AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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:

• Oral ulcers
• Gingivitis, which may lead to early loss of permanent teeth
• Pharyngitis
• Sinusitis, otitis media
• Lymphadenopathy, lymphadenitis
• Bronchitis, pneumonia
• Cellulitis
• Cutaneous abscess, boils
• Omphalitis
• Perianal abscess
• Lung abscess
• Liver abscess
• Peritonitis
• Enteritis with chronic diarrhea and vomiting
• Bacteremia and/or septicemia, most commonly caused by streptococci or staphylococci (Other commonly encountered organisms include Pseudomonas, fungi, and, in rare cases, Clostridium species.)
• Urinary tract infection
• Fractures or bone pain
• Splenomegaly
• Neurological symptoms, including epilepsy and neuropsychological deficits²

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}

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Cyclic neutropenia
Chediak-Higashi syndrome
Myelokathexis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• 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⁺ (FCgRI receptor) expression on neutrophils occurs. This does not occur in healthy patients.
  • CD16⁺ (FCgRIII 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.

Imaging Studies

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

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.

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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Treating Kostmann disease with prophylactic antibiotics may be considered but are not usually required (see Medication).
• Granulocyte colony stimulating factor (G-CSF) is administered to stimulate neutrophil production (see Medication). Ninety percent of cases respond with increased neutrophil count and less infections. Some patients need doses of as much as 120 μg/kg.⁶
• Therapy with steroids and testosterone is not effective.

Surgical Care

• Drain abscess as needed.
• Splenectomy is not effective.
• Consider bone marrow transplantation only in patients unresponsive to therapy with G-CSF or in those with leukemic transformation.

Consultations

• Pediatric immunologist
• Pediatric hematologist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Select antibiotics for infections according to the same principles and standards of care as for other patients. Prophylactic antibiotics may be considered but are required infrequently since the advent of granulocyte colony-stimulating factor (G-CSF) in 1987. Staphylococci and streptococci are the most common causes of infections. Frequent or long-term antibiotic use may result in infections from resistant bacteria, anaerobic bacteria, yeast, fungi, and parasites.

G-CSF requires long-term daily administration to maintain clinical benefit. The absolute neutrophil count (ANC) should not be the sole indicator of clinical efficacy. Individually adjust dosages on the basis of both the patient's clinical course and the ANC.

Consider bone marrow transplantation only in patients unresponsive to therapy with G-CSF or in those with leukemic transformation.

Drug Category: Colony-stimulating factors

These agents are used to stimulate neutrophil production and act as hematopoietic growth factors that stimulate the development of granulocytes. They are used to treat or prevent neutropenia.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

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).

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-37.⁷
• Isolating patients within their homes or away from crowds has shown little practical value.

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.

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.

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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to make the diagnosis of Kostmann disease in an infant with persistent neutropenia is a pitfall because initiation of granulocyte-colony stimulating factor (G-CSF) therapy may be delayed.
• Failure to provide appropriate treatment of clinical infections consistent with established standards of care is a pitfall.
• On the basis of national averages of premature deliveries in the general population, an estimated 8% of patients with Kostmann disease are delivered prematurely and admitted to neonatal intensive care units (NICUs). Although neutropenia is common in ill preterm infants and Kostmann disease is relatively rare, Kostmann disease should be considered if other etiologies for the neutropenia are not found. Therapy with G-CSF can save lives in this clinical setting because of the innate risks of infection in a preterm infant.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• 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].

Article Last Updated: Nov 11, 2008