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Year : 2014  |  Volume : 15  |  Issue : 3  |  Page : 144-146

Autoimmune lymphoproliferative syndrome presenting as urticaria

Department of Paediatrics, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India

Date of Web Publication30-Oct-2014

Correspondence Address:
Parveen Bhardwaj
Department of Pediatrics, Indira Gandhi Medical College, Shimla, Himachal Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2319-7250.143677

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Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder characterized by chronic splenomegaly, lymphadenopaphy hypergammaglobulinemia and autoimmune phenomena especially immune-mediated cytopenias. The disease is characterized by presence of "double-negative (CD3 + CD4 CD8 )" T-cells in the peripheral blood and lymphoid tissue. Rarely it can also present as urticaria. We report a child of ALPS who presented to us with fever, generalized lymphadenopathy, chronic urticaria and hepatosplenomegaly.

Keywords: Autoimmune lymphoproliferative syndrome, double-negative T-cells, urticaria

How to cite this article:
Yadav V, Bhardwaj P. Autoimmune lymphoproliferative syndrome presenting as urticaria. Indian J Paediatr Dermatol 2014;15:144-6

How to cite this URL:
Yadav V, Bhardwaj P. Autoimmune lymphoproliferative syndrome presenting as urticaria. Indian J Paediatr Dermatol [serial online] 2014 [cited 2020 Sep 20];15:144-6. Available from: http://www.ijpd.in/text.asp?2014/15/3/144/143677

  Introduction Top

Autoimmune lymphoproliferative syndrome (ALPS) also known as Canale-Smith syndrome 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] It is an inherited lymphoid disorder which results from mutations in molecules involved in the Fas-Fas ligand pathway. [3]

We present this case as ALPS is a rare disease, and very few cases have been reported from India and none with dermatological presentation in the form of chronic urticaria.

  Case report Top

A 6-year old female child was admitted with a history of intermittent episodes of low-grade fever, arthritis of knee joints and urticaria for last 1 year [Figure 1]. The family, birth, and developmental histories were uneventful. On examination, her blood pressure was more than 95 th centile. Her general physical examination showed moderate pallor and generalized Lymphadenopathy (LAP) of size 2-3 cm, nontender, mobile, not fixed to underlying structures. Her weight was 15 kg (˂3 rd percentile), height and head circumference were normal. On skin examination, she had features of chronic urticaria and her systemic examination revealed hepatosplenomegaly (liver was 4 cm below costal margin [BCM] with span of 11.5 cm, spleen was 5 cm BCM). Rest of the systemic examination was normal.
Figure 1: Facial urticaria

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Investigation: Complete blood count revealed leukocytosis (15,900/mm 3 ) with neutrophillia of 80%, red blood cell-count of 3.65 m/mm 3 with thrombocytopenia (67,000/mm 3 ), and erythrocyte sedimentation rate was 40 mm/h. Tuberculin test was nonreactive. Kidney function tests, liver function tests, lipid profile, calcium, phosphorus and fibrinogen were normal. Direct coombs test was positive. Chest X-ray revealed mediastinal lymphadenopathy and ultrasonography abdomen was showing moderate splenomegaly, hepatomegaly, and abdominal LAP. Urine microscopy was showing microscopic hematuria with albuminuria of Grade 1. Urinary 24 h protein was 12 mg/m 2 /h, urine culture was sterile. Hepatitis B surface antigen was negative, HIV enzyme-linked immunosorbent assay was nonreactive. C3 was in normal range, ANA, DsDNA were negative. Serology for (Epstein-Barr virus) was negative. Fine-needle aspiration cytology of inguinal node revealed benign lymphoidal hyperplasia. Immunoglobulins levels (by immunoturbidimetry) - IgA-379 mg/dl (35-200) IgG-1749 mg/dl (460-1240). Peripheral blood lymphocytes were analyzed by flow cytometry (by single platform bead based assay) CD3 + 86%, CD 4+ 57%, CD 8+ 23%, CD 3+ CD 4− /CD 8− (double-negative T-cells) were 6.92% (normally in healthy individuals it is <1%). Bone marrow aspiration showed-M:E (3:1), Dimorphic erythropoisis, with normal megakaryocytes and myelogram. Based on the duration of more than 6 months and clinical features of lymphadenopathy with hepatosplenomegaly, chronic urticaria and arthritis and lab findings of benign lymphoidal hyperplasia, raised circulating double-negative T-cells (6.92%), bicytopenia and increased IgG, the patient was diagnosed to have probable ALPS according to Revised Diagnostic Criteria for ALPS [Table 1]. [4] We could not perform T-cell receptor (TCR) alpha beta expression due to lack of availability of this test at our center. She was started on oral steroid, 1 mg/kg/day in two divided doses, during her regular follow-up after 3 months of steroids, her lymph nodes size has decreased, and hepatosplenomegaly has resolved. Urticaria has also resolved, and her blood pressure is in normal range and urinalysis is normal.
Table 1: ALPS case criteria and ALPS classification

