Characteristics of neutropenia in IEI commonly encountered by hematologists
| IEI . | Frequency of neutropenia . | Proposed mechanism of neutropenia . | Neutropenia-directed therapy . | Comments . |
|---|---|---|---|---|
| Chediak-Higashi syndrome | Common57 | -Accelerated granulocyte turnover secondary to intramedullary granulocyte destruction compounded by hypersplenism.9 -Abnormal bone marrow reserves with defective granulocyte mobilization from the marrow space.9 | G-CSF Antimicrobials HSCT58 | -Phagocyte intracellular killing and NK cytotoxicity is impaired. |
| CVID | 1%-8.4%10,12 | -Autoimmune clearance as supported by the identification of antineutrophil antibodies and evidence of hyperplastic yet inefficient germinal center responses.11,59 -Hypersplenism -Postinfectious -Drug-related | Corticosteroids G-CSF Rapamycin | -Neutropenia does not improve with IgG replacement -Neutropenia is associated with increased infections, increased polyclonal lymphoproliferation, and autoimmunity.12 -Increased mortality rate associated with neutropenia in CVID patients.11,12 |
| DADA2 | 7%-15%14,60 | -Decreased ADA2 protein function in severely deleterious variants is proposed to lead to decreased marrow production.17 -Immune-mediated destruction is also hypothesized. | Corticosteroids Rituximab Anti-TNF agents HSCT61 | -ADA2 is highly expressed in myeloid cells and produced by activated macrophages, monocytes, and dendritic cells when stimulated by an inflammatory response.14 |
| Hyper IgM syndrome | 41%18 | -Decreased CD16 expression and dysregulated transcriptome resulting in impaired differentiation.62 -Disrupted cytokine or growth factor support in the bone marrow.63 | G-CSF | -Neutropenia may be chronic or intermittent. -Bone marrow evaluation may demonstrate maturation arrest.62 |
| GATA2 haploinsufficiency | 47%21 | -Reduction of the primitive HSC pool20 | G-CSF HSCT | -Mild chronic neutropenia may be the first manifestation of disease with other clinical features, eg, monocytopenia or MDS/AML presenting later. -Maturation of neutrophils in the bone marrow is generally preserved.20 |
| WHIM syndrome | Near universal | -Diminished egress from the bone marrow secondary to gain of function mutations in CXCR423 | G-CSF CXCR4 antagonists | -Bone marrow is hypercellular with full maturation and classic pyknotic nuclei. |
| XLA | 10%-26%64-66 | -Decreased bone marrow precursors25 -Decreased maturation of myeloid precursors secondary to changes in BTK-related signal transduction25 -Decreased cytokine/chemokine production from monocytes, esp decreased IL-1825 | G-CSF IVIG | -BTK expressed in myeloid and B-cell differentiation (limited to hematopoietic cells). -Neutropenia may be a presenting sign of XLA. -Neutropenia generally resolves with initiation of IVIG, allowing G-CSF withdrawal. -Neutropenia generally documented only in conjunction with an active infection. |
| IEI . | Frequency of neutropenia . | Proposed mechanism of neutropenia . | Neutropenia-directed therapy . | Comments . |
|---|---|---|---|---|
| Chediak-Higashi syndrome | Common57 | -Accelerated granulocyte turnover secondary to intramedullary granulocyte destruction compounded by hypersplenism.9 -Abnormal bone marrow reserves with defective granulocyte mobilization from the marrow space.9 | G-CSF Antimicrobials HSCT58 | -Phagocyte intracellular killing and NK cytotoxicity is impaired. |
| CVID | 1%-8.4%10,12 | -Autoimmune clearance as supported by the identification of antineutrophil antibodies and evidence of hyperplastic yet inefficient germinal center responses.11,59 -Hypersplenism -Postinfectious -Drug-related | Corticosteroids G-CSF Rapamycin | -Neutropenia does not improve with IgG replacement -Neutropenia is associated with increased infections, increased polyclonal lymphoproliferation, and autoimmunity.12 -Increased mortality rate associated with neutropenia in CVID patients.11,12 |
| DADA2 | 7%-15%14,60 | -Decreased ADA2 protein function in severely deleterious variants is proposed to lead to decreased marrow production.17 -Immune-mediated destruction is also hypothesized. | Corticosteroids Rituximab Anti-TNF agents HSCT61 | -ADA2 is highly expressed in myeloid cells and produced by activated macrophages, monocytes, and dendritic cells when stimulated by an inflammatory response.14 |
| Hyper IgM syndrome | 41%18 | -Decreased CD16 expression and dysregulated transcriptome resulting in impaired differentiation.62 -Disrupted cytokine or growth factor support in the bone marrow.63 | G-CSF | -Neutropenia may be chronic or intermittent. -Bone marrow evaluation may demonstrate maturation arrest.62 |
| GATA2 haploinsufficiency | 47%21 | -Reduction of the primitive HSC pool20 | G-CSF HSCT | -Mild chronic neutropenia may be the first manifestation of disease with other clinical features, eg, monocytopenia or MDS/AML presenting later. -Maturation of neutrophils in the bone marrow is generally preserved.20 |
| WHIM syndrome | Near universal | -Diminished egress from the bone marrow secondary to gain of function mutations in CXCR423 | G-CSF CXCR4 antagonists | -Bone marrow is hypercellular with full maturation and classic pyknotic nuclei. |
| XLA | 10%-26%64-66 | -Decreased bone marrow precursors25 -Decreased maturation of myeloid precursors secondary to changes in BTK-related signal transduction25 -Decreased cytokine/chemokine production from monocytes, esp decreased IL-1825 | G-CSF IVIG | -BTK expressed in myeloid and B-cell differentiation (limited to hematopoietic cells). -Neutropenia may be a presenting sign of XLA. -Neutropenia generally resolves with initiation of IVIG, allowing G-CSF withdrawal. -Neutropenia generally documented only in conjunction with an active infection. |
AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.