{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T06:05:33Z","timestamp":1760853933893},"reference-count":43,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,12,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neutrophil granulocytes are the most abundant immune cells in the blood yet the pathways orchestrating their differentiation and biological function remain incompletely understood. Studying (ultra-) rare patients with monogenetic defects of neutrophil granulocytes may open new horizons to understand basic principles of hematopoiesis and innate immunity. Here, recent insights into genetic factors controlling myelopoiesis and their more general role in biology will be presented in a clinical perspective. Advances in supportive care, first and foremost the use of recombinant human granulocyte-colony stimulating factor, has made a substantial difference for the quality of life and life expectancy of patients with congenital neutropenia (CN). Up to date, the only definitive cure can be provided by transplantation of allogeneic hematopoietic stem cells. The elucidation of the underlying molecular factors contributing to defective differentiation and function of neutrophil granulocytes nurtures new ideas of targeted individualized therapies.<\/jats:p>","DOI":"10.1182\/asheducation-2016.1.33","type":"journal-article","created":{"date-parts":[[2016,12,2]],"date-time":"2016-12-02T16:05:27Z","timestamp":1480694727000},"page":"33-37","update-policy":"http:\/\/dx.doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":9,"title":["Children with rare diseases of neutrophil granulocytes: from therapeutic orphans to pioneers of individualized medicine"],"prefix":"10.1182","volume":"2016","author":[{"given":"Christoph","family":"Klein","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Dr. von Hauner Children\u2019s Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","reference":[{"key":"2019111703032452200_B1","first-page":"553","article-title":"Methodologische Beitr\u00e4ge zur Physiologie und Pathologie der verschiedenen Formen der Leukozyten","volume":"1","author":"Ehrlich","year":"1880","journal-title":"Z Klin Med"},{"key":"2019111703032452200_B2","first-page":"141","article-title":"Untersuchungen \u00fcber die intrazellul\u00e4re Verdauung bei wirbellosen Tieren","volume":"5","author":"Metschnikoff","year":"1883","journal-title":"Arb. Zool. Inst. Wien"},{"key":"2019111703032452200_B3","first-page":"649","article-title":"A fatal case of acute primary infectious pharyngitis with extreme leukopenia","volume":"3","author":"Brown","year":"1902","journal-title":"Am Med"},{"key":"2019111703032452200_B4","first-page":"1495","article-title":"\u00dcber eigenartige Halserkrankungen","volume":"48","author":"Schultz","year":"1922","journal-title":"Dtsch Med Wochenschr"},{"key":"2019111703032452200_B5","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1146\/annurev-immunol-030409-101259","article-title":"Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes","volume":"29","author":"Klein","year":"2011","journal-title":"Annu Rev Immunol"},{"key":"2019111703032452200_B6","first-page":"2861","article-title":"Heredit\u00e4r reticulos - en ny systemsjukdom","volume":"47","author":"Kostmann","year":"1950","journal-title":"Svenska L\u00e4kartidningen"},{"key":"2019111703032452200_B7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1651-2227.1956.tb06875.x","article-title":"Infantile genetic agranulocytosis; agranulocytosis infantilis hereditaria","volume":"45","author":"Kostmann","year":"1956","journal-title":"Acta Paediatr Suppl"},{"issue":"7","key":"2019111703032452200_B8","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1517\/14712598.2014.905537","article-title":"G-CSF: filgrastim, lenograstim and biosimilars","volume":"14","author":"Welte","year":"2014","journal-title":"Expert Opin Biol Ther"},{"issue":"2015","key":"2019111703032452200_B9","first-page":"1","article-title":"Game of clones: the genomic evolution of severe congenital neutropenia","author":"Touw","year":"2015","journal-title":"Hematology Am Soc Hematol Educ Program"},{"issue":"16","key":"2019111703032452200_B10","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1182\/blood-2015-02-628859","article-title":"Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation","volume":"126","author":"Fioredda","year":"2015","journal-title":"Blood"},{"issue":"1","key":"2019111703032452200_B11","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.hoc.2012.10.004","article-title":"ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology","volume":"27","author":"Horwitz","year":"2013","journal-title":"Hematol Oncol Clin North Am"},{"issue":"5","key":"2019111703032452200_B12","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1182\/blood-2006-08-019166","article-title":"Neutrophil elastase in cyclic and severe congenital