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Kostmann Syndrome

Severe Congenital Neutropenia

Kostmann syndrome is a condition also known as severe congenital neutropenia. It has multiple genetic etiologies, the earliest described being autosomal recessive. Patients present with severe infections early in life.


Presentation

Kostmann syndrome (KS) is named after Rolf Kostmann, who reported a condition he described as infantile agranulocytosis in 1956 and it was later termed as KS [1]. The ailment that Kostmann described is autosomal recessive. Since then, it has been discovered that KS is a genetically heterogeneous set of disease conditions, and thus the more commonly used term is severe congenital neutropenia (SCN). Modes of inheritance include autosomal dominant, autosomal recessive, X-linked, and a number of cases are sporadic. It is a rare disorder that affects both males and females in equal proportions.

Gene mutations include the gene encoding neutrophil elastase (ELA2) (the most frequent cause of SCN), colony stimulating factor 3 receptor (CSF3R) gene, and the HS1-associated protein X1 (HAX1) gene (responsible for autosomal recessive KS) [2] [3]. The same genes can be affected by different mutations, hence the varying presentation and treatment outcomes [4].

Affected individuals suffer from a wide range of opportunistic infections at a young age, ranging from minor infections to fatal illness. Examples include gingivitis, otitis media, upper respiratory tract infections, liver abscesses, various skin infections, omphalitis, and fever. Many of these infections are bacterial, although other organisms have been identified, such as fungi. The most common bacteria cultured are the Streptococcus and Staphylococcus species.

Congenital neutropenias represent a group of disorders, usually characterized by a low neutrophil count. Other features may be present, to varying degrees, depending on the genetic origin of the illness. SCN often involves failure of neutrophils to reach maturation in the bone marrow as well [5] [6]. The autosomal recessive form of KS is characterized by a more marked neutropenia than the other variants [7]. KS may be present as a part of another disorder, such as Fanconi pancytopenic syndrome or Chediak-Higashi syndrome.

A long-term complication of KS is the higher incidence of myelodysplastic syndrome (MDS) and leukemia (acute myeloid leukemia in particular), among those affected [5] [8]. The prognosis is often poor. Furthermore, the mutation in the HAX1 gene is associated with neurological impairment, manifesting as epilepsy, as well as cognitive and developmental delay [9].

Recurrent Bacterial Infection
  • bacterial infections (e.g. otitis media, pneumonia, sinusitis, urinary tract infections, abscesses of skin and/or liver) and increased promyelocytes in the bone marrow.[orpha.net]
  • Abstract Kostmann syndrome (KS) is an autosomal recessive disorder characterized by a low neutrophil count and recurrent bacterial infections, including periodontal disease.[ncbi.nlm.nih.gov]
  • bacterial infections from early infancy.[ajol.info]
  • Symptoms of Costman's syndrome Kostmann's syndrome is the debut of the disease in the first months of life or during the newborn period in the form of severe recurrent bacterial infections: stomatitis, chronic gingivitis, repeated pneumonia, including[m.iliveok.com]
  • bacterial infections Bacterial infections, recurrent Frequent bacterial infections Increased susceptibility to bacterial infections Recurrent major bacterial infections [ more ] 0002718 Thrombocytosis Increased number of platelets in blood 0001894 Showing[rarediseases.info.nih.gov]
Rapidly Progressive Glomerulonephritis
  • Manabu Sotomatsu, Takashi Kanazawa, Chitose Ogawa, Toshio Watanabe and Akihiro Morikawa, Complication of rapidly progressive glomerulonephritis in severe congenital neutropenia treated with long‐term granulocyte colony‐stimulating factor (filgrastim),[doi.org]
Psychomotor Retardation
  • ., psychomotor retardation and seizures), which result from mutations of HAX1 isoforms 1 and 5. Management Filgrastim, a granulocyte colony-stimulating factor analog, improves neutrophil counts and immune function.[medical-dictionary.thefreedictionary.com]
Speech Disorders
  • GRIN2A -Related Speech Disorders and Epilepsy Kenneth A Myers and Ingrid E Scheffer. Initial Posting: September 29, 2016. GRIN2B -Related Neurodevelopmental Disorder Konrad Platzer and Johannes R Lemke. Initial Posting: May 31, 2018.[ncbi.nlm.nih.gov]

Workup

The diagnosis of Kostmann syndrome is made when blood results drawn from successive differential counts, reveal an absolute neutrophil count (ANC) below 500 cells per microliter. Bone marrow analysis showing numerous immature promyelocytes also supports the diagnosis [5] [6] [10]. Furthermore, the bone marrow biopsy may show decreased cellularity and is important in ruling out possible malignancies [11]. Autosomal recessive KS, as described by Kostmann, has a neutrophil count less than 200 cells per microliter [7] [12].

Other features that might be present in the full blood count are anemia, in addition to elevated levels of platelets, monocytes, and eosinophils. The total white cell count remains within the average range, while the immunoglobulin G (IgG) is high. Other chemical parameters are usually normal, and patients respond normally to vaccinations. However, antinuclear antibodies (ANA) may be high if the underlying cause is autoimmune.

Genetic testing may also be conducted, in order to delineate the specific genetic mutation. Imaging modalities are sometimes used, and these include:

  • X-rays,
  • Dual-energy X-ray absorptiometry (DEXA) scanning. This is done to determine bone density, as patients with KS may have osteoporosis.

