Genetic and Phenotypically Heterogeneity of Patients with Congenital Neutropenia.

Blood ◽  
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.

scholarly journals Impaired myelopoiesis in congenital neutropenia: insights into clonal and malignant hematopoiesis

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 514-520
Author(s):  
Julia T. Warren ◽  
Daniel C. Link
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Bone Marrow Failure ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Hematopoietic Stem ◽  
Myeloid Malignancy ◽  
Bone Marrow Failure Syndromes ◽  
Increased Risk ◽  
Shwachman Diamond Syndrome

Abstract A common feature of both congenital and acquired forms of bone marrow failure is an increased risk of developing acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Indeed, the development of MDS or AML is now the major cause of mortality in patients with congenital neutropenia. Thus, there is a pressing clinical need to develop better strategies to prevent, diagnose early, and treat MDS/AML in patients with congenital neutropenia and other bone marrow failure syndromes. Here, we discuss recent data characterizing clonal hematopoiesis and progression to myeloid malignancy in congenital neutropenia, focusing on severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome. We summarize recent studies showing excellent outcomes after allogenic hematopoietic stem cell transplantation for many (but not all) patients with congenital neutropenia, including patients with SCN with active myeloid malignancy who underwent transplantation. Finally, we discuss how these new data inform the current clinical management of patients with congenital neutropenia.

scholarly journals Novel HAX1 Gene Mutation in a Vietnamese Boy with Severe Congenital Neutropenia

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Tham Thi Tran ◽  
Quang Van Vu ◽  
Taizo Wada ◽  
Akihiro Yachie ◽  
Huong Le Thi Minh ◽  
...  
Keyword(s):  
Early Onset ◽  
Bacterial Infections ◽  
Complete Blood Count ◽  
Hereditary Diseases ◽  
Severe Neutropenia ◽  
Sequencing Analysis ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Direct Dna Sequencing ◽  
Life Threatening

Severe congenital neutropenia (SCN) is a rare disease that involves a heterogeneous group of hereditary diseases. Mutations in the HAX1 gene can cause an autosomal recessive form of SCN-characterized low blood neutrophil count from birth, increased susceptibility to recurrent and life-threatening infections, and preleukemia predisposition. A 7-year-old boy was admitted due to life-threatening infections, mental retardation, and severe neutropenia. He had early-onset bacterial infections, and his serial complete blood count showed persistent severe neutropenia. One older sister and one older brother of the patient died at the age of 6 months and 5 months, respectively, because of severe infection. Bone marrow analysis revealed a maturation arrest at the promyelocyte/myelocyte stage with few mature neutrophils. In direct DNA sequencing analysis, we found a novel homozygous frameshift mutation (c.423_424insG, p.Gly143fs) in the HAX1 gene, confirming the diagnosis of SCN. The patient was successfully treated with granulocyte colony-stimulating factor (G-CSF) and antibiotics. A child with early-onset recurrent infections and neutropenia should be considered to be affected with SCN. Genetic analysis is useful to confirm diagnosis. Timely diagnosis and suitable treatment with G-CSF and antibiotics are important to prevent further complication.

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

2006 ◽  
Vol 26 (2) ◽  
pp. 153-154
Author(s):  
Ümit Çelik ◽  
Derya Alabaz ◽  
Emine Kocabas ◽  
Goksel Leblebisatan
Keyword(s):  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Kostmann Syndrome

Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2317-2322 ◽  
Author(s):  
David C. Dale ◽  
Richard E. Person ◽  
Audrey Anna Bolyard ◽  
Andrew G. Aprikyan ◽  
Cindy Bos ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Rna Splicing ◽  
Bacterial Infections ◽  
Autosomal Dominant ◽  
Mononuclear Cells ◽  
Mutational Analysis ◽  
Congenital Neutropenia ◽  
Gene Encoding ◽  
Cyclic Neutropenia ◽  
Shwachman Diamond Syndrome

Abstract Congenital neutropenia and cyclic neutropenia are disorders of neutrophil production predisposing patients to recurrent bacterial infections. Recently the locus for autosomal dominant cyclic neutropenia was mapped to chromosome 19p13.3, and this disease is now attributable to mutations of the gene encoding neutrophil elastase (the ELA2 gene). The authors hypothesized that congenital neutropenia is also due to mutations of neutrophil elastase. Patients with congenital neutropenia, cyclic neutropenia, or Shwachman-Diamond syndrome were referred to the Severe Chronic Neutropenia International Registry. Referring physicians provided hematologic and clinical data. Mutational analysis was performed by sequencing polymerase chain reaction (PCR)-amplified genomic DNA for each of the 5 exons of the neutrophil ELA2 gene and 20 bases of the flanking regions. RNA from bone marrow mononuclear cells was used to determine if the affected patients expressed both the normal and the abnormal transcript. Twenty-two of 25 patients with congenital neutropenia had 18 different heterozygous mutations. Four of 4 patients with cyclic neutropenia and 0 of 3 patients with Shwachman-Diamond syndrome had mutations. For 5 patients with congenital neutropenia having mutations predicted to alter RNA splicing or transcript structure, reverse transcriptase-PCR showed expression of both normal and abnormal transcripts. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. This study indicates that mutations of the gene encoding neutrophil elastase are probably the most common cause for severe congenital neutropenia as well as the cause for sporadic and autosomal dominant cyclic neutropenia.

