Possible clinical presentation (apart from symptoms of cytopenia), laboratory parameters of PID with cytopenia, and treatment options
| Type . | Disorders* . | Possible symptoms . | Typical laboratory parameters . | Treatment 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) |
| Type . | Disorders* . | Possible symptoms . | Typical laboratory parameters . | Treatment 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).