{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T01:04:58Z","timestamp":1760576698658,"version":"build-2065373602"},"reference-count":29,"publisher":"Georg Thieme Verlag KG","issue":"05","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hamostaseologie"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In the case of familial thrombocytopenia, a congenital defect should be considered; however, in particular older patients who have had thrombocytopenia for a long time have often not yet been genetically analyzed using modern sequencing methods. Remarkably, sometimes they are still suspected of suffering from chronic immune thrombocytopenia until genetic testing reveals a congenital defect. We report on elderly Finnish siblings (both older than 60 years) with lifelong thrombocytopenia. The lifelong bleeding tendency in both the siblings was usually treated with tranexamic acid and platelet transfusions when necessary. In 2022, the older brother presented at the University Hospital in Helsinki because he had recently been suffering from gastrointestinal bleeding and also had mild pancytopenia. Because his sister lived abroad, the Finnish colleagues recommended that the sister should present to the University Hospital in Freiburg. Independent genetic testing of both the siblings using NGS identified the diagnosis of NBEAL2-associated gray platelet syndrome. The disease comprises macrothrombocytopenia and a reduction of \u03b1-granules in platelets, resulting in a grayish appearance of platelets on the blood smear. Patients usually suffer from a mild to moderate bleeding diathesis. Interestingly, during the last years a more syndromic character of the disease has been described: besides the platelet phenotype, the immune system can also be affected. In the course of the disease patients may develop pancytopenia, splenomegaly, and bone marrow fibrosis. Comprehensive diagnostics including molecular genetic analyses are particularly important to provide these patients with adequate care and treatment.<\/jats:p>","DOI":"10.1055\/a-2698-0341","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T22:56:20Z","timestamp":1760568980000},"page":"414-418","source":"Crossref","is-referenced-by-count":0,"title":["Late Diagnosis of NBEAL2-related Gray Platelet Syndrome in Finnish Siblings with Lifelong Thrombocytopenia"],"prefix":"10.1055","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9238-2904","authenticated-orcid":false,"given":"Doris","family":"Boeckelmann","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children's Hospital, Medical Center \u2013 University of Freiburg, Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3713-2499","authenticated-orcid":false,"given":"Terhi","family":"Friman","sequence":"additional","affiliation":[{"name":"Rare Hematological Disorders Clinic, Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2750-7229","authenticated-orcid":false,"given":"Hannah","family":"Glonnegger","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children's Hospital, Medical Center \u2013 University of Freiburg, Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2803-2712","authenticated-orcid":false,"given":"Ulla","family":"Wartiovaara-Kautto","sequence":"additional","affiliation":[{"name":"Rare Hematological Disorders Clinic, Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4954-7029","authenticated-orcid":false,"given":"Barbara","family":"Zieger","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children's Hospital, Medical Center \u2013 University of Freiburg, Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"issue":"08","key":"ref1","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.3324\/haematol.2019.233197","article-title":"Inherited thrombocytopenias: history, advances and perspectives","volume":"105","author":"A T Nurden","year":"2020","journal-title":"Haematologica"},{"issue":"07","key":"ref2","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1055\/s-0041-1742207","article-title":"Novel GNE gene variants associated with severe congenital thrombocytopenia and platelet sialylation defect","volume":"122","author":"B Zieger","year":"2022","journal-title":"Thromb Haemost"},{"issue":"05","key":"ref3","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1080\/09537100410001714872","article-title":"Neutrophils in the gray platelet syndrome","volume":"15","author":"J G White","year":"2004","journal-title":"Platelets"},{"issue":"06","key":"ref4","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1016\/0002-9343(71)90311-1","article-title":"Gray platelet syndrome. A variety of qualitative platelet disorder","volume":"51","author":"G Raccuglia","year":"1971","journal-title":"Am J Med"},{"issue":"08","key":"ref5","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1038\/ng.884","article-title":"Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome","volume":"43","author":"W H Kahr","year":"2011","journal-title":"Nat Genet"},{"issue":"08","key":"ref6","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/ng.883","article-title":"NBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet \u03b1-granules","volume":"43","author":"M Gunay-Aygun","year":"2011","journal-title":"Nat Genet"},{"issue":"08","key":"ref7","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/ng.885","article-title":"Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome","volume":"43","author":"C A Albers","year":"2011","journal-title":"Nat Genet"},{"issue":"07","key":"ref8","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1111\/tra.12069","article-title":"The BEACH is hot: a LYST of emerging roles for BEACH-domain containing proteins in human disease","volume":"14","author":"A R Cullinane","year":"2013","journal-title":"Traffic"},{"issue":"10","key":"ref9","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1161\/ATVBAHA.118.311270","article-title":"NBEAL2 (neurobeachin-like 2) is required for retention of cargo proteins by \u03b1-granules during their production by megakaryocytes","volume":"38","author":"R W Lo","year":"2018","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"09","key":"ref10","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1182\/blood-2017-08-800359","article-title":"Nbeal2 