neutropenia","volume":"109","author":"Horwitz","year":"2007","journal-title":"Blood"},{"issue":"13","key":"2019111703032452200_B13","doi-asserted-by":"crossref","first-page":"4179","DOI":"10.1182\/blood-2006-11-057299","article-title":"Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis","volume":"110","author":"Grenda","year":"2007","journal-title":"Blood"},{"issue":"2","key":"2019111703032452200_B14","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1182\/blood-2005-11-4689","article-title":"Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response","volume":"108","author":"K\u00f6llner","year":"2006","journal-title":"Blood"},{"issue":"8","key":"2019111703032452200_B15","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1172\/JCI80924","article-title":"Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells","volume":"125","author":"Nayak","year":"2015","journal-title":"J Clin Invest"},{"issue":"4","key":"2019111703032452200_B16","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1182\/blood-2013-07-513242","article-title":"Neutropenia-associated ELANE mutations disrupting translation initiation produce novel neutrophil elastase isoforms","volume":"123","author":"Tidwell","year":"2014","journal-title":"Blood"},{"issue":"10","key":"2019111703032452200_B17","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1038\/nm.2958","article-title":"Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis","volume":"18","author":"Skokowa","year":"2012","journal-title":"Nat Med"},{"issue":"16","key":"2019111703032452200_B18","doi-asserted-by":"crossref","first-page":"2550","DOI":"10.1182\/blood-2012-09-456889","article-title":"Bortezomib inhibits STAT5-dependent degradation of LEF-1, inducing granulocytic differentiation in congenital neutropenia CD34(+) cells","volume":"123","author":"Gupta","year":"2014","journal-title":"Blood"},{"issue":"24","key":"2019111703032452200_B19","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1182\/blood-2015-06-655043","article-title":"From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation","volume":"126","author":"M\u00f6r\u00f6y","year":"2015","journal-title":"Blood"},{"issue":"1","key":"2019111703032452200_B20","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/ng1940","article-title":"HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease)","volume":"39","author":"Klein","year":"2007","journal-title":"Nat Genet"},{"issue":"6","key":"2019111703032452200_B21","doi-asserted-by":"crossref","first-page":"2736","DOI":"10.4049\/jimmunol.158.6.2736","article-title":"HAX-1, a novel intracellular protein, localized on mitochondria, directly associates with HS1, a substrate of Src family tyrosine kinases","volume":"158","author":"Suzuki","year":"1997","journal-title":"J Immunol"},{"issue":"10","key":"2019111703032452200_B22","doi-asserted-by":"crossref","first-page":"4954","DOI":"10.1182\/blood-2007-11-120667","article-title":"Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype-phenotype associations","volume":"111","author":"Germeshausen","year":"2008","journal-title":"Blood"},{"issue":"12","key":"2019111703032452200_B23","doi-asserted-by":"crossref","first-page":"3157","DOI":"10.1002\/ajmg.a.33748","article-title":"HAX1 mutations causing severe congenital neuropenia and neurological disease lead to cerebral microstructural abnormalities documented by quantitative MRI","volume":"152A","author":"Boztug","year":"2010","journal-title":"Am J Med Genet A"},{"issue":"7183","key":"2019111703032452200_B24","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nature06604","article-title":"Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons","volume":"452","author":"Chao","year":"2008","journal-title":"Nature"},{"issue":"29","key":"2019111703032452200_B25","doi-asserted-by":"crossref","first-page":"22461","DOI":"10.1074\/jbc.M109.086587","article-title":"Deregulation of mitochondrial membrane potential by mitochondrial insertion of granzyme B and direct Hax-1 cleavage","volume":"285","author":"Han","year":"2010","journal-title":"J Biol Chem"},{"issue":"4","key":"2019111703032452200_B26","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.bbrc.2010.02.084","article-title":"Molecular interaction between HAX-1 and XIAP inhibits apoptosis","volume":"393","author":"Kang","year":"2010","journal-title":"Biochem Biophys Res Commun"},{"issue":"6","key":"2019111703032452200_B27","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1097\/ACI.0000000000000014","article-title":"Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes","volume":"13","author":"Hauck","year":"2013","journal-title":"Curr Opin Allergy Clin Immunol"},{"issue":"12","key":"2019111703032452200_B28","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1038\/nm.3740","article-title":"Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis","volume":"20","author":"Baumann","year":"2014","journal-title":"Nat Med"},{"issue":"3","key":"2019111703032452200_B29","doi-asserted-by":"crossref","first-page":"4071","DOI":"10.3892\/mmr.2015.3905","article-title":"Expression of HAX-1 in colorectal cancer and its role