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Rituximab resistant evans syndrome and autoimmunity in Schimke immuno-osseous dysplasia Zieg, Jakub; Krepelova, Anna; Baradaran-Heravi, Alireza; Levtchenko, Elena; Guillén-Navarro, Encarna; Balascakova, Miroslava; Sukova, Martina; Seeman, Tomas; Dusek, Jiri; Simankova, Nadezda; Rosik, Tomas; Skalova, Sylva; Lebl, Jan; Boerkoel, Cornelius F Sep 13, 2011

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CASE REPORT Open AccessRituximab resistant evans syndrome andautoimmunity in Schimke immuno-osseousdysplasiaJakub Zieg1*, Anna Krepelova2, Alireza Baradaran-Heravi3, Elena Levtchenko4, Encarna Guillén-Navarro5,Miroslava Balascakova2, Martina Sukova6, Tomas Seeman1, Jiri Dusek1, Nadezda Simankova1, Tomas Rosik1,Sylva Skalova7, Jan Lebl1 and Cornelius F Boerkoel3AbstractAutoimmunity is often observed among individuals with primary immune deficiencies; however, the frequency androle of autoimmunity in Schimke immuno-osseous dysplasia (SIOD) has not been fully assessed. SIOD, which iscaused by mutations of SMARCAL1, is a rare autosomal recessive disease with its prominent features being skeletaldysplasia, T cell deficiency, and renal failure. We present a child with severe SIOD who developed rituximabresistant Evans syndrome (ES). Consistent with observations in several other immunodeficiency disorders, a reviewof SIOD patients showed that approximately a fifth of SIOD patients have some features of autoimmune disease.To our best knowledge this case represents the first patient with SIOD and rituximab resistant ES and the firststudy of autoimmune disease in SIOD.Keywords: Schimke immuno, osseous dysplasia, Unilateral renal agenesis, Nephrotic syndrome, Evans syndrome,RituximabBackgroundThe immune system has evolved to clear pathogens effi-ciently and to tolerate self. The establishment and main-tenance of self-tolerance is a requirement of adaptiveimmunity. To accomplish this, central tolerance removesself-reactive T cells during thymic development and per-ipheral tolerance represses self-reactive T cells thatescape central tolerance checkpoints. Breakdown ofeither central or peripheral tolerance can lead toautoimmunity.One such autoimmune disease is Evans syndrome(ES), which was first described in 1951 [1]. ES is definedby a combination (either simultaneously or sequentially)of autoimmune hemolytic anemia (AIHA) and idiopathicthrombocytopenic purpura (ITP) in the absence of anidentifiable underlying pathology; ES can also includeimmune neutropenia [1]. Pediatric ES generally has achronic course of frequent exacerbations and remissionsand a mortality of 7-36%. Most patients respond to cor-ticosteroids and/or intravenous immunoglobulins(IVIG), but relapse is frequent. Second-line therapiestherefore include splenectomy or immunosuppressivedrugs such as cyclosporine A (CsA), mycophenolatemophetil [1]. Recently, consistent with the hypothesisthat ES arises from dysregulation of B cells, the mono-clonal antibody against the B-cell antigen CD20, rituxi-mab, has shown much promise for treatment of ES [1].ES may be associated with other diseases or conditionssuch as systemic lupus erythematosus [2], lymphoproli-ferative disorders [3,4], or primary immunodeficiencies[5]. The primary immunodeficiencies, which are geneticdisorders causing partial immune system dysfunction,are often characterised by aberrant inflammatoryresponses and autoimmunity [6]. Well-studied examplesof this include autoimmune polyendocrinopathy candi-diasis and ectodermal dystrophy (APECED), immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), autoimmune lymphoprolifera-tive syndrome (ALPS), Wiskott-Aldrich syndrome(WAS), Omenn syndrome, C1q deficiency, interleukin-2* Correspondence: jakubzieg@hotmail.com1Department of Pediatrics, Second Faculty of Medicine, Charles