interacts with Dock7, Sec16a, and Vac14","volume":"131","author":"L Mayer","year":"2018","journal-title":"Blood"},{"issue":"03","key":"ref11","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.blre.2014.10.003","article-title":"Platelet secretion: from haemostasis to wound healing and beyond","volume":"29","author":"E M Golebiewska","year":"2015","journal-title":"Blood Rev"},{"issue":"02","key":"ref12","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1080\/09537104.2017.1280599","article-title":"\u03b1-granule biogenesis: from disease to discovery","volume":"28","author":"C H Chen","year":"2017","journal-title":"Platelets"},{"issue":"20","key":"ref13","doi-asserted-by":"crossref","first-page":"3092","DOI":"10.1182\/bloodadvances.2018020834","article-title":"Megakaryocytes package contents into separate \u03b1-granules that are differentially distributed in platelets","volume":"3","author":"E M Battinelli","year":"2019","journal-title":"Blood Adv"},{"issue":"02","key":"ref14","doi-asserted-by":"crossref","first-page":"E20","DOI":"10.1002\/ajh.24610","article-title":"Gray platelet syndrome: novel mutations of the NBEAL2 gene","volume":"92","author":"R Bottega","year":"2017","journal-title":"Am J Hematol"},{"issue":"01","key":"ref15","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.blre.2005.12.003","article-title":"The gray platelet syndrome: clinical spectrum of the disease","volume":"21","author":"A T Nurden","year":"2007","journal-title":"Blood Rev"},{"issue":"08","key":"ref16","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1161\/ATVBAHA.118.311332","article-title":"Nbeal2 deficiency increases organ damage but does not affect host defense during gram-negative pneumonia-derived sepsis","volume":"38","author":"T AM Claushuis","year":"2018","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"08","key":"ref17","doi-asserted-by":"crossref","first-page":"2948","DOI":"10.4049\/jimmunol.1700556","article-title":"The neurobeachin-like 2 protein regulates mast cell homeostasis","volume":"199","author":"S Drube","year":"2017","journal-title":"J Immunol"},{"issue":"17","key":"ref18","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1182\/blood.2019004776","article-title":"Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome","volume":"136","author":"M C Sims","year":"2020","journal-title":"Blood"},{"issue":"01","key":"ref19","doi-asserted-by":"crossref","first-page":"3728","DOI":"10.1038\/s41467-023-39295-7","article-title":"NBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells","volume":"14","author":"L Delage","year":"2023","journal-title":"Nat Commun"},{"issue":"02","key":"ref20","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1093\/ajcp\/aqaa229","article-title":"Gray platelet syndrome presenting with pancytopenia, splenomegaly, and bone marrow fibrosis","volume":"156","author":"H Tariq","year":"2021","journal-title":"Am J Clin Pathol"},{"issue":"03","key":"ref21","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1056\/NEJMoa1308130","article-title":"A dominant-negative GFI1B mutation in the gray platelet syndrome","volume":"370","author":"D Monteferrario","year":"2014","journal-title":"N Engl J Med"},{"issue":"08","key":"ref22","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1182\/blood-2006-02-004101","article-title":"X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation","volume":"109","author":"V N Tubman","year":"2007","journal-title":"Blood"},{"issue":"01","key":"ref23","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/cm.21479","article-title":"Hereditary neuralgic amyotrophy in childhood caused by duplication within the SEPT9 gene: a family study","volume":"76","author":"K Neubauer","year":"2019","journal-title":"Cytoskeleton (Hoboken)"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"786937","DOI":"10.3389\/fphar.2021.786937","article-title":"Hermansky-Pudlak syndrome: identification of novel variants in the genes HPS3, HPS5, and DTNBP1 (HPS-7)","volume":"12","author":"D Boeckelmann","year":"2022","journal-title":"Front Pharmacol"},{"issue":"07","key":"ref25","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1002\/ajh.24359","article-title":"Should any genetic defect affecting \u03b1-granules in platelets be classified as gray platelet syndrome?","volume":"91","author":"A T Nurden","year":"2016","journal-title":"Am J Hematol"},{"issue":"09","key":"ref26","doi-asserted-by":"crossref","first-page":"4521","DOI":"10.3390\/ijms22094521","article-title":"Inherited platelet disorders: an updated overview","volume":"22","author":"V Palma-Barqueros","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"06","key":"ref27","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1055\/a-1665-6249","article-title":"Pathogenic aspects of inherited platelet disorders","volume":"41","author":"D Boeckelmann","year":"2021","journal-title":"Hamostaseologie"},{"issue":"02","key":"ref28","first-page":"445","article-title":"Ultrastructural studies of the gray platelet syndrome","volume":"95","author":"J G White","year":"1979","journal-title":"Am J Pathol"},{"issue":"06","key":"ref29","doi-asserted-by":"crossref","first-page":"868","DOI":"10.3324\/haematol.2012.075861","article-title":"Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and \u03b1-granule deficiency","volume":"98","author":"R Bottega","year":"2013","journal-title":"Haematologica"}],"container-title":["H\u00e4mostaseologie"],"original-title":[],"language":"de","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2698-0341.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T22:56:54Z","timestamp":1760569014000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2698-0341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":29,"journal-issue":{"issue":"05","published-online":{"date-parts":[[2025,10,15]]},"published-print":{"date-parts":[[2025,10]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2698-0341","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0720-9355","2567-5761"],"issn-type":[{"value":"0720-9355","type":"print"},{"value":"2567-5761","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10]]}}}