CLINICAL

AND

LABORATORY OBSERVATIONS

Autoimmune Thrombocytopenic Purpura in Partial DiGeorge Syndrome: Case Presentation

ndez-Nieto, MD,* Marco Antonio Yamazaki-Nakashimada, MD,* Leticia Herna Esther Lieberman-Hernandez, MD,w and Sara Elva Espinosa-Padilla, MDz

Summary: The absence of an appropriate central tolerance in primary immunodeciencies favors proliferation of autoreactive lymphocyte clones, causing a greater incidence of autoimmunity. Del 22q11.2 syndrome presents an increased incidence of allergic and autoimmune diseases. One of the most relevant and frequent immune manifestations is autoimmune thrombocytopenia. We present the case of a pediatric patient with autoimmune thrombocytopenia due to the immunological dysregulation observed in partial DiGeorge syndrome. Key Words: autoimmune thrombocytopenia, DiGeorge syndrome, autoimmunity, primary immunodeciency

(J Pediatr Hematol Oncol 2011;33:465466)

he 22q11.2 deletion syndrome is one of the most common chromosomic entities; its prevalence ranges from 1:7000 to 1:2000 newborns.1,2 It includes various syndromes (DiGeorge, Sedlackova, Shprintzen or velocardiofacial syndrome) that overlap in a continuous clinical spectrum. The clinical manifestations are broad and the immunologic compromise also has a variable presentation: cellular, humeral or an altered regulation. The DiGeorge sequence includes hypoparathyroidism, absent thymus, and conotruncal congenital heart disease, which is called complete DiGeorge syndrome. Partial DiGeorge syndrome is an incomplete presentation that includes a variety of clinical phenotypes of 22q11.2 deletion with various immunologic defects. It has been described that approximately 80% of the patients present with a diminished number of T lymphocytes due to thymic alteration,3 and in some cases autoimmunity can be observed.

referred to the Immunology Department at the age of 5 years. Initial studies showed hypergammaglobulinemia, elevated IgE, hypocomplementemia and a platelet count of 140,000/mL. She was screened for immunologic alterations, which showed positive anticardiolipins IgM 150 U/Mpl (0 to 12 U/Mpl) and positive antinuclear antibodies; therefore, it was decided to start hydroxycloroquine and acetyl-salicylic acid due to positive serology. After a few months, acetyl-salicylic acid was discontinued because of frequent bruising and she was kept under surveillance. When she turned 6 years she relapsed with a severe thrombocytopenia, a platelet count of 2000/mL, and splenomegaly 2 cm below the costal border with no signs of active bleeding. Systemic evaluation ruled out other organ involvement and treatment with cyclophosphamide and steroid was initiated with adequate response. After 2 years, she developed arthralgia, again the platelet count diminished, suspecting the possibility of a systemic lupus erythematosus, which was ruled out; there was no other organ alteration and the serology was negative (Table 1). Owing to the autoimmune process, the frequent upper airway infections, and velopharyngeal incompetence, DiGeorge syndrome was suspected. Genetic evaluation was done with intentional search of the clinical features of the disease, revealing short stature, long face, narrow palpebral ssures, prominent nose, malar atness, bid uvula, nasal voice, velopharyngeal incompetence with normal mental status. Studies for parathyroid hormones were normal. Genetic study found uorescence in situ hybridization test positive for 22q11.2 deletion, whereas both her parents showed negative result. Immunologic evaluation showed diminished levels of T lymphocytes (Table 1). Owing to autoimmune thrombocytopenia, steroids and azathioprine were indicated and due to recurrent infections, prophylaxis with TABLE 1. Laboratory Results

Laboratory Studies
DNAn antibodies Sm antibodies C3 (initial) C4 (initial) Total lymphocytes CD3+ CD4+ CD8+ CD19+

Result
Negative Negative 43 mg/dL 7 mg/dL 24% Total 792 67% Total 531 49% Total 260 42% Total 224 12.7% Total 101 24.7% Total 196 9.0 mg/dL 4.5 mg/dL 5 mg/dL 1631 mg/dL 82.5 mg/dL 130.2 mg/dL 924 UI/mL

