Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches.

Primary immunodeficiencies (PIDs) are classified into nine subclasses, depending on their underlying immunologic defect or predominant symptom.1-3  The current view of PIDs includes an increasing number of syndromes that are associated with immune dysregulation and autoimmunity as a predominant feature rather than an overt pathologic risk of infections. Cytopenia, defined as the reduction of one or more mature blood cell types (eg, neutropenia, anemia, or thrombocytopenia) in the peripheral blood, may be a typical first symptom of such an immunodeficiency. Possible causes of cytopenia in PIDs comprise cellular or humoral autoimmunity, immune dysregulation in form of hemophagocytosis or lymphoproliferation with or without splenic sequestration, bone marrow failure and myelodysplasia, or secondary myelosuppression. In some patients, cytopenia may be detected as an incidental finding, whereas other patients may be severely ill. Because primary defects in the number or function of phagocytes are classified under their own group of PIDs,3  the syndromes of severe congenital neutropenia (based on defects in ELANE,GFI1, HAX1, G6PC3, VPS45, and CSFR3 genes, or activating mutations in the Wiskott-Aldrich syndrome [WAS] gene)4-6  and cytopenia-linked metabolic diseases are not included in this overview. Similarly, isolated lymphopenia syndromes are excluded if they present without neutropenia, anemia, or thrombocytopenia; also excluded are non-PID inherited bone marrow failure syndromes such as Fanconi anemia, congenital amegakaryocytic thrombocytopenia, bone marrow failure with radioulnar synostosis, and others (Table 1 and footnotes). These syndromes are beyond the scope of this review because they do not represent a concurrence of immunodeficiency with cytopenia nor do they harbor an underlying defect of the immune system.

Table 1

Possible clinical presentation (apart from symptoms of cytopenia), laboratory parameters of PID with cytopenia, and treatment options

TypeDisorders*Possible symptomsTypical laboratory parametersTreatment options
Antibody-mediated autoimmunity CVID, ALPS, [cITP, Evans syndrome] [SLE], CID,§ Good syndrome, LRBA deficiency May be asymptomatic, bacterial infection, multiorgan autoimmunity, thymoma, inflammatory bowel disease Hypogammaglobulinemia, csBm cells reduced, DNT cells increased, vitamin B12, sFasL, IL-10, IL-18 IVIG, corticosteroids, MMF, plasmapheresis/exchange, anti-CD20, CY, purine analogs, TPOR agonists, HSCT 
Cellular autoimmunity CID,§ PCID,§ WAS, WIP, 22q11, [SAA, RCC/MDS RC] May be asymptomatic, opportunistic infection, eczema, atopy, syndromic features, pancytopenia, autoimmunity Empty bone marrow, lack of naïve T cells, microplatelets, MLPA, B-cell and NK-cell deficiency, T cells nonfunctional Calcineurin inhibitors, ATG, alemtuzumab, MMF, mTOR inhibitors, CY, MTX, purine analogs, Vcr, Vbl, HSCT 
Immune dysregulation IPEX(-like), XLP, CD27, ITK, XMEN, ALPS, HLH, FHL, Griscelli syndrome, CHS, HPS Often severely ill patient, fever, organomegaly, lymphoma,positive family history, partial albinism Stat5b-P, EBV viremia, hyperferritinemia, sIL2R, genetic testing, DNT cells increased, iNKT cells reduced, vitamin B12, sFasL, NK/CTL cytotxicity corticosteroids, calcineurin inhibitors, etoposide, ATG, alemtuzumab, anti-CD20, mTOR inhibitors, MMF, HSCT 
Bone marrow failure, myelodysplasia DKC, CHH, Schimke syndrome, RD, SDS, MonoMac syndrome, PNH, other|| May be asymptomatic, syndromal features, skin, bones, deafness, maldigestion, hemolysis, dystonia Telomere length, genetic testing, lymphopenia, pancreatic insufficiency, altered pDC/mDC ratio Eltrombopag, G(M)CSF, HSCT, eculizumab 
Myelosuppression Various, WHIM syndrome Viral infection, toxic, malignant (nutritional) deficiency Pancytopenia, myelokathexis Treat underlying disease, infection intoxication/deficiency state, CXCR4 antagonist (in WHIM) 
TypeDisorders*Possible symptomsTypical laboratory parametersTreatment options
Antibody-mediated autoimmunity CVID, ALPS, [cITP, Evans syndrome] [SLE], CID,§ Good syndrome, LRBA deficiency May be asymptomatic, bacterial infection, multiorgan autoimmunity, thymoma, inflammatory bowel disease Hypogammaglobulinemia, csBm cells reduced, DNT cells increased, vitamin B12, sFasL, IL-10, IL-18 IVIG, corticosteroids, MMF, plasmapheresis/exchange, anti-CD20, CY, purine analogs, TPOR agonists, HSCT 
Cellular autoimmunity CID,§ PCID,§ WAS, WIP, 22q11, [SAA, RCC/MDS RC] May be asymptomatic, opportunistic infection, eczema, atopy, syndromic features, pancytopenia, autoimmunity Empty bone marrow, lack of naïve T cells, microplatelets, MLPA, B-cell and NK-cell deficiency, T cells nonfunctional Calcineurin inhibitors, ATG, alemtuzumab, MMF, mTOR inhibitors, CY, MTX, purine analogs, Vcr, Vbl, HSCT 
Immune dysregulation IPEX(-like), XLP, CD27, ITK, XMEN, ALPS, HLH, FHL, Griscelli syndrome, CHS, HPS Often severely ill patient, fever, organomegaly, lymphoma,positive family history, partial albinism Stat5b-P, EBV viremia, hyperferritinemia, sIL2R, genetic testing, DNT cells increased, iNKT cells reduced, vitamin B12, sFasL, NK/CTL cytotxicity corticosteroids, calcineurin inhibitors, etoposide, ATG, alemtuzumab, anti-CD20, mTOR inhibitors, MMF, HSCT 
Bone marrow failure, myelodysplasia DKC, CHH, Schimke syndrome, RD, SDS, MonoMac syndrome, PNH, other|| May be asymptomatic, syndromal features, skin, bones, deafness, maldigestion, hemolysis, dystonia Telomere length, genetic testing, lymphopenia, pancreatic insufficiency, altered pDC/mDC ratio Eltrombopag, G(M)CSF, HSCT, eculizumab 
Myelosuppression Various, WHIM syndrome Viral infection, toxic, malignant (nutritional) deficiency Pancytopenia, myelokathexis Treat underlying disease, infection intoxication/deficiency state, CXCR4 antagonist (in WHIM) 

Square brackets indicate diseases not considered primary immunodeficiencies but representing frequent hematologic/rheumatologic diagnoses with cytopenia and immunologic pathomechanims.

