Congenital Neutrophil Disorders

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics

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

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

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.

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Neutrophil-Associated Antibodies 0055506
Method: Qualitative Flow Cytometry

Follow-up 

May need to repeat complete blood count

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

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

Limitations 

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: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations 

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: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations 

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

Guidelines

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar B, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan K, Tang ML. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014; 5: 162. PubMed

General References

Chinen J, Shearer WT. Advances in basic and clinical immunology in 2008. J Allergy Clin Immunol. 2009; 123(2): 328-32. PubMed

Dinauer MC. Disorders of neutrophil function: an overview. Methods Mol Biol. 2007; 412: 489-504. PubMed

Freeman AF, Holland SM. The hyper-IgE syndromes. Immunol Allergy Clin North Am. 2008; 28(2): 277-91, viii. PubMed

Immune Deficiency Foundation. Towson, MD [Accessed: Nov 2015]

Kaplan J, De Domenico I, Ward DM. Chediak-Higashi syndrome. Curr Opin Hematol. 2008; 15(1): 22-9. PubMed

Newburger PE, Dale DC. Evaluation and management of patients with isolated neutropenia. Semin Hematol. 2013; 50(3): 198-206. PubMed

Newburger PE. Disorders of neutrophil number and function. Hematology Am Soc Hematol Educ Program. 2006; 104-10. PubMed

Ochs HD, Hagin D. Primary immunodeficiency disorders: general classification, new molecular insights, and practical approach to diagnosis and treatment. Ann Allergy Asthma Immunol. 2014; 112(6): 489-95. PubMed

Paulson ML, Freeman AF, Holland SM. Hyper IgE syndrome: an update on clinical aspects and the role of signal transducer and activator of transcription 3. Curr Opin Allergy Clin Immunol. 2008; 8(6): 527-33. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Borges WG, Hensley T, Carey JC, Petrak BA, Hill HR. The face of Job. J Pediatr. 1998; 133(2): 303-5. PubMed

Erdos M, Garami M, Rákóczi E, Zalatnai A, Steinbach D, Baumann U, Kropshofer G, Tóth B, Marodi L. Neuroendocrine carcinoma associated with X-linked hyper-immunoglobulin M syndrome: report of four cases and review of the literature. Clin Immunol. 2008; 129(3): 455-61. PubMed

Nester TA, Wagnon AH, Reilly WF, Spitzer G, Kjeldsberg CR, Hill HR. Effects of allogeneic peripheral stem cell transplantation in a patient with job syndrome of hyperimmunoglobulinemia E and recurrent infections. Am J Med. 1998; 105(2): 162-4. PubMed

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Last Update: September 2016