{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:58:54Z","timestamp":1787162334729,"version":"build-2736575974"},"reference-count":28,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T00:00:00Z","timestamp":1747008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Children\u2019s Hospital of Philadelphia Pediatrics Department Chair\u2019s Initiative"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Pathogenic variants in the growth differentiation factor 2 (GDF2) gene have been linked to a hereditary hemorrhagic telangiectasia (HHT)-like syndrome, yet their clinical significance remains under investigation. This study reports seven pediatric patients with GDF2 variants from a single center. Methods: We identified children with GDF2 pathogenic variants and variants of uncertain significance (VUS) from the Children\u2019s Hospital of Philadelphia Comprehensive HHT Program and cross-referenced the list with a full-text query by GDF2 gene name on &gt;53,000,000 visits to ensure complete ascertainment. Medical records were reviewed retrospectively, and variables of interest were abstracted. Results: The median age at genetic testing was 12 years (range 1.75\u201316). Reasons for genetic testing included telangiectasias, pulmonary hypertension, familial testing, respiratory symptoms, seizures, developmental disabilities, and lung arteriovenous malformations (AVMs). Four patients had missense VUS, including two novel VUS (c.34C&gt;G; p.Leu12Val, c.41C&gt;T; p.Ser14Phe), while three had pathogenic deletions. All patients experienced epistaxis, starting at a median age of 6 years (range 2\u201312). Three had telangiectasias. One patient had both a GDF2 VUS and a de novo partial endoglin (ENG) gene deletion. While this patient\u2019s symptoms of HHT are likely related to her ENG variant, synergy cannot be excluded, and two first-degree family members with clinically significant epistaxis also have the same GDF2 VUS. Notably, two patients had visceral AVMs\u2014one with a lung AVM and another with a vein of Galen malformation. Conclusions: Interpretation of GDF2 VUS and their relationship to clinical symptoms is challenging given the rarity of these genetic variants and the inadequate diagnostic utility of the current clinical criteria for HHT in the pediatric population. Further research with larger cohorts is necessary to improve the genotype\u2013phenotype correlation in GDF2-related HHT. Carefully collected clinical information with longitudinal follow-up may also assist in refining classification of GDF2 VUS as benign or pathogenic in the future.<\/jats:p>","DOI":"10.3390\/jcm14103359","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T09:13:38Z","timestamp":1747041218000},"page":"3359","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Clinical Phenotypes of a Pediatric Cohort with GDF2-Related Hereditary Hemorrhagic Telangiectasia"],"prefix":"10.3390","volume":"14","author":[{"given":"Owen","family":"Oliver","sequence":"first","affiliation":[{"name":"Division of Neurology, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison D.","family":"Britt","sequence":"additional","affiliation":[{"name":"Comprehensive Vascular Anomalies Program, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7316-8643","authenticated-orcid":false,"given":"Alexandra J.","family":"Borst","sequence":"additional","affiliation":[{"name":"Comprehensive Vascular Anomalies Program, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA"},{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA"},{"name":"Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2936-4396","authenticated-orcid":false,"given":"Elizabeth","family":"Goldmuntz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA"},{"name":"Division of Cardiology, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nihal","family":"Bakeer","sequence":"additional","affiliation":[{"name":"Comprehensive Vascular Anomalies Program, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA"},{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA"},{"name":"Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-shan","family":"Lang","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA"},{"name":"Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5836-7866","authenticated-orcid":false,"given":"Stephanie","family":"Fuller","sequence":"additional","affiliation":[{"name":"Division of Cardiac Surgery, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA"},{"name":"Department of Cardiothoracic Surgery, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1346-427X","authenticated-orcid":false,"given":"Arastoo","family":"Vossough","sequence":"additional","affiliation":[{"name":"Division of Neuroradiology, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA"},{"name":"Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0571-980X","authenticated-orcid":false,"given":"Lauren A.","family":"Beslow","sequence":"additional","affiliation":[{"name":"Division of Neurology, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA"},{"name":"Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA"},{"name":"Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"989","DOI":"10.7326\/M20-1443","article-title":"Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia","volume":"173","author":"Faughnan","year":"2020","journal-title":"Ann. 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