Neutrophil Dysfunction

Numerous disorders may cause neutropenia, which is defined as an absolute reduction in the number of circulating neutrophils.

Epidemiology

• Incidence – each individual disorder is rare except for autoimmune disorders
• Age – most often discovered before 1 year old
• Gender – no gender preference except for X-linked disorders

Classification

• Congenital
  • Cyclic hematopoiesis (cyclic neutropenia)
  • Severe chronic neutropenia
  • Familial benign neutropenia
  • Myelokathexis
• Immune-mediated
  • Autoimmune neutropenia of infancy (ANI)
  • Immune-mediated neutropenia in the neonate
• Complex syndromes
  • Chronic granulomatous disease
  • Primary immunodeficiencies (X-linked hyper IgM syndrome, hyper IgE syndrome)
  • Chédiak-Higashi syndrome
  • Shwachman-Diamond syndrome
  • Cartilage hair hypoplasia (onychotrichodysplasia)
  • Metabolic disorders – glycogen storage disease
  • Reticular dysgenesis
  • Fanconi anemia

Specific Diseases

• Cyclical neutropenia
  • Genetics – autosomal dominant
  • Clinical presentation – recurring fever, mucosal ulcers and occasional life-threatening infections
• Severe chronic neutropenia (Kostmann syndrome)
  • Genetics
    • Autosomal dominant, autosomal recessive, sporadic
  • Clinical presentation
    • Early onset of severe neutropenia and life-threatening infections
      • Cellulitis, omphalitis, stomatitis, sepsis, meningitis
      • Common organisms include S. aureus, E. coli and Pseudomonas spp
    • Late developing myelodysplastic syndrome and acute myelogenous leukemia
• Autoimmune neutropenia of infancy (ANI)
  • Clinical presentation
    • Later onset of mild to severe infections (8-10 months old)
      • Pyoderma, URIs, otitis media
• Immune-mediated neutropenia in the neonate
  • Clinical Presentation
    • Similar to ANI
• Hyper IgE syndrome (Jobs syndrome)
  • Clinical Presentation
    • Recurrent boils
    • Coarse facies
    • Impaired resorption of primary teeth
    • Recurrent mucocutaneous candida infections
• Chédiak-Higashi
  • Genetics – autosomal recessive
  • Clinical Presentation
    • Partial albinism
    • Severe infections – particularly with encapsulated organisms
    • Defective platelets
• Shwachman-Diamond syndrome
  • Genetics – autosomal recessive
  • Clinical Presentation
    • Pancreatic insufficiency, neutropenia, chronic eczema and metaphyseal dysostosis
• Onychotrichodysplasia
  • Genetics – autosomal recessive
  • Clinical Presentation
    • Hypoplastic nails
    • Neutropenia
    • Sparse hair
• Glycogen storage disease type 1b (GSD 1b)
  • Clinical Presentation (identical to von Gierke type [GSD 1a])
    • Hypoglycemia, hyperlipidemia and lactic acidosis
    • Hepatomegaly
    • Recurrent infections – oral and perianal abscesses
• Reticular dysgenesis
  • Clinical Presentation
    • Lymphoid and thymic hypoplasia with severe combined immune deficiency
    • Overwhelming infections in the first two weeks of life

Bruton Agammaglobulinemia

Chronic Granulomatous Disease - Neutrophil Oxidative Burst

Complement Deficiency - Complement Activity  

Immunodeficiency, Innate System  

Immunoglobulin Disorders  

Leukocyte Adhesion Deficiency  

T-Cell Deficiency Disorders, Inherited

Diagnosis

• Cyclical neutropenia
  • CBC (cyclical changes every 21 days in neutrophil counts)
• Severe chronic neutropenia (Kostmann syndrome)
  • Serial CBC testing will generally be adequate for initial diagnosis
  • Bone marrow reveals myeloid hyperplasia with maturation arrest
  • Genotyping confirms the diagnosis
• Autoimmune neutropenia of infancy (ANI)
  • CBC shows non-cyclical neutropenia
  • Antineutrophil antibodies are present for >6 months
    • Antibodies are not found in severe chronic neutropenia or for >6 months in immune neutropenia of the neonate
• Immune-mediated neutropenia in the neonate
  • Neutrophil antibody testing – antibodies are not present after 6 months
• Hyper IgE syndrome (Jobs syndrome)
  • Immunoglobulin testing
    • IgE levels – elevated
    • All other levels – normal
  • Chemotaxis studies which need to include Candida-specific IgE neutrophil chemotaxis – abnormal
• Chédiak-Higashi
  • CBC with differential testing
    • Peripheral smear demonstrates large cytoplasmic granules in the neutrophils and lymphocytes
    • Defective chemotaxis and intracellular killing
• Shwachman-Diamond syndrome
  • CBC testing
    • Cyclic or persistent neutropenia
    • Normal total lymphocyte counts common
    • Anemia in 50%
  • Immunoglobulin testing
    • Low IgG or IgG subclasses
  • Neutrophil chemotaxis (neutrophil mitogens)
    • Abnormal
  • Fecal fat (72 hr)
    • Abnormal
  • Liver transaminases
    • Frequently elevated
• Onychotrichodysplasia
  • CBC testing
    • Presence of neutropenia and lymphopenia
    • Clinical presentation with persistent neutropenia
• Glycogen storage disease type 1b (GSD 1b)
  • CBC testing
  • Clinical presentation with neutropenia
• Reticular dysgeneses
  • CBC shows neutropenia and lymphopenia
  • Lymphocyte subsets show severe deficiency of all types of lymphocytes

Indications for Ordering

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory