Inheritance patterns, pathogenic mechanisms and important hematological or extrahematopoietic features of primary immunodeficiency diseases associted with neutropenia.
Phagocytes including neutrophil granulocytes and macrophages are important cells of the innate immune system whose primary function is to ingest and destroy microorganisms. Neutrophils help their host fight infections by phagocytosis, degranulation, and neutrophil extracellular traps. Neutrophils are the most common type of circulating white blood cells and the principal cell type in acute inflammatory reactions. A total absence of neutrophils or a significant decrease in their number leads to severe immunodeficiency that renders patients vulnerable to recurrent infections by Staphylococcus aureus and Gram-negative bacteria being the most life-threatening. Neutropenia may be classified as mild, moderate or severe in terms of numbers in the peripheral blood, and intermittent, cyclic, or chronic in terms of duration. Besides well-known classic severe congenital neutropenia, chronic neutropenia appears to be associated with an increasing number of primary immunodeficiency diseases (PIDs), including those of myeloid and lymphoid lineage. A comprehensive overview of the diverse clinical presenting symptoms, classification, aetiological and genetic etiologies of chronic isolated and syndromic neutropenia is aimed to be reviewed.
- immune system
Inborn errors of immunity, traditionally called primary immunodeficiency diseases (PIDs) are a group of genetic defects that interfere with a component of the human immune system. Over the past decade, substantial knowledge has been gained regarding the genetic abnormalities involved in the pathogenesis of PIDs. More than 400 distinct disorders with 430 gene defects have been reported in the 2019 International Union of Immunological Societies (IUIS) phenotypical classification of human inborn errors of immunity . Despite developmental changes in normal values for white blood cell counts during childhood and discrepancies in the mean value of neutrophil counts observed in people from different ethnicities, an absolute neutrophil count of less than 1500/μL is accepted as neutropenia. Absolute neutrophil count (ANC) is determined by multiplying the total leukocyte count by the percentage of segmented neutrophils and bands in the peripheral blood. Neutropenia may be defined as mild neutropenia, with an ANC of 1000–1500/μL; moderate neutropenia, with an ANC of 500–1000/μL; severe neutropenia, with an ANC <500/μL or agranulocytosis (ANC <200/μL). Neutropenia is defined to be chronic if it lasts longer than 3 months. Neutropenia may be chronic, intermittent, or cyclic. Peripheral neutrophil granulocyte counts show sinusoidal variation with 21 days in cyclic neutropenia.
Neutropenia is a common hematological manifestation of several PIDs with diverse genetic defects varying from congenital defects of phagocytes, to combined immunodeficiencies, and is often discovered in the course of an evaluation for acute infection. Congenital neutropenias associated with primary immunodeficiency diseases range from isolated severe congenital neutropenia to complex inherited disorders that comprise intellectual disabilities, organ abnormalities, facial dysmorphism or skin hypopigmentation. In IUIS classification, congenital defects of phagocytes are listed in two main groups; I. Defects of phagocyte number (neutropenia), and II. Functional defects of phagocytes . In addition to the IUIS classification, chronic or intermittent neutropenia can be observed in other inborn errors of immune system, such as X-linked agammaglobulinemia, CD40L deficiency, reticular dysgenesis, WHIM syndrome, or in diseases of immune dysregulation. Defective myeloid cell differentiation, defective release of granulocytes from the bone marrow, enhanced apoptosis, or increased destruction of peripheral blood granulocytes are the main pathophysiological mechanisms underlying chronic severe or intermittent neutropenia in PID patients [1, 2, 3]. Primary immunodeficiency disorders associated with chronic or intermittent neutropenia are listed in Table 1.
|Inheritance||Gene||Pathogenic mechanism||Clinical and laboratory features in addition to neutropenia|
|Neutrophil elastase deficiency||AD, sporadic||ELANE /ELA2||Activation of the unfolded protein response (UPR), apoptosis of myeloid progenitor cells||Leukemia and myelodysplastic syndrome predisposition|
|HAX1 deficiency||AR||HAX1||Destabilization of mitochondrial membrane potential, abgrogated G-CSFR signaling, enhanced apoptosis of myeloid and neuronal cells||Leukemia and myelodysplastic syndrome predisposition, mental retardation, seizures|
|Glucose-6-phosphatase deficiency||AR||G6PC3||Impaired intracellular glucose homeostasis, dysglycosylation and UPR lead to enhanced apoptosis of myeloid cells||Thrombocytopenia, visible superficial veins, congenital heart defects, uropathy, cryptorchidism|
|X-linked neutropenia||XL||WASP||Disturbed actin polymerization, altered cytoskeletal responses, defective mitosis and cytokinesis||Lymphopenia, leukemia predisposition|
|Jagunal homolog 1 deficiency||AR||JAGN1||Aberrant N-glycosylation of multiple proteins, elevated apoptosis||CSF3 hypo/un-responsiveness|
