Neutropenia

Neutropenia is a deficiency in the number of neutrophils, also known as polymorphonuclear leukocytes, or PMNs. Neutropenia is generally defined as an absolute neutrophil count <1,500/mL. Counts of <500/mL represent severe, life-threatening deficiency. Neutropenia often accompanies other disorders, but here we describe neutropenia when it occurs in isolation or as the predominant characteristic of disease. Most cases are acquired due to increased destruction of neutrophils (eg, from infections, drugs, immune defects) or decreased production of neutrophils (eg, from nutritional defects, malignancies). Chemotherapeutic treatment is a common cause of neutropenia. Some congenital disorders are also associated with neutropenia and vary in severity, from mild conditions such as benign familial or constitutional neutropenia, which may not lead to infections, to severe congenital disorders that result in serious chronic infections (Gibson, 2014). Infection-related neutropenia in children may be caused by a virus (Gibson, 2014). Laboratory testing for neutropenia includes CBC, immunoglobulin evaluation, flow cytometry, and genetic testing.

Quick Answers for Clinicians

Diagnosis

Indications for Testing

  • In neonates – recurrent bacterial infections
  • In older children, adolescents, adults
    • Low neutrophil count as incidental finding on CBC
    • Recurrent infections, oral ulcerations, or delayed healing
    • Acute febrile illness or sepsis
    • Existing ​neutropenia, which must be monitored for severity

Laboratory Testing

  • Initial testing
    • CBC
      • At least three CBCs recommended to demonstrate persistent neutropenia
    • Blood smear
    • Lymphocyte flow cytometry panel testing – to rule out cellular defects
  • Other testing based on clinical presentation
    • Neutrophil antibody testing
    • Rheumatic disorder testing (eg, antinuclear antibodies [ANAs])
    • Nutritional assessment (eg, B12)
    • Bone marrow biopsy and aspirate
    • Genetic testing – may be necessary to confirm specific disorder

Differential Diagnosis

Background

Epidemiology

  • Neutropenia
    • Increased prevalence in African Americans; less common in Whites and Mexican Americans (Hsieh, 2007)
  • Congenital neutrophil disorders
    • Incidence – rare (3-8/million) (Donadieu, 2013)
    • Age – more severe disorders usually discovered before 1 year; less severe disorders may be discovered later
    • Sex – M:F, equal (except for X-linked disorders)

Clinical Presentation

  • Clinical presentation and severity vary based on etiology (Gibson, 2014)
    • Benign familial or constitutional neutropenia
      • Typically not associated with clinical sequelae; no follow-up is needed after diagnosis is established
    • Congenital neutropenia
      • Recurrent infections – omphalitis, septicemia, abscess formation early in life
      • Those who survive infancy frequently show progressive periodontitis
      • May occur as part of a syndrome (eg, Chediak-Higashi syndrome, Shawchman-Diamond, or cartilage hair hypoplasia; see Specific Diseases below)
    • Cyclic neutropenia
      • Congenital disease – neutropenic episodes occur every 2-5 weeks
      • Typically mild, but infections or mouth ulcers can develop during neutropenic period
    • Drug-induced agranulocytosis (absence of granulocytes)
      • Acute febrile illness or sepsis
    • Primary autoimmune neutropenia
      • Typically occurs during infancy (first year)
      • May be severe, with serious infections, but usually resolves within 2 years
    • Secondary autoimmune neutropenia
      • Typically in adults in connection with systemic autoimmune disease
      • Recurrent infections and neutrophil count <500/mL
    • Felty’s syndrome
    • Large granular lymphocyte leukemia-associated neutropenia
    • Chronic idiopathic neutropenia
      • Unknown pathogenesis
      • Diagnosis of exclusion
      • Often benign but occasionally results in recurrent infections

