Recurrent epididymo-orchitis in an 8-year-old child with Kostmann syndrome (severe congenital neutropenia)

Severe congenital neutropenia (SCN), also known as Kostmann Syndrome, is characterized by a maturation arrest of myelopoiesis at the level of promyelocytes with absence of neutrophils in bone marrow (BM) and blood. Hypotheses of the pathophysiology of SCN include (1) defective production of granulocyte colony-stimulating factor (G-CSF), and/or (2) defective response to G-CSF. To exclude defective G-CSF production we tested sera from patients with SCN for the presence of G-CSF using Western blot analysis and NFS-60 proliferation assay. Using these assays we were able to detect increased G-CSF serum levels in SCN patients (150 to 910 pg/mL) as compared with normal controls (between undetectable and 100 pg/mL). These results suggest that patients with SCN have no defect in G-CSF production but a defective response of neutrophil precursors to endogenous G-CSF.

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Differential expression and regulation of GTPases (RhoA and Rac2) and GDIs (LyGDI and RhoGDI) in neutrophils from patients with severe congenital neutropenia

Blood ◽

10.1182/blood.v95.9.2947.009k10_2947_2953 ◽

2000 ◽

Vol 95 (9) ◽

pp. 2947-2953 ◽

Cited By ~ 23

Author(s):

Brigitte Kasper ◽

Nicola Tidow ◽

Dirk Grothues ◽

Karl Welte

Keyword(s):

Superoxide Anion ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Severe Congenital Neutropenia ◽

Congenital Neutropenia ◽

Maturation Arrest ◽

Guanosine Diphosphate ◽

Kostmann Syndrome ◽

Gdp Dissociation Inhibitor ◽

Stimulating Factor

Severe congenital neutropenia (SCN) or Kostmann syndrome is a disorder of myelopoiesis characterized by a maturation arrest at the stage of promyelocytes or myelocytes in bone marrow and absolute neutrophil counts less than 200/μL in peripheral blood. Treatment of these patients with granulocyte colony-stimulating factor (G-CSF) leads to a significant increase in circulating neutrophils and a reduction in infection-related events in more than 95% of the patients. To date, little is known regarding the underlying pathomechanism of SCN. G-CSF-induced neutrophils of patients with SCN are functionally defective (eg, chemotaxis, superoxide anion generation, Ca++mobilization). Two guanosine triphosphatases (GTPases), Rac2 and RhoA, were described to be involved in many neutrophil functions. The expression of these GTPases and their regulation in patients' neutrophils were of interest. This study determined that the guanosine diphosphate (GDP)-dissociation inhibitor RhoGDI is overexpressed at the protein level in patients' neutrophils and that overexpression is a result of G-CSF treatment. RhoA and LyGDI are expressed at similar levels, whereas Rac2 shows a decreased expression. In addition, association of Rac2 and RhoGDI or LyGDI is abrogated or not detectable based on the low Rac2 expression in patients' neutrophils.

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Increased serum levels of granulocyte colony-stimulating factor in patients with severe congenital neutropenia

Blood ◽

10.1182/blood.v77.9.1919.1919 ◽

1991 ◽

Vol 77 (9) ◽

pp. 1919-1922 ◽

Cited By ~ 89

Author(s):

K Mempel ◽

T Pietsch ◽

T Menzel ◽

C Zeidler ◽

K Welte

Keyword(s):

Serum Levels ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Severe Congenital Neutropenia ◽

Congenital Neutropenia ◽

Maturation Arrest ◽

Kostmann Syndrome ◽

Stimulating Factor ◽

Normal Controls ◽

Csf Production

Abstract Severe congenital neutropenia (SCN), also known as Kostmann Syndrome, is characterized by a maturation arrest of myelopoiesis at the level of promyelocytes with absence of neutrophils in bone marrow (BM) and blood. Hypotheses of the pathophysiology of SCN include (1) defective production of granulocyte colony-stimulating factor (G-CSF), and/or (2) defective response to G-CSF. To exclude defective G-CSF production we tested sera from patients with SCN for the presence of G-CSF using Western blot analysis and NFS-60 proliferation assay. Using these assays we were able to detect increased G-CSF serum levels in SCN patients (150 to 910 pg/mL) as compared with normal controls (between undetectable and 100 pg/mL). These results suggest that patients with SCN have no defect in G-CSF production but a defective response of neutrophil precursors to endogenous G-CSF.