|GFI1 deficiency||AD||GFI1||Impaired neutrophil differentiation, lymphoid immunodeficiency||Monocytosis, lymphopenia|
|SEC61A1 deficiency||AD||Disturbed protein translocation, and dysregulation of the UPR||Recurrent sinopulmonary infections, skin abscess, oral aphthosis and enteritis|
|Bi-allelic CSF3R deficiency||AR||CSF3R||Transmembran GCSF receptor/intracellular signaling||CSF3 unresponsiveness|
|Somatic mutation of CSF3R||No genetic inheritance||CSF3R|
|Chediak-Higashi syndrome||AR||LYST||Defective biogenesis of lysosomes, cytotoxic granules and melanosomes||Partial oculocutaneous albinism, recurrent infections, fever, hepatosplenomegaly, bleeding tendency, neurological dysfuntions, giant lysosomes (leukocytes), hair shaft anomaly|
|Griscelli syndrome type IIb||AR||RAB27a||Defective priming of cytotoxic granules and melanosomes||Recurrent infections, fever, hepatosplenomegaly, specific hair shaft anomaly|
|Cohen syndrome||AR||COH1, VPS13B||Altered vesicle sorting and transport||Psychomotor retardation, microcephaly, facial dysmorphism, hypotonia, joint laxity, obesity, retinochoroidal dsytrophy|
|Hermansky-Pudlak syndrome||AR||AP3P1||Defective endosome formation and lysosomal protein sorting,in immune cells||Recurrent infections, pulmonary fibrosis|
|VPS45 deficiency||AR||VPS45||Defective endosomal trafficking leads to impaired differentiation and motility and increased apoptosis of myeloid and mesenchymal cells||Myelofibrosis, nepromegaly, hepatomegaly, mental retardation|
|P14 deficiency||AR||LAMTOR2||Aberrant distribution of late endosomes, defective MAPK and ERK signaling, diminished phagocytosis||Growth delay, short stature, oculocutaneous hypopigmentation, partial albinism, coarse facial features|
|Shwachman-Diamond syndrome||AR||SBDS||Mitotic spindle destabilization, genomic instability, enhanced apoptosis||Exocrine pancreas deficiency, metaphyseal dysplasia, mental retardation, cardiomyopathy|
|Dyskeratosis congenita||XL||DKC1||Dysfunctional telomere maintenance||Skin pigmentation, nail dysplasia, oral leucoplakia, pulmonary fibrosis, stenosis of the oesophagus, liver diseas|
|Glycogen storage disease type 1b||AR||SLC37A4||Impaired intracellular glucose homeostasis||Hypoglycemia, fasting hyerlacticacidemia, hepatomegaly|
|Barth syndrome||XL||TAZ1||Mitochondrial dysfunction, destabilization of mitochondrial respiratory chain complexes, increased apoptosis in myeloid cells||Cardiomyopathy, endomyocardial fibrosis|
|Pearson syndrome||Mitochondrial||Deletion of mtDNA||Variably sized mtDNA deletion, variable heteroplasmy, and mosaicism lead to metabolic disorder/energy failure and apoptosis in affected tissues||Bone marrow failure, vacuoles in erythroid precursors, exocrine pancreas insufficiency, hepatopathy, nephropathy, endocrinopathy, neuromuscular degeneration|
|X-linked agammaglobulinemia||XL||BTK||unclear||Recurrent bacterial infections, hypogammaglobulinemia, absent B cells|
|Hyper IgM syndrome||AR||CD40||Abrogated CD40LG:CD40-signalling, autoimmunity||Class-switch recombination deficiency, combined immunodeficiency oppurtunistic infections, biliary tract and liver disease, Cryptosporidium infections, intermittent neutropenia|
|WHIM syndrome||AD||CXCR4||Constitutively activated CXCR4 impairs chemokinesis of neutrophils, dendritic cells and B cells from the bone marrow||Warts, hypogammaglobulinemia, immunodeficiency, myelokathexis|
|Reticular dysgenesis||AR||AK2||Defective mitochondrial adenine nucleotide homeostasis, enhanced apoptosis||Lymphopenia (T-B-NK- SCID), deafness|
|GATA2 deficiency||AD||GATA2||Complex ontogenic dysregulation of hematopoiesis and vascularization, reduced numbers of hematopoietic stem cells||Sensoryneural deafness, lymphoedema, pulmonary alveolar proteinosis|
|STK4/MST1 deficiency||AR||STK4||Disturbed mitochondrial membrane potential, enhanced apoptosis||Intermittent neutropenia, bacterial, viral (HPV, EBV, molluscum), candidal infections, lymphoproliferation, combined immunodeficiency, congenital heart defects|
|Cartilage-Hair hypoplasia||AR||RMRP||Defective ribosome assembly, aberrant cell cycle control and telomere function||Short-limbed dwarfism, metaphyseal dysostosis, sparse hair, autoimmunity, lymhopenia, bone marrow failure, lymphoma predisposition|
Neutropenia increases host susceptibility to bacterial and fungal infections, primarily from their endogenous flora in the gut, mouth and skin as well as from nosocomial organisms, and usually presents with infections of mucous membranes, gingiva, and skin.
1.1 Primary genetic defects of severe congenital neutropenia
Severe congenital neutropenia (SCN) comprise multiple hereditary syndromes, with or without extrahaematopoietic manifestations. It is characterized by an arrest in myeloid maturation at the promyelocyte-myelocyte stage and an absence of mature neutrophils in the bone marrow. Regardless of the molecular etiology, congenital neutropenia is rare with an estimated prevalence of <1/100,000 [4, 5, 6]. Patients are prone to recurrent infections such as otitis, sinusitis, gingivitis, stomatitis, skin infections, pneumonia, deep abscesses, and septicemia beginning in their first months of life. Furthermore, SCN patients have an increased risk of malignant transformation, AML, or MDS.
