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David C Dale - One of the best experts on this subject based on the ideXlab platform.
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long term effects of g csf therapy in Cyclic Neutropenia
The New England Journal of Medicine, 2017Co-Authors: David C Dale, Audrey Anna Bolyard, Peter E Newburger, Mary Ann Bonilla, Daniel C Link, Laurence A Boxer, Tracy M Marrero, Vahagn Makaryan, Akiko Shimamura, Charles SpiekermanAbstract:The use of granulocyte colony-stimulating factor in patients with Cyclic Neutropenia is associated with long-term survival and a decreased risk of serious infections and sepsis.
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application of spectral density periodogram analysis to serial neutrophil counts to diagnose Cyclic Neutropenia
Blood, 2015Co-Authors: Nicholas J Dobbins, Audrey Anna Bolyard, Robert T Chang, Julian Self, Gabriel P Langlois, Michael C Mackey, David C DaleAbstract:Background: Cyclic Neutropenia is characterized by oscillatory fluctuations in blood neutrophil counts, usually with nadirs 9 /L at approximately 3 week intervals. Visual inspection of graphs of serial counts is usually the basis for diagnosis. Detection of mutations in ELANE is helpful but not diagnostic because of the overlap of the specific mutation patterns with those associated with severe congenital Neutropenia. Making the correct diagnosis of Cyclic Neutropenia is important because these patients are not thought to be at risk of developing myelodysplasia or acute myeloid leukemia (MDS/AML). In contrast, patients with severe congenital Neutropenia, whose counts are usually lower, are at risk of developing MDS/AML. Methods: We have implemented a website application for easy and direct data entry of serial blood counts to detect statistically significant periodicities using the Lomb periodogram. Physicians, nurses, other healthcare providers or patients can directly enter the blood count data for analysis on a website to allow immediate visualization of the serial counts and calculation of the probability of statistically significant cycling and the period, i.e., length of the cycle. Results: We have analyzed the counts from 42 patients (21 ELANE positive, 8 ELANE negative, 13 ELANE unknown) enrolled in the Severe Chronic Neutropenia International Registry with a clinical diagnosis of Cyclic Neutropenia to determine the accuracy of clinical diagnoses based on this form of statistical analysis. Our preliminary results showed that it is easy to learn how to use this program. We estimate that at least 20 counts obtained at 2-3 day intervals for 6 weeks are the minimum needed to detect Cyclic Neutropenia on a statistically sound basis, while 20-40 counts obtained at 2-3 day intervals over an 8-10 week period was more likely to yield statistical and clinical certainty about the diagnosis. The figure below shows readouts for the periodogram analysis for one patient. It shows the influence of 17 counts versus 31 counts for a patient with the clinical diagnosis of Cyclic Neutropenia and a mutation in ELANE . The confidence intervals (95%) and (99%) are exceeded for the series of 31 counts but not for the shorter series. The peak, approximate cycle length is 22 days for this series of counts. As of yet, we do not have the sufficient daily count data to determine if more frequent testing (e.g. daily testing) is better than testing every 2-3 days. We are currently testing the patterns of neutrophil fluctuations in patients on G-CSF to see if Cyclic Neutropenia can be diagnosed in patients that are on (or during) treatment. We have learned that many patients with the clinical diagnosis of CyN do not have sufficient serial blood cell count data to confirm this diagnosis on a statistical basis. Conclusion: We have developed a simple method for making periodogram analysis much more widely available to clinicians and patients on a world-wide basis. Statistical analysis of carefully collected serial data will help to secure the diagnosis of Cyclic Neutropenia and provide patients with important prognostic information. Disclosures Dale: Amgen: Consultancy, Honoraria, Research Funding.