Reference Value
Negative Negative 55-128 mg/dL 19-58 mg/dL 36-43% Total 2000-2700 66-76% 1400-2000 33-41% Total 700-1100 27-35% Total 600-900 12-22% 300-500 10-19% 200-400 8.5-10.2 mg/dL 4.4-6 mg/dL 2.5-5 mg/dL 607-1228 mg/dL 45-196 mg/dL 35-198 mg/dL 0-52 U/mL

CASE REPORT
A 13-year-old girl was referred to our institution at the age of 8 months due to persistent ductus arteriosus and renal agenesis for cardiac surgical correction. At the age of 2 years, she developed autoimmune thrombocytopenia (gingival bleeding, petechiaes, and a platelet count of 62,000/mL). She was treated with a course of prednisone (2 mg/kg/d) with remission of the symptoms and normalization of the platelets count. During the next few years, she presented with recurrent upper airway infections and was
Received for publication December 17, 2010; accepted March 17, 2011. From the *Department of Immunology, Instituto Nacional de Pediatria; wDepartment of Genetics, Instituto Nacional de Pediatr a; and zPrimary Immunodeciency Research Unit, Instituto Nacional de Pediatr a, Mexico City, Mexico. The authors declare no conict of interest. Reprints: Marco Antonio Yamazaki-Nakashimada, MD, Instituto Nacional de Pediatr a, Insurgentes Sur 3400-C, Col. Insurgentes Cuicuilco, ZC 04530, Mexico City, Mexico (e-mail: yamazakimarco@gmail. com). Copyright r 2011 by Lippincott Williams & Wilkins

CD16/56+ Ca Ca (i) P IgG IgA IgM IgE

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azitromycin was begun. Clinical response was good. Splenomegaly remitted, anticardiolipins serology became negative, and hypocomplementemia resolved being able to taper and suspend steroids. The actual platelet count number was maintained at 150,000/mL.

REFERENCES
1. Shprintzen RJ. Velo-cardio-facial syndrome: 30 years of study. Dev Disabil Res Rev. 2008;14:310. 2. Robin N, Shprintzen R. Dening the clinical spectrum of deletion 22q11.2. J Pediatr. 2005;147:9096. 3. Sullivan K. Chromosome 22q11.2 Deletion syndrome: DiGeorge Syndrome/Velocardiofacial syndrome. Immunol Allergy Clin North Am. 2008;28:353366. 4. Goyal R, Bulua AC, Nikolov NP, et al. Rheumatologic and autoimmune manifestations of primary immunodeciency disorders. Curr Opin Rheumatol. 2009;21:7884. 5. Chang A, Achdjian R, Gallagher K, et al. Type III mixed cryoglobulinemia and antiphospolipid syndrome in a patient with partial DiGeorge syndrome. Clin Dev Immunol. 2006;13:261264. 6. Nucera C, Vaccaro M, Moleti M, et al. Antiphospolipid antibodies syndrome associated with hyperohomocysteinemia related to MTHFR gene C677T and A1298C heterozygous mutations in a young man with idiopathic hypoparathyroidism (DiGeorge Syndrome). J Clin Endocrinol Metab. 2006;91: 20212026. 7. Gottlieb C, Li Z, Uzel G, et al. Uveitis in DiGeorge syndrome: a case of autoimmune ocular inammation in a patient with deletion 22q11.2. Ophtalmic Genet. 2010;31:2429. 8. Brown JJ, Datta V, Browning M, et al. Graves disease in DiGeorge syndrome: patient report with a review of endrocrine autoimmunity associated with 22q.11.2 deletion. J Pediatr Endrocrinol Metab. 2004;17:15751579. 9. Kawamura T, Nimura I, Hanafusa M, et al. DiGeorge syndrome with Graves disease: a case Report. Endocr J. 2000;47:9195. 10. Davies K, Stiehm ER, Woo P, et al. Juvenile idiopathic polyarticular arthritis and IgA deciency in the 22q11 deletion syndrome. J Rheumatol. 2001;28:23262334. 11. Davies JK, Telfer P, Cavenagh JD, et al. Case report Autoimmune cytopenias in the 22q11.2 deletion syndrome. Clin Lab Haematol. 2003;25:195197. 12. Jawad AF, McDonald-McGinn D, Zackai E, et al. Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Pediatr. 2001;139:715723. 13. Akar NA, Adekile AD. Chromosome 22q.11.2 deletion presenting with immune-mediated cytopenias, macrothrombocytopenia and platelet dysfunction. Med Princ Pract. 2007;16: 318320. 14. Shah SS, Lai SY, Ruchelli E, et al. Retropharyngeal aberrant thymus. Pediatrics. 2001;108:E94. 15. McLean-Tooke A, Spickett GP, Gennery AR. Immunodeciency and Autoimmunity in 22q11.2 deletion syndrome. Scand J Immunol. 2007;66:17. 16. Gennery A, Barge D, OSullivan J, et al. Antibody deciency and autoimmunity in 22q11.2 deletion syndrome. Arch Dis Child. 2002;86:422425. kova J, Zachova R, et al. Early development of 17. Bartu n immunity in DiGeorge syndrome. Med Sci Monit. 2005;11: CR182CR187. 18. Sullivan K, Mc Donald-Mc Ginn D, Zackai E. CD4(+) CD25(+) T-Cell production in healthy humans and in patients with thymic hypoplasia. Clin Diagn Lab Immunol. 2002;9: 11291131. 19. Kanaya Y, Ohga S, Ikeda K, et al. Maturational alterations of peripheral T cell subsets and cytokine gene expression in 22q11.2deletion syndrome. Clin Exp Immunol. 2006; 144:8593. 20. Zemble R, Luning Prak E, McDonald-McGinn D, et al. Secondary immunologic consequences in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Immunol. 2010;136:409418.