22q11, microdeletion syndrome (MIM# 188400); ATG, antithymocyte globulin; CD27, CD27 deficiency (MIM# 615122); CHH, cartilage hair hypoplasia (RMRP deficiency, MIM# 250250); CHS, Chediak-Higashi syndrome; csBm, class-switched memory B cells; CTL, cytolytic T lymphocyte; CY, cyclophosphamide; DKC, dyskeratosis congenita; DNT cells, T cell receptor α/β-positive CD4 and CD8-double negative T cells; FHL, familial hemophagocytic lymphohistiocytosis; G(M)CSF, granulocyte (monocyte) colony-stimulating factor; HLH, hemophagocytic lymphohistiocytosis; HPS, Hermansky-Pudlak syndrome; HSCT, hematopoietic stem cell transplantation; iNKT cells, invariant T-cell receptor natural killer T cells; ITK, IL-2–inducible T-cell kinase deficiency (MIM# 613011); IVIG, intravenous immunoglobulin; LRBA, lipopolysaccharide-responsive beige-like anchor deficiency (MIM# 606453); MLPA, multiplex ligation-dependent probe amplification; MMF, mycophenolate mofetil; MonoMAC syndrome (GATA2 deficiency, MIM# 137295); mTOR, mammalian target of rapamycin; MTX, methotrexate; PCID, profound combined immunodeficiency;pDC/mDC, ratio of plasmacytoid dendritic cells to monocytoid dendritic cells in peripheral blood; PNH, paroxysmal nocturnal hemoglobinuria (CD59 deficiency, MIM# 107271); RD, reticular dysgenesis (AK2 deficiency, MIM# 103020); Schimke syndrome (SMARCAL1 deficiency, MIM# 242900); SDS, Shwachman-Diamond syndrome (SBDS deficiency, MIM# 260400); sFasL, soluble Fas ligand; sIL-2R, soluble IL-2 receptor; TPOR, thrombopoietin receptor; Vbl, vinblastine; Vcr, vincristine; WAS, Wiskott-Aldrich syndrome (MIM# 301000); WHIM, warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (CXCR4 gain-of-function, MIM# 193670).WIP, WAS protein-interacting protein (MIM# 602357); XLP, X-linked lymphoproliferative disease; XMEN, X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (MAGT1 deficiency, MIM# 300715).

*

The potentially involved gene defects of disorders that are not mentioned here or in the abbreviations are listed in Table 2 and Al-Herz et al.3 

Phase 2/3 studies for novel drugs such as TPOR agonists, bortezomib, belimumab, epratuzumab, anti-APRIL, and tocilizumab.

Treatment according to prospective clinical study protocols strongly recommended.

§

Including hypomorphic SCIDs, CD40/CD40L deficiency, and Ca++ channel deficiencies.

||

Inherited bone marrow failure syndromes not associated with PID include Fanconi anemia (MIM# of Fanconi anemia complementation group A: 227650; a phenotypic series of 16 genes exists), Bloom syndrome (MIM# 210900), congenital amegakaryocytic thrombocytopenia (MIM# 604498), bone marrow failure with radioulnar synostosis (MIM#605432), Pearson syndrome (MIM# 557000), Dubowitz syndrome (MIM# 223370), and Seckel syndrome (MIM# 210600; phenotypic series); inherited syndromes with predominant anemia include Diamond-Blackfan anemia (MIM# 105650), methylmalonaciduria (MIM# 251110, 613646), and thiamin-responsive megaloblastic anemia (MIM# 249270); inherited syndromes with predominant neutropenia include glycogen storage disease 1b (MIM# 232220), p14-deficiency (MIM# 610389), Barth syndrome (MIM# 302060), Cohen syndrome (MIM# 216550), and Clericuzio syndrome (MIM#613276).

Table 2

Genes and MIM numbers of disease entities caused by multiple different genes

Disorder*Involved genesMIM#
CVID TACI, BAFF-R, CD19, CD20, CD21, CD81, ICOS, LRBA, TWEAK 604907, 606269, 107265, 112210, 614699, 186845, 604558, 606453, 602695 
ALPS TNFRSF6 (CD95/Fas; germline or somatic), TNFSF6 (CD95L/FasL), CASP10, CASP8, FADD, CARD11, PRKCD, K/NRAS 601859, 134638, 603909, 607271, 613759, 606445, 615559, 614470 
CID RAG1/2, ARTEMIS, ADA, PNP, CD40L, CD40, ZAP70, SH2D1A, RMRP, STK4, TCRA, LCK, PI3KD, ORAI1, STIM1, TPP2 601457, 602450, 102700, 164050, 300386, 109535, 269840, 308240, 250250, 614868, 615387, 153390, 602839, 610277, 605921, 190470 
IPEX, IPEX-like FOXP3, CD25, STAT5b, STAT1 304790, 606367, 245590, 600555 
XLP SH2D1A, XIAP/BIRC4 308240, 300635 
FHL with or without hypopigmentation (including CHS, HPS, GS2) PRF1, UNC13D, STX11, STXBP2, LYST, AP3B4, RAB27A 603553, 608898, 603552, 613101, 214500, 608233, 607624 
DKC DKC1, NHP2, NOP10, RTEL1, TERC, TERT, TINF2 305000, 613987, 224230, 608833, 127550, 614742, 613990 
Disorder*Involved genesMIM#
CVID TACI, BAFF-R, CD19, CD20, CD21, CD81, ICOS, LRBA, TWEAK 604907, 606269, 107265, 112210, 614699, 186845, 604558, 606453, 602695 
ALPS TNFRSF6 (CD95/Fas; germline or somatic), TNFSF6 (CD95L/FasL), CASP10, CASP8, FADD, CARD11, PRKCD, K/NRAS 601859, 134638, 603909, 607271, 613759, 606445, 615559, 614470 
CID RAG1/2, ARTEMIS, ADA, PNP, CD40L, CD40, ZAP70, SH2D1A, RMRP, STK4, TCRA, LCK, PI3KD, ORAI1, STIM1, TPP2 601457, 602450, 102700, 164050, 300386, 109535, 269840, 308240, 250250, 614868, 615387, 153390, 602839, 610277, 605921, 190470 
IPEX, IPEX-like FOXP3, CD25, STAT5b, STAT1 304790, 606367, 245590, 600555 
XLP SH2D1A, XIAP/BIRC4 308240, 300635 
FHL with or without hypopigmentation (including CHS, HPS, GS2) PRF1, UNC13D, STX11, STXBP2, LYST, AP3B4, RAB27A 603553, 608898, 603552, 613101, 214500, 608233, 607624 
DKC DKC1, NHP2, NOP10, RTEL1, TERC, TERT, TINF2 305000, 613987, 224230, 608833, 127550, 614742, 613990 

See Al-Herz et al 3 for more detailed PID disease classification.

*

In the same order of appearance as in Table 1.

Listed unless gene name is identical with disease name and thus is mentioned in Table 1 (see also Al-Herz et al3).

Like the self-limited benign forms of post- or parainfectious autoimmune cytopenia or acquired autoimmune neutropenia of childhood that typically occur independently of a (recognized) underlying PID, many but importantly not all cytopenias in patients with underlying PIDs are mediated by autoantibodies. Thus, it is essential that clinicians take an underlying PID into account in patients with clear antibody-mediated cytopenia and also in other situations as described. This review provides a conceptual synopsis of cytopenias in PIDs and aims to increase the awareness of hematologists as well as immunologists for this manifestation of PID.

Cytopenia in PID may have a variety of causes. In some instances, it is a primary feature of the immunodeficiency, and in others, it is a secondary phenomenon. This review will focus on the clinical relevance of cytopenias and suggest the following grouping: (1) classic autoimmune cytopenias, further subdivided into autoantibody-mediated and cellular autoimmunity; (2) cytopenias in the context of immune dysregulation, lymphoproliferation, and inflammation in PID; (3) PID with bone marrow failure; and (4) toxic or infectious myelosuppression secondary or concomitant to PID (Figure 1).