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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 ◽

10.1182/blood-2003-04-1011 ◽

2004 ◽

Vol 103 (9) ◽

pp. 3355-3361 ◽

Cited By ~ 67

Author(s):

Göran Carlsson ◽

Andrew A. G. Aprikyan ◽

Ramin Tehranchi ◽

David C. Dale ◽

Anna Porwit ◽

...

Keyword(s):

Bone Marrow ◽

Cytochrome C ◽

Progenitor Cells ◽

B Cell Lymphoma ◽

Severe Congenital Neutropenia ◽

Congenital Neutropenia ◽

Cytochrome C Release ◽

Myeloid Progenitor ◽

Kostmann Syndrome ◽

Myeloid Progenitor Cells

Abstract Kostmann syndrome, or severe congenital neutropenia (SCN), is an autosomal recessive disorder of neutrophil production. To investigate the potential role of apoptosis in SCN, bone marrow aspirates and biopsies were obtained from 4 patients belonging to the kindred originally described by Kostmann and 1 patient with SCN of unknown inheritance. An elevated degree of apoptosis was observed in the bone marrow of these patients, and a selective decrease in B-cell lymphoma-2 (Bcl-2) expression was seen in myeloid progenitor cells. Furthermore, in vitro apoptosis of bone marrow-derived Kostmann progenitor cells was increased, and mitochondrial release of cytochrome c was detected in CD34+ and CD33+ progenitors from patients, but not in controls. Administration of granulocyte colony-stimulating factor (G-CSF) restored Bcl-2 expression and improved survival of myeloid progenitor cells. In addition, cytochrome c release was partially reversed upon incubation of progenitor cells with G-CSF. In sum, these studies establish a role for mitochondria-dependent apoptosis in the pathogenesis of Kostmann syndrome and yield a tentative explanation for the beneficial effect of growth factor administration in these patients. (Blood. 2004;103:3355-3361)

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Kostmann syndrome and severe congenital neutropenia

Seminars in Hematology ◽

10.1053/shem.2002.31913 ◽

2002 ◽

Vol 39 (2) ◽

pp. 82-88 ◽

Cited By ~ 68

Author(s):

Cornelia Zeidler ◽

Karl Welte

Keyword(s):

Severe Congenital Neutropenia ◽

Congenital Neutropenia ◽

Kostmann Syndrome

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Kostmann syndrome or infantile genetic agranulocytosis, part two: understanding the underlying genetic defects in severe congenital neutropenia

Acta Paediatrica ◽

10.1111/j.1651-2227.2007.00274.x ◽

2007 ◽

Vol 96 (6) ◽

pp. 813-819 ◽

Cited By ~ 44

Author(s):

Göran Carlsson ◽

Malin Melin ◽

Niklas Dahl ◽

Kim Göransdotter Ramme ◽

Magnus Nordenskjöld ◽

...

Keyword(s):

Genetic Defects ◽

Severe Congenital Neutropenia ◽

Congenital Neutropenia ◽

Kostmann Syndrome

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Usefulness of Bronchoalveolar Lavage for the Diagnosis and Treatment of Refractory Pneumonia in a Patient with Kostmann Syndrome, a Severe Congenital Neutropenia

Journal of Nippon Medical School ◽

10.1272/jnms.68.340 ◽

2001 ◽

Vol 68 (4) ◽

pp. 340-343 ◽

Cited By ~ 1

Author(s):

Takashi Chiba ◽

Jun Hayakawa ◽

Takahiro Ueda ◽

Makoto Migita ◽

Miho Maeda ◽

...

