Kostmann Disease Workup

  • Author: Michael S Tankersley, MD, FAAAAI, FACAAI, FAAP; Chief Editor: Harumi Jyonouchi, MD   more...
 
Updated: Aug 11, 2010
 

Laboratory Studies

With regard to CBC count with differential, an absolute neutrophil count (ANC) less than 200/μL is seen in classic cases. Monocytosis and eosinophilia may be evident. Total leukocyte counts are frequently normal because of the monocytosis. Mild anemia may be present from chronic inflammation, and thrombocytosis may be present.

Quantitative immunoglobulins may show hypergammaglobulinemia. Patients have a normal response to vaccinations.

Complement levels are typically normal.

Antineutrophil antibodies are absent but should be checked to exclude an autoimmune etiology when the diagnosis is entertained in the first few months of life.

In vitro studies include the following:

  • Neutrophil phagocytosis, generation of reactive oxygen intermediates, and intracellular killing of bacteria are all normal.
  • CD64+ (FC γ RI receptor) expression on neutrophils occurs. This does not occur in healthy patients.
  • CD16+ (FC γ RIII receptor) expression on neutrophils is decreased.
  • Neutrophil mobilization of intracellular calcium in response to N -formyl-methionyl-leucyl-phenylalanine (FMLP) or interleukin-8 (IL-8) is decreased.

Electrolyte levels and renal and liver function test results are within the reference range.

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Imaging Studies

  • Imaging studies are performed only as clinically indicated to evaluate an infection or any associated osteopenia, osteoporosis, or both.
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Procedures

  • Bone marrow aspiration or biopsy: When leukemic or myelodysplastic transformation occurs, bone marrow cytogenetics exhibit monosomy 7 in 50% of cases. Granulocyte colony-stimulating factor (G-CSF) receptor mutations occur within an intracellular part of the receptor and can be identified from either blood or bone marrow samples. As G-CSF receptor mutations are not present at birth, they do not represent the underlying defect for the disease.
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Histologic Findings

  • In the absence of myelodysplastic or leukemic changes, bone marrow aspiration or biopsy findings reveal an arrest of neutrophil precursor maturation at the promyelocyte or myelocyte level. Cytogenetic analysis typically reveals a normal bone marrow karyotype.
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Contributor Information and Disclosures
Author

Michael S Tankersley, MD, FAAAAI, FACAAI, FAAP  Program Director, Allergy and Immunology Fellowship; Division Chief, Allergy and Immunology, Department of Medicine, Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, Texas

Michael S Tankersley, MD, FAAAAI, FACAAI, FAAP is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, and Joint Council of Allergy, Asthma and Immunology

Disclosure: Nothing to disclose.

Specialty Editor Board

James M Oleske, MD, MPH  François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School

James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

David J Valacer, MD  Consulting Staff, Hoffman La Roche Pharmaceuticals

David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, and New York Academy of Sciences

Disclosure: Nothing to disclose.

David Pallares, MD  Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville

David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD  Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

References

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  2. Carlsson G, van't Hooft I, Melin M, et al. Central nervous system involvement in severe congenital neutropenia: neurological and neuropsychological abnormalities associated with specific HAX1 mutations. J Intern Med. Oct 2008;264(4):388-400. [Medline].

  3. Weinblatt ME, Scimeca P, James-Herry A, et al. Transformation of congenital neutropenia into monosomy 7 and acute nonlymphoblastic leukemia in a child treated with granulocyte colony- stimulating factor. J Pediatr. Feb 1995;126(2):263-5. [Medline].

  4. Smith BN, Ancliff PJ, Pizzey A, Khwaja A, Linch DC, Gale RE. Homozygous HAX1 mutations in severe congenital neutropenia patients with sporadic disease: a novel mutation in two unrelated British kindreds. Br J Haematol. Mar 2009;144(5):762-70. [Medline].

  5. Chao JR, Parganas E, Boyd K, Hong CY, Opferman JT, Ihle JN. Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature. Mar 6 2008;452(7183):98-102. [Medline].

  6. Germeshausen M, Grudzien M, Zeidler C, et al. Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype-phenotype associations. Blood. May 15 2008;111(10):4954-7. [Medline].

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  8. Putsep K, Carlsson G, Boman HG, Andersson M. Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study. Lancet. Oct 12 2002;360(9340):1144-9. [Medline].

  9. Baehner RL, Miller DR. Disorders of granulopoiesis. In: Blood Diseases of Infancy and Childhood. 1995:555-92.

  10. Barnes C, Gerstle JT, Freedman MH, Carcao MD. Clostridium septicum myonecrosis in congenital neutropenia. Pediatrics. Dec 2004;114(6):e757-60. [Medline]. [Full Text].

  11. Calhoun DA, Christensen RD. The occurrence of Kostmann syndrome in preterm neonates. Pediatrics. Feb 1997;99(2):259-61. [Medline].

  12. Carlsson G, Aprikyan AA, Tehranchi R, et al. Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells. Blood. May 1 2004;103(9):3355-61. [Medline]. [Full Text].

  13. Dale DC, Cottle TE, Fier CJ, et al. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol. Feb 2003;72(2):82-93. [Medline].

  14. Hakki SS, Aprikyan AA, Yildirim S, et al. Periodontal status in two siblings with severe congenital neutropenia: diagnosis and mutational analysis of the cases. J Periodontol. May 2005;76(5):837-44. [Medline].

  15. Hsiao CC, Chen CL, Eng HL. Inflammatory pseudotumor of the liver in Kostmann's disease. Pediatr Surg Int. 1999;15(3-4):266-9. [Medline].

  16. Levine JE, Wiley J, Kletzel M, et al. Cytokine-mobilized allogeneic peripheral blood stem cell transplants in children result in rapid engraftment and a high incidence of chronic GVHD. Bone Marrow Transplant. Jan 2000;25(1):13-8. [Medline].

  17. Shekhter-Levin S, Penchansky L, Wollman MR, et al. An abnormal clone with monosomy 7 and trisomy 21 in the bone marrow of a child with congenital agranulocytosis (Kostmann disease) treated with granulocyte colony-stimulating factor. Cancer Genet Cytogenet. Oct 15 1995;84(2):99-104. [Medline].

  18. Tidow N, Kasper B, Welte K. SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 are dramatically increased at the protein level in neutrophils from patients with severe congenital neutropenia (Kostmann's syndrome). Exp Hematol. Jun 1999;27(6):1038-45. [Medline].

  19. Welte K, Boxer LA. Severe chronic neutropenia: pathophysiology and therapy. Semin Hematol. Oct 1997;34(4):267-78. [Medline].

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  21. Yakisan E, Schirg E, Zeidler C, Bishop NJ, Reiter A, Hirt A, et al. High incidence of significant bone loss in patients with severe congenital neutropenia (Kostmann's syndrome). J Pediatr. Oct 1997;131(4):592-7. [Medline].

 
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