Mutations in numerous genes have been identified in SCN [1, 4, 5]. The prevalence of some genetic subtypes of SCN is dependent on ethnicity. Autosomal dominant heterozygous mutations of
Several genetic defects have been identified as being responsible for SCN and there is currently no clear genotype–phenotype correlation for this syndrome. Patients with
Homozygous mutations in the antiapoptotic gene
GFI1 (Growth factor independent 1) is a zinc finger transcription factor important in myeloid and lymphoid differentiation. Dominant-negative GFI1 mutations cause a severe maturation arrest of myeloid cells [4, 13].
Inactivating, X-linked mutations in
Homozygous mutations in protein jagunal homolog 1 (
Colony stimulating factor 3 (CSF3), the main growth factor that controls both the proliferation and differentiation of myeloid progenitor cells into neutrophils, is the primary ligand for granulocyte colony-stimulating factor receptor (G-CSFR). G-CSFR is encoded by the colony-stimulating factor 3 receptor gene (
Recently, an autosomal dominant mutation in
Compensatory monocytosis, hypereosinophilia, and polyclonal hypergammaglobulinaemia appeared to be frequently associated with neutropenia and inversely proportional to its severity in SCN patients [13, 23].
Treatment of severe chronic neutropenia should focus on the prevention of infections. It includes antimicrobial prophylaxis, generally with trimethoprim-sulfamethoxazole, and also Colony Stimulating Factor 3 (CSF3). Prior to the era of filgastrim/CSF3 therapy, most patients died of infectious complications within the first 1–2 years of life despite antibiotic prophylaxis. More than 95% of SCN patients respond to CSF3 treatment with an increase in the ANC, a decrease in infections, and a great improvement in life expectancy [24, 25]. The dose and frequency of injection of CSF3 vary widely. For most patients, 5–8 micrograms (mcg) per kilogram (kg) of body weight of CSF3 given as a daily subcutaneous injection is usually sufficient. SCN is a premalignant condition. Studies showed the cumulative incidence of malignant transformation towards AML/MDS as about 22% after 8–15 years of CSF3 treatment [13, 25, 26, 27]. Patients who do not respond to filgrastim or who require high doses (>8–10 mcg/kg/day) and patients who develop AML or MDS should be considered for hematopoietic stem cell transplantation (HSCT). The strongly increased AML/MDS risk is a feature shared between
1.2 Disorders of molecular processing
Shwachmann-Diamond syndrome and dyskeratosis congenita are in the group of diseases due to defective ribosomal biogenesis and RNA processing.
1.2.1 Shwachmann-Diamond syndrome
Shwachmann-Diamond syndrome is an autosomal recessive bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, hepatic dysfunction, short stature and a wide spectrum of skeletal abnormalities. In addition to neutropenia, some children with SDS have defects in neutrophil chemotaxis or in the number and function of T, B and natural killer cells . Bone marrow examination revealing condensed chromatin and hyposegmented neutrophils are in favor of Shwachman-Diamond syndrome.
1.2.2 Dyskeratosis congenita
Dyskeratosis congenita is a disorder of telomerase activity, usually presenting with neutropenia or pancytopenia due to bone marrow failure, cutaneous findings such as nail dystrophy, leukoplakia, malformed teeth, palmar hyperkeratosis, and hyperpigmentation of the skin [28, 29].
1.3 Disorders of metabolism
1.3.1 Glycogen storage disease type Ib
Glycogen storage disease type Ib is caused by mutations in the
1.3.2 Barth syndrome
Barth syndrome is a rare X-linked genetic disease characterized by cardiomyopathy, skeletal myopathy, growth delay, neutropenia, and increased urinary excretion of 3-methylglutaconic acid. Neutropenia can be constant, intermittent, or cyclic. Disabling mutations or deletions of
1.3.3 Pearson syndrome
Pearson syndrome is an extremely rare mitochondrial disorder presenting with early-onset transfusion-dependent macrocytic sideroblastic anemia, neutropenia, and thrombocytopenia . Additional clinical findings are failure to thrive, exocrine pancreatic insufficiency, and liver dysfunction. Bone marrow analyses show characteristic vacuolization of erythroid and myeloid precursor cells and ringed sideroblasts.
1.4 Vesicular trafficking disorders
Autosomal recessive vesicular trafficking disorders are caused by defects in the biogenesis or intracellular trafficking of lysosomes and related endosomal organelles . Neutropenia, low natural killer and cytotoxic T lymphocyte activities and abnormal platelet functions can be observed in the patients.
1.4.1 Chediak-Higashi syndrome
Chediak-Higashi syndrome (CHS) is a rare autosomal recessive lysosomal disorder characterized by frequent infections, oculocutaneous albinism, bleeding diathesis, progressive neurologic deterioration and a high risk of developing hemophagocytic lymphohistiocytosis characterized by pancytopenia, high fever, and lymphohistiocytic infiltration of liver, spleen, and lymph nodes [33, 34]. Treatment of accelerated phase is difficult with poor prognosis. Observation of giant cytoplasmic granulations helps dicrimination of CHS from other PIDs with partial albinism and neutropenia.
1.4.2 Griscelli syndrome type 2
Griscelli syndrome type 2 (GS2) is a rare, autosomal recessive immunodeficiency caused by mutations in
1.4.3 Hermansky-Pudlac syndrome type 2
Hermansky-Pudlac syndrome type 2 (HPS-2) is caused by mutations in the
Examination of the hair shaft of patients with partial albinism can be helpful diagnostically, as irregular large melanin granules can be seen in Griscelli syndrome type 2, poorly distributed regular melanin granules in CHS, and small pigment clumps in Hermansky-Pudlac syndrome type 2 .