Figure 1

Synopsis of cytopenias in PID. Conceptual overview, excluding primary defects of phagocyte number or function, inherited non-PID bone marrow failure syndromes, and disorders of isolated lymphopenia (without other cytopenia). *Includes hypomorphic mutations in SCID genes, CD40, CD40L, and other combined immunodeficiencies such as radiosensitive disorders, defects in the Ca++ channel, and activating PI3K syndrome. AIHA, autoimmune hemolytic anemia; AIN, autoimmune neutropenia; CHH, cartilage hair hypoplasia; CHS, Chediak-Higashi syndrome; DKC, dyskeratosis congenita; FHL1-5, familial hemophagocytic lymphohistiocytosis 1-5; HPS-2, Hermansky-Pudlak syndrome 2; ITK, IL-2–inducible T-cell kinase deficiency; LRBA, lipopolysaccharide-responsive beige-like anchor deficiency; PNH, paroxysmal nocturnal hemoglobinuria; RCC, refractory cytopenia of childhood; RD, reticular dysgenesis; SCN1, severe congenital neutropenia 1; SDS, Shwachman-Diamond syndrome; WHIM, warts, hypogammaglobulinemia, immunodeficiency, myelokathexis; WIP, WAS protein-interacting protein; XLP-1,2, X-linked lymphoproliferative disease 1,2.

Figure 1

Synopsis of cytopenias in PID. Conceptual overview, excluding primary defects of phagocyte number or function, inherited non-PID bone marrow failure syndromes, and disorders of isolated lymphopenia (without other cytopenia). *Includes hypomorphic mutations in SCID genes, CD40, CD40L, and other combined immunodeficiencies such as radiosensitive disorders, defects in the Ca++ channel, and activating PI3K syndrome. AIHA, autoimmune hemolytic anemia; AIN, autoimmune neutropenia; CHH, cartilage hair hypoplasia; CHS, Chediak-Higashi syndrome; DKC, dyskeratosis congenita; FHL1-5, familial hemophagocytic lymphohistiocytosis 1-5; HPS-2, Hermansky-Pudlak syndrome 2; ITK, IL-2–inducible T-cell kinase deficiency; LRBA, lipopolysaccharide-responsive beige-like anchor deficiency; PNH, paroxysmal nocturnal hemoglobinuria; RCC, refractory cytopenia of childhood; RD, reticular dysgenesis; SCN1, severe congenital neutropenia 1; SDS, Shwachman-Diamond syndrome; WHIM, warts, hypogammaglobulinemia, immunodeficiency, myelokathexis; WIP, WAS protein-interacting protein; XLP-1,2, X-linked lymphoproliferative disease 1,2.

Autoimmune-mediated cytopenia in PID

According to the causal involvement of autoantibodies against hematopoietic cells or predominant cellular cytotoxicity, the autoimmune-mediated cytopenias may be further subgrouped into antibody-mediated and cellular autoimmunity (Figure 1, upper left quadrant).

Autoantibody production may occur in B-cell–intrinsic defects or in disorders with disturbed T-cell–B-cell interaction and regulation. When B-cell maturation is impaired, vital mechanisms of B-cell tolerance induction, such as central and peripheral checkpoints of B-cell receptor generation to eliminate autoreactive clones, may be defective.7,8  Depending on the impaired maturation step and the affected pre-B-cell subtype, this may lead to hypogammaglobulinemia, at least to a specific antibody formation defect (eg, against polysaccharide antigens) and is often linked to the presence of autoreactive B cells. Common variable immunodeficiency (CVID), along with autoimmune lymphoproliferative syndrome (ALPS; the second most typical PID associated with autoantibody-mediated cytopenias),9-11  is the result of impaired B-cell maturation; both clinical and immune phenotypical classifications have been established as diagnostic criteria and to distinguish between CVID subgroups.12-14  ALPS represents a group of disorders with a primary defect in T-cell development and apoptosis that secondarily affects B cells and causes antibody-mediated autoimmunity.15,16  In addition to these two entities, overlapping syndromes have been reported between CVID and ALPS (with ALPS-linked increased T-cell receptor α/β- positive CD4 and CD8 double-negative T [DNT] cells in CVID patients or reduced CD27+ immunoglobulin D [IgD]+ and CD27+IgD memory B cells and hypogammaglobulinemia as in CVID in ALPS patients).17  One of the novel PIDs in this subgroup of autoantibody-mediated cytopenia is lipopolysaccharide-responsive beige-like anchor deficiency, a rare B-cell defect involving autophagy and apoptosis that, along with immune cytopenia, is often linked to inflammatory bowel disease, multiorgan autoimmune phenomena, severe infections, and hypogammaglobulinemia18-20  [Markus G. Seidel, Tatjana Hirschmugl, Wolfgang Schwinger, Laura Gamez-Diaz, Nina Serwas, Andrea Deutschmann, Gregor Gorkiewicz, Werner Zenz, Christian Windpassinger, Bodo Grimbacher, Christian Urban, and Kaan Boztug; manuscript submitted July 2014]. Although the pathomechanism of this novel disease is incompletely understood, in vitro and in vivo immunologic analyses and human clinical data point toward a B-cell intrinsic defect in lipopolysaccharide-responsive beige-like anchor deficiency.18-20  An example of impaired T-cell–B-cell interaction is CD40/CD40L deficiency, in which the missing signal from T cells causes humoral autoimmunity as well as other severe immunologic symptoms; the phenotype for this deficiency is classified as combined immunodeficiency (CID).3,21 

In addition to these primary or secondary humoral defects, intrinsic defects in T-effector cells may lead to cellular autoimmunity. The simplified principle is similar to that of B-cell maturation defects described above, namely that impaired T-cell development may lead to a lack of functional effectors against non-self or dangerous antigens and simultaneously yield “uneliminated” autoreactive clones with T-cell receptors directed against self-antigens. Defects in signaling or in T-cell receptor recombination or editing may result in both a deficit of FOXP3-positive regulatory T cells (Tregs) and an incomplete development of autoimmune regulator transcription factor–expressing medullary thymus epithelial cells that result in peripheral and central tolerance defects.22  Thus, many classic T-cell disorders such as combined immunodeficiencies (CIDs) that lack naïve T cells based on hypomorphic mutations in genes usually associated with severe CID (SCID; ie, leaky SCIDs such as RAG1, RAG2, adenosine desaminase, artemis, and purine nucleoside phosphorylase23-27 ) and well-known syndromes with immunodeficiency such as WAS, WAS protein-interacting protein deficiency, and 22q11 microdeletion syndrome may show some extent of autoimmunity as a result of autoreactive T cells and reduced T-cell regulation. Furthermore, certain T-cell signaling defects that may cause SCID or CID, such as ORAI-1, STIM-1, MAGT1, STK4, or LCK deficiencies as well as activating mutations of PI3KD, predispose to autoimmunity including cytopenias.3,28-32  Recently, loss of function of tripeptidyl peptidase 2 was demonstrated to cause CID with autoimmune cytopenia (manuscript by Polina Stepensky, Anne Rensing-Ehl, Ruth Gather, Shoshana Revel Vilk, Ute Fischer, Schafiq Nabhani, Sebastian Fuchs, Simon Zenke, Elke Firat, Vered Molho Pessach, Arndt Borkhardt, Mirzokhid Rakhmanov, Baerbel Keller, Klaus Warnatz, Hermann Eibel, Gabriele Niedermann, Orly Elpeleg, and Stephan Ehl, submitted August 2014; Hambleton et al33 ). In WAS, however, the basis of thrombocytopenia and microplatelets is the underlying cytoskeletal dysfunction.34,35  A close connection between T-cell and B-cell pathology exists (eg, in 22q11 syndrome and WAS) in which, in addition to T-cell dysfunction, there is also an altered B-cell differentiation/maturation pattern with predisposition to humoral autoimmunity.36,37  Conversely, PIDs with humoral autoimmune mechanisms that have historically been considered the principal cytopenia-linked PIDs, such as ALPS or CVID, have been shown to have impaired T-cell maturation38  or reduced Treg function,39-41  respectively.