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Application of Spectral Density/Periodogram Analysis to Serial Neutrophil Counts to Diagnose Cyclic Neutropenia
Blood, 2015Co-Authors: Nicholas J Dobbins, Audrey Anna Bolyard, Robert T Chang, Julian Self, Gabriel P Langlois, Michael C Mackey, David C DaleAbstract:Background: Cyclic Neutropenia is characterized by oscillatory fluctuations in blood neutrophil counts, usually with nadirs 9 /L at approximately 3 week intervals. Visual inspection of graphs of serial counts is usually the basis for diagnosis. Detection of mutations in ELANE is helpful but not diagnostic because of the overlap of the specific mutation patterns with those associated with severe congenital Neutropenia. Making the correct diagnosis of Cyclic Neutropenia is important because these patients are not thought to be at risk of developing myelodysplasia or acute myeloid leukemia (MDS/AML). In contrast, patients with severe congenital Neutropenia, whose counts are usually lower, are at risk of developing MDS/AML. Methods: We have implemented a website application for easy and direct data entry of serial blood counts to detect statistically significant periodicities using the Lomb periodogram. Physicians, nurses, other healthcare providers or patients can directly enter the blood count data for analysis on a website to allow immediate visualization of the serial counts and calculation of the probability of statistically significant cycling and the period, i.e., length of the cycle. Results: We have analyzed the counts from 42 patients (21 ELANE positive, 8 ELANE negative, 13 ELANE unknown) enrolled in the Severe Chronic Neutropenia International Registry with a clinical diagnosis of Cyclic Neutropenia to determine the accuracy of clinical diagnoses based on this form of statistical analysis. Our preliminary results showed that it is easy to learn how to use this program. We estimate that at least 20 counts obtained at 2-3 day intervals for 6 weeks are the minimum needed to detect Cyclic Neutropenia on a statistically sound basis, while 20-40 counts obtained at 2-3 day intervals over an 8-10 week period was more likely to yield statistical and clinical certainty about the diagnosis. The figure below shows readouts for the periodogram analysis for one patient. It shows the influence of 17 counts versus 31 counts for a patient with the clinical diagnosis of Cyclic Neutropenia and a mutation in ELANE . The confidence intervals (95%) and (99%) are exceeded for the series of 31 counts but not for the shorter series. The peak, approximate cycle length is 22 days for this series of counts. As of yet, we do not have the sufficient daily count data to determine if more frequent testing (e.g. daily testing) is better than testing every 2-3 days. We are currently testing the patterns of neutrophil fluctuations in patients on G-CSF to see if Cyclic Neutropenia can be diagnosed in patients that are on (or during) treatment. We have learned that many patients with the clinical diagnosis of CyN do not have sufficient serial blood cell count data to confirm this diagnosis on a statistical basis. Conclusion: We have developed a simple method for making periodogram analysis much more widely available to clinicians and patients on a world-wide basis. Statistical analysis of carefully collected serial data will help to secure the diagnosis of Cyclic Neutropenia and provide patients with important prognostic information. Disclosures Dale: Amgen: Consultancy, Honoraria, Research Funding.