in cancer cell growth","volume":"12","author":"Li","year":"2015","journal-title":"Mol Med Rep"},{"issue":"1","key":"2019111703032452200_B30","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3324\/haematol.2013.083873","article-title":"Genetic correction of HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis","volume":"99","author":"Morishima","year":"2014","journal-title":"Haematologica"},{"issue":"1","key":"2019111703032452200_B31","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1056\/NEJMoa0805051","article-title":"A syndrome with congenital neutropenia and mutations in G6PC3","volume":"360","author":"Boztug","year":"2009","journal-title":"N Engl J Med"},{"issue":"3","key":"2019111703032452200_B32","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1007\/s10875-012-9833-6","article-title":"Inflammatory bowel disease and T cell lymphopenia in G6PC3 deficiency","volume":"33","author":"B\u00e9gin","year":"2013","journal-title":"J Clin Immunol"},{"issue":"4","key":"2019111703032452200_B33","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.jpeds.2011.09.019","article-title":"Extended spectrum of human glucose-6-phosphatase catalytic subunit 3 deficiency: novel genotypes and phenotypic variability in severe congenital neutropenia","volume":"160","author":"Boztug","year":"2012","journal-title":"J Pediatr"},{"key":"2019111703032452200_B34","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/1750-1172-8-84","article-title":"A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations","volume":"8","author":"Banka","year":"2013","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"2019111703032452200_B35","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1056\/NEJMoa1301296","article-title":"A congenital neutrophil defect syndrome associated with mutations in VPS45","volume":"369","author":"Vilboux","year":"2013","journal-title":"N Engl J Med"},{"issue":"12","key":"2019111703032452200_B36","doi-asserted-by":"crossref","first-page":"3214","DOI":"10.1002\/ajmg.a.37367","article-title":"Severe congenital neutropenia with neurological impairment due to a homozygous VPS45 p.E238K mutation: a case report suggesting a genotype-phenotype correlation","volume":"167A","author":"Meerschaut","year":"2015","journal-title":"Am J Med Genet A"},{"issue":"9","key":"2019111703032452200_B37","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1038\/ng.3069","article-title":"JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia","volume":"46","author":"Boztug","year":"2014","journal-title":"Nat Genet"},{"issue":"9","key":"2019111703032452200_B38","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/ng.3070","article-title":"Jagunal homolog 1 is a critical regulator of neutrophil function in fungal host defense","volume":"46","author":"Wirnsberger","year":"2014","journal-title":"Nat Genet"},{"issue":"24","key":"2019111703032452200_B39","doi-asserted-by":"crossref","first-page":"3811","DOI":"10.1182\/blood-2013-11-535419","article-title":"Inherited biallelic CSF3R mutations in severe congenital neutropenia","volume":"123","author":"Triot","year":"2014","journal-title":"Blood"},{"issue":"15","key":"2019111703032452200_B40","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1182\/blood-2015-07-661264","article-title":"GM-CSF stimulates granulopoiesis in a congenital neutropenia patient with loss-of-function biallelic heterozygous CSF3R mutations","volume":"126","author":"Klimiankou","year":"2015","journal-title":"Blood"},{"issue":"18","key":"2019111703032452200_B41","doi-asserted-by":"crossref","first-page":"4963","DOI":"10.1182\/blood-2011-06-360586","article-title":"The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome","volume":"118","author":"Dale","year":"2011","journal-title":"Blood"},{"issue":"18","key":"2019111703032452200_B42","doi-asserted-by":"crossref","first-page":"4957","DOI":"10.1182\/blood-2011-07-368084","article-title":"The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome","volume":"118","author":"McDermott","year":"2011","journal-title":"Blood"},{"issue":"4","key":"2019111703032452200_B43","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.cell.2015.01.014","article-title":"Chromothriptic cure of WHIM syndrome","volume":"160","author":"McDermott","year":"2015","journal-title":"Cell"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/hematology\/article-pdf\/2016\/1\/33\/1251163\/hem088410.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/hematology\/article-pdf\/2016\/1\/33\/1251163\/hem088410.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T05:01:20Z","timestamp":1692594080000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2016\/1\/33\/21081\/Children-with-rare-diseases-of-neutrophil"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,2]]},"references-count":43,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2016,12,2]]}},"URL":"https:\/\/doi.org\/10.1182\/asheducation-2016.1.33","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,2]]}}}