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  Discussion Top

Autoimmune lymphoproliferative syndrome is a disorder of abnormal lymphocyte apoptosis leading to polyclonal population of T-cells (double-negative T-cells), which express CD3 and α/β antigen receptors, but do not have CD4 or CD8 co-receptors (CD 3+ TCR α/β+ CD4 CD8 ). These T-cells respond poorly to antigens or mitogens and do not produce growth survival factors (interleukin 2). [5]

There is also an accumulation of phenotypically normal CD 3+ CD4 CD8 T-cells (CD3 + DNT). [4],[6] Autosomal recessive and dominant mutations have been described. The molecular basis of ALPS was identified in 1995 as a Fas-encoding gene mutation. Fas is a receptor expressed on activated lymphocytes that programs cell death. [7],[8] Most of the patients manifest between 6 months and 18 years. Autoimmune lymphoproliferative syndrome is characterized by autoimmunity, chronic persistent or recurrent lymphadenopathy, splenomegaly, hepatomegaly (in 50%), and hypergammaglobulinemia (IgG, IgA). Splenomegaly may produce hypersplenism with cytopenias. Autoimmunity also produces anemia (coombs positive hemolytic anemia) or thrombocytopenia or a mild neutropenia. Other autoimmune features include utricaria, uveitis, glomerulonephritis, hepatitis, vasculitis, arthritis and central nervous system involvement (seizures, headache, encephalopathy). [5]

Our patient had nonmalignant enlargement of lymph nodes, and bicytopenia (anemia and thrombocytopenia), chronic urticaria, hepatosplenomegaly and features of nephritis and hypergammaglobulinemia along with increased double-negative T-cells (CD 3+ CD4 CD8 ) of 6.92%, in the normal person <1% of CD 3+ T-cells are double-negative; however, we were not able to perform the mutation assessment as that was not available in our institute. Chronic urticaria, arthritis and nephritis are not mentioned in other case reports. The clinical manifestations and laboratory data of ALPS raise a broad differential diagnosis such as hematologic malignancies, storage diseases, infections, rosai-dorfman syndrome and others. However, it seems that ALPS is under-diagnosed. So far there are no curative of this entity. Initial treatment can be tried with steroids and immunoglobulins, mycophenolate mofetil, cyclophosphamide, methotrexate and azathioprine and immunomodulation with vincristine and rituximab have also been tried. Bone marrow transplant has been done successfully in two cases with severe, worsening clinical phenotype. [9] We have given oral steroid to our patient, and she has shown improvement. In conclusion, ALPS should be suspected in all patients with massive lymphadenopathy and hepatosplenomegaly, with evidence of cytopenia and hypergammaglobulinemia. It is important to accurately diagnose this entity both for appropriate supportive treatment and for accurate prognostication. [10]

  References Top

1.Clementi R, Dagna L, Dianzani U, Dupré 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;351:1419-24.  Back to cited text no. 1
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;25:227-38.  Back to cited text no. 2
3.Worth A, Thrasher AJ, Gaspar HB. Autoimmune lymphoproliferative syndrome: Molecular basis of disease and clinical phenotype. Br J Haematol 2006;133:124-40.  Back to cited text no. 3
4.Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): Report from the 2009 NIH International Workshop. Blood 2010;116:e35-40.  Back to cited text no. 4
5.Kliegman R, Nelson WE. Nelson Textbook of Pediatrics. Philadelphia: Saunders; 2007. p. 893.  Back to cited text no. 5
6.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;335:1643-9.  Back to cited text no. 6
7.Teachey DT, Seif AE, Grupp SA. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Br J Haematol 2010;148:205-16.  Back to cited text no. 7
8.Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995;81:935-46.  Back to cited text no. 8
9.Sleight BJ, Prasad VS, DeLaat C, Steele P, Ballard E, Arceci RJ, et al. Correction of autoimmune lymphoproliferative syndrome by bone marrow transplantation. Bone Marrow Transplant 1998;22:375-80.  Back to cited text no. 9
10.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;43:164-9.  Back to cited text no. 10


  [Figure 1]

  [Table 1]


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