Congenital Neutrophil Disorders

Diagnosis

Indications for Testing

  • Recurrent bacterial infections in the early neonatal period

Laboratory Testing

  • Initial testing
    • CBC
      • Recommend at least 3 CBCs to demonstrate persistent neutropenia
      • Severe neutropenia most common in defects of neutrophil function
    • Immunoglobulin evaluation
    • Lymphocyte flow cytometry panel testing
    • Other testing based on clinical presentation – includes molecular testing for specific disorder
      • Nutritional assessment (eg, B12)
      • Neutrophil antibody testing
      • Rheumatic disorder testing (eg, ANA)
      • Genetic testing – may be necessary to confirm disorder

Differential Diagnosis

Clinical Background

Most cases of neutropenia are acquired, due to increased destruction (eg, infections, drugs, immune defects) or decreased production (eg, nutritional defects, malignancies). Congenital neutrophil disorders are rare disorders associated with significant morbidity and mortality.

Epidemiology

  • Incidence – rare
  • Age – usually discovered <1 year for more severe disorders; may be later for midlevel disorders
  • Sex – M:F, equal, except for X-linked disorders

Clinical Presentation

  • 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
      • Chediak-Higashi syndrome, Hermansky-Pudlak syndrome type 2, Griscelli syndrome, P14/LAMTOR2 deficiency – lead to neutropenia associated with pigmentation defects
      • Immune-osseous dysplasias (eg, cartilage hair hypoplasia) – associated with short-limbed short stature
      • Glycogen storage disease type 1b (G6PT1 deficiency) – associated with short stature and hypoglycemia
      • See Specific Diseases section below
  • Cyclic neutropenia
    • Regular oscillations – ~21 day cycles of blood neutrophil counts

Pathophysiology

  • Exact molecular pathogenesis of congenital neutropenias 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)
  • Neutropenia is generally defined as an absolute neutrophil count <1500/mL
  • Benign ethnic neutropenia is usually >1000/mL
  • Risk of infection (<1000/mL) increases with decreasing absolute neutrophil counts; severe, life-threatening deficiency <500 mL
  • Agranulocytosis (absence of granulocytes) might refer to <200/mL or <500/mL
  • Other immunological and hematological parameters are diverse (see Specific Diseases section below)

Genetics

  • Recessive, dominant, or X-linked inheritance (see Specific Diseases section below)

Specific Diseases

  • Neutrophil defects of function

    Neutrophil Defects of Function

    Disorder

    Gene(s)

    Inheritance

    Associated Features

    Cyclic neutropenia

    ELANE

    AD

    21 day periodicity to neutropenia

    Severe congenital neutropenias (SCN)

    SCN1

    ELANE

    AD

    Susceptibility to MDS/leukemia

    SCN2

    GFI1

    AD

    B-cell/T-cell lymphopenia

    SCN3 (Kostmann disease)

    HAX1

    AR

    Cognitive defects, susceptibility to MDS/leukemia

    SCN4 (G6PC3 deficiency)

    G6PC3

    AR

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

    SCN5

    VPS45

    AR

    Bone marrow fibrosis, nephromegaly, extramedullary hematopoiesis

    Glycogen storage disease type 1b

    G6PT1

    AR

    Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly

    X-linked neutropenia

    WAS

    XL

    Monocytopenia

    P14/LAMTOR2

    ROBLD3/LAMTOR2

    AR

    Neutropenia, hypogammaglobulinemia, partial albinism, growth failure

    Barth syndrome

    TAZ

    XL

    Cardiomyopathy, myopathy, growth retardation

    Cohen syndrome

    COH1

    AR

    Retinopathy, developmental delay, facial dysmorphisms

    Clericuzio syndrome

    C16ORF57

    AR

    Neutropenia, poikiloderma, MDS

    Familial hemophagocytic lymphohistiocytosis syndromes (FHL)

    Familial Hemophagocytic Lymphohistiocytosis Syndromes (FHL)

    Disorder

    Gene

    Inheritance

    Associated Features

    Without hypopigmentation

    Perforin deficiency

    PRF1

    AR

    Cytopenias, fever, hepatosplenomegaly (HSMG), hemophagocytic lymphohistiocytosis (HLH)