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Cyclic Neutropenia is not associated with transformation to mds and aml
Blood, 2007Co-Authors: David C Dale, Audrey Anna Bolyard, Peter E Newburger, Mary Ann Bonilla, George Kannourakis, Yigal Dror, Daniel C Link, Blanche P Alter, Philip S Rosenberg, Laurence A BoxerAbstract:Cyclic Neutropenia is a rare hematological disorder characterized by recurrent severe Neutropenia, mouth ulcers, fever and infections beginning soon after birth. The diagnosis depends primarily on observing regular periods of severe Neutropenia (neutrophils <500/μL, usually <200/μL) lasting for 2–4 days at approximately 21-day intervals, documented by serial blood counts (a minimum of 2–3 complete blood counts per week for at least six weeks). Severe congenital Neutropenia is a similar, but usually more severe disease. Mutations of the ELA2 gene are regarded as the cause of most cases of both Cyclic Neutropenia and severe congenital Neutropenia. However, only patients with severe congenital Neutropenia, not Cyclic Neutropenia, are thought to be at risk of evolution to MDS/AML. Since its founding in 1994, the Severe Chronic Neutropenia International Registry (SCNIR) has utilized data from previous studies and enrolled patients with Cyclic Neutropenia based on the clinical information from their treating physicians. We reviewed 190 cases of Cyclic Neutropenia (including 30 families) enrolled for 0.5 to 19.9 years, (median 11 years) with a total of 2,035 patient years of observation. 173 of 190 patients were treated with G-CSF (median dose 2.82 mcg/kg/day). We identified three patients who were reported to have developed MDS/AML. Further analysis by three experts from the SCNIR revealed that all three patients lacked sufficient serial blood count data to show well-defined neutrophil cycles prior to G-CSF. Two of the three patients lacked a clinical history of mouth ulcers and fevers consistent with the diagnosis, and the bone marrow evaluation was not consistent with Cyclic Neutropenia in all three cases. One of two patients tested did not have an ELA2 mutation. Thus, using standard criteria for the diagnosis of Cyclic Neutropenia, none of the three patients fully satisfied the criteria for this diagnosis. In addition, previous family studies, reviews of the published literature, and personal experience of the authors have revealed only one case of leukemia. This case of CML emerged in a 35 year-old patient, who was never treated with G-CSF, 31 years after the diagnosis of Cyclic Neutropenia. Based upon the review of these cases, we believe it is extremely important to make the diagnosis of Cyclic Neutropenia by careful analysis of serial blood counts. When the diagnosis is made confidently, it is also important to assure patients that with or without G-CSF treatment, the possibility of evolution to leukemia is unlikely.
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Cyclic Neutropenia Is Not Associated with Transformation to MDS and AML.
Blood, 2007Co-Authors: David C Dale, Audrey Anna Bolyard, Peter E Newburger, Mary Ann Bonilla, George Kannourakis, Yigal Dror, Daniel C Link, Blanche P Alter, Philip S Rosenberg, Laurence A BoxerAbstract:Cyclic Neutropenia is a rare hematological disorder characterized by recurrent severe Neutropenia, mouth ulcers, fever and infections beginning soon after birth. The diagnosis depends primarily on observing regular periods of severe Neutropenia (neutrophils
Audrey Anna Bolyard - One of the best experts on this subject based on the ideXlab platform.
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long term effects of g csf therapy in Cyclic Neutropenia
The New England Journal of Medicine, 2017Co-Authors: David C Dale, Audrey Anna Bolyard, Peter E Newburger, Mary Ann Bonilla, Daniel C Link, Laurence A Boxer, Tracy M Marrero, Vahagn Makaryan, Akiko Shimamura, Charles SpiekermanAbstract:The use of granulocyte colony-stimulating factor in patients with Cyclic Neutropenia is associated with long-term survival and a decreased risk of serious infections and sepsis.