COMMENT
Many primary immunodeciencies can be complicated by autoimmunity, being common in Wiskott-Aldrich Syndrome, common variable immunodeciency, and hyper IgM, among others.4 Autoimmunity processes in patients with del22q11.2 are diverse: antiphospolipid syndrome,5,6 ocular autoimmunity,7 endocrine autoimmunity,8,9 juvenile idiopathic polyarthritis,10 and autoimmune cytopenias.11 Frequency of autoimmune thrombocytopenia in patients with 22q11.2 deletion is higher than in the general population12 and considered to be 200 times more frequent.13 The autoimmunity mechanism in 22q11.2 deletion has not been elucidated yet. It is known that the thymus inhibits autoreactive cells from entering the circulation. Although complete DiGeorge syndrome has an absent thymus, the partial syndrome can have an aberrant localization that allows lymphocyte development.14 Besides a thymic alteration, peripheral mechanisms through anergy or deletion could be disrupted in immunodeciencies causing an increased incidence of autoimmunity.15 Thymus implication for auto-tolerance seems to be essential15 and it is suggested that thymic hypoplasia causes a decient T cell education16 with an altered negative selection allowing the survival of autoreactive clones. The homeostatic expansion in these autoreactive clones and T cells with low anity can be an explanation,3 T cells have a diminished number and the repertoire seems to be restricted.12 Studies suggest that proliferation is greater in patients with 22q11deletion than in control population after stimulus,17 but the cellular response comparing patients with and without autoimmunity showed no dierence.12 Another relevant aspect for autoimmunity are the regulatory T cells (T reg or CD4+CD25+), the production of which seems to be altered by thymic hypoplasia during infancy. Even though they are present, they seem to be markedly diminished, which can be an important predisposing factor for autoimmune diseases.18 Taking this into consideration theoretically Foxp3, the gene that regulates CD4+CD25+, could be diminished in del22q11.2; nevertheless no statistical dierence was observed in Foxp3 gene expression between patients and control population. However, with aging patients over 6 years show a diminished expression of the gene, suggesting that through the years there is an insucient production of T reg.19 Lymphocyte B population has also being analyzed, studies show diminished memory cells that could result from T cell compartment dysregulation.20

CONCLUSION
Autoimmunity and immunodeciency is not an unusual association and it is a complex one. Although the most common presentation is autoimmunity following the primary immunodeciency, the autoimmune aection can be the initial presentation. The del22q11.2 phenotype being so variable, the suggestive features of DiGeorge syndrome can be mild and outlooked. As other researchers have commented recurrent or combined immune cytopenias in children can be the initial manifestation of a partial DiGeorge syndrome. Autoimmunity-immunodeciency is a clinical scenario that makes treatment more complicated due to the need for immunosuppression in a patient, who is predisposed to infections. Each case requires an individual approach, but the use of a low-to-moderate immunomodulation associated with prophylaxis may favor clinical improvement as in our case.

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