Autoimmune lymphoproliferative syndrome is a disorder of lymphoid system regulation characterized by chronic splenomegaly, lymphadenopathy and autoimmune phenomena especially immune-mediated cytopenias. The hallmark of the disease is the presence in peripheral blood and lymphoid tissue of increased numbers of a normally rare T lymphocyte subset, usually referred to as “double-negative” T cells. Here the authors report a 16-year-old boy when he was first hospitalized for diffuse petechiae, purpura and epistaxis at 9 years of age.One year later,he was readmitted for high fever and recurring cytopenia. On examination several enlarged, nontender lymph nodes involving cervical and submandibular areas and a huge spleen were detected.Lymph node biopsy was performed two times. According to flowcytometry of peripheral blood and immunophenotyping of lymph node tissues which revealed increased numbers of CD3+CD4-CD8-T lymphocytes, autoimmune lymphoproliferative syndrome was suggested for him. Autoimmune lymphoproliferative syndrome should be considered in differential diagnosis of any patient with unexplained Coomb’s positive cytopenias, hypergammaglobulinemia, generalized lymphadenopathy and splenomegaly. The confirmation of the diagnosis should be based upon genetic analysis and detection of the affected genes involved in fas pathway

Maryam Esteghamati

Mohammad Taghei Arzanian

Samin Alavi

Zahra Chavoshzadeh

Iranian Journal of Allergy Asthma and Immunology

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Vol. 4, No. 3, September 2005        IRANIAN JOURNAL OF ALLERGY, ASTHMA AND IMMUNOLOGY /149 Autoimmune Lymphoproliferative Syndrome; A Case Report  Samin Alavi1, Mohammad Taghi Arzanian1, Zahra Chavoshzadeh2, and Maryam Esteghamati1  1 Department of Pediatric Hematology/Oncology, Shaheed Beheshti Medical University, Tehran, Iran 2 Department of Pediatric Immunology, Shaheed Beheshti Medical University, Tehran, Iran  ABSTRACT  Autoimmune lymphoproliferative syndrome is a disorder of lymphoid system regulation characterized by chronic splenomegaly, lymphadenopathy and autoimmune phenomena especially immune-mediated cytopenias. The hallmark of the disease is the presence in peripheral blood and lymphoid tissue of increased numbers of a normally rare T lymphocyte subset, usually referred to as “double-negative” T cells. Here the authors report a 16-year-old boy when he was first hospitalized for diffuse petechiae, purpura and epistaxis at 9 years of age.One year later,he was readmitted for high fever and recurring cytopenia. On examination several enlarged, nontender lymph nodes involving cervical and submandibular areas and a huge spleen were detected.Lymph node biopsy was performed two times. According to flowcytometry of peripheral blood and immunophenotyping of lymph node tissues which revealed increased numbers of CD3+CD4-CD8- T-lymphocytes autoimmune lymphoproliferative syndrome was suggested for him. Autoimmune lymphoproliferative syndrome should be considered in differential diagnosis of any patient with unexplained Coomb’s positive cytopenias, hypergammaglobulinemia, generalized lymphadenopathy and splenomegaly. The confirmation of the diagnosis should be based upon genetic analysis and detection of the affected genes involved in fas pathway.  Keywords: Autoimmunity; Lymphadenopathy; Pancytopenia; Splenomegaly    INTRODUCTION  Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder in children  characterized  by splenomegaly, massive lymphadenopathy, autoimmune phenomena such as thrombocytopenia, neutropenia, hemolytic anemia and accumulation of double-negative (CD3+CD4-CD8-)T cells in the blood.1,2 In the majority of patients, ALPS is due to inherited mutations in genes encoding  proteins of  the Fas  pathway, which mediates programmed cell death or apoptosis.3 The ALPS phenotype is associated with inherited mutations in the CD95 gene (ALPS Type Ia) or the CD95 ligand gene (ALPS Type Ib).   Corresponding Author: Samin Alavi, MD;  Mofid Children’s Hospital, Shaheed Beheshti Medical University, Tehran, Iran. Tel: (+98 21) 2222 7020-9, Fax: (+98 21) 2222 0254,  E-mail:saminalavi@hotmail.com In ALPS Type II, a more severe clinical phenotype is presumed to be caused by an undefined inherited gene defect in the absence of mutations in the CD95 or CD95 ligand genes.4 Heterozygous dominant mutations of Fas gene were found in children with the autoimmune lymphoproliferative syndrome, which is also known as the Canale-Smith syndrome. The main clinical features of this disease are splenomegaly, lymphadenopathy, hypergammaglobulinemia, and autoimmunity.5 Characteristic laboratory features of ALPS include: Defective lymphocyte apoptosis,the accumulation of double-negative (CD3+ CD4- CD8-) T lymphocytes, and heterozygous mutations in CD95-CD95 ligand genes.4 This report describes a 16-year-old boy which based on clinical and laboratory findings ALPS was suggested for him.     