto-antiparathyroid autoimmunity but concluded that hypoparathyroidism and autoimmunity occurred frequently in the 22q11 deletion population [26].
MANAGEMENT GUIDELINES Athymic 22q11 deletion syndrome is rare, but incomplete 22q11 deletion syndrome is a common condition, with increasing numbers of patients being born to parents who also share the chromosome abnormality. Partial antibody deficiency is a common manifestation of incomplete 22q11 deletion syndrome, which may persist into adulthood, and autoimmunity is also more common than found in the normal population. Malignancy is a rare but recognized risk, particularly associated with lymphoreticular tissue. Therefore, careful follow-up of these patients is required. Guidelines for patient management have recently been published or made available on patients’ websites. Bassett et al.
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Allergy, immunology and related disorders &&
[27 ] have written practical guidelines for managing patients with 22q11 deletion syndrome, including a systemic checklist for systems affected in 22q11 deletion. Investigations into immune-related problems, including recurrent infections, impaired T lymphocyte function and autoimmunity, are recommended for infants and children, as well as teens and adults. The key immunological management decisions are as follows: (1) Irradiated, cytomegalovirus-negative blood products if immune status severely affected or unknown. (2) Urgent referral to specialist centre for further treatment if absent or very low T lymphocytes. (3) Assess vaccination status – live viral vaccines not contra-indicated unless severe immunocompromise present. (If Tetanus or Hib responses are normal and CD4 cell count more than 400, should receive Measles, Mumps and Rubella vaccination.) (4) If recurrent respiratory infection – refer to an immunologist to exclude underlying immunodeficiency. (5) Consider antibiotic prophylaxis if recurrent respiratory infection or evidence of poor specific antibody response to vaccine antigens. (6) Patients with recurrent or severe respiratory symptoms should be assessed by a respiratory paediatrician or physician. (7) Regular monitoring for autoimmunity, particularly autoimmune cytopenias and thyroid disease. Special considerations include the administration of influenza vaccination, but also recommendation of a special protocol for infants including minimization of infectious exposures, withholding live vaccines until the immune responses are investigated and use of cytomegalovirus-negative irradiated blood products until immune function has been tested. UK paediatricians have been involved in writing similar guidelines that are available on the Max Appeal website [http://www.maxappeal.org.uk/knowledge/consen sus_document; accessed 12 July 2013 (This important article details optimum multidisciplinary management and has a parent/patient friendly version)].
CONCLUSION 22q11 deletion syndrome is common and patients with complex heart disease are increasingly surviving into adulthood. Adult patients with 22q11 deletion are also being diagnosed. Predominant features include sinopulmonary infections, more 734
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common in early childhood, which may be prevented with prophylactic antibiotics. For a small but significant number of patients, immunoglobulin replacement may be indicated. Autoimmunity is more common within this cohort than in the general paediatric population. The incidence of 22q11 deletion syndrome within the adult population is as yet unknown. Adult patients do have significant immunological problems and should be investigated and followed when identified. National and international guidelines in the management of these patients should aid physicians in making appropriate age-related investigations and treatment. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. 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–e877. 2. Sanlaville D, Etchevers HC, Gonzales M, et al. Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development. J Med Genet 2006; 43:211– 217. 3. Le Lievre CS, Le Douarin NM. Mesenchymal derivatives of the neural crest: analysis of chimeric quail and chick embryos. J Embryol Exp Morphol 1975; 34:125–154. 4. Haynes BF, Heinly CS. Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment. J Exp Med 1995; 181:1445–1458. 5. Poliani PL, Facchetti F, Ravanini M, et al. Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome. Blood 2009; 114:105–108. 6. Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 1997; 34:798–804. 7. Kwan A, Church JA, Cowan MJ, et al. Newborn screening for severe && combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years. J Allergy Clin Immunol 2013; 132:140–150. This article demonstrates that a screening programme introduced to identify patients with SCID will also detect the most severely affected 22q11 deletion syndrome patients. 8. Puck JM. Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: the winner is T-cell receptor excision circles. J Allergy Clin Immunol 2012; 129:607–616. 9. Treleaven J, Gennery A, Marsh J, et al. Guidelines on the use of irradiated blood components prepared by the British Committee for Standards in Haematology blood transfusion task force. Br J Haematol 2011; 152:35–51. 10. Janda A, Sedlacek P, Ho¨nig M, et al. Multicenter survey on the outcome of && transplantation of hematopoietic cells in patients with the complete form of DiGeorge anomaly. Blood 2010; 116:2229–2236. This important article demonstrates that outcome for patients receiving haematopoietic stem cell transplantation is significantly better if they have an HLA-matched sibling donor, but if not, then thymic transplantation should be considered. 11. Markert ML, Devlin BH, Alexieff MJ, et al. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood 2007; 109:4539–4547.
