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Kostmann Disease

  • Author: Peter N Huynh, MD; Chief Editor: Harumi Jyonouchi, MD  more...
 
Updated: Aug 31, 2015
 

Background

Kostmann disease was first described in 1956 as an autosomal recessive disorder characterized by severe neutropenia and onset of severe bacterial infections early in life.[1] In his pivotal doctoral thesis, Rolf Kostmann studied 14 affected children from an inbred family from the province of Norrbotten, Sweden. He reported that the neutropenia was accompanied by "a primary insufficiency of the bone marrow" and that the disease is determined by a "single recessive gene difference." Fifty years later, homozygous mutations in the gene encoding the mitochondrial protein HCLS1-associated X1 (HAX1) were found in affected descendants of the original Kostmann family.[2]

Today, the condition initially described by Kostmann is referred to as Kostmann disease. However, it is now apparent that congenital neutropenia is a genetically heterogeneous group of related disorders and, therefore, is designated as severe congenital neutropenia. Severe congenital neutropenia demonstrates several modes of inheritance, including autosomal recessive, autosomal dominant, sporadic, and X-linked forms.

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Pathophysiology

Neutrophils are the most prevalent type of white blood cell and are an essential part of the innate immune system. They act as initial responders to inflammation and ingest, or phagocytize, microorganisms or particles. A phagosome is formed around the ingested microbes, and an oxidative burst is generated in the phagosome. They also release neutrophil granules that kill the invading microorganism. Neutrophils undergo apoptosis and are then cleared by macrophages or other phagocytic cells, which clear the toxic contents.[3, 4]

Neutropenia is a disorder characterized by an abnormally low absolute number of neutrophils in the blood. Mild neutropenia is classified as less than 1500 granulocytes/μL, moderate is less than 1000/μL, severe is less than 500/μL, and very severe is less than 200/μL. Severe congenital neutropenia usually presents in infancy with an absolute neutrophil count of less than 200/μL.[5, 6]

Several genetic causes of severe congenital neutropenia have been identified, but a common thread among the variants is excessive neutrophil apoptosis. A decrease in the production or shorter half-life of neutrophils results in fewer cells in the periphery.

The unfolded protein response (UPR) has been recently proposed as a potential explanation for increased apoptosis seen in severe congenital neutropenia. Increased endoplasmic reticulum stress leads to the activation of the UPR. When an accumulation of unfolded or misfolded proteins occurs in the lumen of the endoplasmic reticulum, the UPR works to protect the cell against the damage caused by these improperly folded proteins. The goals of the UPR are to maintain homeostasis in the cell by arresting protein translation and promoting signaling pathways that lead to increased production of molecular chaperones to help with protein folding. If this does not happen, the UPR initiates apoptosis.[7, 8, 9, 10]

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Epidemiology

Frequency

International

Epidemiological data are limited given the overlapping case definitions of congenital neutropenia and few patient registries.

According to International Neutropenia Registry data from 2003 covering areas with a total population of 700 million in United States, Canada, Australia, and Europe (excluding France), 731 cases were reported, with a prevalence of about 1 case per million people.

A French registry reported an incidence as high as 6 cases per million people. Of the patients from the French survey, 30% had ELANE mutations (20% with severe congenital neutropenia and 10% with cyclic neutropenia), 30% had Shwachman-Diamond syndrome (SBDS), 5% had glycogen storage disease type 1b, and 35% had other disorders (1 or 2% each).[5]

In another study from the North American Severe Chronic Neutropenia Tissue Repository, mutations in ELANE genes were found in 90 (55.6%) of 162 patients. Of 72 patients with normal ELANE genes, 45 had sufficient DNA to undergo throughput sequencing to determine prevalence of other mutations(HAX1, -WASp, SBDS, GFI1, and G6PC3). Five of these patients were found to have mutations: G6PC3 in 2, GFI1 in 1, SBDS in 1, and WASp in 1. In 40% of patients, a genetic etiology for severe congenital neutropenia was unknown.[11]

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.[12]

