{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:41:49Z","timestamp":1790649709347,"version":"4.1.0"},"reference-count":37,"publisher":"American Academy of Pediatrics (AAP)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,1]]},"abstract":"<jats:p>Hereditary hemorrhagic telangiectasia (HHT) can be clinically diagnosed, but children often lack characteristic features. We report a family with homozygous growth differentiation factor 2 (GDF2)\u2013related HHT diagnosed by genetic testing. A boy aged 5 years and 2 months presented with isolated hypoxemia. He was the product of a consanguineous marriage; his parents were second cousins. Physical examination revealed cyanosis of nail beds and clubbed fingers. Pulse oxygen saturation was 84% to 89%. Lung function, contrast-enhanced lung computed tomography, and noncontrast echocardiography were normal. A pulmonary perfusion scan revealed radioactivity in the brain and bilateral kidney, suggesting the existence of a intrapulmonary shunt. Whole-exome sequencing revealed a homozygous variant [c.1060_1062delinsAG (p.Tyr354ArgfsTer15)] in GDF2, which was found to be inherited from his heterozygous parents. At the age of 8 years, he developed epistaxis, and an angiogram revealed diffuse pulmonary arteriovenous malformations. At the age of 9 years, he was treated with sirolimus, and his condition improved significantly. However, his now 7-year-old sister with the same homozygous variant currently has no symptoms. Physical examinations revealed 1 pinpoint-sized telangiectasia on the chest of his mother and a vascular lesion on the forehead of his sister. Additionally, the patient\u2019s father and great-uncle had a history of mild to moderate epistaxis. Mutation in GDF2 is a rare cause of HHT. Ours is the first report of homozygous GDF2-related HHT; in addition, this variant has not been reported previously. In our report, we also confirm variable expressivity, even with the same pathogenic variant in GDF2-related HHT.<\/jats:p>","DOI":"10.1542\/peds.2019-1970","type":"journal-article","created":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T12:29:37Z","timestamp":1594816177000},"source":"Crossref","is-referenced-by-count":28,"title":["Homozygous <i>GDF2<\/i>-Related Hereditary Hemorrhagic Telangiectasia in a Chinese Family"],"prefix":"10.1542","volume":"146","author":[{"given":"Jinrong","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine, Beijing Children\u2019s Hospital, National Center for Children\u2019s Health and Capital Medical University, Xicheng District, Beijing, People\u2019s Republic of China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jigang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Beijing Friendship Hospital and Capital Medical University, Xicheng District, Beijing, People\u2019s Republic of China; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Beijing Children\u2019s Hospital, National Center for Children\u2019s Health and Capital Medical University, Xicheng District, Beijing, People\u2019s Republic of China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Beijing Children\u2019s Hospital, National Center for Children\u2019s Health and Capital Medical University, Xicheng District, Beijing, People\u2019s Republic of China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuelin","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Beijing Children\u2019s Hospital, National Center for Children\u2019s Health and Capital Medical University, Xicheng District, Beijing, People\u2019s Republic of China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyue","family":"Gu","sequence":"additional","affiliation":[{"name":"Data and Analysis Center for Genetic Diseases, Beijing Chigene Translational Medicine Research Center Co, Ltd, Tongzhou District, Beijing, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunying","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Beijing Children\u2019s Hospital, National Center for Children\u2019s Health and Capital Medical University, Xicheng District, Beijing, People\u2019s Republic of China;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"417","published-online":{"date-parts":[[2020,8,1]]},"reference":[{"issue":"2","key":"2021121016450160700_B1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1136\/jmg.2009.069013","article-title":"International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia","volume":"48","author":"Faughnan","year":"2011","journal-title":"J Med Genet"},{"issue":"5","key":"2021121016450160700_B2","doi-asserted-by":"crossref","first-page":"e230441","DOI":"10.1136\/bcr-2019-230441","article-title":"Arteriovenous malformations in multiple organs in a patient presenting with hereditary haemorrhagic telangiectasia","volume":"12","author":"Kodati","year":"2019","journal-title":"BMJ Case Rep"},{"issue":"5","key":"2021121016450160700_B3","doi-asserted-by":"crossref","first-page":"BSR20182320","DOI":"10.1042\/BSR20182320","article-title":"Endoglin is a conserved regulator of vasculogenesis in zebrafish - implications for hereditary haemorrhagic telangiectasia","volume":"39","author":"Zhang","year":"2019","journal-title":"Biosci Rep"},{"issue":"3","key":"2021121016450160700_B4","doi-asserted-by":"crossref","first-page":"2045894018786696","DOI":"10.1177\/2045894018786696","article-title":"Pulmonary arteriovenous malformations in children with hereditary