Many hematologic conditions such as refractory cytopenia of childhood (RCC), myelodysplastic syndrome (MDS), severe aplastic anemia (SAA), chronic immune thrombocytopenia (cITP), Evans syndrome (ES), and/or rheumatologic diseases such as systemic lupus erythematosus (SLE) (shown in square brackets in Figure 1) are either the result of an unrecognized PID or are based on a variety of polygenetic or epigenetic defects in hematopoietic stem cells or within the immune system that in turn lead to autoimmune reactions. Both SAA and RCC/MDS, if no cytogenetic aberration or clonal evolution is detected, are being treated with T-cell–directed immunosuppression or hematopoietic stem cell transplantation, indirectly confirming a primary or secondary involvement of autoreactive T cells in pathogenesis.42-45  A variety of pathomechanisms underlying the antiplatelet autoimmunity in cITP has been suggested, ranging from dysfunctional Tregs and lacking regulatory B cells to cytokine gene polymorphisms, disturbed antigen presentation, and autoreactive B cells.46-50  The detection of CVID- or ALPS-like immune phenotypical parameters in a subgroup of patients with ES has recently been reviewed.9  SLE is a descriptive symptom complex mainly ascribed to humoral autoimmunity that may arise in PIDs, typically caused by deficiencies in the classical complement pathway (eg, C1q, C1R, C1s, C2, C4, C5, C6, C7, C8A, and C8B).1,3  In addition to these recognized PIDs, there are SLE-CVID/SLE-CID overlap syndromes and SLE features in hyper-IgM syndromes, including constitutive mismatch repair defects.1,3,51,52  However, because the diagnostic algorithms are not standardized and because existing recommendations (such as those for cITP53  or those within RCC/SAA international treatment guidelines from the European Working Group for childhood MDS54 ) are often not sufficiently executed before initiating immunosuppressive treatment, a substantial number of unrecognized PIDs may be hidden among these allegedly hematologic disorders. International initiatives for prospective registries aim to establish and continuously update diagnostic, prognostic, and therapeutic algorithms for immune cytopenias (eg, the intercontinental cooperative ITP study group, the French Reference Center for Rare Diseases and Autoimmune Cytopenias of Childhood, and the German Pediatric Hematology-Oncology Working Group ITP/ES prospective studies).55,56 

Practically all conditions within this first group of diseases may lead to cytopenia without any previous history of infections or autoimmunity and may present with mild or absent clinical symptoms. However, acute hemolytic anemia, as well as newly diagnosed immune thrombocytopenia, are potentially life-threatening conditions.

Immune dysregulation underlying cytopenia in PID

One classical PID with immune dysregulation linked to cellular autoimmunity is immune dysregulation, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome, which is the result of a lack of functional FOXP3-positive Tregs that leads to a peripheral T-cell tolerance defect and often to cytopenia.57-59  In addition to the mutations in FOXP3 that cause IPEX,60,61  other components of the Treg activation pathway may be defective and may thus reduce the function and/or number of Tregs and lead to an IPEX-like syndrome (eg, deficiency of CD25 or STAT5b and gain-of-function mutations in STAT1).62-65  Interestingly, the classical central T-cell tolerance defect, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome ([APECED] due to a defect of the autoimmune regulator transcription factor) is not typically associated with cytopenias.66  Furthermore, immune dysregulatory processes such as hemophagocytosis or lymphoproliferation (and subsequent splenic sequestration of blood cells) may cause secondary cytopenia in critically ill patients. The underlying pathomechanisms are pathological macrophage activation, functional natural killer (NK) cell defects, and polyclonal or oligoclonal lymphoproliferation. These dysfunctions may arise as complications of certain infections, oncologic treatments including hematopoietic stem cell transplantation (often referred to as infection-associated macrophage-activation syndrome or secondary hemophagocytic lymphohistiocytosis67  or lymphoproliferative syndrome [with unknown genetic predisposition]), or as a main symptom of PIDs that stem from monogenetic communication defects between B and T cells. The manifestation of lymphoproliferative disorders is often triggered by primary Epstein-Barr virus (EBV) infection and is associated with a lack of invariant T-cell receptor NKT (iNKT) cells (eg, X-linked lymphoproliferative syndrome, CD27 deficiency, and interleukin-2 (IL-2)–inducible kinase deficiency). Likewise, interaction defects between T cells and the innate immune system are found in this category (familial hemophagocytic lymphohistiocytosis and immunodeficiencies with hypopigmentation; Figure 1, upper right quadrant) (Alkhairy O, Perez-Becker R, Driessen G, et al, manuscript submitted June 2014).67-71  Another newly identified PID with increased susceptibility to EBV-induced lymphoproliferation and development of lymphoma—the X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia syndrome, which is due to a magnesium transporter MAGT1 defect—also appears to predispose to autoimmune cytopenia,30  most likely as a result of autoantibodies generated on the basis of the underlying T-cell defect similar to the Ca-signaling defects ORAI-1 and STIM-1 (see above). ALPS should be mentioned again in this context, because splenic sequestration contributes to cytopenia in ALPS as in other lymphoproliferative syndromes (and sometimes also in CVID).

Bone marrow failure in PID

If pancytopenia is the initial clinical symptom, diagnostic algorithms in hematology-oncology exclude malignoma, RC/MDS, acquired and inherited bone marrow failure syndromes such as paroxysmal nocturnal hemoglobinuria, and Fanconi anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita, and may end up with a diagnosis of exclusion such as SAA (depending on bone marrow cellularity, morphology, and cytogenetics), but do not always consider immunodeficiencies as the underlying cause. Because rare and novel PIDs such as immune osseous dysplasias (cartilage hair hypoplasia, Schimke syndrome) or MonoMac syndrome (GATA2 deficiency) may cause bone marrow failure and are not widely taken into consideration, these entities need to be mentioned here (Figure 1, lower right quadrant; Table 1).3,72-74  In contrast to the widespread view of a PID diagnosis being dependent on compromised immunity, patients with GATA2 deficiency, as with other PID-linked cytopenias, may be asymptomatic and may lack a history of severe infections.74  Because of its presentation as SCID with granulocytopenia or pancytopenia and deafness, reticular dysgenesis (deficiency of AK2) is unlikely to be missed during a differential diagnosis. The deficiency of IKAROS, a zinc finger transcription factor essential during hematopoiesis,75  has been reported to be associated with hematologic malignancies (reviewed in Wang et al76 ) and also with congenital pancytopenia in humans.77  It is known to impede B- and NK-cell development and is thus suspected to cause an immunodeficiency with antibody deficiency and cytopenia3  (reviewed in John and Ward78 ).