The Incidence of Leukemia and Mortality from Sepsis in Patients with Severe Congenital Neutropenia Receiving Long-Term G-CSF Therapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 669-669 ◽  
Author(s):  
Philip S. Rosenberg ◽  
Blanche P. Alter ◽  
Audrey A. Bolyard ◽  
Mary A. Bonilla ◽  
Laurence A. Boxer ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Intermediate Group ◽  
Cell Counts ◽  
Secondary Analyses ◽  
Shwachman Diamond Syndrome ◽  
Pre Treatment ◽  
Stimulating Factor

Abstract Background: In patients with severe congenital neutropenia (SCN), mortality from sepsis is reduced by treatment with granulocyte colony-stimulating factor (G-CSF), but myelodsyplastic syndrome and acute myeloid leukemia (MDS/AML) have been reported in treated and untreated patients. Methods: We studied 374 patients with SCN and 29 patients with Shwachman-Diamond Syndrome (SDS) on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. Results: In SCN, mortality from sepsis was stable at 0.9%/year. The hazard of MDS/AML increased significantly over time, from 2.9%/year after 6 years to 8.0%/year after 12 years on G-CSF. After 10 years, the cumulative incidence was 8% for mortality from sepsis and 21% for MDS/AML. The hazard of MDS/AML increased with the dose of G-CSF. Twenty-nine percent of SCN patients received more than the median dose of G-CSF (≥8 μg/kg/day), but achieved less than the median absolute neutrophil count (ANC) response (ANC <2188 cells/μL at 6–18 months). In these less responsive patients, the cumulative incidence of adverse events was highest: after 10 years, 40% developed MDS/AML and 14% died of sepsis, compared to 11% and 4%, respectively, of more responsive patients whose ANC was above the median on doses of G-CSF below the median. An intermediate group achieved an ANC above the median on doses of G-CSF above the median; among them, the 10 year cumulative incidence was 15% for MDS/AML and 3% for mortality from sepsis. In secondary analyses, we found that pre-treatment blood cell counts could not predict the subsequent clinical outcome. Furthermore, on therapy, patients who were less responsive vis-à-vis their neutrophil counts had similar increases in eosinophils, basophils, monocytes, and lymphocytes, and similar decreases in platelets, as other patients maintained on ≥8 μg/kg/day. Consistent with the SCN results, in SDS patients, the limited available data do not suggest that G-CSF therapy is a risk factor for MDS/AML in SDS. Conclusions: The risk of MDS/AML was similarly low in all patients who achieved an ANC above the median on any dose of G-CSF. It appears that G-CSF has reduced mortality from sepsis, and revealed the underlying leukemic predisposition of SCN.

The Association Between STAT5a Activation, LEF-1 Down Regulation and Leukemic Transformation in Patients with Severe Congenital Neutropenia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 316-316
Author(s):  
Kshama Gupta ◽  
Julia Skokowa ◽  
Karl Welte
Keyword(s):  
Malignant Transformation ◽  
Upstream Region ◽  
Dependent Manner ◽  
Severe Congenital Neutropenia ◽  
Healthy Individuals ◽  
Granulocytic Differentiation ◽  
Congenital Neutropenia ◽  
Down Regulation ◽  
Increased Risk ◽  
Cd34 Cells