University,University Hospital Motol, Prague, Czech RepublicFull list of author information is available at the end of the articleZieg et al. Pediatric Rheumatology 2011, 9:27http://www.ped-rheum.com/content/9/1/27© 2011 Zieg et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.receptor alpha-chain deficiency and common variableimmunodeficiency [7-11].A less well-studied immunodeficiency is Schimkeimmunoosseous dysplasia (SIOD) [12]. SIOD, which wasfirst described by Schimke et al. in 1971 [13], is a raremultisystem autosomal recessive disorder consisting offacial dysmorphism, spondyloepiphyseal dysplasia lead-ing to dysproportionate growth failure, T-cell immuno-deficiency and nephropathy characterised by steroidresistant nephrotic syndrome and frequently focal seg-mental glomerulosclerosis [14,15]. Additional featuresinclude ischemic cerebral attacks, migraine-like head-aches, hematologic abnormalities of leucopenia, anemiaand thrombocytopenia, enteropathy, hyperpigmentedskin macules, unusual hair and microdontia [15-17].The course of the disease varies from severe withintrauterine or early childhood onset and death in child-hood [15,18,19] to milder disease with survival intoadulthood [15,20]. For both severe and mild disease, thetherapy is mainly symptomatic [15].SIOD is caused by biallelic mutations in SMARCAL1(SWI/SNF-related matrix-associated actin-dependentregulator of chromatin, subfamily-a-like-1), whichencodes a DNA annealing helicase with homology tothe SNF2 chromatin remodelling proteins [21]. TheSMARCAL1 enzyme plays a role in the DNA stressresponse and regulates gene expression [22-27].We report a child with severe SIOD and rituximabresistant Evans syndrome (ES) preceeding the bone mar-row failure that can be associated with SIOD. Combinedwith prior reports of other autoimmune disordersamong individuals with SIOD and upon review of ourSIOD patient database, we conclude that the T cellimmunodeficiency of SIOD compromises self-tolerance.MaterialsPatientsPatients referred to this study gave informed consent.The study was approved by the Institutional ReviewBoards of Baylor College of Medicine (Houston, TXUSA), the Hospital for Sick Children (Toronto, ONCanada), and the University of British Columbia (Van-couver, BC Canada). Clinical data were obtained fromquestionnaires completed by the attending physician aswell as medical summaries.QuestionnairesPhysicians referring SIOD patients for molecular testingfor SIOD complete a questionnaire on the patient beingreferred. Included in this questionnaire, is a question onwhether the patient has an autoimmune disorder and ifso to specify the problem, serology and therapy. In addi-tion, there are specific questions asking if the patienthad lymphocytopenia, neutropenia, anemia, orthrombocytopenia as well as the nature of the cytopeniaand any effective therapies.ResultsCaseThe proposita was a 4.5-year-old girl born to non-con-sanguineous parents by caesarean section at 36 weeks ofgestation following a pregnancy complicated by intrau-terine growth retardation. Her birth weight, length andhead circumference were 1450 g (< 3rd percentile), 39cm (< 3rd percentile) and 34 cm (25th percentile),respectively. She did well in the newborn period withthe exception of a self-limited thrombocytopenia. Herabdominal ultrasound detected left-sided unilateral renalagenesis (URA), but her voiding cystography wasnormal.She was presented to our centre at the age of 3 yearswith nephrotic proteinuria of 1-2 g/m2/day withouthematuria and a blood pressure of 90/65 mmHg (diasto-lic - 95th percentile for height). On clinical examination,she had a high-pitched voice, low nasal bridge, shortneck and trunk, disproportionate short stature, lumbarlordosis, protruding abdomen and numerous pigmentedmacules predominantly on her trunk. Her weight was7.3 kg (< 3rd percentile), and her