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application of spectral density periodogram analysis to serial neutrophil counts to diagnose Cyclic Neutropenia
Blood, 2015Co-Authors: Nicholas J Dobbins, Audrey Anna Bolyard, Robert T Chang, Julian Self, Gabriel P Langlois, Michael C Mackey, David C DaleAbstract:Background: Cyclic Neutropenia is characterized by oscillatory fluctuations in blood neutrophil counts, usually with nadirs 9 /L at approximately 3 week intervals. Visual inspection of graphs of serial counts is usually the basis for diagnosis. Detection of mutations in ELANE is helpful but not diagnostic because of the overlap of the specific mutation patterns with those associated with severe congenital Neutropenia. Making the correct diagnosis of Cyclic Neutropenia is important because these patients are not thought to be at risk of developing myelodysplasia or acute myeloid leukemia (MDS/AML). In contrast, patients with severe congenital Neutropenia, whose counts are usually lower, are at risk of developing MDS/AML. Methods: We have implemented a website application for easy and direct data entry of serial blood counts to detect statistically significant periodicities using the Lomb periodogram. Physicians, nurses, other healthcare providers or patients can directly enter the blood count data for analysis on a website to allow immediate visualization of the serial counts and calculation of the probability of statistically significant cycling and the period, i.e., length of the cycle. Results: We have analyzed the counts from 42 patients (21 ELANE positive, 8 ELANE negative, 13 ELANE unknown) enrolled in the Severe Chronic Neutropenia International Registry with a clinical diagnosis of Cyclic Neutropenia to determine the accuracy of clinical diagnoses based on this form of statistical analysis. Our preliminary results showed that it is easy to learn how to use this program. We estimate that at least 20 counts obtained at 2-3 day intervals for 6 weeks are the minimum needed to detect Cyclic Neutropenia on a statistically sound basis, while 20-40 counts obtained at 2-3 day intervals over an 8-10 week period was more likely to yield statistical and clinical certainty about the diagnosis. The figure below shows readouts for the periodogram analysis for one patient. It shows the influence of 17 counts versus 31 counts for a patient with the clinical diagnosis of Cyclic Neutropenia and a mutation in ELANE . The confidence intervals (95%) and (99%) are exceeded for the series of 31 counts but not for the shorter series. The peak, approximate cycle length is 22 days for this series of counts. As of yet, we do not have the sufficient daily count data to determine if more frequent testing (e.g. daily testing) is better than testing every 2-3 days. We are currently testing the patterns of neutrophil fluctuations in patients on G-CSF to see if Cyclic Neutropenia can be diagnosed in patients that are on (or during) treatment. We have learned that many patients with the clinical diagnosis of CyN do not have sufficient serial blood cell count data to confirm this diagnosis on a statistical basis. Conclusion: We have developed a simple method for making periodogram analysis much more widely available to clinicians and patients on a world-wide basis. Statistical analysis of carefully collected serial data will help to secure the diagnosis of Cyclic Neutropenia and provide patients with important prognostic information. Disclosures Dale: Amgen: Consultancy, Honoraria, Research Funding.
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Application of Spectral Density/Periodogram Analysis to Serial Neutrophil Counts to Diagnose Cyclic Neutropenia
Blood, 2015Co-Authors: Nicholas J Dobbins, Audrey Anna Bolyard, Robert T Chang, Julian Self, Gabriel P Langlois, Michael C Mackey, David C DaleAbstract:Background: Cyclic Neutropenia is characterized by oscillatory fluctuations in blood neutrophil counts, usually with nadirs 9 /L at approximately 3 week intervals. Visual inspection of graphs of serial counts is usually the basis for diagnosis. Detection of mutations in ELANE is helpful but not diagnostic because of the overlap of the specific mutation patterns with those associated with severe congenital Neutropenia. Making the correct diagnosis of Cyclic Neutropenia is important because these patients are not thought to be at risk of developing myelodysplasia or acute myeloid leukemia (MDS/AML). In contrast, patients with severe congenital Neutropenia, whose counts are usually lower, are at risk of developing MDS/AML. Methods: We have implemented a website application for easy and direct data entry of serial blood counts to detect statistically significant periodicities using the Lomb periodogram. Physicians, nurses, other healthcare providers or patients can directly enter the blood count data for analysis on a website to allow immediate visualization of the serial counts and calculation of the probability of statistically significant cycling and the period, i.e., length