    UNCI3D/Munc13-4 deficiency

    UNC13D

    AR

    Cytopenias, fever, HSMG, HLH

    Syntaxin 11 deficiency

    STX11

    AR

    Cytopenias, fever, HSMG, HLH

    STXPB2/Munc18-2 deficiency

    STXBP2

    AR

    Cytopenias, fever, HSMG, HLH,

    With hypopigmentation

    Chediak-Higashi syndrome

    LYST

    AR

    Cytopenias, partial albinism, fever, HSMG, HLH, bleeding tendency

    Griscelli syndrome

    RAB27A

    AR

    Cytopenias, partial albinism, fever, HSMG, HLH

    Hermansky-Pudlak syndrome

    AP3B1

    AR

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

    Defects in leukocyte motility

    Defects in Leukocyte Motility

    Disorder

    Gene

    Inheritance

    Associated Features

    Leukocyte adhesion deficiency type 1 (LAD1)

    ITGB2

    AR

    Leukocytosis, delayed cord separation, skin ulcers, periodontitis

    LAD2

    FUCT1

    AR

    Mild LAD1 features plus intellectual disability (ID) and growth retardation

    LAD3

    KINDLIN3

    AR

    LAD1 features plus bleeding tendency

    Rac2 deficiency

    RAC2

    AD

    Leukocytosis, poor wound healing

    B-actin deficiency

    ACTB

    AD

    ID, short stature

    Localized juvenile periodontitis

    FPR1

    AR

    Periodontitis

    Papillon-Lefèvre syndrome

    CTSC

    AR

    Periodontitis, palmoplantar hyperkeratosis

    Specific granule deficiency

    C/EBPE

    AR

    Absent secondary neutrophil granules, bilobed nuclei in neutrophils

    Shwachman-Diamond syndrome

    SBDS

    AR

    Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia

    Immune-osseous dysplasias

    Immune-osseous Dysplasias

    Disorder

    Gene

    Inheritance

    Associated Features

    Cartilage hair hypoplasia

    RMRP

    AR

    Short-limbed dwarfism with metaphysial dysotosis, sparse hair, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasias of the intestine

    Schimke syndrome

    SMARCAL1

    AR

    Short stature, spondyloepiphyseal dysplasia, intrauterine growth retardation, nephropathy, bacterial/viral/fungal infections, may present as SCID, bone marrow failure

    Immune dysfunction syndromes (combined immunodeficiency)

    Immune Dysfunction Syndromes

    Disorder

    Gene

    Inheritance

    Associated Features

    CD40 deficiency

    CD40

    AR

    Neutropenia, GI and liver/biliary tract disease, opportunistic infections

    CD40L deficiency

    CD40LG (also known as TNFSF5 or CD154)

    XL

    Neutropenia, bacterial and opportunistic infections, autoimmune disease, biliary tract and liver disease

    WHIM syndrome

    CXCR4

    AD

    Neutropenia, warts/HPV infection, reduced B cell number, hypogammaglobulinemia

    TWEAK

    TWEAK

    AD

    Neutropenia, pneumonia, bacterial infections, warts, thrombocytopenia

    MST1 deficiency

    STK4

    AR

    Intermittent neutropenia; autoimmune cytopenias; recurrent bacterial, viral and candidal infections; EBV-driven lymphoproliferation; lymphoma; congenital heart disease; HPV infection

    IKAROS deficiency

    IKAROS

    AD; often de novo

    Pancytopenia

    Dyskeratosis congenital (DKC)

    XL-DKC

    DKC1

    XL

    Pancytopenia, intrauterine growth retardation, microcephaly, nail dystrophy, recurrent infections, digestive tract involvement, reduced number and function of NK cells

    AR-DKC due to NHP2 deficiency

    NOLA2 (NHP2)

    AR

    Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails

    AR-DKC due to NOP10 deficiency

    NOLA3 (NOP10)

    AR

    Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails

    AR-DKC due to RTEL1 deficiency

    RTEL1

    AR

    Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails

    AD-DKC due to TERC deficiency

    TERC

    AD

    Pancytopenia, reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis, premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis

    AD-DKC due to TERT deficiency

    TERT

    AD

    Pancytopenia, reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis, premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis

    AD-DKC due to TINF2 deficiency

    TINF2

    AD

    Pancytopenia, reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis, premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis

    Hyper IgE syndromes

    AD-HIES (Job syndrome)

    STAT3

    AD; often de novo intact

    Distinctive facial features, eczema, osteoporosis and fractures, scoliosis, delay of shedding primary teeth, hyperextensible joints, aneurysm formation, bacterial infections due to S. aureus or candidiasis