length was 72 cm (<3rd percentile). She had normal neurologic development.Initial laboratory studies showed a normal blood count(WBC 5.2 cells per nl, HGB 13.8 g/dl, PLT 415 cells pernl), urea (3 mmol/l), creatinine (28 μmol/l), albumin(38.1 g/l), total protein (65.4 g/l), triglycerides (0.66mmol/l), cholesterol (7 mmol/l), TSH (4.5 mIU/l), andfree T4 (18.1 pmol/l). She also had normal growth hor-mone function tests. Immunological exam revealed defi-ciency of CD4+ and CD8+ cells and increased CD4+/CD8+ ratio. Her laboratory results are summarised intables 1 and 2.Because of her immunodeficiency, she developed mul-tiple infections. At the age of 3.5 years, she had Myco-plasma pneumoniae pneumonia with positive serologyand required hospitalization for parenteral antibiotics.By the age of 4.5 years, she developed severe leucopeniaand recurrent protracted infections including Candidaalbicans sepsis and Epstein Barr virus infection withfever and persistently high viral load associated with adecreased WBC.At 4 years, she was hospitalized in status epilepticus.Cerebral magnetic resonance imaging showed multipleischemic changes and narrowing of the middle cerebralartery bilaterally. The seizures responded to phenobarbi-tal; however, she had additional cerebral infarcts andbecame triplegic with motoric aphasia.To treat her multiple problems, we initated severaltherapies. For her nephrotic syndrome, we tried a 6week course of prednisone (60 mg/m2/day); however,Zieg et al. Pediatric Rheumatology 2011, 9:27http://www.ped-rheum.com/content/9/1/27Page 2 of 6she did not respond and her subsequent renal biopsyshowed focal segmental glomerulosclerosis. For treat-ment of her hypertension, we intially used the ACE inhi-bitor ramipril (2.5 mg daily) and subsequently theangiotensin receptor blocker losartan (12.5 mg daily);her arterial blood pressure declined to the normal rangefor her age and height. For treatment of her hypercho-lesterolemia, we introduced simvastatin therapy (5 mgdaily), and her cholesterol level declined from 11 mmol/l back to 7.1 mmol/l. To control her recurrentTable 1 Evolution of laboratory values for the propositaTest results at the indicated agesAge (years) 3§ 3.5 4 4.5 5 5.5Test(normal values)WBC (cells per nl)(4-13)6.5 6.1 4.1 2.8 1.2 1.1HGB (g/dl)(11-15)11.2 10.8 10.8 7 9.5 8.5PLT (cells per nl)(140-440)435 335 63 8 11 5urea (mmol/l)(1.8-6.7)3 5.2 7.1 10 6.6 10creatinine (μmol/l)/GFR(ml/min/1.73 m2)28/127 26/140 26/142 38/97 31/119 35/108albumin (g/l)(35-53)40.8 43.4 43.8 38 23.3 21.3urine- protein/creatinine (mg/mmol)(< 20)501 145 216 297 1321 1755§While receiving prednisone (60 mg/m2/day)Table 2 Evolution of the immune and autoimmune status of the propositaTest results at the indicated agesAge (years) 3§ 4 5¶Test(normal values)IgG (g/l)(5.53-10.20)7.72 12.1 1.63IgA (g/l)(0.33-0.91)0.83 1.66 0.43IgM (g/l)(0.47-1.67)0.97 2.19 3.49C3 (g/l)(0.83-2.25)1.06 1.47 1.41C4 (g/l)(0.14-0.35)0.18 0.10 0.11ANA negative negative negativeANCA negative negative negativeACLA (GPL/ml)(0.8-11)7.0 6.3 4.3ENA screening negative negative NMATA IgA (U/ml)(0-10)2.09 2.11 NMCD4 absolute count x103/ml (35-51%) 130 (12%) 200 (13%) 70 (50%)CD8 absolute count x103/ml (18-40%) 20 (1.8%) 170 (11%) 60 (44%)CD4/CD8(1-3%)6.7% 1.2% 1.1%CD19 absolute count x103/ml (9-35%) 0.440 (45%) 530 (35%) 0 (0%)*§While receiving prednisone (60 mg/m2/day)¶Nephrotic syndrome worsened and proteinuria increased during the 5th year of life.