of the cycle. Results: We have analyzed the counts from 42 patients (21 ELANE positive, 8 ELANE negative, 13 ELANE unknown) enrolled in the Severe Chronic Neutropenia International Registry with a clinical diagnosis of Cyclic Neutropenia to determine the accuracy of clinical diagnoses based on this form of statistical analysis. Our preliminary results showed that it is easy to learn how to use this program. We estimate that at least 20 counts obtained at 2-3 day intervals for 6 weeks are the minimum needed to detect Cyclic Neutropenia on a statistically sound basis, while 20-40 counts obtained at 2-3 day intervals over an 8-10 week period was more likely to yield statistical and clinical certainty about the diagnosis. The figure below shows readouts for the periodogram analysis for one patient. It shows the influence of 17 counts versus 31 counts for a patient with the clinical diagnosis of Cyclic Neutropenia and a mutation in ELANE . The confidence intervals (95%) and (99%) are exceeded for the series of 31 counts but not for the shorter series. The peak, approximate cycle length is 22 days for this series of counts. As of yet, we do not have the sufficient daily count data to determine if more frequent testing (e.g. daily testing) is better than testing every 2-3 days. We are currently testing the patterns of neutrophil fluctuations in patients on G-CSF to see if Cyclic Neutropenia can be diagnosed in patients that are on (or during) treatment. We have learned that many patients with the clinical diagnosis of CyN do not have sufficient serial blood cell count data to confirm this diagnosis on a statistical basis. Conclusion: We have developed a simple method for making periodogram analysis much more widely available to clinicians and patients on a world-wide basis. Statistical analysis of carefully collected serial data will help to secure the diagnosis of Cyclic Neutropenia and provide patients with important prognostic information. Disclosures Dale: Amgen: Consultancy, Honoraria, Research Funding.
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Cyclic Neutropenia is not associated with transformation to mds and aml
Blood, 2007Co-Authors: David C Dale, Audrey Anna Bolyard, Peter E Newburger, Mary Ann Bonilla, George Kannourakis, Yigal Dror, Daniel C Link, Blanche P Alter, Philip S Rosenberg, Laurence A BoxerAbstract:Cyclic Neutropenia is a rare hematological disorder characterized by recurrent severe Neutropenia, mouth ulcers, fever and infections beginning soon after birth. The diagnosis depends primarily on observing regular periods of severe Neutropenia (neutrophils <500/μL, usually <200/μL) lasting for 2–4 days at approximately 21-day intervals, documented by serial blood counts (a minimum of 2–3 complete blood counts per week for at least six weeks). Severe congenital Neutropenia is a similar, but usually more severe disease. Mutations of the ELA2 gene are regarded as the cause of most cases of both Cyclic Neutropenia and severe congenital Neutropenia. However, only patients with severe congenital Neutropenia, not Cyclic Neutropenia, are thought to be at risk of evolution to MDS/AML. Since its founding in 1994, the Severe Chronic Neutropenia International Registry (SCNIR) has utilized data from previous studies and enrolled patients with Cyclic Neutropenia based on the clinical information from their treating physicians. We reviewed 190 cases of Cyclic Neutropenia (including 30 families) enrolled for 0.5 to 19.9 years, (median 11 years) with a total of 2,035 patient years of observation. 173 of 190 patients were treated with G-CSF (median dose 2.82 mcg/kg/day). We identified three patients who were reported to have developed MDS/AML. Further analysis by three experts from the SCNIR revealed that all three patients lacked sufficient serial blood count data to show well-defined neutrophil cycles prior to G-CSF. Two of the three patients lacked a clinical history of mouth ulcers and fevers consistent with the diagnosis, and the bone marrow evaluation was not consistent with Cyclic Neutropenia in all three cases. One of two patients tested did not have an ELA2 mutation. Thus, using standard criteria for the diagnosis of Cyclic Neutropenia, none of the three patients fully satisfied the criteria for this diagnosis. In addition, previous family studies, reviews of the published literature, and personal experience of the authors have revealed only one case of leukemia. This case of CML emerged in a 35 year-old patient, who was never treated with G-CSF, 31 years after the diagnosis of Cyclic Neutropenia. Based upon the review of these cases, we believe it is extremely important to make the diagnosis of Cyclic Neutropenia by careful analysis of serial blood counts. When the diagnosis is made confidently, it is also important to assure patients that with or without G-CSF treatment, the possibility of evolution to leukemia is unlikely.
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Cyclic Neutropenia Is Not Associated with Transformation to MDS and AML.
