{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T22:36:17Z","timestamp":1775774177816,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background: MYH9-related disease (MYH9-RD) is the most common form of inherited thrombocytopenia (IT). It is caused by pathogenic variants in the MYH9 gene. It manifests as early-onset macrothrombocytopenia with variable later-onset extra-hematological features, including hearing loss, renal disease, and cataracts. In pediatric patients, early recognition is critical to avoid misdiagnosis as immune thrombocytopenia (ITP) and unnecessary immunosuppressive therapy. Methods: We conducted a retrospective unicentric study at the Pediatric Oncology and Hematology Department, Fundeni Clinical Institute, Bucharest, Romania, including patients aged 0\u201318 years with suspected IT, tested between 2017 and 2025 by next-generation sequencing (NGS). Clinical, laboratory, and genetic data were reviewed. Results: Among 66 patients who underwent genetic testing, 31 (48.5%) had IT-associated genetic variants; 8 (25.8%) carried MYH9 mutations. Four patients (50%) had disease onset before age 1 year, three with neonatal presentation; 3 (37.5%) reported a family history of thrombocytopenia. Six variants were previously reported, and two were novel variants. Five variants (62.5%) were pathogenic, while three (37.5%) were initially classified as variants of uncertain significance (VUS). Most mutations were missense in the coiled-coil tail domain, correlating with milder thrombocytopenia and absence of extra-hematological features. No life-threatening bleeding was recorded; hemorrhagic symptoms were limited to minor mucocutaneous bleeding. Conclusions: This is the first Romanian pediatric cohort and one of the few existing pediatric cohorts describing the genetic and clinical spectrum of MYH9-RD. Early genetic confirmation enables precise diagnosis, tailored management, and family screening, while preventing inappropriate therapies.<\/jats:p>","DOI":"10.3390\/children12111563","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T15:38:09Z","timestamp":1763393889000},"page":"1563","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical and Molecular Spectrum of MYH9-Thrombocytopenia: Insights from a Single Centric Pediatric Cohort"],"prefix":"10.3390","volume":"12","author":[{"given":"Radu","family":"Obrisca","sequence":"first","affiliation":[{"name":"Department 7\u2014Pediatrics, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Fundeni Clinical Institute, 020021 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreea","family":"Serbanica","sequence":"additional","affiliation":[{"name":"Department 7\u2014Pediatrics, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Fundeni Clinical Institute, 020021 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3706-6620","authenticated-orcid":false,"given":"Andra","family":"Marcu","sequence":"additional","affiliation":[{"name":"Department 7\u2014Pediatrics, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Fundeni Clinical Institute, 020021 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Bica","sequence":"additional","affiliation":[{"name":"Department 7\u2014Pediatrics, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Fundeni Clinical Institute, 020021 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Jercan","sequence":"additional","affiliation":[{"name":"Department 7\u2014Pediatrics, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Fundeni Clinical Institute, 020021 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Avramescu","sequence":"additional","affiliation":[{"name":"Department 7\u2014Pediatrics, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Fundeni Clinical Institute, 020021 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1677-5479","authenticated-orcid":false,"given":"Letita","family":"Radu","sequence":"additional","affiliation":[{"name":"Department 7\u2014Pediatrics, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Fundeni Clinical Institute, 020021 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cerasela","family":"Jardan","sequence":"additional","affiliation":[{"name":"Department 7\u2014Pediatrics, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Fundeni Clinical Institute, 020021 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6031-8190","authenticated-orcid":false,"given":"Anca","family":"Colita","sequence":"additional","affiliation":[{"name":"Department 7\u2014Pediatrics, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Fundeni Clinical Institute, 020021 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1182\/blood-2008-07-162503","article-title":"Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: Report from an international working group","volume":"113","author":"Rodeghiero","year":"2009","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1182\/bloodadvances.2017010942","article-title":"Misdiagnosis of primary immune thrombocytopenia and frequency of bleeding: Lessons from the McMaster ITP Registry","volume":"1","author":"Arnold","year":"2017","journal-title":"Blood Adv."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Almazni, I., Stapley, R., and Morgan, N.V. (2019). Inherited Thrombocytopenia: Update on Genes and Genetic Variants Which may be Associated With Bleeding. Front. Cardiovasc. Med., 6.","DOI":"10.3389\/fcvm.2019.00080"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3109\/09537104.2016.1171835","article-title":"Inherited thrombocytopenia-recent advances in clinical and molecular aspects","volume":"28","author":"Balduini","year":"2017","journal-title":"Platelets"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.gene.2018.04.048","article-title":"MYH9: Structure, functions and role of non-muscle myosin IIA in human disease","volume":"664","author":"Pecci","year":"2018","journal-title":"Gene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3681","DOI":"10.1073\/pnas.0506307103","article-title":"New insights into myosin evolution and classification","volume":"103","author":"Foth","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1055\/s-0029-1220327","article-title":"MYH9-Related Platelet Disorders","volume":"35","author":"Althaus","year":"2009","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/humu.20661","article-title":"Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease\u2020","volume":"29","author":"Pecci","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1002\/humu.22476","article-title":"MYH9-related disease: A novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations","volume":"35","author":"Pecci","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1182\/blood-2014-03-564328","article-title":"Platelet diameters in inherited thrombocytopenias: Analysis of 376 patients with all known disorders","volume":"124","author":"Noris","year":"2014","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1097\/AUD.0000000000000198","article-title":"Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease","volume":"37","author":"Verver","year":"2016","journal-title":"Ear Hear."