*After rituximab treatment.Zieg et al. Pediatric Rheumatology 2011, 9:27http://www.ped-rheum.com/content/9/1/27Page 3 of 6infections, she was placed on prophylactic cotrimoxa-zole; however, the infections persisted and ultimatelyshe died at 5.5 years from multiorgan failure secondaryto Enterobacter cloacae sepsis.Based on her renal failure, T-cell deficiency and dys-morphic features, we suspected the diagnosis of SIOD.Her skeletal radiographs also demonstrated the typicalfeatures including flattened capital femoral epiphyses,dysplastic acetabular fossae and marked thoracic kypho-sis. To confirm the diagnosis molecularly, we sequencedPCR amplification products for the coding exons ofSMARCAL1. This identified mutations c.2542G > T (p.Glu848X) in exon 17 and c.1439C > T (p.Pro480Leu) inexon 8; both of these mutations have been describedpreviously in patients with SIOD [20,21]. Confirmingcompound heterozygosity, c.2542G > T was inheritedfrom her mother and c.1439C > T was inherited fromher father.In addition to the above problems, the propositadeveloped ITP and anemia without splenomegaly in thelatter half of her 5th year of life. The ITP was charac-terised by severe thrombocytopenia (8 cells per nl) andantiplatelet antibodies detectable by the immunobeadassay. A year after her mycoplasma pneumonia, twomonths after onset of her ITP and before therapy withIVIG, she developed anemia (HGB 7 g/dl, reticulocytes3.1%, LDH 7.61 μkat/l, bilirubin 11 μmol/l); this wasaccompanied by a direct antiglobulin test (DAT) thatwas positive for auto-antierythrocyte antibodies. Shereceived one platelet transfusion and two red blood celltransfusions shortly after the diagnosis of her ITP andDAT-positive anemia, respectively.Bone marrow aspirations performed at the onset ofher ITP and again 3 months later revealed reduced pla-telet production despite normal numbers, size and mor-phology (nuclear separation) of megakaryocytes. Eachalso showed normal to hypercellular trilinear hematopo-esis without dysplasia (myeloid precursors 47.2%, ery-throid precursors 25%). Overall the bone marrowmorphology was compatible with immune cytopeniaand atypical for bone marrow failure. Based on thiscombination of findings and her clinical features, theproposita was diagnosed with ES.Her ES responded poorly to standard therapies. It didnot respond to corticosteroids or to IVIG alone. How-ever, after a month of combination therapy with predni-sone (2 mg/kg/day) and CyA (3-4 mg/kg/day) theplatelet count and HGB level rose to the lower normalrange. Unfortunately, the thrombocytopenia reoccuredwhen the prednisone dose was weaned after 2 months;the relapse, which precipitated bleeding complications,was unresponsive to combined therapy with IVIG andhigh dose steroids as well as to rituximab (4 doses of375 mg/m2). Throughout this time, the persistentlyDAT-positive anemia progressed such that she required8 transfusions in the last months of her life.Ten months after presenting with thrombocytopeniaand eight months after the development of anemia, theproposita had the onset of progressive neutropenia. Shedid not have anti-neutrophil antibodies; therefore, weinterpreted this as the onset of bone marrow failure.Concomitent with this she developed a severe coagulo-pathy and required four platelet transfusions.Autoimmune disease occurs commonly in SIOD patientsTo ascertain whether the autoimmune disease observedin the proposita was unique to her or part of the clinicalsymptoms of SIOD, we sent questionnaires to 63 physi-cians of SIOD patients in whom we had identifiedSMARCAL1 mutations (Table 3), and 41 physiciansreported checking for autoimmune disease in theirpatients. Among the 41 patients, 2 female and 6 malepatients had one or more indications of autoimmunedisease. These manifestations included thrombocytope-nia, hemolytic anemia, enteropathy, and pericarditis withanti-cardiolipin antibodies. In one patient with thrombo-cytopenia, the autoimmune features resolved sponta-neously, in another after bone marrow transplantationand in another after splenectomy. All other patientswere successfully treated with immunosuppressive ther-apy: steroids, cyclophosphamide or IVIG.DiscussionAs observed for SIOD [15,28,29], many other primaryimmune deficiencies