Pathophysiology

  • Immunologic and hematologic parameters are diverse (see Specific Diseases below)
  • Congenital neutropenias
    • Exact molecular pathogenesis varies by genetic defect, but all lead to maturation arrest of precursor myeloid cells due to increased apoptosis
    • Increased apoptosis might be caused by the unfolded protein response due to accumulation of misfolded proteins (eg, ELANE, G6PC3), mitochondrial membrane potential (HAX1), or defective mitosis and cytokinesis (WAS)

Genetics

Autosomal recessive (AR), autosomal dominant (AD), or X-linked (XL) inheritance (see Specific Diseases below)

Specific Diseases

The following tables are based on the International Union of Immunological Societies 2017 Primary Immunodeficiencies report (Picard, 2018)

Congenital Neutropenias Related to Functional Neutrophil Defects
Disorder Gene(s) Inheritance Associated Features

SCN1 (elastase deficiency)

ELANE

AD

Severe congenital or cyclic neutropenia; susceptibility to MDS/leukemia

SCN2 (GFI1 deficiency)

GFI1

AD

B-cell/T-cell lymphopenia

SCN3 (Kostmann disease; HAX1 deficiency)

HAX1

AR

Cognitive/neurologic defects, susceptibility to MDS/leukemia

SCN4 (G6PC3 deficiency)

G6PC3

AR

Heart defects, urogenital abnormalities, inner ear deafness, venous angiectasias of trunk and limbs

SCN5 (VPS45 deficiency)

VPS45

AR

Bone marrow fibrosis, nephromegaly, extramedullary hematopoiesis

Glycogen storage disease type 1b

G6PT1

AR

Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly

X-linked neutropenia/myelodysplasia WAS GOF

WAS

XL

Neutropenia, monocytopenia, myeloid maturation arrest, variable lymphoid anomalies

P14/LAMTOR2 deficiency

LAMTOR2

AR

Neutropenia, hypogammaglobulinemia, partial albinism, growth failure

Barth syndrome

TAZ

XL

Cardiomyopathy, myopathy, growth retardation, neutropenia

Cohen syndrome

VPS13B

AR

Dysmorphism, deafness, mental retardation, obesity, neutropenia

Clericuzio syndrome

USB1

AR

Retinopathy, poikiloderma, developmental delay, facial dysmorphisms

JAGN1 deficiency

JAGN1

AR

Myeloid maturation arrest, osteopenia

3-methylglutaconic aciduria

CLPB

AR

Neurocognitive developmental abnormalities, microcephaly, hypoglycemia, seizures, hypotonia, ataxia, intrauterine growth retardation, cataracts

G-CSF receptor deficiency

CSF3R

AR

 

SMARCD2 deficiency

SMARCD2

AR

Neutropenia, developmental and skeletal abnormalities, hematopoietic stem cells, myelodysplasia

HYOU1 deficiency

HYOU1

AR

Hypoglycemia, inflammatory complications

WDR1 deficiency

WDR1

AR

Mild neutropenia, poor wound healing, neutrophil nuclei herniate, severe stomatitis

Neutropenia with combined immunodeficiency as result of MKL1 deficiency

MKL1

AR

Mild thrombocytopenia

GOF, gain of function; MDS, myelodysplastic syndrome; WAS, Wiskott-Aldrich syndrome

Neutropenic Conditions Resulting from Combined Immunodeficiencies with Syndromic/Associated Characteristics
Disorder Gene(s) Inheritance Associated Features

Wiskott-Aldrich syndrome

WAS

XL

Thrombocytopenia, recurrent bacterial/viral infections, bloody diarrhea, eczema, lymphoma, autoimmune disease, IgA nephropathy, vasculitis; XL neutropenia is caused by missense mutations in GTPase binding domain of WASp

GINS1 deficiency

GINS1

AR

Neutropenia, IUGR, low NK cells

MTHFD1 deficiency

MTHFD1

AR

Neutropenia, recurrent bacterial infections, Pneumocystis jirovecii, megaloblastic anemia, seizures, intellectual disability, folate responsive