1.4.4 P14 deficiency
A ubiquitously expressed endosomal protein MAPBPIP or p14, encoded by the
1.4.5 Cohen syndrome
Cohen syndrome, associated with an arrest of myeloid differentiation is caused by an AR mutation of the vacuolar protein sorting 13 homolog B (
1.4.6 VPS45 deficiency
Vacuolar sorting protein 45 (VPS45) is a peripheral membrane protein that controls membrane fusion through the endosomal/lysosomal trafficking and the release of inflammatory mediators. Autosomal recessive inherited
1.5 Well-known primary immunodeficiency diseases associated with neutropenia
Primary immunodeficiency diseases are characterized by recurrent or chronic infections, autoimmunity, inflammation, allergy, or malignancy as a consequence of genetic alterations affecting the immune system. These disorders were initially considered to be rare, but many patients with PIDs have been recognized over the 3 decades with the increase in awareness and availability of better diagnostic facilities. The prevalence and distribution of the ten groups of inborn errors of immunity vary worldwide. Additionally, patients with the same disease may present a different clinical profile and outcome. Due to the limited number of registries, inconsistency in diagnostic criteria, different clinical phenotypes, and lack of molecular diagnosis, the global perspective of these diseases remains unclear. Reports from several PID registries in different countries show a prevalence of 1:8500 to 1:100000 for symptomatic patients [44, 45, 46]. Predominantly B-cell deficiencies encompass the main category of PIDs. Although the exact data about the frequency is lacking, a great number of immune deficiencies are known to be associated with mild or severe neutropenia as a result of close interactions both in their ontogeny and during their functional life of myeloid and lymphoid cells. Most of such cases of neutropenia are observed at diagnosis and may recover once appropriate therapy is administered, such as parenteral immunoglobulin replacement in B cell deficiency.
1.5.1 Bruton’s disease
X-linked agammaglobulinemia (XLA) is a rare primary immune deficiency characterized by the absence of circulating B cells with a severe reduction in all serum immunoglobulin levels due to mutations in the
1.5.2 CD40LG deficiency (Hyper IgM syndrome type I)
The Hyper IgM (HIGM) syndromes are a group of rare genetic disorders leading to loss of T cell-driven immunoglobulin class switch recombination (CSR) and/or defective somatic hypermutation (SHM) with elevated or normal serum IgM and decreased IgG, IgA, and IgE. The most common causes are mutations in the CD40 Ligand (CD154) (
1.5.3 Severe combined immunodeficiency
Severe combined immunodeficiency (SCID) syndromes are characterized by a block in T lymphocyte differentiation that is variably associated with abnormal development of other lymphocyte lineages (B and/or natural killer [NK] cells), leading to death early in life unless treated urgently by hematopoietic stem cell transplantation. The overall frequency is estimated to 1 in 75 000–100 000 births [44, 57]. Reticular dysgenesis, caused by a mutation in the
1.5.4 Wiskott Aldrich syndrome
Wiskott Aldrich syndrome (WAS) results from a loss of function mutation in Wiskott-Aldrich syndrome protein (
1.5.5 WHIM syndrome
WHIM syndrome (WHIM) is an autosomal dominant congenital immune deficiency with susceptibility to human papillomavirus infection-induced warts, B cell lymphopenia, hypogammaglobulinema, bone marrow myelokathexis (increase in the granulocyte pool, with hyper mature dystrophic neutrophils), and neutropenia . Gain-of-function mutations in the G protein-coupled chemokine receptor
1.5.6 Cartilage-hair hypoplasia
Cartilage-hair hypoplasia is a rare form of skeletal dysplasia, but also a syndromic primary immunodeficiency disorder due to a mutation in the RNase MRP RNA gene (RMRP), a non-coding RNA gene. The main clinical features are chondrodysplasia, short-limbed short stature, sparse and fine hair, Hirschsprung disease, macrocytic anemia, defective T cell-mediated immunity and predisposition to severe infections and cancer .
1.5.7 STK4/MST1 deficiency
Biallelic mutations in
1.5.8 GATA2 deficiency
GATA2 is a transcription factor required for stem cell homeostasis. Clinical presentation of GATA2 deficiency varies from typical Emberger syndrome (deafness and lymphoedema), MonoMac syndrome (susceptibility to mycobacteria, myelodysplasia, cytogenetic abnormalities, myeloid leukemias, pulmonary alveolar proteinosis) . A significant proportion of patients have monocytopenia and macrocytosis in addition to mild neutropenia.
2. Diagnostic work-up in chronic neutropenia
Children with a history of recurrent or unusual infections present a diagnostic challenge. A high index of suspicion could lead to an early diagnosis and treatment of underlying immune deficiency disease. Several points should be taken into consideration in the examination of the patient. These are;
Age at the first detection of neutropenia;
The indication that required performing a complete blood cell count (CBC) (mild infection/fever, severe infection, fungal infection, aphthous, gingivitis stomatitis, diarrhea, developmental delay);
A family history of neutropenia, consanguinity, pregnancy losses, or infectious deaths, and geographic origin;
The presence of any severe infections, bacterial or fungal;
A physical examination that focuses on the oral cavity (ulceration, gingivitis or stomatitis), skin, lungs, and perirectal area for infection is important. Lymphadenopathy and hepatosplenomegaly must be determined.
The presence of any congenital malformation and/or any organ dysfunction;
The complete blood count with differential, performed at the time of diagnosis (including the ANC, absolute eosinophil count, absolute monocyte count, absolute lymphocyte count, hemoglobin levels, and platelet levels).
Some specific cytological abnormalities observed on the blood, such as large granular lymphocytes, suggestive of Chediak-Higashi syndrome.
The initial workup may also reveal a particular etiology, such as viral infections. After this screening evaluation, bone marrow aspiration, immunological tests (e.g., immunoglobulin G, A, M, E levels, T and B immunophenotype), pancreas markers (serum trypsinogen, fecal elastase), and auto-antibodies against neutrophils may help to determine the diagnosis. The diagnoses according to the system involvement are depicted in Figure 1.
Targeted next-generation sequencing panels on the initial genetic investigations, followed-by whole-exome sequencing appears to be the most efficient strategy to identify the molecular etiology. In addition, the search for pathogenic copy-number variants or for regions of homozygosity in the case of consanguineous individuals should be considered. Mutations in some genes such as CSF3R and GATA2 can be either germline or somatic. As hematopoietic cells may acquire somatic mutations, non-hematopoietic tissue may be tested to distinguish germline versus somatic mutations. Buccal swabs or saliva samples may be contaminated by hematopoietic cells. Therefore, the germline status of a mutation should therefore be confirmed by analyzing DNA extracted from non-hematopoietic tissue, such as nails, hair follicles, or fibroblasts.
3. Treatment and follow-up
Treatment of severe chronic neutropenia in PIDs should focus on the prevention of infections, the management of associated organ dysfunction, and the prevention of leukemic transformation. The management of neutropenia will require a flexible, empiric, and patient-centered approach based on the use of cytokines and HSCT with consideration of antibiotic prophylaxis. Although many different genetic mutations may cause neutropenia, the clinical picture is similar. Most SCN patients find great benefit from subcutaneous CSF3 administration, which causes a significant decrease in the frequency of severe bacterial infections and increases the quality of life. The starting dose is 5 mcg/kg with dose modification according to the patient’s absolute neutrophil count and the rate of infections. It should be kept in mind that neutropenia in JAGN1 and VPS45 deficiencies do not respond to CSF3. Patients who do not respond to CSF3 or who require high doses (>8–10 mcg/kg/day) and patients who develop AML or MDS should be treated by HSCT.
The treatment of neutropenia should be decided on a patient basis for the other disease groups. For example, patients with Shwachmann-Diamond syndrome require transfusions, pancreatic enzymes, antibiotics, and CSF3. The only definitive therapy for marrow failure is HSCT. Neutropenia, which is frequently detected at the time of diagnosis in XLA (Bruton agammaglobulinemia) patients, improves with regular IVIG replacement. XHIGM (CD40 Ligand deficiency) patients can be cured by HSCT. Future treatment strategies including gene therapy or novel genome editing technologies using CRISPR/Cas9 or TALEN systems will permit the correction of monogenic neutropenia disorders.
The rate of hematological malignancy in many of the inherited neutropenia disorders, regardless of genetic subtype, is far higher than that observed in the general population. The rate of transformation is not precisely documented, but the leukemic transformation has been reported in patients with
Blood neutrophils and monocytes are the cells both produced in the bone marrow, circulate in the blood, and are recruited to sites of inflammation. Compensatory monocytosis help SCN patients overcome infections. Although both are actively phagocytic, they differ in significant ways. The neutrophil response is more rapid and the lifespan of these cells is short, whereas monocytes become macrophages in the tissues, can live for long periods, and maintain tissue integrity by eliminating/repairing damaged cells. Over the recent years, an increasing amount of knowledge has been gained in the field of phagocytic cell subpopulations [67, 68]. In addition to their protective role against invading pathogens, the field has highlighted roles for inflammatory conditions including sterile injury, tumor development, atherosclerosis, and autoimmunity. With regard to their high plasticity, neutrophils and macrophages are shown to acquire an anti-tumorigenic N1/M1 or a pro-tumorigenic N2/M2 phenotype, respectively. The impact of M1 macrophages which have overlapping features with N1 subsets of neutrophils need further investigation in PIDs.
Neutropenia is a common hematologic manifestation of a wide range of diseases. Paying careful attention to associated features of a patient provides valuable clues leading to a narrow spectrum of differential diagnosis. Genetic investigation may be helpful in making a definitive diagnosis. This is of utmost importance since timely diagnosis helps the patient benefit from available therapeutic modalities such as HSCT and CSF3 administration.
Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, Klein C, Morio T, Ochs HD, Oksenhendler E, Puck J, Torgerson TR, Casanova JL, Sullivan KE, Tangye SG. Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification. J Clin Immunol. 2020;40:66-81.
Cunningham-Rundles C. Hematologic complications of primary immune deficiencies. Blood Rev 2002;16:61-4.
Rezaei N ,Moazzami K, Aghamohammadi A, Klein C. Neutropenia and primary immunodeficiency diseases. Int Rev Immunol 2009;28:335-66.
Donadieu J ,Beaupain B , Fenneteau O, Bellanné-Chantelot C. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br J Haematol 2017;179:557-574.
Welte K, Zeidler C, Dale DC. Severe congenital neutropenia. Semin Hematol. 2006;43:189-95.
Ancliff PJ. Congenital neutropenia. Blood Rev. 2003;17:209-16.
