eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Kostmann Disease

Author: Michael S Tankersley, MD, FAAAAI, FACAAI, FAAP, Chief, Division of Allergy and Immunology, Department of Medicine, Wilford Hall Medical Center, Lackland Air Force Base
Contributor Information and Disclosures

Updated: Nov 11, 2008

Introduction

Background

Originally described in 1956 in a Swedish kindred, Kostmann disease is a rare autosomal recessive disorder of neutrophil number.1 The absolute neutrophil count (ANC) is characteristically less than 200/μL. Severe persistent neutropenia results in an increased susceptibility to frequent bacterial infections.

Pathophysiology

Neutropenia refers to an ANC that is 2 or more standard deviations below the age-matched control mean. ANC is calculated by multiplying the total leukocyte count per milliliter by the percentage of neutrophils and immature neutrophil forms. Normal neutrophil levels differ according to age and race. In general, an ANC of 1000-1500/μL indicates mild neutropenia, 500-1000/μL  indicates moderate neutropenia, and less than 500/μL indicates severe neutropenia. This classification is useful for predicting risk of infection.

Frequency

International

Neutropenia occurs in 1-2 cases per million population.

Mortality/Morbidity

The mortality rate is 70% within the first year of life in the absence of medical intervention with granulocyte colony-stimulating factor (G-CSF), bone marrow transplantation, or peripheral blood stem cell transplantation.

Race

Most of the initial patients reported by Kostmann were seen in Överkalix parish in northern Sweden, a geographic region with excessive inbreeding.

Sex

Incidence is equal in males and females.

Age

Classic Kostmann disease is recognized in early infancy.

Clinical

History

Severe neutropenia is brought to clinical attention after an initial infection, which typically occurs shortly after birth. Symptoms of Kostmann disease include the following:

  • Temperature instability in newborn period
  • Fever
  • Irritability
  • Localized site(s) of infection

Physical

Signs and symptoms of Kostmann disease include the following:

Causes

  • Classic Kostmann disease, as originally reported in 1956, is inherited in an autosomal recessive pattern.1  Severe congenital neutropenia, in general, consists of a heterogeneous group of blood disorders that may also be inherited in an autosomal dominant fashion or may occur via sporadic mutation.
  • An abnormal granulocyte colony-stimulating factor (G-CSF)–induced intracellular signal transduction pathway has been suggested as a potential cause of the underlying genetic defect. Neutrophils from patients are shown to have dramatically increased levels of 2 cytosolic protein tyrosine phosphatases that contain src-homology 2 (SH2): SHP-1 and SHP-2. One hypothesis is that overexpression of these proteins, which are involved in cytokine receptor signaling, plays a role in altering intracellular signal transduction processes.
  • A selective decrease of B-cell lymphoma-2 (Bcl-2) expression in myeloid cells and an increase in apoptosis in bone marrow progenitor cells have been observed. The primary function of Bcl-2, a mitochondria-targeted protein, is the prevention of cytochrome c release from mitochondria. Cytochrome c can activate a cytosolic caspase cascade. Caspases are integral proteolytic enzymes involved in cellular apoptosis. Caspases are activated through one of two pathways: (1) an extrinsic, death receptor–dependent pathway or (2) an intrinsic, mitochondria–dependent pathway. Mitochondrial release of cytochrome c initiates the cytosolic caspase cascade through the second pathway. Thus, decreased Bcl-2 results in enhanced release of cytochrome c, which then perpetuates the caspase cascade leading to more pronounced apoptosis. G-CSF offers clinical protection to patients with Kostmann disease by diminishing this mitochondria-dependent apoptotic death pathway.
  • G-CSF receptors are expressed on myeloid cells in slightly increased numbers, and the binding affinity for G-CSF to its receptor is normal. This is in contrast to the original theory that the underlying Kostmann defect was related to either decreased G-CSF production or diminished binding of G-CSF to its receptor.
  • Although neutrophil elastase mutations (ELA2) have been found in a subgroup of patients with Kostmann disease, as in cyclic neutropenia, these mutations are also found in some phenotypically healthy family members. In contrast to the inheritance pattern seen in Kostmann disease (autosomal recessive), these elastase mutations are inherited in an autosomal dominant fashion. Phenotypically, these patients are identical to the patients with classic Kostmann syndrome and may be more predominant in cases of congenital neutropenia.
  • While G-CSF receptor mutations have not been detected at birth, patients with Kostmann disease who develop leukemia have been found to have acquired G-CSF receptor mutations. Considerable variability between the onset of G-CSF receptor mutation and the development of leukemia has been noted.3
  • Autosomal recessive inheritance of homozygous hematopoietic cell-specific protein-1 (HS1)-associated protein X-1 (HAX-1) mutations appear to lead to the increased apoptosis of myeloid precursors seen in patients with severe congenital neutropenia.  HAX-1 functions include signal transduction, cytoskeletal control, and regulation of apoptosis.2 . HAX-1 is reported to play a role in suppression of apoptosis in lymphocytes and neurons, resulting in prolonged survival of these cells.4 Not surprisingly, certain HAX-1 mutations are now shown to be associated with neurological and neuropsychological abnormalities, including neurodevelopmental delay and epilepsy.4,5

More on Kostmann Disease

Overview: Kostmann Disease
Differential Diagnoses & Workup: Kostmann Disease
Treatment & Medication: Kostmann Disease
Follow-up: Kostmann Disease
References
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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. 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].

  5. 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].

  6. 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].

  7. 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].

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

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

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

  11. 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].

  12. 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].

  13. 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].

  14. 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].

  15. 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].

  16. 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].

  17. 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].

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

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

  20. 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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Further Reading

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Keywords

Kostmann disease, Kostmann's disease, Kostmann syndrome, Kostmann's syndrome, congenital neutropenia, severe congenital neutropenia, infantile genetic agranulocytosis, infantile agranulocytosis, congenital agranulocytosis, severe neutropenia of infancy, bone marrow transplantation, peripheral blood stem cell transplantation, oral ulcers, gingivitis, pharyngitis, sinusitis, otitis media, lymphadenopathy, lymphadenitis, bronchitis, cellulitis, omphalitis, pneumonia, omphalitis, perianal abscess, lung abscess, liver abscess, peritonitis, enteritis, diarrhea, vomiting, bacteremia, septicemia, urinary tract infection, epilepsy, neuropsychological deficits, splenomegaly, congenital neutropenia

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Contributor Information and Disclosures

Author

Michael S Tankersley, MD, FAAAAI, FACAAI, FAAP, Chief, Division of Allergy and Immunology, Department of Medicine, Wilford Hall Medical Center, Lackland Air Force Base
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.

Medical Editor

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.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

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.

CME Editor

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.

 
 
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