Indian J Pediatr DOI 10.1007/s12098-015-1779-2
CLINICAL BRIEF
Autoimmune Lymphoproliferative Syndrome with Red Cell Aplasia K. R. Meena 1 & Supriya Bisht 1 & K. C. Tamaria 1
Received: 28 January 2015 / Accepted: 16 April 2015 # Dr. K C Chaudhuri Foundation 2015
Abstract Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare inherited disorder of abnormal lymphocyte apoptosis, leading to chronic lymphoproliferation. It presents as lymphadenopathy, hepatosplenomegaly and autoimmune phenomena. Pure red cell aplasia is characterized by normochromic normocytic anemia, reticulocytopenia, and absence of erythroblasts from a normal bone marrow. Only few lymphoproliferative disorders have been associated with erythroid aplasia. The authors are reporting a case of ALPS associated with red cell aplasia in a 7-y-old girl. Keywords Autoimmunelymphoproliferative syndrome . Red cell aplasia . Cytopenia
Introduction Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of lymphocyte homeostasis characterized by non-malignant lymphoproliferation and autoimmunity toward blood cells [1]. It presents as chronic persistent or recurrent lymphadenopathy, hepatosplenomegaly and hypergammaglobulinemia, with elevated double-negative CD3+CD4-CD8-TCRα/β+Tcells in the blood (DNT Cells). The genetic defect mostly is germ line or somatic mutation in FAS gene, which leads to defective lymphocyte apoptosis causing persistence of autoreactive cells [2]. Pure red cell
* Supriya Bisht [email protected] 1
Department of Pediatrics, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi 110029, India
aplasia (PRCA) is also a rare syndrome characterized by normochromic normocytic anemia, reticulocytopenia, and absence of erythroblasts in an otherwise normal bone marrow [3]. Lymphoproliferative syndrome has rarely been associated with erythroid aplasia. The authors present a rare case of ALPS in a 7-y-old girl having red cell aplasia.
Case Report A 7-y-old girl was referred with complaints of fever and paleness since 3 mo. She had received whole blood 4 times during previous hospital admission. There was past history of prolonged per rectal bleed for few months 3–4 y back, which improved by itself, without any episode of repeat bleed. Family history for similar illness was negative, and she was born of non-consanguineous marriage. Anemia, hepatosplenomegaly and rectal polyp were documented in the previous hospital, and in view of non-improvement, was brought to authors’ institution. Physical examination revealed pallor, along with bilateral cervical and left axillary lymphadenopathy (1.5 cm, nontender and firm). Liver 2 cm and spleen 3 cm below costal margin, also non-tender and firm, were palpable. Investigations at admission revealed anemia (Hb: 6.2 g/dl), mild leucopenia (TLC: 3.2×109/L, with neutrophils 55 %, lymphocytes 40 %) and normal platelets count (2.4×109/L). Peripheral smear suggested normocytic normochromic anemia. Red cell indices and RDW were normal and reticulocyte count was decreased (0.12 %). Serum lactate dehydrogenase (LDH) was 340 U/L. Bone marrow biopsy revealed predominantly myeloid cell (M:E=33:1) with marked paucity of erythroid cell suggestive of PRCA. Serology for parvovirus, anti Hepatitis C and EBV was negative. Sepsis screen, mantoux test, malarial antigen test, RK39 antigen, HIV, HBsAg were
Indian J Pediatr
negative. Liver and kidney function tests, coagulation profile and X ray chest were normal. USG abdomen showed hepatosplenomegaly with hypoechoic lesions in spleen with multiple mesentric lymph nodes. Fine needle aspiration cytology (FNAC) and biopsy of lymph nodes revealed reactive lymphoid hyperplasia. Immunohistochemistry was positive for CD20+, CD3+ (paracortical region), consistent with reactive lymphadenopathy. CECT abdomen showed hepatosplenomegaly with multiple mesenteric and retroperitoneal lymph nodes with nodular opacities in bilateral lung fields. HRCT chest was suggestive of bilateral lung nodules. USG-guided FNAC of mesenteric lymph nodes showed reactive lymphadenitis. Colonoscopy revealed multiple polyps, which were suggestive of juvenile polyps on histopathology. During 3 mo of further workup, her hemoglobin level had decreased, despite of initial improvement after repeated blood transfusions. Lymphadenopathy and splenomegaly increased, and she developed vitiligo. In view of non improvement, whole body PET scan (Fig. 1) was done which revealed metabolic active lymphoproliferative disease involving bilateral cervical, axillary, mesenteric, common iliac, left external iliac, inguinal lymph nodes, pleural nodules and spleen. Patient was symptomatic for more than 6 mo, hence possibility of autoimmune disorder was considered. Direct coombs test came positive, and serum immunoglobulin levels revealed hypergammaglobulinemia (Serum IgM 309.1 mg/dl and IgG3150 mg/dl). ANA and anti dsDNA antibody were negative. Serum vitamin B12 level was high (1563 pg/ml). Flowcytometry of peripheral blood revealed DNT cells as 6.76 % (raised).