hemorrhagic telangiectasia: a longitudinal study","volume":"8","author":"Mowers","year":"2018","journal-title":"Pulm Circ"},{"issue":"1","key":"2021121016450160700_B5","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P","article-title":"Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)","volume":"91","author":"Shovlin","year":"2000","journal-title":"Am J Med Genet"},{"key":"2021121016450160700_B6","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.jpeds.2017.11.047","article-title":"Echocardiography grading for pulmonary arteriovenous malformation screening in children with hereditary hemorrhagic telangiectasia","volume":"195","author":"Fernandopulle","year":"2018","journal-title":"J Pediatr"},{"issue":"9","key":"2021121016450160700_B7","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1002\/ppul.23686","article-title":"Asymptomatic pulmonary arteriovenous malformations in children with hereditary hemorrhagic telangiectasia","volume":"52","author":"Gefen","year":"2017","journal-title":"Pediatr Pulmonol"},{"issue":"4","key":"2021121016450160700_B8","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/j.jaad.2018.11.014","article-title":"Localization and age distribution of telangiectases in children and adolescents with hereditary hemorrhagic telangiectasia: a retrospective cohort study","volume":"81","author":"Gonzalez","year":"2019","journal-title":"J Am Acad Dermatol"},{"issue":"7","key":"2021121016450160700_B9","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1002\/lary.27015","article-title":"Epistaxis in children and adolescents with hereditary hemorrhagic telangiectasia","volume":"128","author":"Gonzalez","year":"2018","journal-title":"Laryngoscope"},{"key":"2021121016450160700_B10","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.jpeds.2018.01.079","article-title":"Applicability of the Cura\u00e7ao criteria for the diagnosis of hereditary hemorrhagic telangiectasia in the pediatric population","volume":"197","author":"Pahl","year":"2018","journal-title":"J Pediatr"},{"issue":"4","key":"2021121016450160700_B11","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/ng1294-345","article-title":"Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1","volume":"8","author":"McAllister","year":"1994","journal-title":"Nat Genet"},{"issue":"7","key":"2021121016450160700_B12","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1136\/jmg.2004.028712","article-title":"A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5","volume":"42","author":"Cole","year":"2005","journal-title":"J Med Genet"},{"issue":"20","key":"2021121016450160700_B13","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1002\/ajmg.a.31450","article-title":"A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7","volume":"140","author":"Bayrak-Toydemir","year":"2006","journal-title":"Am J Med Genet A"},{"issue":"3","key":"2021121016450160700_B14","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1016\/j.ajhg.2013.07.004","article-title":"BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia","volume":"93","author":"Wooderchak-Donahue","year":"2013","journal-title":"Am J Hum Genet"},{"issue":"5","key":"2021121016450160700_B15","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1002\/ajmg.a.33968","article-title":"SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction","volume":"155A","author":"Andrabi","year":"2011","journal-title":"Am J Med Genet A"},{"key":"2021121016450160700_B16","doi-asserted-by":"crossref","first-page":"15040","DOI":"10.1038\/hgv.2015.40","article-title":"Mutations in RASA1 and GDF2 identified in patients with clinical features of hereditary hemorrhagic telangiectasia","volume":"2","author":"Hernandez","year":"2015","journal-title":"Hum Genome Var"},{"key":"2021121016450160700_B17","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s12890-016-0183-7","article-title":"Novel homozygous BMP9 nonsense mutation causes pulmonary arterial hypertension: a case report","volume":"16","author":"Wang","year":"2016","journal-title":"BMC Pulm Med"},{"issue":"3","key":"2021121016450160700_B18","doi-asserted-by":"crossref","first-page":"1801609","DOI":"10.1183\/13993003.01609-2018","article-title":"Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension","volume":"53","author":"Wang","year":"2019","journal-title":"Eur Respir J"},{"issue":"11","key":"2021121016450160700_B19","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1161\/CIRCULATIONAHA.116.026886","article-title":"Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling","volume":"136","author":"Amyere","year":"2017","journal-title":"Circulation"},{"key":"2021121016450160700_B20","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3389\/fgene.2015.00115","article-title":"Research on potential biomarkers in hereditary hemorrhagic telangiectasia","volume":"6","author":"Botella","year":"2015","journal-title":"Front Genet"},{"issue":"1","key":"2021121016450160700_B21","first-page":"18","article-title":"Plasma VEGF - a candidate biomarker for response to treatment with bevacizumab in HHT patients","volume":"58","author":"Liu","year":"2020","journal-title":"Rhinology"},{"issue":"5","key":"2021121016450160700_B22","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"issue":"pt 6","key":"2021121016450160700_B23","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1242\/jcs.002949","article-title":"BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis","volume":"120","author":"Scharpfenecker","year":"2007","journal-title":"J