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]

  Age Patients are diagnosed shortly after birth with recurrent bacterial infections within the first few months of life. [emedicine.com]

• 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]

• Recurrent Oral Ulceration

  Congenital forms of severe chronic neutropenia: Characterized by fevers, recurrent pneumonia, ear infections, gingivitis, and stomatitis. Periodontitis is often present. Recurrent oral ulcerations are common. [accessanesthesiology.mhmedical.com]

• Psychomotor Retardation

  Some patients also have neurological manifestations (e.g., psychomotor retardation and seizures), which result from mutations of HAX1 isoforms 1 and 5. [medical-dictionary.thefreedictionary.com]

• Neurologic Manifestation

  Some patients also have neurological manifestations (e.g., psychomotor retardation and seizures), which result from mutations of HAX1 isoforms 1 and 5. [medical-dictionary.thefreedictionary.com]

  Griscelli syndrome type 3, characterized by hypomelanosis with no immunologic or neurologic manifestations, is caused by mutation in the melanophilin (MLPH gene). [primaryimmune.org]

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.

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]

Without special treatment, patients died before 2-3 years. [m.iliveok.com]

Treatment. Treatment is aimed at immediate withdrawal of the drug or chemical causing the disorder, and control of infection. In most cases control can be achieved by the administration of antibiotics. [medical-dictionary.thefreedictionary.com]

Prior to G-CSF treatment, some patients developed aggressive periodontitis already at preschool age. The dental status improved on G-CSF treatment, but the patients still suffer from periodontal disease. [openarchive.ki.se]

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 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]

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]

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]

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

Neutropenia is very common in preterm infants, and certainly very few of these will have Kostmann syndrome as the etiology. [nature.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]

Frequency International Epidemiological data are limited given the overlapping case definitions of congenital neutropenia and few patient registries. [emedicine.com]

[…] 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: http://Insights.ovid.com/pubmed?pmid=17133096] Smith, B. [ncbi.nlm.nih.gov]

She has an active role in Public Education to minimize and control inherited blood diseases, environmental pollution and cancer prevention. Email: [email protected] [longdom.org]

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]

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]

If it achieves funding, they will provide "adequate remuneration for the provision of data and samples and invite you for co-authorship of any subsequent research publications." 11 JAN 2015 Science Patient compliance rates for SIT therapy to prevent peri-implantitis [efp.org]

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]

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.