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s00467-010-1735-3","article-title":"Renal manifestations of patients with MYH9-related disorders","volume":"26","author":"Han","year":"2011","journal-title":"Pediatr. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.ejmg.2009.01.006","article-title":"Identification of the first duplication in MYH9-related disease: A hot spot for unequal crossing-over within exon 24 of the MYH9 gene","volume":"52","author":"Pecci","year":"2009","journal-title":"Eur. J. Med. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pecci, A., Biino, G., Fierro, T., Bozzi, V., Mezzasoma, A., Noris, P., Ramenghi, U., Loffredo, G., Fabris, F., and Momi, S. (2012). Alteration of liver enzymes is a feature of the MYH9-related disease syndrome. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035986"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1007\/s100380170007","article-title":"Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions","volume":"46","author":"Kunishima","year":"2001","journal-title":"J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cenni, C., Mansard, L., Blanchet, C., Baux, D., Vach\u00e9, C., Baudoin, C., Moclyn, M., Faug\u00e8re, V., Mondain, M., and Jeziorski, E. (2021). When Familial Hearing Loss Means Genetic Heterogeneity: A Model Case Report. Diagnostics, 11.","DOI":"10.3390\/diagnostics11091636"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1182\/blood.V97.4.1147","article-title":"Mutations in the NMMHC-A gene cause autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly\/Sebastian syndrome)","volume":"97","author":"Kunishima","year":"2001","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1681\/ASN.2024xknfhpc9","article-title":"Unwrapping the Enigma: A Rare Case of MYH9 Nephropathy: TH-PO496","volume":"35","author":"Yasin","year":"2024","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1681\/ASN.V13165","article-title":"Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndromes","volume":"13","author":"Arrondel","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1159\/000342123","article-title":"Clinical, pathological, and genetic analysis of ten patients with MYH9-related disease","volume":"129","author":"Sun","year":"2013","journal-title":"Acta Haematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1111\/jth.13843","article-title":"Thrombocytopenia and CD34 expression is decoupled from \u03b1-granule deficiency with mutation of the first growth factor-independent 1B zinc finger","volume":"15","author":"Rabbolini","year":"2017","journal-title":"J. Thromb. Haemost."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1111\/hae.12917","article-title":"Congenital macrothrombocytopenia is a heterogeneous disorder in India","volume":"22","author":"Ali","year":"2016","journal-title":"Haemophilia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"36","DOI":"10.15746\/sms.24.006","article-title":"A Case of Thrombocytopenia with MYH9 Gene Mutation Found in Siblings","volume":"30","author":"Kim","year":"2024","journal-title":"Soonchunhyang Med. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/ncpneph0076","article-title":"Drug-associated renal dysfunction and injury","volume":"2","author":"Choudhury","year":"2006","journal-title":"Nat. Clin. Pract. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1055\/s-0032-1333540","article-title":"Diagnosis and management of inherited thrombocytopenias","volume":"39","author":"Balduini","year":"2013","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e31005","DOI":"10.1002\/pbc.31005","article-title":"Successful hematopoietic stem cell transplantation in MYH9-related congenital thrombocytopenia","volume":"71","author":"Ussowicz","year":"2024","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e29711","DOI":"10.1002\/pbc.29711","article-title":"Umbilical cord blood transplantation for MYH9-related disorders","volume":"69","author":"Li","year":"2022","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"102552","DOI":"10.1016\/j.rpth.2024.102552","article-title":"MYH9-related inherited thrombocytopenia: The genetic spectrum, underlying mechanisms, clinical phenotypes, diagnosis, and management approaches","volume":"8","author":"Shen","year":"2024","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1055\/s-0032-1328881","article-title":"Drugs that affect platelet function","volume":"38","author":"Scharf","year":"2012","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1182\/asheducation-2009.1.267","article-title":"Antiplatelet agents","volume":"2009","author":"Varon","year":"2009","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.3324\/haematol.2016.160754","article-title":"Bleeding risk of surgery and its prevention in patients with inherited platelet disorders","volume":"102","author":"Orsini","year":"2017","journal-title":"Haematologica."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/bjh.14423","article-title":"Guidelines for the use of platelet transfusions","volume":"176","author":"Estcourt","year":"2017","journal-title":"Br. J. Haematol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1182\/hematology.2020000137","article-title":"Platelet transfusion refractoriness: How do I diagnose and manage?","volume":"2020","author":"Cohn","year":"2020","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1002\/ajh.20446","article-title":"Perioperative management of a patient with May-Hegglin anomaly requiring craniotomy","volume":"79","author":"Sehbai","year":"2005","journal-title":"Am. J. Hematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5832","DOI":"10.1182\/blood-2010-08-304725","article-title":"Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations","volume":"116","author":"Pecci","year":"2010","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"820","DOI":"10.3324\/haematol.2019.223966","article-title":"Eltrombopag for the treatment of inherited thrombocytopenias: A phase II clinical trial","volume":"105","author":"Zaninetti","year":"2020","journal-title":"Haematologica"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lassandro, G., Carriero, F., Noviello, D., Palladino, V., Del Vecchio, G.C., Faienza, M.F., and Giordano, P. (2022). Successful Eltrombopag Therapy in a Child with MYH9-Related Inherited Thrombocytopenia. Children, 9.","DOI":"10.3390\/children9121839"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e298","DOI":"10.1097\/MAO.0000000000003450","article-title":"Characterization of sensorineural hearing loss in patients with MYH9-related disease: A systematic review","volume":"43","author":"Peddu","year":"2022","journal-title":"Otol. Neurotol."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/12\/11\/1563\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T10:40:37Z","timestamp":1763635237000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/12\/11\/1563"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,17]]},"references-count":38,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["children12111563"],"URL":"https:\/\/doi.org\/10.3390\/children12111563","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,17]]}}}