Secondary myelosuppression in PID

Unspecific secondary bone marrow suppression may occur in PID as in secondary states of immunosuppression due to viral (or rarely bacterial) infections, toxic marrow damage from drugs used to treat infections or autoimmunity in PID, extrusion and/or suppression of hematopoiesis by malignant cells, or simply in states of nutritional deficiencies (eg, resulting from inflammatory bowel disease, metabolic disorders, or wasting conditions involving vitamin B12, folate, or iron; Figure 1, lower left quadrant). Myelokathexis (trapping of neutrophils in the bone marrow) is a rare condition involving pseudosuppression of the marrow in which the marrow is unable to release mature neutrophils into the periphery because of a gain-of-function mutation in CXCR479 ; this PID (warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis [WHIM] syndrome) is usually diagnosed based on the typical symptoms indicated in its name. X-linked agammaglobulinemia is not typically linked with cytopenia; however, it is listed here because some patients experience neutropenia, which may be an underestimated clinical concern; its mechanisms include enhanced neutrophil apoptosis and have recently been demonstrated.80 

The following recommendations should be considered as general background information for the differential diagnostic workup and consideration of treatment options for cytopenia in the context of PIDs. They are not guaranteed to be complete for any individual situation nor are they designed for hematologic emergency situations or for managing forms of cytopenia other than those associated with PID (such as hemoglobinopathies). This review should not and cannot replace a consultation with a pediatric hematologist or hematologist-oncologist and a pediatric immunologist who can perform the differential diagnostic procedures for PIDs associated with cytopenia. Likewise, this review cannot provide a general diagnostic algorithm or therapeutic guideline because the spectrum of possible underlying diseases is too vast and heterogeneous for one tool to suffice.

Diagnostic analyses

In PID-associated cytopenia, the first question to answer is whether it is a result of the increased loss or the decreased production of blood cells. This may be an emergency situation because autoimmune hemolytic anemia may evolve into a life-threatening situation within hours. Therefore, the first laboratory analyses that should be performed are for cell lysis parameters (eg, potassium, lactate dehydrogenase, aspartate transaminase, uric acid); for anemia, additional parameters include those for hemolysis (indirect bilirubin, absolute reticulocyte count, haptoglobin) and immunologic and metabolic parameters (eg, direct and indirect Coombs test; IgG, IgA, and IgM; fluorescence-activated cell sorter analyses for T-, B-, and NK-cell counts; serum ferritin concentration; vitamin B12; and folate [soluble IL-2 receptor, IL-18, soluble Fas ligand]) (Table 1 and Sills81 ). Antiplatelet antibodies are of no help in the differential diagnostic process because they are present in less than two-thirds of patients with immune thrombocytopenia and are not predictive, specific, or prognostically relevant,82-84  whereas antierythrocyte (bound or soluble) and antigranulocyte antibodies have a rather high specificity for autoimmune hemolytic anemia and autoimmune neutropenia, respectively. Of note, the detection of antibodies against granulocyte surface antigens (not to be confused with antineutrophil cytoplasma antibodies) is a delicate analysis that depends on using specialized reference laboratories to perform tests and interpret results; it is not a test that can be performed under emergency conditions. Before an immunosuppressive treatment is initiated, at least some of the following special immunologic tests should be performed to exclude diseases that can not be easily diagnosed under intravenous immunoglobulin or pharmacologic immunosuppression. Parameters that are impacted by intravenous immune globulin are mainly the serologic tests such as quantitative immunoglobulins, antibodies against vaccination antigens and previous infectious diseases (protein and polysaccharide antigens), and isohemagglutinins. Analyses that should be done before pharmacologic immunosuppression (including the use of corticosteroids) are immune cellular tests such as quantification of T-, B-, and NK cells, T-cell receptor α/β-positive CD4 and CD8 double-negative T cells, CD27+IgD+ and CD27+IgD memory B cells; functional assays such as in vitro lymphocyte proliferation, NK/cytolytic T lymphocyte cytotoxicity; and CD107a degranulation assays to exclude functional T- or NK-cell defects. If a primary lymphoproliferative disorder is suspected, invariant T-cell receptor NKT (iNKT) cells should be quantified (Table 1). Infection serology should be analyzed for EBV, cytomegalovirus, parvovirus B19, and other DNA viruses, as well as HIV and hepatitis viruses; and if an antibody formation defect is suspected, a virus nucleic acid detection test may be needed. In many cases, bone marrow smears and trephine biopsies will need to be assessed and, ideally, they should be sent to reference laboratories for evaluation, as is done in international treatment optimization studies. More specific laboratory tests and genetic analyses depend on the clinical situation, the immune hematologic phenotype, and patient’s history, as outlined in Table 1.

Treatment options

The main intention of this review is to increase awareness of and to classify the types of cytopenia that occur in the context of PID to facilitate correct management. Table 1 provides an overview of typical and potential treatment approaches. However, it is not feasible to provide general treatment guidelines for cytopenias in PID because of the heterogeneity of underlying causes and mechanisms, as outlined above and in Figure 1 and Table 1. Although PIDs with autoimmune-mediated cytopenia most often respond well to various degrees and modes of immunosuppression (recently reviewed by Teachey and Lambert11 ), certain diseases might represent an indication for early hematopoietic stem cell transplantation, which should be performed according to international transplantation guidelines (such as those recommended by the European Group for Blood and Marrow Transplantation85 ) and within well-controlled clinical trials. Rituximab is used when autoreactive CD20-expressing B-cell clones need to be eradicated and also in EBV-mediated immune dysregulation such as hemophagocytosis and lymphoproliferation (eg, in X-linked lymphoproliferative syndrome, CD27, and IL-2–inducible kinase deficiency), because B cells represent the main pool of EBV and are therefore the trigger for subsequent dysregulated immune processes. A novel group of substances for treating immune-mediated thrombocytopenia (and potentially also pancytopenia resulting from RC/MDS) are thrombopoietin receptor agonists such as romiplostim and eltrombopag.44,86-89  Although this treatment option appears even less causal than immunosuppression, at least short-term side effects are low and response rates are promising in adults and children. The future will tell whether long-term follow-up remains acceptable and whether the spectrum for clinical use of thrombopoietin receptor agonists will be extended. In the future, other novel substances for use in antibody-mediated cytopenias may include the proteasome inhibitor bortezomib, the anti-B-cell–activating factor antibody belimumab, the anti-IL-6–directed antibody tocilizumab, the anti-CD22 antibody epratuzumab, and an anti-APRIL antibody, which are currently used only within phase 1 to 3 clinical trials against refractory autoimmunity in certain indications such as in subgroups of patients with SLE, multiple sclerosis, other severe autoimmune diseases, in antibody-mediated graft rejection, or as a treatment adjunct in certain B-cell malignancies.90-92  The recommendation to avoid splenectomy, which is still one of the widely accepted (and likely least expensive) options for treating hypersplenism-associated thrombocytopenia associated with the risk of overwhelming post-splenectomy infection, is increasingly confirmed and corroborated by long-term follow-up data (eg, from ALPS patients in Price et al15 ).

In conclusion, this review provides a conceptual description of known and novel observations of cytopenias in PID and their management. Cytopenia may be the initial presenting symptom of patients with PID, irrespective of a previous history of severe infections, autoimmunity, or a familial predisposition. Because hematologic diagnostic procedures rarely include the differential diagnosis of PIDs and because clinical immunologists often have little experience in the management of newly diagnosed cytopenias, awareness of this challenging and growing field is critical. Hence, the hematologists’ and immunologists’ diagnostic approaches should be combined before immunosuppressive treatment is initiated, ideally within prospective clinical studies.

The author thanks all participants of the 2014 Annual Meeting of the Arbeitsgemeinschaft Pädiatrische Immunologie (German Working Group of Pediatric Immunology) for constructive criticism of figure and table drafts. Fruitful discussions on immune tolerance and inborn errors of hematopoiesis with A. Heitger and O.A. Haas, Vienna, Austria, are highly appreciated and have substantially contributed to this work. The author thanks C. Urban and the team of Pediatric Hematology-Oncology, Graz, for being supportive.

Contribution: M.G.S. designed the concept of the article, drew the figure, and wrote the final draft.

