Recurrent Venous Thrombosis in an Adolescent Male with CBS Mutation and Persistent Antiphospholipid Antibody Positivity: A Case Report

Recurrent Venous Thrombosis in an Adolescent Male with CBS Mutation and Persistent Antiphospholipid Antibody Positivity: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Recurrent Venous Thrombosis in an Adolescent Male with CBS Mutation and Persistent Antiphospholipid Antibody Positivity: A Case Report Yuebing Wang, Ru Li, Chun Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6756359/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Feb, 2026 Read the published version in Thrombosis Journal → Version 1 posted 8 You are reading this latest preprint version Abstract Homocysteine (Hcy) contributes to endothelial dysfunction and impaired thrombolysis, and genetic polymorphisms that elevate plasma Hcy concentrations have been linked to an increased risk of thrombosis. Notably, mutations in the cystathionine β-synthase (CBS) gene, which reduce enzymatic activity, are a well-established cause of hyperhomocysteinemia (HHcy). This case report presents a 15-year-old male with recurrent, severe deep vein thrombosis (DVT) of the lower extremities, accompanied by persistent positivity for antiphospholipid antibodies. Laboratory evaluation revealed elevated homocysteine levels and mutations in the CBS gene, highlighting an underlying genetic predisposition. The persistent presence of antiphospholipid antibodies further underscores the multifactorial nature of his thrombophilic condition, involving genetic, metabolic, and autoimmune mechanisms. Antiphospholipid Syndrome Hyperhomocysteinemia Cystathionine beta synthase (CBS) Venous Thromboembolism Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) of the lower limb and pulmonary embolism (PE), is a common and clinically significant condition 1 . Epidemiological evidence has demonstrated an independent association between elevated plasma homocysteine (Hcy) levels and an increased risk of VTE 2 , likely mediated through mechanisms such as endothelial dysfunction and impaired thrombolysis 3 . Genetic polymorphisms play a contributory role in thrombosis predisposition by elevating plasma Hcy concentrations 4 . Notably, mutations in the cystathionine β-synthase (CBS) gene lead to reduced enzymatic activity, resulting in elevated plasma Hcy levels, a condition known as hyperhomocysteinemia (HHcy) 5 . Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by diverse vascular and obstetric manifestations associated with antiphospholipid antibodies (aPLs). Hyperhomocysteinemia is not an uncommon finding in patients with primary APS and has been linked to cerebral microangiopathy, multiple aPL positivity, and the concurrent involvement of various vascular territories 6 . However, extremely elevated Hcy is uncommon. In a prospective study at Peking Union Medical College Hospital from 2013 to 2020, the median blood homocysteine levels were 11.20 (9.70–14.60) µmol/L in patients with isolated thrombotic APS and 9.9 (8.10–12.10) µmol/L in those with isolated obstetric APS 7 . This report describes a 15-year-old male with a history of recurrent severe deep vein thrombosis (DVT) of the lower extremities, congenital lens subluxation, aneurysm-like bone cysts, and persistent aPL positivity. He was found to have elevated homocysteine levels and mutations in the CBS gene. Case presentation In March 2024, a 15-year-old male presented with left lower abdominal pain, which was partially alleviated by applying pressure to the affected area. The patient also reported intermittent nausea, without accompanying vomiting, diarrhea, or fever, and maintained normal bowel movements. Subsequently, the patient developed gradual swelling of the left lower extremity, accompanied by localized skin temperature elevation, though without systemic fever. Notably, the patient had recently undergone surgical intervention for bilateral congenital lens subluxation. The patient initially presented to the General Surgery Department, where acute abdominal pathology was ruled out. Subsequently, color Doppler ultrasonography of the deep veins in both lower extremities was performed, revealing thrombosis in the left common femoral vein, great saphenous vein, upper femoral vein, and deep femoral vein. Additional color Doppler ultrasonography of the iliac veins indicated thrombosis in the left common iliac vein, the proximal segment of the internal iliac vein, and the external iliac vein. A pulmonary CT angiography (CTA) showed that he had pulmonary embolism (Fig. 1 ). Laboratory investigations revealed that the patient's white blood cell, red blood cell, and platelet counts, as well as liver and kidney functions, electrolytes, and routine urine and stool analyses, were within normal limits. Coagulation studies showed a prothrombin time of 17.0 seconds (reference range: 11.5–14.5 seconds), with normal prothrombin activity. The prothrombin international normalized ratio (INR) was 1.35 (reference range: 0.8–1.2), and the D-dimer level was elevated at 0.76 mg/L FEU (reference range: 0–0.5). Further testing of coagulation factor activities and plasma coagulation-related proteins revealed: plasma protein C activity at 81.0% (reference range: 70–140%), plasma protein S activity at 76.3% (reference range: 63.5–149%), and plasma antithrombin activity at 40.0% (reference range: 83–128%). The patient was diagnosed with venous thrombosis of the lower extremities, common iliac vein compression syndrome (Cockett's syndrome), left common iliac vein occlusion, and left external iliac vein occlusion. On March 31, 2024, the patient underwent inferior vena cava (IVC) filter placement, followed by percutaneous iliac vein balloon dilatation and percutaneous perforation of the inferior vena cava for thrombolysis on the subsequent day. The patient also had a history of pathologic fracture, and on April 8, 2024, an aspiration biopsy of a lesion in the left distal femur confirmed the diagnosis of a benign bone tumor—aneurysm-like bone cyst in the left distal