Germeshausen M, Deerberg S, Peter Y, Reimer C, Kratz CP, Ballmaier M. The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. Hum Mutat.2013;34:905-914.
Horwitz MS, Corey SJ, Grimes HL, Tidwell T. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am.2013;27:19-41.
Nanua S, Murakami M, Xia J, et al. Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane. Blood.2011;117:3539-3547.
Klein C, Grudzien M, Appaswamy G, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet.2007;39:86-92.
Devriendt K, Kim AS, Mathijs G, et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet.2001;27:313-317.
Germeshausen M, Zeidler C, Stuhrmann M, Lanciotti M, Ballmaier M, Welte K. Digenic mutations in severe congenital neutropenia. Haematologica.2010;95:1207-1210.
Touw IP. Game of clones: the genomic evolution of severe congenital neutropenia. Hematology Am Soc Hematol Educ Program 2015;2015:1-7.
Yılmaz Karapınar D, Patıroğlu T, Metin A, Çalışkan Ü, Celkan T, Yılmaz B, Karakaş Z, Karapınar TH, Akıncı B, Özkınay F, Onay H, Yeşilipek MA, Akar HH, Tüysüz G, Tokgöz H, Özdemir GN, Aslan Kıykım A, Karaman S, Kılınç Y, Oymak Y, Küpesiz A, Olcay L, Keskin Yıldırım Z, Aydoğan G, Gökçe M, İleri T, Aral YZ, Bay A, Atabay B, Kaya Z, Söker M, Özdemir Karadaş N, Özbek U, Özsait Selçuk B, Özdemir HH, Uygun V, Tezcan Karasu G, Yılmaz Ş. Homozygous c.130-131 ins A (pW44X) mutation in the HAX1 gene as the most common cause of congenital neutropenia in Turkey: Report from the Turkish Severe Congenital Neutropenia Registry. Pediatr Blood Cancer. 2019;66:e27923.
Keszei M, Record J, Kritikou JS, Wurzer H, Geyer C, Thiemann M, Drescher P, Brauner H, Köcher L, James J, He M, Baptista MA, Dahlberg CI, Biswas A, Lain S, Lane DP, Song W, Pütsep K, Vandenberghe P, Snapper SB, Westerberg LS. Constitutive activation of WASp in X-linked neutropenia renders neutrophils hyperactive. J Clin Invest. 2018 ;128:4115-4131.
Boztug K, Appaswamy G, Ashikov A, Schaffer AA, Salzer U, Diestelhorst J, Germeshausen M, Brandes G, Lee-Gossler J, Noyan F, Gatzke AK, Minkov M, Greil J, Kratz C, Petropoulou T, Pellier I, Bellanne-Chantelot C, Rezaei N, Monkemoller K, Irani-Hakimeh N, Bakker H, Gerardy-Schahn R, Zeidler C, Grimbacher B, Welte K, Klein C. A syndrome with congenital neutropenia and mutations in G6PC3. New England Journal of Medicine, 2009; 360, 32-43.
Kiykim A, Baris S, Karakoc-Aydiner E, Ozen AO, Ogulur I, Bozkurt S, Ataizi CC, Boztug K, Barlan IB G6PC3 Deficiency: Primary Immune Deficiency Beyond Just Neutropenia. J Pediatr Hematol Oncol. 2015;37:616-22.
Boztug K, Jarvinen PM, Salzer E, et al. JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. Nat Genet.2014;46:1021-1027.
Baris S, Karakoc-Aydiner E, Ozen A, Delil K, Kiykim A, Ogulur I, Baris I, Barlan IB. JAGN1 Deficient Severe Congenital Neutropenia: Two Cases from the Same Family. J Clin Immunol. 2015. PMID: 25851723
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;123:2229- 2237.
Triot A, Järvinen PM, Arostegui JI, et al. Inherited biallelic CSF3R mutations in severe congenital neutropenia. Blood. 2014;123:3811-3817.
Van Nieuwenhove E, Barber JS, Neumann J, Smeets E, Willemsen M, Pasciuto E, Prezzemolo T, Lagou V, Seldeslachts L, Malengier-Devlies B, Metzemaekers M, Haßdenteufel S, Kerstens A, van der Kant R, Rousseau F, Schymkowitz J, Di Marino D, Lang S, Zimmermann R, Schlenner S, Munck S, Proost P, Matthys P, Devalck C, Boeckx N, Claessens F, Wouters C, Humblet-Baron S, Meyts I, Liston A. Defective Sec61alpha1 underlies a novel cause of autosomal dominant severe congenital neutropenia. J Allergy Clin Immunol. 2020;146:1180-1193.
Jean Donadieu, Odile Fenneteau, Blandine Beaupain, Nizar Mahlaoui, Christine Bellanné Chantelot. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis 2011;6:26
Dale DC, Bonilla MA, Davis MW, et al. A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood.1993; 81:2496-2502.
Freedman MH, Bonilla MA, Fier C, et al. Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy. Blood.2000;96:429-436.
Rosenberg PS, Zeidler C, Bolyard AA, et al. Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br J Haematol.2010;150:196-199.
Donadieu J, Leblanc T, Bader Meunier B, Barkaoui M, Fenneteau O, Bertrand Y, Maier-Redelsperger M, Micheau M, Stephan JL, Phillipe N, Bordigoni P, Babin-Boilletot A, Bensaid P, Manel AM, Vilmer E, Thuret I, Blanche S, Gluckman E, Fischer A, Mechinaud F, Joly B, Lamy T, Hermine O, Cassinat B, Bellanné-Chantelot C, Chomienne C; French Severe Chronic Neutropenia Study Group. Analysis of risk factors for myelodysplasias, leukemias and death from infection among patients with congenital neutropenia. Experience of the French Severe Chronic Neutropenia Study Group. Haematologica. 2005;90:45-53.