Conflict-of-interest disclosure: The author declares no competing financial interests.

Correspondence: Markus G. Seidel, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology-Oncology, Medical University Graz, Auenbruggerplatz 38, 8036 Graz, Austria; e-mail: markus.seidel@medunigraz.at.

1
Bousfiha
 
AA
Jeddane
 
L
Ailal
 
F
, et al. 
A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside.
J Clin Immunol
2013
, vol. 
33
 
6
(pg. 
1078
-
1087
)
2
Parvaneh
 
N
Casanova
 
JL
Notarangelo
 
LD
Conley
 
ME
Primary immunodeficiencies: a rapidly evolving story.
J Allergy Clin Immunol
2013
, vol. 
131
 
2
(pg. 
314
-
323
)
3
Al-Herz
 
W
Bousfiha
 
A
Casanova
 
JL
, et al. 
Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency.
Front Immunol
2014
, vol. 
5
 pg. 
162
 
4
Vilboux
 
T
Lev
 
A
Malicdan
 
MC
, et al. 
A congenital neutrophil defect syndrome associated with mutations in VPS45.
N Engl J Med
2013
, vol. 
369
 
1
(pg. 
54
-
65
)
5
Skokowa
 
J
Steinemann
 
D
Katsman-Kuipers
 
JE
, et al. 
Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis.
Blood
2014
, vol. 
123
 
14
(pg. 
2229
-
2237
)
6
Boztug
 
K
Klein
 
C
Genetic etiologies of severe congenital neutropenia.
Curr Opin Pediatr
2011
, vol. 
23
 
1
(pg. 
21
-
26
)
7
Meffre
 
E
The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases.
Ann N Y Acad Sci
2011
, vol. 
1246
 (pg. 
1
-
10
)
8
von Boehmer
 
H
Melchers
 
F
Checkpoints in lymphocyte development and autoimmune disease.
Nat Immunol
2010
, vol. 
11
 
1
(pg. 
14
-
20
)
9
Podjasek
 
JC
Abraham
 
RS
Autoimmune cytopenias in common variable immunodeficiency.
Front Immunol
2012
, vol. 
3
 pg. 
189
 
10
Notarangelo
 
LD
Primary immunodeficiencies (PIDs) presenting with cytopenias.
Hematology (Am Soc Hematol Educ Program)
2009
(pg. 
139
-
143
)
11
Teachey
 
DT
Lambert
 
MP
Diagnosis and management of autoimmune cytopenias in childhood.
Pediatr Clin North Am
2013
, vol. 
60
 
6
(pg. 
1489
-
1511
)
12
Chapel
 
H
Lucas
 
M
Lee
 
M
, et al. 
Common variable immunodeficiency disorders: division into distinct clinical phenotypes.
Blood
2008
, vol. 
112
 
2
(pg. 
277
-
286
)
13
Warnatz
 
K
Wehr
 
C
Dräger
 
R
, et al. 
Expansion of CD19(hi)CD21(lo/neg) B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia.
Immunobiology
2002
, vol. 
206
 
5
(pg. 
502
-
513
)
14
Wehr
 
C
Kivioja
 
T
Schmitt
 
C
, et al. 
The EUROclass trial: defining subgroups in common variable immunodeficiency.
Blood
2008
, vol. 
111
 
1
(pg. 
77
-
85
)
15
Price
 
S
Shaw
 
PA
Seitz
 
A
, et al. 
Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations.
Blood
2014
, vol. 
123
 
13
(pg. 
1989
-
1999
)
16
Rensing-Ehl
 
A
Völkl
 
S
Speckmann
 
C
, et al. 
Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency.
Blood
2014
, vol. 
124
 
6
(pg. 
851
-
860
)
17
Rensing-Ehl
 
A
Warnatz
 
K
Fuchs
 
S
, et al. 
Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency.
Clin Immunol
2010
, vol. 
137
 
3
(pg. 
357
-
365
)
18
Alangari
 
A
Alsultan
 
A
Adly
 
N
, et al. 
LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency.
J Allergy Clin Immunol
2012
, vol. 
130
 
2
(pg. 
481
-
488
)
19
Burns
 
SO
Zenner
 
HL
Plagnol
 
V
, et al. 
LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia.
J Allergy Clin Immunol
2012
, vol. 
130
 
6
(pg. 
1428
-
1432
)
20
Lopez-Herrera
 
G
Tampella
 
G
Pan-Hammarström
 
Q
, et al. 
Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity.
Am J Hum Genet
2012
, vol. 
90
 
6
(pg. 
986
-
1001
)
21
Davies
 
EG
Thrasher
 
AJ
Update on the hyper immunoglobulin M syndromes.
Br J Haematol
2010
, vol. 
149
 
2
(pg. 
167
-
180
)
22
Anderson
 
G
Baik
 
S
Cowan
 
JE
, et al. 
Mechanisms of thymus medulla development and function.
Curr Top Microbiol Immunol
2014
, vol. 
373
 (pg. 
19
-
47
)
23
Felgentreff
 
K
Perez-Becker
 
R
Speckmann
 
C
, et al. 
Clinical and immunological manifestations of patients with atypical severe combined immunodeficiency.
Clin Immunol
2011
, vol. 
141
 
1
(pg. 
73
-
82
)
24
Speckmann
 
C
Neumann
 
C
Borte
 
S
, et al. 
Delayed-onset adenosine deaminase deficiency: strategies for an early diagnosis.
J Allergy Clin Immunol
2012
, vol. 
130
 
4
(pg. 
991
-
994
)
25
Schuetz
 
C
Pannicke
 
U
Jacobsen
 
EM
, et al. 
Lesson from hypomorphic recombination-activating gene (RAG) mutations: Why asymptomatic siblings should also be tested.
J Allergy Clin Immunol
2014
, vol. 
133
 
4
(pg. 
1211
-
1215
)
26
Henderson
 
LA
Frugoni
 
F
Hopkins
 
G
, et al. 
Expanding the spectrum of recombination-activating gene 1 deficiency: a family with early-onset autoimmunity.
J Allergy Clin Immunol
2013
, vol. 
132
 
4
(pg. 
969
-
971
)
27
Chen
 
K
Wu
 
W
Mathew
 
D
, et al. 
Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations.
J Allergy Clin Immunol
2014
, vol. 
133
 
3
(pg. 
880
-
882
)
28
Shaw
 
PJ
Feske
 
S
Regulation of lymphocyte function by ORAI and STIM proteins in infection and autoimmunity.
J Physiol
2012
, vol. 
590
 
Pt 17
(pg. 
4157
-
4167
)
29
Hauck
 
F
Randriamampita
 
C
Martin
 
E
, et al. 
Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency.
J Allergy Clin Immunol
2012
, vol. 
130
 
5
(pg. 
1144
-
1152
)
30
Li
 
FY
Chaigne-Delalande
 
B
Su
 
H
Uzel
 
G
Matthews
 
H
Lenardo
 
MJ
XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus.
Blood
2014
, vol. 
123
 
14
(pg. 
2148
-
2152
)
31
Abdollahpour
 
H
Appaswamy
 
G
Kotlarz
 
D
, et al. 
The phenotype of human STK4 deficiency.
Blood
2012
, vol. 
119
 
15
(pg. 
3450
-
3457
)
32
Angulo
 
I
Vadas
 
O
Garçon
 
F
, et al. 
Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.
Science
2013
, vol. 
342
 