are characterized by infections aswell as a defect in self-tolerance. For example, APECED,ALPS and IPEX are defined by the occurrence of auto-immune diseases, whereas for other immune deficienciesthe autoimmune manifestations are not as prominent[7-11]. Immunodeficiencies with less prominent autoim-mune manifestations include common variable immuno-deficiency [30,31], Good syndrome [32], hyper-IgMsyndrome [33], WAS [34,35], and idiopathic CD4+ lym-phocytopenia [36]. About 22% of individuals with com-mon variable immunodeficiency have autoimmuneproblems, and these include autoimmune cytopenias,pernicious anemia, thyroiditis, rheumatoid arthritis andvitiligo [30,31]. Approximately a quarter of individualswith hyper-IgM syndrome develop an autoimmune pro-blem such as cytopenia, nephritis, enteropathy, hepatitis,arthritis, hypothyroidism or systemic lupus erythemato-sus (SLE) [33]. About half of individuals with WAS haveautoimmune problems including neutropenia, arthritis,vasculitis, uveitis, enteropathy and nephritis [34,35].Similarly, about 20-25% of those with idiopathic CD4+lymphocytopenia develop an autoimmune problem suchas SLE, antiphospholipid syndrome, Grave’s disease,colitis, thyroiditis and vitiligo [36]. Similar to theseZieg et al. Pediatric Rheumatology 2011, 9:27http://www.ped-rheum.com/content/9/1/27Page 4 of 6diseases, SIOD also has variable expression of autoim-mune manifestations (Table 3).The etiology of the autoimmune problems among SIODpatients remains undefined and no consistent inflamma-tory or serological markers have been reported [15]. As forthe immunodeficiency, however, it likely arises from a dys-function of SMARCAL1, the enzyme mutated in SIOD[21], within the lymphocytic lineages. Consistent with sucha cell autonomous model, SMARCAL1 is highly expressedin the bone marrow lineages, and the limited data on oneSIOD patient suggests that bone marrow transplantationcan ameliorate the immunodeficiency [37,38].ConclusionIn conclusion, we report the first SIOD patient withautoimmune problems unresponsive to immunosuppres-sion with steroids, CsA and rituximab. Additionally, wedefine the frequency and spectrum of autoimmune man-ifestions in SIOD.ConsentWritten informed consent was obtained from the par-ents for publication of this case report and any accom-panying images. A copy of the written consent isavailable for review by the Editor-in-Chief of thisjournal.AbbreviationsACLA: anti-cardiolipin antibody; ACE: angiotensin-converting enzyme; ALPS:autoimmune lymphoproliferative syndrome; ANA: antinuclear antibody;ANCA: anti-neutrophil cytoplasmatic antibody; APECED: autoimmunepolyendocrinopathy candidiasis and ectodermal dystrophy; ATA: anti-transglutaminase antibody; C1q: complement factor 1q; C3: complementfactor 3; C4: complement factor 4; CD: cluster of differentiation protein; cm:centimeter; CsA: cyclosporine A; dl: deciliter; DNA: deoxyribonucleic acid;ENA: endonuclear antibody; ES: Evans syndrome; F: female; g: gram; HGB:hemoglobin; Ig: immunoglobulin; IPEX: immunodysregulation;polyendocrinopathy; enteropathy; and X-linked inheritance; IVIG: intravenousimmunoglobulins; l: liter; LDH: lactate dehydrogenase; M: male; m2: squaremeter; mg: milligram; μmol: micro mole; mmol: millimole; nl: nanoliter; NM:not measured; p.: protein; PLT: platelet; SIOD: Schimke immuno-osseousdysplasia; SLE: systemic lupus erythematosus; SMARCAL1: SWI/SNF-relatedmatrix associated actin-dependent regulator of chromatin; subfamily A-likeprotein 1; TSH: thyroid-stimulating hormone; URA: unilateral renal agenesis;WAS: Wiskott-Aldrich syndrome; WBC: white blood cell count.Acknowledgements and FundingThis work was supported in part by grant VZ 0006420301 MZOFNM 2005,the Czech Ministry of Health. It was also supported by the March of Dimes(C.F.B.); the Gillson Longenbaugh Foundation (C.F.B.); the Dana