Abstract Congenital hematological disorders are excellent models for investigating the regulation of hematopoiesis in humans. For instance, Severe Congenital Neutropenia (CN) is a heterogeneous syndrome characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with no mature neutrophils in the peripheral blood. Even though G-CSF treatment results in increased neutrophil numbers in more than 90 % of CN patients, G-CSF-dependent granulocytic differentiation is severely affected in these patients. CN patients are found to be at increased risk of developing acute myeloid leukemia or myelodysplastic syndrome (AML/MDS) (cumulative incidence ~ 20 %). Since AML/MDS are not observed in cyclic or idiopathic neutropenia patients treated with G-CSF, an underlying defect down stream of G-CSF signaling rather than G-CSF therapy per se predisposes to malignant transformation in CN. STAT5 is activated by G-CSF signaling pathway and has also been found to be activated in AML. Recently we found that downregulation of LEF-1 transcription factor and its target gene C/EBPa are a common pathologic mechanism for CN. Therefore, we investigated the effects of G-CSF on the phosphorylation status of STAT5a in CN and whether it leads to the down modulation of LEF-1 expression and functions. Indeed, we detected elevated phosphoSTAT5 expression in CD34+ cells from CN patients before G-CSF stimulation in vitro, as compared to these cells from healthy individuals. Moreover, treatment with G-CSF resulted in a significantly higher phosphorylation of STAT5a in CN. Intriguingly, levels of phosphoSTAT5 in myeloid blast cells from one CN patient who developed AML was even higher and was in line with undetectable LEF-1 protein expression. Transduction of constitutive active STAT5a (STAT5a 1*6) in CD34+ cells from healthy individuals resulted in significant downregulation of LEF1 levels in a dose dependent manner. A screen of 10 kb upstream region of LEF1 gene revealed two putative STAT5 binding sites (−3891bp to −3909bp and −3714bp to −3732bp) and the specificity of this binding was confirmed in the nuclear extracts of CD34+ cells by chromatin immunoprecipitation assay. We found enhanced and prolonged STAT5a binding to the LEF-1 promoter in G-CSF treated CD34+ cells from CN patients, as compared to healthy individuals. Additionally, transfection of CD34+ cells with LEF-1 cDNA resulted in elevation of LEF-1 promoter activity, which suggests a strong LEF-1 autoregulation. Co-transfection with STAT5a 1*6 significantly disrupted LEF-1- dependent activation of LEF-1 promoter. Moreover STAT5a 1*6 severely abrogated the LEF-1 dependent regulation of C/EBPα gene promoter. Taken together phosphorylation of STAT5 is upregulated in hematopoietic progenitors from CN patients which lead to subsequent down regulation of LEF-1. These downstream effects of activated STAT5a may contribute to the malignant transformation of myelopoiesis in CN.

scholarly journals Failure in Implant Rehabilitation in a Patient With Severe Congenital Neutropenia (Kostmann Syndrome)

2012 ◽  
Vol 70 (4) ◽  
pp. e260-e263 ◽  
Author(s):  
Marian Marín-Berná ◽  
Rocío-Trinidad Velázquez-Cayón ◽  
Daniel Torres-Lagares ◽  
Pilar Hita-Iglesias ◽  
Kahina Bouferrache ◽  
...  
Keyword(s):  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Kostmann Syndrome

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

Blood ◽  
1991 ◽  
Vol 77 (9) ◽  
pp. 1919-1922 ◽  
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

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.

scholarly journals Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia

Blood ◽  
1990 ◽  
Vol 75 (5) ◽  
pp. 1056-1063 ◽  
Author(s):  
K Welte ◽  
C Zeidler ◽  
A Reiter ◽  
W Muller ◽  
E Odenwald ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Severe Neutropenia ◽  
Colony Stimulating Factor ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Macrophage Colony Stimulating Factor ◽  
The Absolute ◽  
Macrophage Colony ◽  
Neutrophil Response ◽  
Stimulating Factor

Abstract Severe congenital neutropenia (SCN) is a disorder of myelopoiesis characterized by severe neutropenia secondary to a maturational arrest at the level of promyelocytes. We treated five patients with SCN with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for 42 days and subsequently, between 1 and 3 months later, with rhG-CSF for 142 days. The objective was to evaluate the safety and ability of these factors to elicit a neutrophil response. rhGM-CSF was administered at a dose of 3 to 30 micrograms/kg/d (30 to 60 minutes, intravenously). In all patients, a specific, dose-dependent increase in the absolute granulocyte counts was observed. However, in four patients this increase was due to an increase in eosinophils, and in only one patient it was due to an increase in the absolute neutrophil counts (ANC). Subsequently, all patients received rhG-CSF at a dose of 3 to 15 micrograms/kg/d subcutaneously. In contrast to rhGM-CSF treatment, all five patients responded to rhG-CSF during the first 6 weeks of treatment with an increase in the ANC to above 1,000/microL. The level of ANC could be maintained during maintenance treatment. In one patient, the increase in ANC was associated with an improvement of a severe pneumonitis caused by Peptostreptococcus and resistant to antibiotic treatment. No severe bacterial infections occurred in any of the patients during CSF treatment. All patients tolerated rhGM-CSF and rhG-CSF treatment without severe side effects. These results demonstrate the beneficial effect of rhG-CSF in SCN patients.

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

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2947-2953 ◽  
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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