Nelson AS, Myers KC Diagnosis, Treatment, and Molecular Pathology of Shwachman-Diamond Syndrome. Hematol Oncol Clin North Am. 2018;32:687-700.
Wegman-Ostrosky T, Savage SA. The genomics of inherited bone marrow failure: from mechanism to the clinic. Br J Haematol. 2017;177:526-542.
Sarajlija A, Djordjevic M, Kecman B, Skakic A, Pavlovic S, Pasic S, Stojiljkovic M. Impact of genotype on neutropenia in a large cohort of Serbian patients with glycogen storage disease type Ib. Eur J Med Genet. 2020;63:103767.
Barth PG, Valianpour F, Bowen VM, Lam J, Duran M, Vaz FM, Wanders RJ. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update. Am J Med Genet A. 2004;126A:349-54.
Muraki K, Nishimura S, Goto Y, Nonaka I, Sakura N, Ueda K. The association between haematological manifestation and mtDNA deletions in Pearson syndrome. J Inherit Metab Dis. 1997;20:697-703.
Dotta L, Parolini S, Prandini A, Tabellini G, Antolini M, Kingsmore SF, Badolato R. Clinical, laboratory and molecular signs of immunodeficiency in patients with partial oculo-cutaneous albinism. Orphanet J Rare Dis. 2013 Oct 17;8:168.
Valente NY, Machado MC, Boggio P, Alves AC, Bergonse FN, Casella E, Vasconcelos DM, Grumach AS, de Oliveira ZN. Polarized light microscopy of hair shafts aids in the differential diagnosis of Chediak-Higashi and Griscelli-Prunieras syndromes. Clinics (Sao Paulo). 2006 ;61:327-32.
Meeths M, Bryceson YT, Rudd E, Zheng C, Wood SM, Ramme K, Beutel K, Hasle H, Heilmann C, Hultenby K, Ljunggren HG, Fadeel B, Nordenskjöld M, Henter JI. Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations. Pediatr Blood Cancer. 2010 ;54:563-72.
Ohishi Y, Ammann S, Ziaee V, Strege K, Groß M, Amos CV, Shahrooei M, Ashournia P, Razaghian A, Griffiths GM, Ehl S, Fukuda M, Parvaneh N. Griscelli Syndrome Type 2 Sine Albinism: Unraveling Differential RAB27A Effector Engagement. Front Immunol. 2020;11:612977.
Bowman SL, Bi-Karchin J, Le L, Marks MS. The road to lysosome-related organelles: Insights from Hermansky-Pudlak syndrome and other rare diseases. Traffic. 2019 ;20:404-435.
Bohn G, Allroth A, Brandes G, Thiel J, Glocker E, Schäffer AA, Rathinam C, Taub N, Teis D, Zeidler C, Dewey RA, Geffers R, Buer J, Huber LA, Welte K, Grimbacher B, Klein C. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nat Med. 2007;13:38-45.
Rodrigues JM, Fernandes HD, Caruthers C, Braddock SR, Knutsen AP. Cohen Syndrome: Review of the Literature. Cureus. 2018 ;10:e3330.
Beck KD, Wong RW, Gibson JB, Harper CA. Nonleaking cystoid macular edema in Cohen syndrome. J AAPOS. 2019 ;23:38-39.e1.
Stepensky P, Saada A, Cowan M, Tabib A, Fischer U, Berkun Y, Saleh H, Simanovsky N, Kogot-Levin A, Weintraub M, Ganaiem H, Shaag A, Zenvirt S, Borkhardt A, Elpeleg O, Bryant NJ, Mevorach D. The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy. Blood. 2013 ;121:5078-87.
Shah RK, Munson M, Wierenga KJ, Pokala HR, Newburger PE, Crawford D.A novel homozygous VPS45 p.P468L mutation leading to severe congenital neutropenia with myelofibrosis. Pediatr Blood Cancer. 2017 ;64.
Meerschaut I, Bordon V, Dhooge C, Delbeke P, Vanlander AV, Simon A, Klein C, Kooy RF, Somech R, Callewaert B. Severe congenital neutropenia with neurological impairment due to a homozygous VPS45 p.E238K mutation: A case report suggesting a genotype-phenotype correlation. Am J Med Genet A. 2015 ;167A:3214-8.
GathmannB, GrimbacherB, BeauteJ, et al. The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008. Clin Exp Immunol. 2009;157:3-11.
AbolhassaniH, AghamohammadiA, FangM, et al. Clinical implications of systematic phenotyping and exome sequencing in patients with primary antibody deficiency. Genet Med. 2019;21:243-251.
Condino-NetoA, SorensenRU, Gomez RaccioAC, et al. Current state and future perspectives of the Latin American Society for Immunodeficiencies (LASID). Allergol Immunopathol (Madr). 2015;43:493-497
Stonebraker JS, Farrugia A, Gathmann B. ESID Registry Working Party, Orange JS. Modeling primary immunodeficiency disease epidemiology and its treatment to esti- mate latent therapeutic demand for immunoglobulin. J Clin Immunol. 2014;34: 233-244.