Blood, 2007Co-Authors: David C Dale, Audrey Anna Bolyard, Peter E Newburger, Mary Ann Bonilla, George Kannourakis, Yigal Dror, Daniel C Link, Blanche P Alter, Philip S Rosenberg, Laurence A BoxerAbstract:Cyclic Neutropenia is a rare hematological disorder characterized by recurrent severe Neutropenia, mouth ulcers, fever and infections beginning soon after birth. The diagnosis depends primarily on observing regular periods of severe Neutropenia (neutrophils
Hae Il Cheong - One of the best experts on this subject based on the ideXlab platform.
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a case of systemic amyloidosis associated with Cyclic Neutropenia
Pediatric Nephrology, 2011Co-Authors: Yun Hye Jung, Hee Gyung Kang, Kyung Chul Moon, Il Soo Ha, Yong Choi, Hae Il CheongAbstract:Reactive AA amyloidosis is caused by the accumulation of the acute phase reactant, serum amyloid A (SAA), as a complication of chronic inflammatory conditions. Cyclic Neutropenia is a rare hereditary disorder characterized by repeated episodes of Neutropenia at regular intervals, with or without concurrent infection, and is known to be a rare cause of AA amyloidosis. Here, we report a case of a patient who developed systemic AA amyloidosis following a prolonged course of undiagnosed Cyclic Neutropenia. The patient had a history of recurrent infections since infancy and developed goiter, proteinuria, and azotemia at age 14 years. Her SAA level was markedly increased (601.8 μg/mL, normal range <8 μg/mL), and a thyroid and kidney biopsy revealed typical lesions of AA amyloidosis. Amyloid deposits were also detected in the myocardium, colon, and gallbladder. She had repeated episodes of Neutropenia regularly at 3-week intervals and a pathogenic mutation in the ELA2 gene. After 10 months of treatment with recombinant human granulocyte colony-stimulating factor, her SAA level normalized (<2.5 μg/mL), but her renal function did not recover. This case clearly shows that Cyclic Neutropenia can be complicated by AA amyloidosis unless it is detected early and treated adequately.
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A case of systemic amyloidosis associated with Cyclic Neutropenia.
Pediatric Nephrology, 2010Co-Authors: Yun Hye Jung, Hee Gyung Kang, Kyung Chul Moon, Il Soo Ha, Yong Choi, Hae Il CheongAbstract:Reactive AA amyloidosis is caused by the accumulation of the acute phase reactant, serum amyloid A (SAA), as a complication of chronic inflammatory conditions. Cyclic Neutropenia is a rare hereditary disorder characterized by repeated episodes of Neutropenia at regular intervals, with or without concurrent infection, and is known to be a rare cause of AA amyloidosis. Here, we report a case of a patient who developed systemic AA amyloidosis following a prolonged course of undiagnosed Cyclic Neutropenia. The patient had a history of recurrent infections since infancy and developed goiter, proteinuria, and azotemia at age 14 years. Her SAA level was markedly increased (601.8 μg/mL, normal range
John Whetham - One of the best experts on this subject based on the ideXlab platform.
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pregnancy in patients with Cyclic Neutropenia
American Journal of Obstetrics and Gynecology, 1993Co-Authors: Tibor E Polcz, Robert J Stiller, John WhethamAbstract:Cyclic Neutropenia is characterized by periodic episodes of Neutropenia that are often associated with infectious complications. A patient with Cyclic Neutropenia experienced two pregnancies with an amelioration of her infectious complications and an increase in neutrophil count. Cyclic Neutropenia may follow a benign course during pregnancy.
Laurence A Boxer - One of the best experts on this subject based on the ideXlab platform.