6160
(pg. 
866
-
871
)
33
Hambleton
 
S
McDonald
 
DO
Morgan
 
NV
, et al. 
Autosomal recessive combined immunodeficiency due to loss of function mutation in tripeptidyl peptidase II. [In: 15th Biennial Meeting European Society for Immunodeficiency (ESID). 2012, Florence, Italy: Springer.]
J Clin Immunol
2012
, vol. 
32
 (pg. 
384
-
385
)
34
Massaad
 
MJ
Ramesh
 
N
Geha
 
RS
Wiskott-Aldrich syndrome: a comprehensive review.
Ann N Y Acad Sci
2013
, vol. 
1285
 (pg. 
26
-
43
)
35
Balduini
 
CL
Savoia
 
A
Genetics of familial forms of thrombocytopenia.
Hum Genet
2012
, vol. 
131
 
12
(pg. 
1821
-
1832
)
36
Patel
 
K
Akhter
 
J
Kobrynski
 
L
Benjamin Gathmann
 
MA
Davis
 
O
Sullivan
 
KE
International DiGeorge Syndrome Immunodeficiency Consortium
Immunoglobulin deficiencies: the B-lymphocyte side of DiGeorge Syndrome.
J Pediatr
2012
, vol. 
161
 
5
(pg. 
950
-
953
)
37
Castiello
 
MC
Bosticardo
 
M
Pala
 
F
, et al. 
Wiskott-Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans.
J Autoimmun
2014
, vol. 
50
 (pg. 
42
-
50
)
38
Rensing-Ehl
 
A
Völkl
 
S
Speckmann
 
C
Lorenz
 
MR
Ritter
 
J
Janda
 
A
Abinun
 
M
Pircher
 
H
Bengsch
 
B
Thimme
 
R
Fuchs
 
I
Ammann
 
S
Allgäuer
 
A
Kentouche
 
K
Cant
 
A
Hambleton
 
S
Bettoni da Cunha
 
C
Huetker
 
S
Kühnle
 
I
Pekrun
 
A
Seidel
 
MG
Hummel
 
M
Mackensen
 
A
Schwarz
 
K
Ehl
 
S
Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency.
Blood
2014
, vol. 
124
 
6
(pg. 
851
-
860
)
39
Buckner
 
JH
Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases.
Nat Rev Immunol
2010
, vol. 
10
 
12
(pg. 
849
-
859
)
40
Arumugakani
 
G
Wood
 
PM
Carter
 
CR
Frequency of Treg cells is reduced in CVID patients with autoimmunity and splenomegaly and is associated with expanded CD21lo B lymphocytes.
J Clin Immunol
2010
, vol. 
30
 
2
(pg. 
292
-
300
)
41
Jang
 
E
Cho
 
WS
Cho
 
ML
, et al. 
Foxp3+ regulatory T cells control humoral autoimmunity by suppressing the development of long-lived plasma cells.
J Immunol
2011
, vol. 
186
 
3
(pg. 
1546
-
1553
)
42
Passweg
 
JR
Giagounidis
 
AA
Simcock
 
M
, et al. 
Immunosuppressive therapy for patients with myelodysplastic syndrome: a prospective randomized multicenter phase III trial comparing antithymocyte globulin plus cyclosporine with best supportive care—SAKK 33/99.
J Clin Oncol
2011
, vol. 
29
 
3
(pg. 
303
-
309
)
43
Yoshimi
 
A
Baumann
 
I
Führer
 
M
, et al. 
Immunosuppressive therapy with anti-thymocyte globulin and cyclosporine A in selected children with hypoplastic refractory cytopenia.
Haematologica
2007
, vol. 
92
 
3
(pg. 
397
-
400
)
44
Hasegawa
 
D
Manabe
 
A
Yagasaki
 
H
, et al. 
Japanese Childhood MDS Study Group
Treatment of children with refractory anemia: the Japanese Childhood MDS Study Group trial (MDS99).
Pediatr Blood Cancer
2009
, vol. 
53
 
6
(pg. 
1011
-
1015
)
45
Marsh
 
JC
Kulasekararaj
 
AG
Management of the refractory aplastic anemia patient: what are the options?
Blood
2013
, vol. 
122
 
22
(pg. 
3561
-
3567
)
46
Li
 
X
Zhong
 
H
Bao
 
W
, et al. 
Defective regulatory B-cell compartment in patients with immune thrombocytopenia.
Blood
2012
, vol. 
120
 
16
(pg. 
3318
-
3325
)
47
Nishimoto
 
T
Kuwana
 
M
CD4+CD25+Foxp3+ regulatory T cells in the pathophysiology of immune thrombocytopenia.
Semin Hematol
2013
, vol. 
50
 
Suppl 1
(pg. 
S43
-
S49
)
48
Tesse
 
R
Del Vecchio
 
GC
De Mattia
 
D
Sangerardi
 
M
Valente
 
F
Giordano
 
P
Association of interleukin-(IL)10 haplotypes and serum IL-10 levels in the progression of childhood immune thrombocytopenic purpura.
Gene
2012
, vol. 
505
 
1
(pg. 
53
-
56
)
49
Zhao
 
H
Zhang
 
Y
Xiao
 
G
Wu
 
N
Xu
 
J
Fang
 
Z
Interleukin-18 gene promoter - 607 A/C polymorphism and the risk of immune thrombocytopenia.
Autoimmunity
2014
(pg. 
1
-
4
)
50
Zhao
 
H
Zhang
 
Y
Xue
 
F
Xu
 
J
Fang
 
Z
Interleukin-27 rs153109 polymorphism and the risk for immune thrombocytopenia.
Autoimmunity
2013
, vol. 
46
 
8
(pg. 
509
-
512
)
51
Salzer
 
E
Santos-Valente
 
E
Klaver
 
S
, et al. 
B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ.
Blood
2013
, vol. 
121
 
16
(pg. 
3112
-
3116
)
52
Wimmer
 
K
Kratz
 
CP
Vasen
 
HF
, et al. 
EU-Consortium Care for CMMRD (C4CMMRD)
Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘care for CMMRD’ (C4CMMRD).
J Med Genet
2014
, vol. 
51
 
6
(pg. 
355
-
365
)
53
Neunert
 
C
Lim
 
W
Crowther
 
M
Cohen
 
A
Solberg
 
L
Crowther
 
MA
American Society of Hematology
The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.
Blood
2011
, vol. 
117
 
16
(pg. 
4190
-
4207
)
54
EWOG. European Working Group of MDS and JMML in Childhood; Director: C. Niemeyer; http://www.ewog-mds.org. Accessed August 2014
55
ICIS. Imbach P, Kühne T. Intercontinental Cooperative ITP Study Group (ICIS - PARC-ITP)., CH-4031 Basel. Switzerland: University Children’s Hospital UKBB, Hematology/Oncology; http://www.itpbasel.ch. Accessed August 2014
56
CEREVANCE. Perel Y, Aladjidi N. CEREVANCE / cytopénies auto-immunes de l’enfant Bordeaux, France; http://www.chu-bordeaux.fr/Professionnel-de-sant%C3%A9/Les-maladies-rares/presentation/cerevance-cytopenies-auto-immunes-de-lenfant. Accessed August 2014
57
Barzaghi
 
F
Passerini
 
L
Bacchetta
 
R
Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity.
Front Immunol
2012
, vol. 
3
 pg. 
211
 
58
Ochs
 
HD
Ziegler
 
SF
Torgerson
 
TR
FOXP3 acts as a rheostat of the immune response.
Immunol Rev
2005
, vol. 
203
 (pg. 
156
-
164
)
59
Sakaguchi
 