Patients with severe congenital neutropenia are at an increased risk of bacterial and fungal infections, with most frequent infections involving the skin, mucosa, ears, nose, throat, and lungs. Stomatitis starts after age 2 years with erosive hemorrhagic gingivitis and painful aphthouslike papules on the tongue and cheeks, contributing significantly to morbidity. Chronic periodontal disease has been attributed to deficiency in a defensin, the antimicrobial peptide LL-37.[13] Diffuse gastrointestinal lesions may cause abdominal pain and diarrhea, resembling bacterial enteritis. Bacterial infections involve Staphylococcus aureus and Staphylococcus epidermidis, streptococci, enterococci, pneumococci, Pseudomonas aeruginosa, gram-negative bacilli, and fungal infections with Candida or Aspergillus species.

About 1 in 5 patients with severe congenital neutropenia develop secondary malignancies. The incidence of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) in severe congenital neutropenia after 10 years of G-CSF treatment is 21%. Acquired mutations in G-CSF receptor CSF3R are a highly predictive marker for the progression of severe congenital neutropenia to leukemia.[14] Of patients with severe congenital neutropenia, 20-30% have acquired mutations in the CSF3R gene, which produce C-terminally truncated hyperresponsive forms of the G-CSFRhyper and a strong predisposition for MDS and AML.

Race

No major differences likely exist in prevalence across countries. However, certain mutations are linked to geographic origin, such as HAX1 in Kurdistan and Sweden and G6PC3 in Arameans.[5]

Sex

As the name implies, X-linked severe congenital neutropenia due to WASpmutations are only seen in boys. No sexual predilection is associated with the other causes of severe congenital neutropenia.

Age

Patients are diagnosed shortly after birth with recurrent bacterial infections within the first few months of life.

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Contributor Information and Disclosures
Author

Peter N Huynh, MD Chief of Allergy and Immunology, Kaiser Permanente, Panorama City Medical Center

Peter N Huynh, MD 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, American College of Physicians, American Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Stuart Min, MD Allergist in private practice

Stuart Min, MD 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

Disclosure: Nothing to disclose.

Karine Zakarian, MD Fellow in Allergy and Immunology, LAC+USC Medical Center

Karine Zakarian, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David J Valacer, MD 

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, New York Academy of Sciences

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter's University Hospital

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 Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.

Additional Contributors

James M Oleske, MD, MPH François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, Rutgers New Jersey Medical School; Professor, Department of Quantitative Methods, Rutgers 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 Allergy Asthma and Immunology, American Academy of Hospice and Palliative Medicine, American Association of Public Health Physicians, American College of Preventive Medicine, American Pain Society, Infectious Diseases Society of America, Infectious Diseases Society of New Jersey, Medical Society of New Jersey, Pediatric Infectious Diseases Society, Arab Board of Family Medicine, American Academy of Pain Management, National Association of Pediatric Nurse Practitioners, Association of Clinical Researchers and Educators, American Academy of HIV Medicine, American Thoracic Society, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Acknowledgements

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.

References
  1. Kostmann R. Infantile genetic agranulocytosis; agranulocytosis infantilis hereditaria. Acta Paediatr Suppl. 1956 Feb. 45:1-78. [Medline].

  2. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schäffer AA, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet. 2007 Jan. 39(1):86-92. [Medline].

  3. Boxer LA. Severe congenital neutropenia: genetics and pathogenesis. Trans Am Clin Climatol Assoc. 2006. 117:13-31; discussion 31-2. [Medline]. [Full Text].

  4. Hickey MJ, Kubes P. Intravascular immunity: the host-pathogen encounter in blood vessels. Nat Rev Immunol. 2009 May. 9(5):364-75. [Medline].

  5. Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. 2011. 6:26. [Medline].

  6. Klein C. Congenital neutropenia. Hematology Am Soc Hematol Educ Program. 2009. 344-50. [Medline].

  7. Nanua S, Murakami M, Xia J, Grenda DS, Woloszynek J, Strand M. Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane. Blood. 2011 Mar 31. 117(13):3539-47. [Medline].

  8. Ward AC, Dale DC. Genetic and molecular diagnosis of severe congenital neutropenia. Curr Opin Hematol. 2009 Jan. 16(1):9-13. [Medline].