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Identify the presence of neutropenia

   
Neutrophil-Associated Antibodies 0055506
Method: Qualitative Flow Cytometry

Rule out autoimmune neutropenia

 

May need to repeat complete blood count

Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry

Rule out underlying immunoglobulin disorder

   
Hyper IgM Syndrome Panel, Sequencing (12 Genes) and Deletion/Duplication (10 Genes) 2011154
Method: Massive Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Preferred test for individuals with clinical phenotype of hyper-IgM syndrome or other related immunodeficiency disorders

Genes sequenced – AICDA, ATM, BTK, CD40, CD40LG, IKBKG, MRE11A, NBN/NBS1, NFKBIA, PIK3CD, RAG2, UNG

Genes deletion/duplication – AICDA, ATM, BTK, CD40, CD40LG, MRE11A, NBN/NBS1, NFKBIA, RAG2, UNG

Mutations in genes not included on the panel, deep intronic and regulatory region mutations, breakpoints for large deletions/duplications, and translocations  will not be detected

Deletions/duplications will not be detected in IKBKG and PIK3CD gene

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene mutation does not exclude a diagnosis of hyper-IgM syndrome

 
Primary Antibody Deficiency Panel, Sequencing (35 Genes) and Deletion/Duplication (26 Genes)  2011156
Method: Massive Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Preferred test for individuals with clinical phenotype of

  • Primary antibody deficiency
  • Agammaglobulinemia
  • Hyper-IgM syndrome
  • Common variable immunodeficiency (CVID)
  • Atypical severe combined immunodeficiency
  • Other related immunodeficiency disorder

Genes sequenced – ADA, AICDA, ATM, BLNK, BTK, CD19, CD40, CD40LG, CD79A, CD79B, CD81, CR2, ICOS, IGHM, IGLL1, IKBKG, LRBA, LRRC8A, MRE11A, MS4A1, NBN/NBS1, NFKB2, NFKBIA, PIK3CD, PIK3R1, PLCG2, PRKCD, PTPRC, RAG2, SH2D1A, TNFRSF13B, TNFRSF13C, UNG, VAV1, XIAP/BIRC4

Genes deletion/duplication – ADA, AICDA, ATM, BLNK, BTK, CD19, CD40, CD40LG, CD79A, CD79B, CD81, CR2, ICOS, IGHM, IGLL1, MRE11A, MS4A1, NBN/NBS1, NFKB2, NFKBIA, PTPRC, RAG2, TNFRSF13B, TNFRSF13C, UNG, VAV1

Mutations in genes not included on the panel, deep intronic and regulatory region mutations, breakpoints for large deletions/duplications, and translocations will not be determined or evaluated

Deletions/duplications will not be detected in IKBKG, LRBA, LRRC8A, PIK3CD, PIK3R1, PLCG2, PRKCD, SH2D1A, or XIAP/BIRC4 gene

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene mutation does not exclude diagnosis of primary antibody deficiency

 
Severe Combined Immunodeficiency (SCID) Panel, Sequencing and Deletion/Duplication, 19 Genes 2010219
Method: Massive Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Preferred test for individuals with clinical phenotype of SCID, Omenn syndrome, or other combined immunodeficiency disorders

Preferred test for abnormal newborn screen T-cell receptor excision circles (TREC) test result suggestive of SCID

Genes included – ADA, AK2, CD247, CD3D, CD3E, CORO1A, DCLRE1C, FOXN1, IL2RG, IL7R, JAK3, LIG4, NHEJ1, PNP, PRKDC, PTPRC, RAG1, RAG2, RMRP

Mutations in genes not included on the panel, deep intronic and regulatory region mutations, and breakpoints for large deletions/duplications will not be determined

Deletions/duplications will not be detected in exon 1 in ADA gene; exon 11 in CORO1A gene; exons 4, 6, and 8 in DCLRE1C gene; and exons 3, 6, and 9 in JAK3 gene

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene mutation does not exclude a diagnosis of SCID

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Lymphocyte Subset Panel 4 - T-Cell Subsets Percent and Absolute, Whole Blood 0095950
Method: Quantitative Flow Cytometry

Exclude reticular dysgenesis in infants

Myeloperoxidase Stain 0049030
Method: Cytochemical Stain

Use along with other clinical findings to diagnose chronic granulomatous disease