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long term effects of g csf therapy in Cyclic Neutropenia
The New England Journal of Medicine, 2017Co-Authors: David C Dale, Audrey Anna Bolyard, Peter E Newburger, Mary Ann Bonilla, Daniel C Link, Laurence A Boxer, Tracy M Marrero, Vahagn Makaryan, Akiko Shimamura, Charles SpiekermanAbstract:The use of granulocyte colony-stimulating factor in patients with Cyclic Neutropenia is associated with long-term survival and a decreased risk of serious infections and sepsis.
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Cyclic Neutropenia is not associated with transformation to mds and aml
Blood, 2007Co-Authors: David C Dale, Audrey Anna Bolyard, Peter E Newburger, Mary Ann Bonilla, George Kannourakis, Yigal Dror, Daniel C Link, Blanche P Alter, Philip S Rosenberg, Laurence A BoxerAbstract:Cyclic Neutropenia is a rare hematological disorder characterized by recurrent severe Neutropenia, mouth ulcers, fever and infections beginning soon after birth. The diagnosis depends primarily on observing regular periods of severe Neutropenia (neutrophils <500/μL, usually <200/μL) lasting for 2–4 days at approximately 21-day intervals, documented by serial blood counts (a minimum of 2–3 complete blood counts per week for at least six weeks). Severe congenital Neutropenia is a similar, but usually more severe disease. Mutations of the ELA2 gene are regarded as the cause of most cases of both Cyclic Neutropenia and severe congenital Neutropenia. However, only patients with severe congenital Neutropenia, not Cyclic Neutropenia, are thought to be at risk of evolution to MDS/AML. Since its founding in 1994, the Severe Chronic Neutropenia International Registry (SCNIR) has utilized data from previous studies and enrolled patients with Cyclic Neutropenia based on the clinical information from their treating physicians. We reviewed 190 cases of Cyclic Neutropenia (including 30 families) enrolled for 0.5 to 19.9 years, (median 11 years) with a total of 2,035 patient years of observation. 173 of 190 patients were treated with G-CSF (median dose 2.82 mcg/kg/day). We identified three patients who were reported to have developed MDS/AML. Further analysis by three experts from the SCNIR revealed that all three patients lacked sufficient serial blood count data to show well-defined neutrophil cycles prior to G-CSF. Two of the three patients lacked a clinical history of mouth ulcers and fevers consistent with the diagnosis, and the bone marrow evaluation was not consistent with Cyclic Neutropenia in all three cases. One of two patients tested did not have an ELA2 mutation. Thus, using standard criteria for the diagnosis of Cyclic Neutropenia, none of the three patients fully satisfied the criteria for this diagnosis. In addition, previous family studies, reviews of the published literature, and personal experience of the authors have revealed only one case of leukemia. This case of CML emerged in a 35 year-old patient, who was never treated with G-CSF, 31 years after the diagnosis of Cyclic Neutropenia. Based upon the review of these cases, we believe it is extremely important to make the diagnosis of Cyclic Neutropenia by careful analysis of serial blood counts. When the diagnosis is made confidently, it is also important to assure patients that with or without G-CSF treatment, the possibility of evolution to leukemia is unlikely.
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Cyclic Neutropenia Is Not Associated with Transformation to MDS and AML.
Blood, 2007Co-Authors: David C Dale, Audrey Anna Bolyard, Peter E Newburger, Mary Ann Bonilla, George Kannourakis, Yigal Dror, Daniel C Link, Blanche P Alter, Philip S Rosenberg, Laurence A BoxerAbstract:Cyclic Neutropenia is a rare hematological disorder characterized by recurrent severe Neutropenia, mouth ulcers, fever and infections beginning soon after birth. The diagnosis depends primarily on observing regular periods of severe Neutropenia (neutrophils
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mutations in the gene encoding neutrophil elastase in congenital and Cyclic Neutropenia
Blood, 2000Co-Authors: David C Dale, Audrey Anna Bolyard, Mary Ann Bonilla, George Kannourakis, Laurence A Boxer, Richard E Person, Andrew A G Aprikyan, Cornelia Zeidler, Karl Welte, Kathleen F BensonAbstract: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.