Diagnosis of probable ALPS was suggested, based on revised diagnostic criteria of ALPS (2009 NIH International Workshop), as both required criteria with secondary accessory criteria were present. She was treated with IV methylprednisolone 30 mg/kg for 3 d followed by oral prednisolone 1 mg/kg/d for 1 wk. It was planned to taper steroid gradually over 8–12 wk, but she relapsed on 4th wk. Hence, after repeat prednisolone and IV immunoglobulin, mycophenolate mofetil was started (600 mg/m2 per dose oral BD). Clinical and laboratory improvement was seen after 4 wk, and was continued same and is in follow up since 4 mo.
Discussion ALPS is an inherited disorder of Babnormal lymphocyte survival^ due to defective apoptosis. Earliest clinical description was provided in 1967, and later on was found associated with mutations in gene encoding FAS [4]. Approximately 500 cases have been reported worldwide [5]. It mostly manifests between 6 mo to 18 y of age [6]. ALPS presents in phases of lymphoproliferation, autoimmunity and increased risk of B-cell lymphoma. Increased DNT cells above 3 % of the total lymphocytes (or≥5 % of CD3+ lymphocytes) are pathognomonic. Defective lymphocyte apoptosis assay or mutation analysis is required for definitive diagnosis, but these are very expensive and not done in our country. The pathophysiology of PRCA in lymphoproliferative disorders is multifactorial. It is hypothesized that B cell derived or polyclonal IgG antibodies which can be either complement-binding, directly cytotoxic, or inhibiting haemoglobin synthesis can be involved. Rarely PRCA is associated with antierythropoietin antibodies. Evidences support T-Cell or NK-Cell involvement also. The mechanism of erythroid inhibition may include cytotoxic T-lymphocyte attack on erythroid precursors or release of inhibitory cytokines which affect erythroid lineage [7]. The authors did not come across any reports of co-existence of ALPS with PRCA. This association requires further investigations. Rectal polyposis has also not been previously reported with ALPS. Although rare, ALPS should be considered as a differential in diagnosing children presenting with splenomegaly, lymphadenopathy and unexplained cytopenia, specially immune mediated. Contributions KRM was involved in investigation support and development of the draft. SB was responsible for the care of the patient and draft preparation. KCT was responsible for finalization of the draft and will act as guarantor of the paper. Conflict of Interest None
Fig. 1 PET scan suggesting metabolically active lymphoproliferative disease
Source of Funding None
Indian J Pediatr
References 1.
Madkaikar M, Mishra A, Ghosh K. Diagnostic approach to primary immunodeficiency disorders. Indian Pediatr. 2013;50: 579–86. 2. Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood. 2011;118:5741–51. 3. Sawada K, Fujishima N, Hirokawa M. Acquired pure red cell aplasia: updated review of treatment. Br J Haematol. 2008;142: 505–14. 4. Drappa J, Vaishnaw AK, Sullivan KE, Chu JL, Elkon KB. Fas gene mutations in the Canale-smith syndrome, an inherited
5.
6.
7.
lymphoproliferative disorder associated with autoimmunity. N Engl J Med. 1996;335:1643–9. Oliveira JB, Bleesing JJ, Dianzani U, 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. John MJ, Rajasekhar R, Mathews V. Autoimmune lymphoproliferative syndrome (ALPS): a rare cause of immune cytopenia. Indian Pediatr. 2008;45:148–50. Vlachaki E, Diamantidis MD, Klonizakis P, Haralambidou-Vranitsa S, Ioannidou-Papagiannaki E, Klonizakis I. Pure red cell aplasia and lymphoproliferative disorders: an infrequent association. Sci World J. 2012;2012:475313.
CLINICAL BRIEF
Autoimmune Lymphoproliferative Syndrome with Red Cell Aplasia K. R. Meena 1 & Supriya Bisht 1 & K. C. Tamaria 1
Received: 28 January 2015 / Accepted: 16 April 2015 # Dr. K C Chaudhuri Foundation 2015
Abstract Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare inherited disorder of abnormal lymphocyte apoptosis, leading to chronic lymphoproliferation. It presents as lymphadenopathy, hepatosplenomegaly and autoimmune phenomena. Pure red cell aplasia is characterized by normochromic normocytic anemia, reticulocytopenia, and absence of erythroblasts from a normal bone marrow. Only few lymphoproliferative disorders have been associated with erythroid aplasia. The authors are reporting a case of ALPS associated with red cell aplasia in a 7-y-old girl. Keywords Autoimmunelymphoproliferative syndrome . Red cell aplasia . Cytopenia
Introduction Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of lymphocyte homeostasis characterized by non-malignant lymphoproliferation and autoimmunity toward blood cells [1]. It presents as chronic persistent or recurrent lymphadenopathy, hepatosplenomegaly and hypergammaglobulinemia, with elevated double-negative CD3+CD4-CD8-TCRα/β+Tcells in the blood (DNT Cells). The genetic defect mostly is germ line or somatic mutation in FAS gene, which leads to defective lymphocyte apoptosis causing persistence of autoreactive cells [2]. Pure red cell
* Supriya Bisht [email protected] 1
Department of Pediatrics, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi 110029, India
aplasia (PRCA) is also a rare syndrome characterized by normochromic normocytic anemia, reticulocytopenia, and absence of erythroblasts in an otherwise normal bone marrow [3]. Lymphoproliferative syndrome has rarely been associated with erythroid aplasia. The authors present a rare case of ALPS in a 7-y-old girl having red cell aplasia.
Case Report A 7-y-old girl was referred with complaints of fever and paleness since 3 mo. She had received whole blood 4 times during previous hospital admission. There was past history of prolonged per rectal bleed for few months 3–4 y back, which improved by itself, without any episode of repeat bleed. Family history for similar illness was negative, and she was born of non-consanguineous marriage. Anemia, hepatosplenomegaly and rectal polyp were documented in the previous hospital, and in view of non-improvement, was brought to authors’ institution. Physical examination revealed pallor, along with bilateral cervical and left axillary lymphadenopathy (1.5 cm, nontender and firm). Liver 2 cm and spleen 3 cm below costal margin, also non-tender and firm, were palpable. Investigations at admission revealed anemia (Hb: 6.2 g/dl), mild leucopenia (TLC: 3.2×109/L, with neutrophils 55 %, lymphocytes 40 %) and normal platelets count (2.4×109/L). Peripheral smear suggested normocytic normochromic anemia. Red cell indices and RDW were normal and reticulocyte count was decreased (0.12 %). Serum lactate dehydrogenase (LDH) was 340 U/L. Bone marrow biopsy revealed predominantly myeloid cell (M:E=33:1) with marked paucity of erythroid cell suggestive of PRCA. Serology for parvovirus, anti Hepatitis C and EBV was negative. Sepsis screen, mantoux test, malarial antigen test, RK39 antigen, HIV, HBsAg were
Indian J Pediatr
negative. Liver and kidney function tests, coagulation profile and X ray chest were normal. USG abdomen showed hepatosplenomegaly with hypoechoic lesions in spleen with multiple mesentric lymph nodes. Fine needle aspiration cytology (FNAC) and biopsy of lymph nodes revealed reactive lymphoid hyperplasia. Immunohistochemistry was positive for CD20+, CD3+ (paracortical region), consistent with reactive lymphadenopathy. CECT abdomen showed hepatosplenomegaly with multiple mesenteric and retroperitoneal lymph nodes with nodular opacities in bilateral lung fields. HRCT chest was suggestive of bilateral lung nodules. USG-guided FNAC of mesenteric lymph nodes showed reactive lymphadenitis. Colonoscopy revealed multiple polyps, which were suggestive of juvenile polyps on histopathology. During 3 mo of further workup, her hemoglobin level had decreased, despite of initial improvement after repeated blood transfusions. Lymphadenopathy and splenomegaly increased, and she developed vitiligo. In view of non improvement, whole body PET scan (Fig. 1) was done which revealed metabolic active lymphoproliferative disease involving bilateral cervical, axillary, mesenteric, common iliac, left external iliac, inguinal lymph nodes, pleural nodules and spleen. Patient was symptomatic for more than 6 mo, hence possibility of autoimmune disorder was considered. Direct coombs test came positive, and serum immunoglobulin levels revealed hypergammaglobulinemia (Serum IgM 309.1 mg/dl and IgG3150 mg/dl). ANA and anti dsDNA antibody were negative. Serum vitamin B12 level was high (1563 pg/ml). Flowcytometry of peripheral blood revealed DNT cells as 6.76 % (raised).