Autoimmune Lymphoproliferative Syndrome 150/ IRANIAN JOURNAL OF ALLERGY, ASTHMA AND IMMUNOLOGY              Vol. 4, No. 3, September 2005 CASE REPORT  This patient was a 9-year-old boy when he was first hospitalized for diffuse petechiae, purpura and epistaxis of one week’s duration. On examination, there were extensive purpuric lesions over the upper neck and extremities and the spleen was palpable 2-3 cm below costal margin. Initial complete blood count showed Coomb’s positive hemolytic anemia and severe thrombocytopenia. A bone marrow aspiration was performed which revealed increased megakaryocytic and erythroid series. According to above mentioned findings, Evans syndrome was suggested for the patient and corticosteroids (prednisolone 2mg/Kg/day) plus Intravenous Immunoglobulin was started. After 1 month, in an attempt to taper corticosteroids, thrombocytopenia again developed, so this time Cyclosporin, an immunosuppressive drug was started. One year later, he was readmitted for high fever and recurring cytopenia. On examination several enlarged, nontender lymph nodes involving cervical and submandibular areas and a huge spleen were detected. Chest x-Ray revealed bilateral hilar lymphadenopathy and abdominal ultrasonography showed multiple para-aortic lymph nodes. Severe thrombocytopenia and splenomegaly required splenectomy. Serologic tests for Epstein-Barr virus, Cytomegalovirus and HIV were all negative. Because of persistent lymphadenopathy, lymph node biopsy was performed two times at different intervals, suggestive of “nonspecific follicular hyperplasia”, each time. There was no evidence of malignancy. Repeated bone marrow aspirations were not diagnostic. Flowcytometry of peripheral blood reported increased numbers of CD3+CD4–CD8– T cells (65%).Repeated flowcytometry confirmed this result. Immunohistochemistry of lymph node tissues also showed the same increased double-negative T cells. ALPS was suggested for the patient and he was planned to receive different immunosuppressive drugs. There was a waxing and waning course in his disease. He expired at the age of 16 years due to recurring cytopenia and overwhelming sepsis.  DISCUSSION  Autoimmune lymphoproliferative syndrome is a recently recognized disease which has been defined using a combination of clinical, laboratory and molecular findings. ALPS can cause significant morbidity.2 In some patients solid or hematologic malignancies, including Hodgkin’s and Non-Hodgkin’s lymphoma also develop.6 Three criteria  have been  proposed by the National Institute of  Health ALPS group for diagnosis of ALPS:1) Chronic accumulation of nonmalignant lymphoid cells 2) An increase in DNT cells in the blood, and  3)Defective in vitro Fas-mediated apoptosis.7 In our reported case, all of the above mentioned findings resulted in a broad range of differential diagnosis which included infections, metabolic diseases, hematolymphoid malignancies and other heritable immune disorders such as common variable immune disorders and Wiskott-Aldrich syndrome.3 In this regard; a diagnostic workup for infections such as tuberculosis, toxoplasmosis and infectious mononucleosis was performed. He even received treatment for toxoplasmosis because of hypergammaglobulinemia and a positive titer for toxoplasma gondii (IgG indirect fluorescent antibody), although there was no change in size of lymph nodes and clinical course of the disease. We also performed multiple bone marrow aspirations and bone marrow biopsy to rule out possible  involvement of the bone marrow as these patients are predisposed to the development  of Hodgkin or Non-Hodgkin’s lymphoma.1,2 Defective T lymphocyte apoptosis results in expansion of activated T and double-negative T cells (DNT)-cell populations, while defective B cell apoptosis mediates  hypergamma-globulinemia and increased survival of  antibody  producing B cells.8.9 In the clinical laboratory, the hallmark of ALPS is the presence in peripheral blood and lymphoid tissue of increased numbers of a normally rare T lymphocyte subset, usually referred to as “double-negative” T (DNT) cells, that lack both the CD4 and CD8 surface molecules.3 In normal persons,less than 2 percent of CD3+ T cells are double negative.1 In our case positive Coomb’s test and  hypergammaglobulinemia seemed to be the result of the defect in apoptotic pathways as he showed evidence of DNT cells in flowcytometry of peripheral blood and immunophenotyping of lymph node tissues. In the majority of patients, ALPS is due to inherited mutations in genes encoding proteins of the Fas pathway, which mediates programmed cell death or apoptosis. Apoptosis limits lifespan of S. Alavi, et al. Vol. 4, No. 3, September 2005        IRANIAN JOURNAL OF ALLERGY, ASTHMA AND IMMUNOLOGY /151 peripheral B and T lymphocytes and eliminates autoreactive T-cell clones.3,4 Fas also called Apo-1 or CD95 is a cell surface receptor belonging to the tumor necrosis factor receptor superfamily (TNFRSF6); once triggered by its ligand (Fas ligand), Fas initiates a cascade of events within the cell that culminates in the death of the cell. Fas pathway has a crucial role in lymphocyte homeostasis.1,2,4 Heterozygous dominant mutations of Fas were found in children with ALPS, which is also known as Canale-Smith syndrome.4,5,10 The Canale-Smith syndrome, first described in 1967,is an uncommon cause of lymphadenopathy in children. Patients with this syndrome present within the first two years of life with lymphadenopathy, hepatosplenomegaly, hemolytic anemia and thrombocytopenia.5,11 Lymph node biopsy reveals nonspecific paracortical hyperplasia with increased numbers of lymphocytes,plasma cells and histiocytes.3,4 In our patient, biopsy of lymph nodes was interpreted as “follicular hyperplasia”, without evidence of conversion to Non-Hodgkin’s Lymphoma. In a report from division of pediatrics, university of Pennsylvania, 4 cases with Canale-Smith syndrome have been described. 2 out of 4 cases were 8-year old boys who presented with lymphadenopathy and splenomegaly, respectively. Autoimmune hemolytic anemia and thrombocytopenia developed at the age of 8 months in one of them and at 10 months of age in the other one.8 Immunophenotypic analysis of T cells for 4 of 5 patients with ALPS revealed that all had higher levels of DNT cells.3 The major medical complications in infancy and childhood are autoimmune pancytopenia and infections due to splenectomy or neutropenia, so treatment with corticosteroids and immuno-suppressive drugs can reduce the degree of lymphadenopathy and improve the cytopenia.10 In the oldest report by Canale and Smith most of the patients underwent splenectomy.10,11 In our patient splenectomy was performed because of mechanical embarrassment  and worsening thrombocytopenia. He expired due to overwhelming sepsis while receiving immunosuppressive drugs. In closing, it is  noteworthy  that our patient  fulfilled most of the criteria required for the diagnosis of ALPS, even though we could not evaluate in vitro defect of lymphocyte apoptosis or detect the affected gene due to lack of these technologies in our university. It is strongly advised that immuno-hematology departments should be equipped with such facilities for confirmation of diagnosis and investigational purposes. Finally, ALPS should be considered in differential diagnosis of infants and children presenting with splenomegaly, lympha-denopathy and otherwise unexplained cytopenia. Suspicion should be heightened if cytopenia is immune mediated.3 Greater awareness of ALPS should result in a more directed diagnostic approach and earlier initiation of treatment for this disease.  REFERENCES  1. Clementi R, Dagna L, Dianzani U, Dupre L, Dianzani I, Ponzoni M, et al. Inherited perforin and Fas Mutations in a patient with Autoimmune Lymphoproliferative Syndrome and Lymphoma. N Engl J Med 2004; 351(14):1419-24. 2. Aspinall AI, Pinto A, Auer IA, Bridges P, Luider J, Dimnik L, et al. Identification of New Fas Mutations in a patient with Autoimmune Lymphoproliferative Syndrome (ALPS) and Eosinophilia. Blood cells Mol Dis 1999; 25(3-4):227-38. 3. Alvarado CS, Straus SE, Li S, Dale JK, Mann K, Le A, et al. Autoimmune Lymphoproliferative Syndrome:A cause of chronic splenomegaly,lymphadenopathy,and cytopenias in children-Report on Diagnosis and Management of Five Patients. Pediatr Blood Cancer 2004; 43(2):164-9. 4. Martin DA, Zheng L, Siegel RM, Huang B, Fisher GH, Wang J, et al. Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia. Proc Natl Acad Sci U S A 1999; 96(8):4552-7.  5. Holzelova E, Vonarbourg C, Stolzenberg MC, Arkwright PD, Selz F, Prieur AM, et al. Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med 2004; 351(14):1409-18.  6. Straus SE, Jaffe ES, Puck JM, Dale JK, Elkon KB, Rosen-Wolff A, et al. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 2001; 98(1):194-200. 7. Sneller MC, Dale JK, Straus SE. Autoimmune lymphoproliferative syndrome. Curr Opin Rheumatol 2003; 15(4):417-21. 8. Lopatin U, Yao X, Williams RK, Bleesing JJ, Dale JK, Wong D, et al. Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lympho-Autoimmune Lymphoproliferative Syndrome 152/ IRANIAN JOURNAL OF ALLERGY, ASTHMA AND IMMUNOLOGY              Vol. 4, No. 3, September 2005 proliferative syndrome are associated with disease expression. Blood 2001; 97(10):3161-70. 9. Fuss IJ, Strober W, Dale JK, Fritz S, Pearlstein GR, Puck JM, et al. Characteristic T helper 2 T cell cytokine abnormalities in autoimmune lymphoproliferative syndrome, a syndrome marked by defective apoptosis and humoral autoimmunity. J Immunol 1997; 158(4):1912-8. 10. Drappa J, Vaishnaw AK, Sullivan  KE, Chu JL, Elkon KB. Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med 1996; 335(22):1643-9.  11. Canale VC, Smith CH. Chronic lymphadenopathy simulating malignant lymphoma. J Pediatr 1967; 70(6):891-9.  

Autoimmune Lymphoproliferative Syndrome; A Case Report

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