Cell Sci"},{"issue":"2","key":"2021121016450160700_B24","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s00018-011-0751-1","article-title":"BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain. [published correction appears in Cell Mol Life Sci. 2012;69(3):485]","volume":"69","author":"Bidart","year":"2012","journal-title":"Cell Mol Life Sci"},{"issue":"7","key":"2021121016450160700_B25","doi-asserted-by":"crossref","first-page":"3395","DOI":"10.1074\/jbc.M115.680009","article-title":"Rapid activation of bone morphogenic protein 9 by receptor-mediated displacement of pro-domains","volume":"291","author":"Kienast","year":"2016","journal-title":"J Biol Chem"},{"issue":"33","key":"2021121016450160700_B26","doi-asserted-by":"crossref","first-page":"27313","DOI":"10.1074\/jbc.M112.377960","article-title":"Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex","volume":"287","author":"Townson","year":"2012","journal-title":"J Biol Chem"},{"issue":"9","key":"2021121016450160700_B27","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1016\/j.celrep.2017.05.011","article-title":"Structural basis of the human endoglin-BMP9 interaction: insights into BMP signaling and HHT1","volume":"19","author":"Saito","year":"2017","journal-title":"Cell Rep"},{"issue":"1","key":"2021121016450160700_B28","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/s13023-018-0962-8","article-title":"Comorbidity among HHT patients and their controls in a 20 years follow-up period","volume":"13","author":"Aagaard","year":"2018","journal-title":"Orphanet J Rare Dis"},{"issue":"9","key":"2021121016450160700_B29","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1038\/s41436-019-0443-z","article-title":"Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)?","volume":"21","author":"Wooderchak-Donahue","year":"2019","journal-title":"Genet Med"},{"issue":"3","key":"2021121016450160700_B30","first-page":"60","article-title":"Pulmonary, gastrointestinal and liver vascular malformations in Rendu-Osler disease","volume":"42","author":"Grudeva-Popova","year":"2000","journal-title":"Folia Med (Plovdiv)"},{"issue":"2","key":"2021121016450160700_B31","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1177\/0194599818813521","article-title":"Systemic bevacizumab for hereditary hemorrhagic telangiectasia: considerations from observational studies","volume":"160","author":"Al-Samkari","year":"2019","journal-title":"Otolaryngol Head Neck Surg"},{"issue":"2","key":"2021121016450160700_B32","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1111\/joim.12832","article-title":"Systemic bevacizumab for the treatment of chronic bleeding in hereditary haemorrhagic telangiectasia","volume":"285","author":"Al-Samkari","year":"2019","journal-title":"J Intern Med"},{"issue":"1","key":"2021121016450160700_B33","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s10456-018-9646-1","article-title":"Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia","volume":"22","author":"Faughnan","year":"2019","journal-title":"Angiogenesis"},{"issue":"2","key":"2021121016450160700_B34","doi-asserted-by":"crossref","first-page":"2045894018805406","DOI":"10.1177\/2045894018805406","article-title":"Treatment with low-dose tacrolimus inhibits bleeding complications in a patient with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension","volume":"9","author":"Sommer","year":"2019","journal-title":"Pulm Circ"},{"key":"2021121016450160700_B35","doi-asserted-by":"crossref","first-page":"13650","DOI":"10.1038\/ncomms13650","article-title":"PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia","volume":"7","author":"Ola","year":"2016","journal-title":"Nat Commun"},{"issue":"2","key":"2021121016450160700_B36","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1172\/JCI127425","article-title":"Correcting Smad1\/5\/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models","volume":"130","author":"Ruiz","year":"2020","journal-title":"J Clin Invest"},{"issue":"2","key":"2021121016450160700_B37","doi-asserted-by":"crossref","first-page":"92","DOI":"10.4168\/aair.2012.4.2.92","article-title":"Mycoplasma pneumoniae infection affects the serum levels of vascular endothelial growth factor and interleukin-5 in atopic children","volume":"4","author":"Jeong","year":"2012","journal-title":"Allergy Asthma Immunol Res"}],"container-title":["Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/doi\/10.1542\/peds.2019-1970\/1080830\/peds_20191970.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/doi\/10.1542\/peds.2019-1970\/1080830\/peds_20191970.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,11]],"date-time":"2021-12-11T05:11:32Z","timestamp":1639199492000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.aap.org\/pediatrics\/article\/146\/2\/e20191970\/36926\/Homozygous-GDF2-Related-Hereditary-Hemorrhagic"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,1]]},"references-count":37,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,8,1]]},"published-print":{"date-parts":[[2020,8,1]]}},"URL":"https:\/\/doi.org\/10.1542\/peds.2019-1970","relation":{},"ISSN":["0031-4005","1098-4275"],"issn-type":[{"value":"0031-4005","type":"print"},{"value":"1098-4275","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,1]]},"article-number":"e20191970"}}