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Immunological features of 22q11 deletion syndrome Gennery 12. Knutsen AP, Baker MW, Markert ML. Interpreting low T-cell receptor excision circles in newborns with DiGeorge anomaly: importance of assessing naive T-cell markers. J Allergy Clin Immunol 2011; 128:1375–1376. 13. Heimall J, Keller M, Saltzman R, et al. Diagnosis of 22q11.2 deletion syndrome & and artemis deficiency in two children with T-B-NKþ immunodeficiency. Clin Immunol 2012; 32:1141–1144. This article highlights that 22q11 deletion syndrome may co-exist with other genetic conditions that confound treatment. 14. Li B, Li J, Devlin BH, Markert ML. Thymic microenvironment reconstitution after postnatal human thymus transplantation. Clin Immunol 2011; 140:244–259. 15. Chinn IK, Milner JD, Scheinberg P, et al. Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)(þ) and FoxP3() T cells in complete DiGeorge anomaly. Clin Exp Immunol 2013; 173:140–149. 16. McDonald R, Dodgen A, Goyal S, et al. Impact of 22q11.2 deletion on the postoperative course of children after cardiac surgery. Pediatr Cardiol 2013; 34:341–347. 17. Herwadkar A, Gennery AR, Moran AS, et al. Association between hypoparathyroidism and defective T cell immunity in 22q11.2 deletion syndrome. J Clin Pathol 2010; 63:151–155. 18. McLean-Tooke A, Barge D, Spickett GP, Gennery AR. Flow cytometric analysis of TCR Vbrepertoire in patients with 22q11.2 deletion syndrome. Scand J Immunol 2011; 73:577–578. 19. Patel K, Akhter J, Kobrynski L, et al., International DiGeorge Syndrome && Immunodeficiency Consortium. Immunoglobulin deficiencies: the B-lymphocyte side of DiGeorge Syndrome. J Pediatr 2012; 161:950–953. This important article describes, for the first time, significant defects in B lymphocyte function in a large cohort of patients with 22q11 deletion syndrome.
´ skarsdo´ttir S, Andersson BA, Friman V. Antibody deficiency in adults 20. Bjo¨rk AH, O with 22q11.2 deletion syndrome. Am J Med Genet A 2012; 158A:1934–1940. This article describes antibody deficiency in a cohort of adult patients. 21. Jawad AF, Prak EL, Boyer J, et al. A prospective study of influenza vaccination and a comparison of immunologic parameters in children and adults with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Clin Immunol 2011; 31:927–935. 22. Hirasaki S, Murakami K, Mizushima T, et al. Successful treatment of sepsis caused by Staphylococcus lugdunensis in an adult with 22q11.2 deletion syndrome. Intern Med 2012; 51:377–380. 23. Pongpruttipan T, Cook JR, Reyes-Mugica M, et al. Pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue associated with granulomatous inflammation in a child with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome). J Pediatr 2012; 161:954–958. 24. Itoh S, Ohno T, Kakizaki S, Ichinohasama R. Epstein–Barr virus-positive T-cell lymphoma cells having chromosome 22q11.2 deletion: an autopsy report of DiGeorge syndrome. Hum Pathol 2011; 42:2037–2041. 25. Tison BE, Nicholas SK, Abramson SL, et al. Autoimmunity in a cohort of 130 pediatric patients with partial DiGeorge syndrome. J Allergy Clin Immunol 2011; 128:1115–1117. 26. Lima K, Abrahamsen TG, Wolff AB, et al. Hypoparathyroidism and autoimmunity in the 22q11.2 deletion syndrome. Eur J Endocrinol 2011; 165:345–352. 27. Bassett AS, McDonald-McGinn DM, Devriendt K, et al., International 22q11.2 && Deletion Syndrome Consortium. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr 2011; 159:332–339. This important article by an international consortium details optimum multidisciplinary management. &
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