Diagnosis of probable ALPS was suggested, based on revised diagnostic criteria of ALPS (2009 NIH International Workshop), as both required criteria with secondary accessory criteria were present. She was treated with IV methylprednisolone 30 mg/kg for 3 d followed by oral prednisolone 1 mg/kg/d for 1 wk. It was planned to taper steroid gradually over 8–12 wk, but she relapsed on 4th wk. Hence, after repeat prednisolone and IV immunoglobulin, mycophenolate mofetil was started (600 mg/m2 per dose oral BD). Clinical and laboratory improvement was seen after 4 wk, and was continued same and is in follow up since 4 mo.
Discussion ALPS is an inherited disorder of Babnormal lymphocyte survival^ due to defective apoptosis. Earliest clinical description was provided in 1967, and later on was found associated with mutations in gene encoding FAS [4]. Approximately 500 cases have been reported worldwide [5]. It mostly manifests between 6 mo to 18 y of age [6]. ALPS presents in phases of lymphoproliferation, autoimmunity and increased risk of B-cell lymphoma. Increased DNT cells above 3 % of the total lymphocytes (or≥5 % of CD3+ lymphocytes) are pathognomonic. Defective lymphocyte apoptosis assay or mutation analysis is required for definitive diagnosis, but these are very expensive and not done in our country. The pathophysiology of PRCA in lymphoproliferative disorders is multifactorial. It is hypothesized that B cell derived or polyclonal IgG antibodies which can be either complement-binding, directly cytotoxic, or inhibiting haemoglobin synthesis can be involved. Rarely PRCA is associated with antierythropoietin antibodies. Evidences support T-Cell or NK-Cell involvement also. The mechanism of erythroid inhibition may include cytotoxic T-lymphocyte attack on erythroid precursors or release of inhibitory cytokines which affect erythroid lineage [7]. The authors did not come across any reports of co-existence of ALPS with PRCA. This association requires further investigations. Rectal polyposis has also not been previously reported with ALPS. Although rare, ALPS should be considered as a differential in diagnosing children presenting with splenomegaly, lymphadenopathy and unexplained cytopenia, specially immune mediated. Contributions KRM was involved in investigation support and development of the draft. SB was responsible for the care of the patient and draft preparation. KCT was responsible for finalization of the draft and will act as guarantor of the paper. Conflict of Interest None
Fig. 1 PET scan suggesting metabolically active lymphoproliferative disease
Source of Funding None
Indian J Pediatr
References 1.
Madkaikar M, Mishra A, Ghosh K. Diagnostic approach to primary immunodeficiency disorders. Indian Pediatr. 2013;50: 579–86. 2. Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood. 2011;118:5741–51. 3. Sawada K, Fujishima N, Hirokawa M. Acquired pure red cell aplasia: updated review of treatment. Br J Haematol. 2008;142: 505–14. 4. Drappa J, Vaishnaw AK, Sullivan KE, Chu JL, Elkon KB. Fas gene mutations in the Canale-smith syndrome, an inherited
5.
6.
7.
lymphoproliferative disorder associated with autoimmunity. N Engl J Med. 1996;335:1643–9. Oliveira JB, Bleesing JJ, Dianzani U, 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. John MJ, Rajasekhar R, Mathews V. Autoimmune lymphoproliferative syndrome (ALPS): a rare cause of immune cytopenia. Indian Pediatr. 2008;45:148–50. Vlachaki E, Diamantidis MD, Klonizakis P, Haralambidou-Vranitsa S, Ioannidou-Papagiannaki E, Klonizakis I. Pure red cell aplasia and lymphoproliferative disorders: an infrequent association. Sci World J. 2012;2012:475313.
