{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:35:46Z","timestamp":1785404146803,"version":"3.56.0"},"reference-count":24,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2024ZD0526700"],"award-info":[{"award-number":["2024ZD0526700"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82270428"],"award-info":[{"award-number":["82270428"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82270428"],"award-info":[{"award-number":["82270428"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Research Ethics Committee of Peking University First Hospital, Beijing, China","award":["Apply 2025-341"],"award-info":[{"award-number":["Apply 2025-341"]}]},{"award":["Apply 2025-341"],"award-info":[{"award-number":["Apply 2025-341"]}],"id":[{"id":"https:\/\/ror.org\/02z1vqm45","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background: Pulmonary arterial hypertension is a rare but life-threatening condition in children, with hereditary forms often being linked to mutations in genes such as bone morphogenetic protein receptor type 2 (BMPR2), caveolin 1 (CAV1), and potassium channel subfamily K member 3 (KCNK3). Among these, CAV1 mutations are associated with severe disease phenotypes, though cases resulting from de novo heterozygous CAV1 mutations with multi-system involvement remain rarely reported. The CAV1 mutation (c.424C &gt; T, p.Q142X) disrupts caveolin-1 function, leading to dysregulated pulmonary vascular remodeling and multi-system abnormalities. Methods: This was a retrospective case study of a pediatric patient with hereditary PAH. The patient was followed at our hospital from initial presentation until death. Clinical data were collected from medical records, including physical examinations, laboratory tests, echocardiography, chest X-ray, computed tomography pulmonary angiography (CTPA), and genetic analysis. The patient was treated sequentially with various PAH-targeted medications. This report also includes a review of the relevant literature on CAV1-associated PAH. Results: A female aged 3 years and 11 months was diagnosed with hereditary PAH associated with a de novo heterozygous CAV1 mutation (c.424C &gt; T, p.Q142X). Both parents underwent genetic testing and were negative for the mutation, confirming its de novo origin. Clinical manifestations included special facial features, congenital telangiectasia, cutis marmorata (marbled skin), congenital cataract, hereditary lipodystrophy, and severe PAH. The patient presented with progressive exercise intolerance, syncope, and worsening dyspnea over nine years. Echocardiography revealed pulmonary hypertension with an estimated pulmonary artery systolic pressure of 69\u2013105 mmHg, right heart enlargement, right ventricular hypertrophy, and moderate tricuspid regurgitation. Blood and urine metabolic screenings were normal. A chest X-ray showed progressive enlargement of the cardiac silhouette and bulging of the pulmonary artery segment. CTPA demonstrated pulmonary hypertension, secondary right heart dysfunction, decompensated right ventricular function, and mosaic perfusion in both lungs, suggestive of small arterial branch occlusion. Right heart catheterization was declined by the parents. Thus, the diagnosis of PAH was established based on clinical, echocardiographic, CTPA, and genetic findings. The patient was hospitalized four times and lost to follow-up from 2017 to 2023. She received sequential treatment with digoxin, hydrochlorothiazide, tadalafil, ambrisentan, selexipag, and treprostinil. Despite these therapies, pulmonary artery pressure continued to rise with progressive clinical deterioration. The patient ultimately died at 13 years of age due to a pulmonary hypertensive crisis and multiple organ failure following a severe episode of gastroenteritis. Conclusions: Despite aggressive treatment with multiple targeted reduced pulmonary artery pressure drug therapies, managing hereditary PAH caused by CAV1 mutations in children remains a significant challenge, with a high mortality rate. Early genetic diagnosis, regular follow-up, and individualized treatment are crucial. It requires the joint efforts of patients, parents, and healthcare providers.<\/jats:p>","DOI":"10.3390\/children13050694","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T16:46:18Z","timestamp":1779381978000},"page":"694","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Rare Case of Multi-System Involvement and Hereditary Pulmonary Hypertension Caused by De Novo Heterozygous CAV1 Mutation in a Pediatric Patient"],"prefix":"10.3390","volume":"13","author":[{"given":"Yan","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Peking University First Hospital, Beijing 102600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyou","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University First Hospital, Beijing 102600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqian","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University First Hospital, Beijing 102600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University First Hospital, Beijing 102600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3618","DOI":"10.1093\/eurheartj\/ehac237","article-title":"2022 ESC\/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension","volume":"43","author":"Humbert","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kularatne, M., Gerges, C., Jevnikar, M., Humbert, M., and Montani, D. (2024). Updated Clinical Classification and Hemodynamic Definitions of Pulmonary Hypertension and Its Clinical Implications. J. Cardiovasc. Dev. Dis., 11.","DOI":"10.3390\/jcdd11030078"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Bassareo, P.P., Argiento, P., McMahon, C.J., Dunne, E., Walsh, K.P., Russo, M.G., and D\u2019Alto, M. (2023). Idiopathic Pulmonary Arterial Hypertension in Paediatrics Represents Still a Serious Challenge: A Case Series Study. Children, 10.","DOI":"10.3390\/children10030518"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Dai, L., and Du, L. (2022). Genes in pediatric pulmonary arterial hypertension and the most promising BMPR2 gene therapy. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.961848"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1056\/NEJMra2000348","article-title":"Pulmonary Arterial Hypertension","volume":"385","author":"Hassoun","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Osakwe, O., and Das, B.B. (2022). Successful Pulmonary Endarterectomy after Acute Pulmonary Embolism and Reversal of Acute Cor Pulmonale in an 11-Year-Old Boy with Nephrotic Syndrome. Children, 9.","DOI":"10.3390\/children9101444"},{"key":"ref_7","first-page":"862","article-title":"Genetic diagnostics and molecular approaches in pulmonary arterial hypertension","volume":"77","author":"Eichstaedt","year":"2023","journal-title":"Pneumologie"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100925","DOI":"10.1016\/j.gim.2023.100925","article-title":"Defining the clinical validity of genes reported to cause pulmonary arterial hypertension","volume":"25","author":"Welch","year":"2023","journal-title":"Genet. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jpeds.2020.05.051","article-title":"The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension","volume":"225","author":"Haarman","year":"2020","journal-title":"J. Pediatr."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Mathew, R. (2021). Critical Role of Caveolin-1 Loss\/Dysfunction in Pulmonary Hypertension. Med. Sci., 9.","DOI":"10.3390\/medsci9040058"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e047590","DOI":"10.1161\/JAHA.125.047590","article-title":"Role of Caveolae and Caveolin in Vascular Physiology and Pathology","volume":"15","author":"Zhang","year":"2026","journal-title":"J. Am. Heart Assoc."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Stea, D.M., and D\u2019Alessio, A. (2025). Caveolae: Metabolic Platforms at the Crossroads of Health and Disease. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26072918"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2102643","DOI":"10.1183\/13993003.02643-2021","article-title":"Endothelial PHD2 deficiency induces nitrative stress via suppression of caveolin-1 in pulmonary hypertension","volume":"60","author":"Liu","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s40272-019-00374-2","article-title":"Drug Treatment of Pulmonary Hypertension in Children","volume":"22","author":"Avitabile","year":"2020","journal-title":"Pediatr. Drugs"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1002\/ajmg.a.37115","article-title":"Whole Exome Sequencing Identifies De Novo Heterozygous CAV1 mutations Associated with a novel Neonatal Onset Lipodystrophy Syndrome","volume":"167A","author":"Garg","year":"2015","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.jare.2025.06.034","article-title":"Therapeutic role of caveolin family in stem cell fate and development for management of chronic degenerative diseases: A scientometric study to an in-depth review","volume":"81","author":"Ma","year":"2026","journal-title":"J. Adv. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Fan, J., Zheng, S., Wang, M., and Yuan, X. (2024). The critical roles of caveolin-1 in lung diseases. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1417834"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1530\/EJE-21-0915","article-title":"Biallelic CAV1 null variants induce congenital generalized lipodystrophy with achalasia","volume":"185","author":"Karhan","year":"2021","journal-title":"Eur. J. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e2010206118","DOI":"10.1073\/pnas.2010206118","article-title":"Type I interferon activation and endothelial dysfunction in caveolin-1 insufficiency-associated pulmonary arterial hypertension","volume":"118","author":"Gairhe","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e12100","DOI":"10.1002\/pul2.12100","article-title":"Caveolin-1 associated with severe (pediatric-onset) presentation of pulmonary arterial hypertension","volume":"12","author":"Farrell","year":"2022","journal-title":"Pulm. Circ."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Dalton, C.M., Schlegel, C., and Hunter, C.J. (2023). Caveolin-1: A Review of Intracellular Functions, Tissue-Specific Roles, and Epithelial Tight Junction Regulation. Biology, 12.","DOI":"10.3390\/biology12111402"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s42003-023-05693-2","article-title":"The Cavin-1\/Caveolin-1 interaction attenuates BMP\/Smad signaling in pulmonary hypertension by interfering with BMPR2\/Caveolin-1 binding","volume":"7","author":"Tomita","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.freeradbiomed.2026.03.009","article-title":"Smooth muscle NR4A3 upregulation caused by endothelial Caveolin-1 deficiency mediates vascular remodeling and pulmonary hypertension","volume":"249","author":"Huang","year":"2026","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1186\/s13019-024-03011-3","article-title":"International treatment outcomes of neonates on extracorporeal membrane oxygenation (ECMO) with persistent pulmonary hypertension of the newborn (PPHN): A systematic review","volume":"19","author":"Alhumaid","year":"2024","journal-title":"J. Cardiothorac. 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