Treatment

  • The results of the study indicate that nonsurgical treatment of Kostmann syndrome periodontitis can reduce supragingival and salivary herpes viral loads.[ncbi.nlm.nih.gov]

Prognosis

  • The prognosis is often poor. Furthermore, the mutation in the HAX1 gene is associated with neurological impairment, manifesting as epilepsy, as well as cognitive and developmental delay.[symptoma.com]
  • If the bone marrow is not irreparably damaged, the prognosis is good with proper treatment, and the patient will recover as the production of granulocytes resumes.[medical-dictionary.thefreedictionary.com]
  • The finding of the disease associated variants in this thesis will eventually contribute to improved diagnosis, prognosis, risk assessment and a future treatment of patients.[diva-portal.org]
  • Niemeyer, Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents, Blood, 127, 11, (1387), (2016). Kanwaldeep Mallhi, David B. Dix, Karen Y.[doi.org]
  • This arrest results in severe neutropenia leading to absolute neutrophil counts (ANC) below 0.2 10 9 /l associated with severe bacterial infections. 1 The availability of granulocyte colony-stimulating factor (G-CSF) has changed the prognosis of Kostmann[nature.com]

Etiology

  • It has multiple genetic etiologies, the earliest described being autosomal recessive. Patients present with severe infections early in life.[symptoma.com]
  • 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[emedicine.com]

Epidemiology

  • Frequency International Epidemiological data are limited given the overlapping case definitions of congenital neutropenia and few patient registries.[emedicine.medscape.com]
  • Zeidan, Epidemiology of acute myeloid leukemia: Recent progress and enduring challenges, Blood Reviews, 10.1016/j.blre.2019.04.005, (2019).[doi.org]
Sex distribution
Age distribution

Pathophysiology

  • […] include: Homeostasis and migration of neutrophil granulocytes,Granulocyte-colony Stimulating Factor (G-CSF) receptor signaling,New Granulocyte-colony Stimulating Factor (G-CSF) Receptor Signaling Pathways ,Neutrophil elastase (ELANE) – Genetics and Pathophysiology[books.google.com]
  • The purpose of this project was to improve the understanding of the clinical course and the pathophysiology of autosomal recessive SCN.[openarchive.ki.se]
  • The pathophysiology of mitochondrial death. Science 305, 626–629 (2004). 18. Newmeyer, D.D. & Ferguson-Miller, S. Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112, 481–490 (2003). 19. Maianski, N.A. et al.[doi.org]
  • Severe congenital neutropenia: inheritance and pathophysiology. Curr. Opin. Hemat. 14: 22-28, 2007. Note: Erratum: Curr. Opin. Hemat. 14: 181 only, 2007. [PubMed: 17133096] [Full Text: ] Smith, B. N., Ancliff, P.[ncbi.nlm.nih.gov]
  • Severe chronic neutropenia: pathophysiology and therapy Semin Hematol 1997 34 : 267–278 4 Zeidler C, Welte K, Barak Y et al.[nature.com]

Prevention

  • Comprehensive and up-to-date, Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Practice offers an integrated survey of the role of HGFs in treating and preventing anemia, neutropenia, and thrombocytopenia in patients with malignant[books.google.com]
  • She has an active role in Public Education to minimize and control inherited blood diseases, environmental pollution and cancer prevention. Email: [email protected] PDF HTML[omicsonline.org]
  • The goal is to bring the neutrophil count to normal consistently to prevent infections. Bone marrow transplantation: Bone marrow transplantation can be curative. This is usually considered for people with poor response to G-CSF.[verywell.com]
  • The in vitro efficiency of antibacterial peptides is well documented and we therefore propose an in vivo role of antibacterial peptides in the prevention of bacterial infections in man generally and in patients with SCN in particular.[openarchive.ki.se]
  • Patient was treated with the granulocyte-colony stimulating factor (G-CSF) as prevention of infectious manifestations along with appropriate measure to curb secondary complications.[doi.org]

References

Article

  1. Skokowa J, Germeschausen M, Zeidler C, Welte K. Severe congenital neutropenia: inheritance and pathophysiology. Curr Opin Hematol. 2007;14(1):22-28.
  2. Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood. 2007;109(5):1817-1824.
  3. Touw IP, Bontenbal M. Granulocyte colony-stimulating factor: key (f)actor or innocent bystander in the development of secondary myeloid malignancy. J Natl Cancer Inst. 2007;99(3):183-186.
  4. Ward AC. The role of the granulocyte colony-stimulating factor receptor (G-CSF-R) in disease. Front Biosci. 2007;12:608-618.
  5. Germeshausen M, Ballmaier M, Welte K. Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: results of a long-term survey. Blood. 2007;109(1):93-99.
  6. Berliner N. Lessons from congenital neutropenia: 50 years of progress in understanding myelopoiesis. Blood. 2008;111(12):5427-5432.
  7. Carlsson G, Melin M, Dahl N, et al. Kostmann syndrome or infantile genetic agranulocytosis, part two: understanding the underlying genetic defects in severe congenital neutropenia. Acta Paediatr. 2007;96(6):813-819.
  8. Rosenberg PS, Alter BP, Link DC, et al. Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia. Br J Haematol. 2008;140(2):210-213.
  9. Boztug K, Ding XQ, Hartmann H, et al. HAX1 mutations causing severe congenital neuropenia (sic) and neurological disease lead to cerebral microstructural abnormalities documented by quantitative MRI. Am J Med Genet A. 2010;152A(12):3157-3163.
  10. Welte K, Boxer L. Severe chronic neutropenia: pathophysiology and therapy. Semin Hematol. 1997;34(4):267-278.
  11. 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;144(4):459-467.
  12. 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.

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Last updated: 2019-07-11 21:36