Foundation(C.F.B.), the New Development Award, Microscopy, and AdministrativeCores of the Mental Retardation and Developmental Disabilities ResearchCenter at Baylor College of Medicine (C.F.B.); the Burroughs WellcomeFoundation (C.F.B.); the National Institute of Diabetes, Digestive, andKidney Diseases, National Institutes of Health (C.F.B.); the New InvestigatorGrant: Institute of Human Development, Child and Youth Health from theSickKids Foundation - Canadian Institutes of Health Research (C.F.B.); theAssociation Autour D’Emeric et D’Anthony (C.F.B.); and The Little GiantsFoundation (C.F.B.). C.F.B. is a scholar of the Michael Smith Foundation forHealth Research and a Clinical Investigator of the Child & Family ResearchInstitute.Author details1Department of Pediatrics, Second Faculty of Medicine, Charles University,University Hospital Motol, Prague, Czech Republic. 2Department of Biologyand Medical Genetics, Second Faculty of Medicine, Charles University,University Hospital Motol, Prague, Czech Republic. 3Department of MedicalGenetics, University of British Columbia, Vancouver, Canada. 4Department ofPediatric Nephrology, University Hospitals Leuven, Leuven, Belgium. 5Unidadde Genética Médica, Servicio de Pediatría, Hospital Universitario Virgen de LaArrixaca, Murcia, Spain. 6Department of Pediatric Hematology and Oncology,Second Faculty of Medicine, Charles University, University Hospital Motol,Prague, Czech Republic. 7Department of Pediatrics, Faculty of Medicine andTable 3 Autoimmune features identified in SIOD patientsPedigreenumberGender SMARCAL1mutationsAutoimmune disease Therapy ReferenceSD8 F p.[L397RfsX39]+[*]Autoimmune thrombocytopenia,autoimmune anemiaThrombocytopenia resolved with steroids & IgGinfusion.[39]SD23 M p.[E848X]+[E848X]Autoimmune bowel disease Diarrhea and villous atrophy resolved with steroidtreatment.[16]SD25 F p.[R17X]+[Q34X]Autoimmune thrombocytopenia None; improved spontaneously.SD29 M p.[R645PfsX16]+[D271_M288del]Pericarditis, anti-cardiolipin antibodies ?SD49 M p.[V641GfsX50]+[S774X]Autoimmune bowel disease Patient died before treatment.SD100 M p.[E377Q]+[F279S]Autoimmune thrombocytopenia Thrombocytopenia resolved with splenectomy.SD102 M p.[E848X]+[E848X]Autoimmune bowel disease ?SD111 M p.[E377Q]+[L531P]Autoimmune thrombocytopeniaand anemiaFirst episode improved spontaneously; at secondepisode patient died.SD140¶ F p.[E848X]+[P480L]Evans syndrome Steroid, CSA and rituximab resistant; patient died.* No SMARCAL1 protein was detected in patient cells; therefore, the second allele is a null although a mutation was not detected by sequencing of the codingexons.¶PropositaZieg et al. Pediatric Rheumatology 2011, 9:27http://www.ped-rheum.com/content/9/1/27Page 5 of 6University Hospital Hradec Králové, Charles University, Prague, CzechRepublic.Authors’ contributionsJZ wrote the initial manuscript draft. JD, TS and JL supervised the treatmentof the patient and assisted in preparing the draft. MS, NS, SS and TRcontributed in taking care of the patient and helped the drafting of themanuscript. AK, MB carried out molecular genetic testing and participated inthe drafting of the manuscript. EL and EG-N contributed patient informationnot in the SIOD patient registry. ABH maintains the SIOD patient registryand complied the data in it for this report. CFB provided the SIOD patientregistry and SIOD patient information. All authors critically reviewed andrevised drafts. 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Am J Med Genet 1993, 47:793-796.doi:10.1186/1546-0096-9-27Cite this article as: Zieg et al.: Rituximab resistant evans syndrome andautoimmunity in Schimke immuno-osseous dysplasia. PediatricRheumatology 2011 9:27.Zieg et al. Pediatric Rheumatology 2011, 9:27http://www.ped-rheum.com/content/9/1/27Page 6 of 6


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