S
Miyara
 
M
Costantino
 
CM
Hafler
 
DA
FOXP3+ regulatory T cells in the human immune system.
Nat Rev Immunol
2010
, vol. 
10
 
7
(pg. 
490
-
500
)
60
Fontenot
 
JD
Gavin
 
MA
Rudensky
 
AY
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.
Nat Immunol
2003
, vol. 
4
 
4
(pg. 
330
-
336
)
61
Hori
 
S
Nomura
 
T
Sakaguchi
 
S
Control of regulatory T cell development by the transcription factor Foxp3.
Science
2003
, vol. 
299
 
5609
(pg. 
1057
-
1061
)
62
Caudy
 
AA
Reddy
 
ST
Chatila
 
T
Atkinson
 
JP
Verbsky
 
JW
CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes.
J Allergy Clin Immunol
2007
, vol. 
119
 
2
(pg. 
482
-
487
)
63
Uzel
 
G
Sampaio
 
EP
Lawrence
 
MG
, et al. 
Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome.
J Allergy Clin Immunol
2013
, vol. 
131
 
6
(pg. 
1611
-
1623
)
64
Kanai
 
T
Jenks
 
J
Nadeau
 
KC
The STAT5b Pathway Defect and Autoimmunity.
Front Immunol
2012
, vol. 
3
 pg. 
234
 
65
Barzaghi
 
F
Passerini
 
L
Gambineri
 
E
, et al. 
Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome.
J Autoimmun
2012
, vol. 
38
 
1
(pg. 
49
-
58
)
66
De Martino
 
L
Capalbo
 
D
Improda
 
N
, et al. 
APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors.
Front Immunol
2013
, vol. 
4
 pg. 
331
 
67
Janka
 
GE
Lehmberg
 
K
Hemophagocytic syndromes—an update.
Blood Rev
2014
, vol. 
28
 
4
(pg. 
135
-
142
)
68
Henter
 
JI
Horne
 
A
Aricó
 
M
, et al. 
HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.
Pediatr Blood Cancer
2007
, vol. 
48
 
2
(pg. 
124
-
131
)
69
Huck
 
K
Feyen
 
O
Niehues
 
T
, et al. 
Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation.
J Clin Invest
2009
, vol. 
119
 
5
(pg. 
1350
-
1358
)
70
Salzer
 
E
Daschkey
 
S
Choo
 
S
, et al. 
Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27.
Haematologica
2013
, vol. 
98
 
3
(pg. 
473
-
478
)
71
van Montfrans
 
JM
Hoepelman
 
AI
Otto
 
S
, et al. 
CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia.
J Allergy Clin Immunol
2012
, vol. 
129
 
3
(pg. 
787
-
793, e6
)
72
Bigley
 
V
Collin
 
M
Dendritic cell, monocyte, B and NK lymphoid deficiency defines the lost lineages of a new GATA-2 dependent myelodysplastic syndrome.
Haematologica
2011
, vol. 
96
 
8
(pg. 
1081
-
1083
)
73
Dickinson
 
RE
Griffin
 
H
Bigley
 
V
, et al. 
Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency.
Blood
2011
, vol. 
118
 
10
(pg. 
2656
-
2658
)
74
Dickinson
 
RE
Milne
 
P
Jardine
 
L
, et al. 
The evolution of cellular deficiency in GATA2 mutation.
Blood
2014
, vol. 
123
 
6
(pg. 
863
-
874
)
75
Georgopoulos
 
K
Moore
 
DD
Derfler
 
B
Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment.
Science
1992
, vol. 
258
 
5083
(pg. 
808
-
812
)
76
Wang
 
H
Ouyang
 
H
Lai
 
L
, et al. 
Pathogenesis and regulation of cellular proliferation in acute lymphoblastic leukemia - the role of Ikaros.
J BUON
2014
, vol. 
19
 
1
(pg. 
22
-
28
)
77
Goldman
 
FD
Gurel
 
Z
Al-Zubeidi
 
D
, et al. 
Congenital pancytopenia and absence of B lymphocytes in a neonate with a mutation in the Ikaros gene.
Pediatr Blood Cancer
2012
, vol. 
58
 
4
(pg. 
591
-
597
)
78
John
 
LB
Ward
 
AC
The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity.
Mol Immunol
2011
, vol. 
48
 
9-10
(pg. 
1272
-
1278
)
79
Hernandez
 
PA
Gorlin
 
RJ
Lukens
 
JN
, et al. 
Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease.
Nat Genet
2003
, vol. 
34
 
1
(pg. 
70
-
74
)
80
Honda
 
F
Kano
 
H
Kanegane
 
H
, et al. 
The kinase Btk negatively regulates the production of reactive oxygen species and stimulation-induced apoptosis in human neutrophils.
Nat Immunol
2012
, vol. 
13
 
4
(pg. 
369
-
378
)
81
Sills
 
RH
Practical Algorithms in Pediatric Hematology and Oncology
2003
Basel, Switzerland
Karger
82
Brighton
 
TA
Evans
 
S
Castaldi
 
PA
Chesterman
 
CN
Chong
 
BH
Prospective evaluation of the clinical usefulness of an antigen-specific assay (MAIPA) in idiopathic thrombocytopenic purpura and other immune thrombocytopenias.
Blood
1996
, vol. 
88
 
1
(pg. 
194
-
201
)
83
Warner
 
MN
Moore
 
JC
Warkentin
 
TE
Santos
 
AV
Kelton
 
JG
A prospective study of protein-specific assays used to investigate idiopathic thrombocytopenic purpura.
Br J Haematol
1999
, vol. 
104
 
3
(pg. 
442
-
447
)
84
Raife
 
TJ
Olson
 
JD
Lentz
 
SR
Platelet antibody testing in idiopathic thrombocytopenic purpura.
Blood
1997
, vol. 
89
 
3
(pg. 
1112
-
1114
)
85
EBMT. European Society for Blood and Marrow Transplantation. www.ebmt.org Accessed August 2014
86
Arnold
 
DM
Positioning new treatments in the management of immune thrombocytopenia.
Pediatr Blood Cancer
2013
, vol. 
60
 
Suppl 1
(pg. 
S19
-
S22
)
87
Basciano
 
PA
Bussel
 
JB
Thrombopoietin-receptor agonists.
Curr Opin Hematol
2012
, vol. 
19
 
5
(pg. 
392
-
398
)
88
Wörmann
 
B
Clinical indications for thrombopoietin and thrombopoietin-receptor agonists.
Transfus Med Hemother
2013
, vol. 
40
 
5
(pg. 
319
-
325
)
89
Seidel
 
MG
Urban
 
C
Sipurzynski
 
J
Beham-Schmid
 
C
Lackner
 
H
Benesch
 
M
High response rate but short-term effect of romiplostim in paediatric refractory chronic immune thrombocytopenia.
Br J Haematol
2014
, vol. 
165
 
3
(pg. 
419
-
421
)
90
Jordan
 
SC
Reinsmoen
 
N
Lai
 
CH
Vo
 
A
Novel immunotherapeutic approaches to improve rates and outcomes of transplantation in sensitized renal allograft recipients.
Discov Med
2012
, vol. 
13
 
70
(pg. 
235
-
245
)
91
National Institutes of Health. ClinicalTrials.gov database. Available at: www.clinicaltrials.gov. Accessed August 2014
92
Liu
 
XG
Hou
 
M
Immune thrombocytopenia and B-cell-activating factor/a proliferation-inducing ligand.
Semin Hematol
2013
, vol. 
50
 
Suppl 1
(pg. 
S89
-
S99
)