Neutropenias Related to Phenocopies of Inborn Errors of Immunity
Disorder Gene(s) Associated Features
Large granular lymphocytosis STAT3 (GOF) somatic mutations Neutropenia, anemia, splenomegaly
GOF, gain of function
Neutropenias Related to Diseases of Immune Dysregulation
Disorder Gene(s) Inheritance Associated Features

Chediak-Higashi syndrome

LYST

AR

Neutropenia, cytopenias, partial albinism, recurrent infections, fever, HSMG, HLH, bleeding tendency

Hermansky-Pudlak syndrome, type 2

AP3B1

AR

Neutropenia, partial albinism, pulmonary fibrosis, recurrent infections, increased bleeding, HLH

Hermansky-Pudlak syndrome, type 10

AP3D1

AR

Severe neutropenia, oculocutaneous albinism, seizures, recurrent infections, hearing loss, neurodevelopmental delay

HLH, hemophagocytic lymphohistiocytoses; HSMG, hepatosplenomegaly

Neutropenias Related to Immunodeficiencies Affecting Cellular/Humoral Immunity
Disorder Gene(s) Inheritance Associated Features

CD40 deficiency

CD40a

AR

Neutropenia, gastrointestinal and liver/biliary tract disease, opportunistic infections, Cryptosporidium infections

CD40 ligand deficiency

CD40LGa

XL

Neutropenia, thrombocytopenia, hemolytic anemia, opportunistic infections, liver/biliary tract disease, Cryptosporidium infections

MST1 deficiency

STK4

AR

Intermittent neutropenia, autoimmune cytopenias, recurrent bacterial/viral/candidal infections (including human papillomavirus infection), Epstein-Barr virus-driven lymphoproliferation, lymphoma, congenital heart disease

Moesin deficiency

MSN

XL

Recurrent infections with bacteria, varicella, neutropenia

TFRC

TFRC

AR

Recurrent infections, neutropenia, thrombocytopenia

aGene included on Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication – ARUP test code 2011156
Neutropenias Related to Defects in Intrinsic and Innate Immunity
Disorder Gene(s) Inheritance Associated Features
WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome CXCR4a AD GOF Warts, neutropenia, low B-cell number, hypogammaglobulinemia
aGene included on Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication – ARUP test code 2011156
Neutropenias Related to Predominantly Antibody Deficiencies
Disorder Gene(s) Inheritance Associated Features
TWEAK TNFSF12a AD Neutropenia, pneumonia, bacterial infections, warts, thrombocytopenia
aGene included on Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication – ARUP test code 2011156

ARUP Laboratory Tests

Identify the presence of neutropenia

Use to assist in evaluation of neutropenia

Use to rule out cellular defects

Support the diagnosis of immune neutropenia in various autoimmune disorders

A positive result is not definitive for specific antineutrophil antibodies; anti-HLA antibodies and immune complexes may also cause a positive result; the results of this test should be correlated to clinical history and other data

Related Tests

Preferred genetic test for individual with clinical phenotype of primary antibody deficiency (eg, hyper-IgM syndrome, agammaglobulinemia, or common variable immunodeficiency)

For hyper-IgM syndrome genetic testing, refer to the hyper-IgM sequencing and deletion/duplication panel

For agammaglobulinemia genetic testing, refer to the agammaglobulinemia sequencing and deletion/duplication panel

Refer to Test Fact Sheet for a complete list of the genes tested and test limitations

Preferred test for evaluating vitamin B12 deficiency in individuals with macrocytic or unexplained anemia, or unexplained neurologic disease

Aid in detection of vitamin B12 and folate deficiency in individuals with macrocytic or unexplained anemia, or unexplained neurologic disease

Medical Experts

Contributor

Delgado

Julio Delgado, MD, MS
Executive Vice President, ARUP Laboratories
Division Chief of Clinical Pathology, University of Utah and ARUP Laboratories
Professor of Clinical Pathology, University of Utah
Medical Director, Protein Immunology and Immunologic Flow Laboratories, ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®