{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T20:36:57Z","timestamp":1777408617018,"version":"3.51.4"},"reference-count":36,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The\n                    <jats:italic>TBX4<\/jats:italic>\n                    gene has a critical importance in the development of the lower limbs and lungs. Pathogenic variants in this gene are associated with a variable spectrum of skeletal anomalies of the lower limb and pneumological manifestations, with dominant or recessive inheritance. Heterozygous variants are associated with the \u201cischio\u2010coxo\u2010podo\u2010patellar syndrome with or without pulmonary arterial hypertension (PAH)\u201d. This is an autosomal dominant syndrome characterized by aplasia or hypoplasia of the patellae, anomalies of the pelvis and feet and PAH. The typical onset of PAH in these patients is perinatally or during childhood. We here describe a patient with adult\u2010onset presentation of\n                    <jats:italic>TBX4<\/jats:italic>\n                    \u2010related PAH. The patient is a 64\u2010year\u2010old woman diagnosed with a gastrointestinal stromal tumor (GIST), for which she undertook treatment with Imatinib. After 2\u2009years of treatment, she developed signs of pulmonary hypertension with a pre\u2010capillary phenotype and received the diagnosis of drug\u2010induced PAH. Despite interruption of Imatinib treatment, the patient did not show any improvement, prompting genetic evaluation and the identification of a loss\u2010of\u2010function variant in the\n                    <jats:italic>TBX4<\/jats:italic>\n                    gene: c.810_819delinsCATCATGAGGT, p.(Ser271Ilefs*116). Further clinical and radiological investigations detected a mild skeletal dysplasia, confirming the diagnosis of ischio\u2010coxo\u2010podo\u2010patellar syndrome. We speculate that Imatinib treatment caused the onset of PAH in a patient with genetic predisposition but no previous pneumological manifestations. This would be in line with the hypothesis of additional factors being involved in the determination of\n                    <jats:italic>TBX4<\/jats:italic>\n                    \u2010associated phenotypes.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.64178","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T09:39:13Z","timestamp":1751621953000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pulmonary Arterial Hypertension Onset in an Adult Woman With a\n                    <scp>\n                      <i>TBX4<\/i>\n                    <\/scp>\n                    Likely Pathogenic Variant Following Imatinib Administration: A Case Report"],"prefix":"10.1002","volume":"197","author":[{"given":"Simone","family":"Carbonera","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Scelsi","sequence":"additional","affiliation":[{"name":"Cardiology Division Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Greco","sequence":"additional","affiliation":[{"name":"Cardiology Division Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Schirinzi","sequence":"additional","affiliation":[{"name":"Cardiology Division Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Turco","sequence":"additional","affiliation":[{"name":"Cardiology Division Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Casella","sequence":"additional","affiliation":[{"name":"Neurogenetics Research Center IRCCS Mondino Foundation  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Carboni","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaia","family":"Visani","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mauro","family":"Acquaro","sequence":"additional","affiliation":[{"name":"Cardiology Division Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1858-1152","authenticated-orcid":false,"given":"Stefano","family":"Ghio","sequence":"additional","affiliation":[{"name":"Cardiology Division Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9459-9741","authenticated-orcid":false,"given":"Silvia","family":"Kalantari","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"},{"name":"Medical Genetics Unit, Department of Diagnostic Medicine Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0600-6820","authenticated-orcid":false,"given":"Enza Maria","family":"Valente","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"},{"name":"Neurogenetics Research Center IRCCS Mondino Foundation  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4598-2023","authenticated-orcid":false,"given":"Fabio","family":"Sirchia","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"},{"name":"Medical Genetics Unit, Department of Diagnostic Medicine Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23626"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/144.1.249"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002866"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00585\u20102020"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62656"},{"key":"e_1_2_8_7_1","unstructured":"Durkie M.2024.\u201cACGS Best Practice Guidelines for Variant Classification in Rare Disease 2024.\u201d"},{"key":"e_1_2_8_8_1","volume-title":"StatPearls","author":"Flynn J. 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