Gathmann B, Goldacker S, Klima M, Belohradsky BH, Notheis G, Ehl S, Ritterbusch H, Baumann U, Meyer-Bahlburg A, Witte T, Schmidt R, Borte M, Borte S, Linde R, Schubert R, Bienemann K, Laws HJ, Dueckers G, Roesler J, Rothoeft T, Krüger R, Scharbatke EC, Masjosthusmann K, Wasmuth JC, Moser O, Kaiser P, Groß-Wieltsch U, Classen CF, Horneff G, Reiser V, Binder N, El-Helou SM, Klein C, Grimbacher B, Kindle G. The German national registry for primary immunodeficiencies (PID). Clin Exp Immunol. 2013;173:372-380.
Kozlowski C, Evans DIK: Neutropenia associated with X-linked agammaglobulinemia. J Clin Pathol 44:388-390, 1991 16.
Farrar JE, Rohrer J, Conley ME: Neutropenia in X-linked agammaglobulinemia. Clin Immunol Immunopathol 81:271-276, 1996
Hirokazu Kanegane, Hiromichi Taneichi, Keiko Nomura, Takeshi Futatani, Toshio Miyawaki. Severe neutropenia in Japanese patients with x-linked agammaglobulinemia. J Clin Immunol 2005 ;25:491-5.
Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). 2003;82:373-84.
Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr. 1997;131(1 Pt 1):47-54.
Leven EA, Maffucci P, Ochs HD, Scholl PR, Buckley RH, Fuleihan RL, Geha RS, Cunningham CK, Bonilla FA, Conley ME, Ferdman RM, Hernandez-Trujillo V, Puck JM, Sullivan K, Secord EA, Ramesh M, Cunningham-Rundles C. Hyper IgM Syndrome: a Report from the USIDNET Registry. J Clin Immunol. 2016 ;36:490-501.
Al-Saud B, Al-Mousa H, Al-Ahmari A, Al-Ghonaium A, Ayas M, Alhissi S, Al-Muhsen S, Al-Seraihy A, Arnaout R, Al-Dhekri H, Hawwari A. Hematopoietic stem cell transplant for hyper-IgM syndrome due to CD40L defects: A single-center experience. Pediatr Transplant. 2015;19:634-9.
Mavroudi I, Papadaki HA. The role of CD40/CD40 ligand interactions in bone marrow granulopoiesis. ScientificWorldJournal. 2011;11:2011-9.
Chinn IK, Shearer WT. Severe combined immunodeficiency disorders. Immunol Allergy Clin North Am2015;35:671-94.
Candotti F. Clinical Manifestations and Pathophysiological Mechanisms of the Wiskott-Aldrich Syndrome. J Clin Immunol. 2018;38:13-27.
Badolato R, Donadieu J; WHIM Research Group. How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome. Blood. 2017 ;130:2491-2498.
McDermott DH, Liu Q, Velez D, Lopez L, Anaya-O'Brien S, Ulrick J, Kwatemaa N, Starling J, Fleisher TA, Priel DA, Merideth MA, Giuntoli RL, Evbuomwan MO, Littel P, Marquesen MM, Hilligoss D, DeCastro R, Grimes GJ, Hwang ST, Pittaluga S, Calvo KR, Stratton P, Cowen EW, Kuhns DB, Malech HL, Murphy PM. A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor.Blood. 2014;123:2308-16.
McDermott DH, Pastrana DV, Calvo KR, Pittaluga S, Velez D, Cho E, Liu Q, Trout HH 3rd, Neves JF, Gardner PJ, Bianchi DA, Blair EA, Landon EM, Silva SL, Buck CB, Murphy PM. Plerixafor for the Treatment of WHIM Syndrome. N Engl J Med. 2019 ;380:163-170.
Ammann RA, Duppenthaler A, Bux J, Aebi C. Granulocyte colony-stimulating factor-responsive chronic neutropenia in cartilage-hair hypoplasia. J Pediatr Hematol Oncol. 2004 ;26:379-81.
Abdollahpour H, Appaswamy G, Kotlarz D, Diestelhorst J, Beier R, Schaffer AA, et al. The phenotype of human STK4 deficiency. Blood. 2012;119:3450-3457.
Nehme NT, Pachlopnik Schmid J, Debeurme F, Andre-Schmutz I, Lim A, Nitschke P, et al. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood. 2011;119:3458-3468.
Dang TS, Willet JD, Griffin HR, Morgan NV, O'Boyle G, Arkwright PD, Hughes SM, Abinun M, Tee LJ, Barge D, Engelhardt KR, Jackson M, Cant AJ, Maher ER, Koref MS, Reynard LN, Ali S, Hambleton S. Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency. J Clin Immunol. 2016;36:117-22.
Hsu AP, McReynolds LJ, Holland SM. GATA2 deficiency. Curr Opin Allergy Clin Immunol. 2015;15:104-9.
Kely Campos Navegantes, Rafaelli de Souza Gomes, Priscilla Aparecida Tártari Pereira, Paula Giselle Czaikoski, Carolina Heitmann Mares Azevedo, Marta Chagas Monteiro. Immune modulation of some autoimmune diseases: the critical role of macrophages and neutrophils in the innate and adaptive immunity. J Transl Med. 2017; 15: 36.
Ling Wu, Xiang H.-F. Zhang. Tumor Associated Neutrophils and Macrophages—Heterogenous but Not Chaotic. Front Immunol. 2020; 11: 553967.