  9. Boztug K, Klein C. Genetic etiologies of severe congenital neutropenia. Curr Opin Pediatr. 2011 Feb. 23(1):21-6. [Medline].

  10. Xia J, Link DC. Severe congenital neutropenia and the unfolded protein response. Curr Opin Hematol. 2008 Jan. 15(1):1-7. [Medline].

  11. Xia J, Bolyard AA, Rodger E, Stein S, Aprikyan AA, Dale DC. Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. Br J Haematol. 2009 Nov. 147(4):535-42. [Medline].

  12. Connelly JA, Choi SW, Levine JE. Hematopoietic stem cell transplantation for severe congenital neutropenia. Curr Opin Hematol. 2012 Jan. 19(1):44-51. [Medline]. [Full Text].

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

  14. Germeshausen M, Welte K, Ballmaier M. In vivo expansion of cells expressing acquired CSF3R mutations in patients with severe congenital neutropenia. Blood. 2009 Jan 15. 113(3):668-70. [Medline].

  15. Zeidler C, Germeshausen M, Klein C, Welte K. Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia. Br J Haematol. 2009 Feb. 144(4):459-67. [Medline].

  16. 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. 2008 Oct. 264(4):388-400. [Medline].

  17. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schäffer AA, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet. 2007 Jan. 39(1):86-92. [Medline].

  18. Dong F, Brynes RK, Tidow N, Welte K, Löwenberg B, Touw IP. Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia. N Engl J Med. 1995 Aug 24. 333(8):487-93. [Medline].

  19. Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood. 2007 Mar 1. 109(5):1817-24. [Medline]. [Full Text].

  20. Person RE, Li FQ, Duan Z, Benson KF, Wechsler J, Papadaki HA. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat Genet. 2003 Jul. 34(3):308-12. [Medline].

  21. Carlsson G, Aprikyan AA, Tehranchi R, Dale DC, Porwit A, Hellström-Lindberg E. 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. 2004 May 1. 103(9):3355-61. [Medline].

  22. Boztug K, Appaswamy G, Ashikov A, Schäffer AA, Salzer U, Diestelhorst J. A syndrome with congenital neutropenia and mutations in G6PC3. N Engl J Med. 2009 Jan 1. 360(1):32-43. [Medline].

  23. Choi LM, Guelcher C, Guerrera MF. Novel treatment for severe congenital neutropenia with pegfilgrastim. Blood. 2007 Dec 1. 110(12):4134. [Medline].

  24. Fioredda F, Calvillo M, Lanciotti M, Lanza T, Giunti L, Castagnola E. Pegfilgrastim in children with severe congenital neutropenia. Pediatr Blood Cancer. 2010 Mar. 54(3):465-7. [Medline].

  25. Lähteenmäki PM, Jahnukainen K, Pelliniemi TT, Kainulainen L, Salmi TT. Severe congenital neutropenia and pegfilgrastim. Eur J Haematol. 2009 Jan. 82(1):75-6. [Medline].

  26. Beaupain B, Leblanc T, Reman O, Hermine O, Vannier JP, Suarez F. Is pegfilgrastim safe and effective in congenital neutropenia? An analysis of the French Severe Chronic Neutropenia registry. Pediatr Blood Cancer. 2009 Dec. 53(6):1068-73. [Medline].

  27. Salehi T, Fazlollahi MR, Maddah M, Nayebpour M, Tabatabaei Yazdi M, Alizadeh Z, et al. Prevention and Control of Infections in Patients with Severe Congenital Neutropenia; A Follow up Study. Iran J Allergy Asthma Immunol. 2012 Mar. 11(1):51-6. [Medline].

  28. Carlsson G, Fasth A, Berglöf E, Lagerstedt-Robinson K, Nordenskjöld M, Palmblad J, et al. Incidence of severe congenital neutropenia in Sweden and risk of evolution to myelodysplastic syndrome/leukaemia. Br J Haematol. 2012 Aug. 158(3):363-9. [Medline].

  29. 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. 2008 Mar 6. 452(7183):98-102. [Medline].

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

  31. 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. 2005 May. 76(5):837-44. [Medline].

  32. 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].

 
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