Kostmann Disease Follow-up

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

Further Inpatient Care

  • Admit patients with Kostmann disease who have sepsis and those who fail to respond to outpatient antibiotic therapy for intravenous antibiotic therapy and appropriate supportive therapies.
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Further Outpatient Care

  • Obtain a CBC count with differential twice per week during the first 4 weeks after initiation of granulocyte-colony stimulating factor (G-CSF) or for 2 weeks following any dosage adjustments. Thereafter, obtain a CBC count with differential monthly for 6 months, then at least quarterly.
  • Routine clinical follow-up every 3 months for patients who are stable.
  • Enroll patients in the Severe Chronic Neutropenia International Registry (SCNIR).
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Deterrence/Prevention

  • Provide genetic counseling to parents of these infants because Kostmann disease has an autosomal recessive form of inheritance.
  • Maintaining an adequate absolute neutrophil count (≥ 1000/μL) with G-CSF is central to preventing infections.
  • Annual bone marrow examination for morphology and cytogenetic testing should be performed in order to identify any changes indicating malignant transformation and to allow for early intervention with bone marrow transplantation.
  • Regular G-CSF receptor analysis should be performed to identify mutations. This can be done on either peripheral blood or bone marrow samples by labs headed by the SCNIR.
  • Regular dental and periodontal evaluation and care should be performed in order to minimize dental complications. The characteristic gingivitis and periodontal disease persist even after rG-CSF. Chronic periodontal disease has been attributed to deficiency in a defensin, the antimicrobial peptide LL-37.[8]
  • Isolating patients within their homes or away from crowds has shown little practical value.
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Complications

  • Most complications relate to infections.
  • Bone demineralization occurs in approximately 50% of patients, which may result in bone pain and unusual fractures, either as a part of the pathophysiology of the disease or potentially from either endogenous or exogenous G-CSFs by increased bone resorption.
  • Acute myeloid leukemia may develop in approximately 10% of patients, which suggests that Kostmann disease is a preleukemic syndrome. Because of the prolonged survival rate of patients with G-CSF therapy, the frequency of leukemias may increase. Although G-CSF receptor mutation does not appear responsible for the initial neutropenia in Kostmann disease, leukemic transformation is associated with this spontaneous mutation.
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Prognosis

  • Introduction of G-CSF produces a significant and sustained increase in the absolute neutrophil count (ANC), resulting in fewer infections of shorter duration. This dramatically improves the patient's quality of life and prolongs survival.
  • Leukemic transformation may occur and adversely impacts the prognosis.
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Patient Education

  • Educate patients and their families on the signs and symptoms of infections to ensure appropriate and prompt therapy.
  • Inform patients and their families of the risk for developing leukemia.
  • The Immune Deficiency Foundation is an important resource for education and support for patients and families with any primary immunodeficiency disease. The telephone address is 1-800-296-4433. The Web site is www.primaryimmune.org. The foundation's mailing address is 40 W Chesapeake Ave, Suite 308, Towson, MD 21204; some states have local chapters.
  • The Jeffrey Modell Foundation at 747 3rd Avenue, New York, NY 10017, also provides educational support. The telephone number is 1-866-INFO-4-PI. The Web site is www.jmfworld.org.
  • The SCNIR was established in March of 1994, in the United States, Australia, Canada, and the European Community. The SCNIR is directed by a scientific advisory board of physicians from around the world who care for SCN patients. Their mission is to establish a worldwide database of treatment and disease-related outcomes for persons diagnosed with severe chronic neutropenia. Collection of this information will lead to improved medical care and is used for research to determine the causes of neutropenia. The Web site is www.depts.washington.edu/registry.
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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

  1. Kostmann R. Infantile genetic agranulocytosis (agranulocytosis infantilis hereditaria): a new recessive lethal disease in man. Acta Pediatr Scand. 1956;45:1-78.

  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].

  7. Dror Y, Sung L. Update on childhood neutropenia: molecular and clinical advances. Hematol Oncol Clin North Am. Dec 2004;18(6):1439-58, x. [Medline].

  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].

  20. Welte K, Dale D. Pathophysiology and treatment of severe chronic neutropenia. Ann Hematol. Apr 1996;72(4):158-65. [Medline].

  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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