Keyword(s):

Bronchoalveolar Lavage ◽

Diagnosis And Treatment ◽

Severe Congenital Neutropenia ◽

Congenital Neutropenia ◽

Kostmann Syndrome

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Kostmann Syndrome With Neurological Abnormalities: A Case Report and Literature Review

Frontiers in Pediatrics ◽

10.3389/fped.2020.586859 ◽

2020 ◽

Vol 8 ◽

Author(s):

Baiyu Lyu ◽

Wei Lyu ◽

Xiaoying Zhang

Keyword(s):

Gene Mutations ◽

Severe Neutropenia ◽

Severe Congenital Neutropenia ◽

Congenital Neutropenia ◽

Hematopoietic Stem ◽

Case Presentation ◽

Neurological Abnormalities ◽

Kostmann Syndrome ◽

History Of

Background: Severe congenital neutropenia (SCN), also known as Kostmann syndrome, is a rare heterogeneous group of diseases characterized by arrested neutrophil maturation in the bone marrow.Case Presentation: We report a case of Kostmann syndrome and review previously reported SCN cases with neurological abnormalities. A 10-year-old boy had a history of recurrent, once a month, infection starting at 6 months of age. He had neutropenia for more than 9 years, as well as intellectual disability. He was homozygous for the exon 3 c.430dupG mutation of the HAX1 gene NM-006118. After treatment of antibiotics and G-CSF, his symtoms were relieved and was 3 months free of infection. The search revealed 29 articles related to Kostmann syndrome caused by HAX1 gene mutation; they were screened, and the main clinical features of 13 cases of Kostmann syndrome with neurological abnormalities were summarized and analyzed.Conclusions: Kostmann syndrome has three main characteristics: severe neutropenia (<0.2 × 109/L), maturation arrest of granulopoiesis at the promyelocyte stage, and death due to infections. HAX1 gene mutations affecting both isoforms A and B are associated with additional neurological symptoms. G-CSF can improve and maintain neutrophil counts, and improve prognosis and quality of life. At present, hematopoietic stem cell transplantation is the only cure.

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Genetic and Phenotypically Heterogeneity of Patients with Congenital Neutropenia.

Blood ◽

10.1182/blood.v106.11.95.95 ◽

2005 ◽

Vol 106 (11) ◽

pp. 95-95

Author(s):

Cornelia Zeidler ◽

Beate Schwinzer ◽

Audrey A. Bolyard ◽

Gusal Pracht ◽

Blanche P. Alter ◽

...

Keyword(s):

Bacterial Infections ◽

Early Stage ◽

Barth Syndrome ◽

Severe Congenital Neutropenia ◽

Congenital Neutropenia ◽

Whim Syndrome ◽

Increased Risk ◽

Kostmann Syndrome ◽

Shwachman Diamond Syndrome

Abstract Severe congenital neutropenia (CN) is a general term for a group of disorders characterized by extremely low blood neutrophil counts (ANC < 0.5 x 109 ), early stage maturation arrest of myelopoiesis, and recurrent bacterial infections. More than 90% of CN patients respond to daily G-CSF treatment with a sustained neutrophil increase associated with a significant reduction of infections and improved quality of life. However, prolonged survival unmasks an increased risk of leukemic transformation in some, but not all, subcategories of CN patients. The Severe Chronic Neutropenia International Registry (SCNIR) has collected longitudinal data on on more than 400 patients with various causes of CN. This unique resource allows classification of different subtypes of CN and estimation of the relative frequency of these conditions. Our new classification scheme is as follows: By inheritance - autosomal dominant severe congenital neutropenia (ADCN), autosomal recessive (ARCN, Kostmann syndrome), sporadic CN. By genetic aberrations - ELA2 related CN, SBDS related CN-(Shwachman-Diamond syndrome), G 4.5 on Xq28related neutropenia (Barth syndrome), CXCR4 related neutropenia (myelokathexis and WHIM syndrome). By clinical phenotype - associated symptoms (e. g. metabolic disorders, such as Shwachman-Diamond syndrome, glycogen storage disease 1b, Barth syndrome), G-CSF responsive or non-responsive CN, with or without G-CSF receptor mutations, with or without osteoporosis, or dysplastic features (e. g. organ abnormalities). By ethnic origin - e.g. CN in consanguineous Kurdish families, recessive neutropenia in Swedish family (Kostmann syndrome). Recent research and the work of the SCNIR now permit a much improved classification of CN. The identification of subtypes of CN, their distinctive risks of malignant transformation, and their responses to treatment has contributed substantially to our general understanding of the problem of neutropenia. This knowledge also now allows clinicians to give patients and families much improved prognostic information and better guidelines for therapy.

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