femur. As a result, the patient underwent surgical intervention for the bone tumor on May 13, 2024. The patient was readmitted on May 27 for lower extremity deep vein thrombosis, experiencing intermittent swelling and pain. Ultrasound and CTV confirmed thrombosis and occlusion in multiple veins (Fig. 1 ). On May 30, the patient underwent angiography, IVC filter removal, and iliac vein balloon dilatation under local anesthesia. Post-procedure, anticoagulation therapy of edoxaban was initiated. On June 27, the patient was readmitted to the Vascular Surgery Unit with left lower extremity swelling and pain. CTV revealed filling defects in multiple veins, indicating common iliac vein compression syndrome. On July 1, balloon dilatation and stent implantation were performed via left lateral percutaneous puncture. Postoperatively, symptoms significantly improved. Further laboratory tests revealed an elevated lupus anticoagulant screening ratio (dRVVT), along with elevated anticardiolipin antibody IgG levels of 1.31 (reference range: <1.2) and 57.80 U/mL (reference range: 0–20), respectively. The Anti-nuclear antibody was negative. Complement C3 was mildly reduced at 0.74 g/L (reference range: 0.79–1.52 g/L). Notably, the patient's blood homocysteine level was significantly elevated at 180.7 µmol/L. On September 12, the patient's anti-beta2 glycoprotein I antibody testing was negative, while anti-cardiolipin antibody IgG was markedly elevated at 74 CU. Whole exome sequencing was performed on the patient's blood samples to screen for inherited disorders. The results identified two single nucleotide variants in the CBS gene that may be associated with the patient's clinical phenotype (Fig. 2 ). The first variant, c.1499C > A (p.Ser500), is a nonsense mutation in the CBS gene that could lead to loss of normal protein function via nonsense-mediated mRNA decay (NMD) or premature termination of the coding amino acid sequence. The second variant, c.502G > A (p.Val168Met), is a missense mutation in the CBS gene (Fig. 3 ). This variant, which has been identified in two heterozygous cases in the large-scale population frequency database gnomAD, has not been previously reported in pure heterozygotes. It has been documented in patients with cystathionine beta-synthase-deficient hyperhomocystinuria in a compound heterozygous state 8 . The patient was started on a regimen of oral aspirin (75 mg daily) and warfarin (4.5 mg daily) for anticoagulation therapy, along with hydroxychloroquine. To manage hyperhomocysteinemia, oral folic acid, betaine, vitamins B12 and B6 were prescribed to support homocysteine metabolism. By February 2025, his blood homocysteine levels had decreased to 10.5 µmol/L, demonstrating the treatment's effectiveness. Our patient presented with extensive venous thrombosis involving the left iliac and femoral veins and underwent multiple interventions, including inferior vena cava (IVC) filter placement and iliac vein stenting. Blood analysis revealed markedly elevated homocysteine (Hcy) levels (180.7 µmol/L). According to recent guidelines, mild-to-moderate hyperhomocysteinemia (HHcy) is characterized by Hcy concentrations between 10 and 100 µM, while severe HHcy is defined as levels exceeding 100 µM, the latter often associated with genetic mutations in the CBS or MTHFR genes 9 . The patient’s significantly elevated Hcy levels warranted further genetic analysis, which identified CBS gene mutations, including one nonsense mutation and one missense mutation. The patient's medical history includes multisystem involvement, with recurrent severe DVT of the lower extremities, congenital lens subluxation, aneurysm-like bone cyst (Fig. 4 ). CBS deficiency, a rare inborn error of metabolism resulting from mutations in the CBS gene, is characterized by severely elevated levels of the sulfur-amino acid homocysteine and its metabolites 10 . Classical homocystinuria, primarily caused by pathogenic missense mutations in CBS, is an autosomal recessive disorder and represents the most common cause of hyperhomocysteinemia. It can affect three major systems: the vasculature, connective tissue, and nervous system. Clinical manifestations include thromboembolism, myopia, lens ectopia, osteoporosis, lateral spine shift, intellectual disability, and seizures 11 , 12 . Ectopia lentis, a hallmark feature of CBS deficiency, occurs due to abnormalities in the structural proteins of the lens zonules, which disrupt the microfibrillar components and cause lens dislocation 13 , 14 . The prevalence of thrombotic complications among patients with CBS deficiency has been reported to range between 25% and 42% 15 . Elevated homocysteine levels contribute to disease pathogenesis through mechanisms such as smooth muscle proliferation, promoting vascular sclerosis, LDL cholesterol oxidation, and exacerbation of atherosclerosis. Additionally, homocysteine induces endoplasmic reticulum stress, impairs protein function, causes endothelial dysfunction, and inhibits anticoagulant protein activity, increasing the risk of thrombosis and vascular disease 16 , 17 . In conclusion, the pathological mechanisms of homocystinuria-associated thrombotic disorders include vascular sclerosis and hypercoagulability. The coexistence of multiple thrombophilic defects significantly increases the risk of thrombosis. Lopez et al. were the first to report a case of a 28-year-old man with extensive spontaneous deep vein thrombosis, attributed to a heterozygous factor V Leiden mutation along with the presence of lupus anticoagulant (LA) and elevated IgM anticardiolipin antibodies (ACA) 18 . More recently, Muñoz-Moreno et al. described a 25-year-old woman who presented with a high-risk, large, occlusive pulmonary embolism and was later diagnosed with primary antiphospholipid syndrome and hyperhomocysteinemia 6 . Similarly, our patient exhibited persistent positivity for antiphospholipid antibodies. Although both antiphospholipid antibodies and elevated homocysteine levels have overlapping effects on hemostasis, their precise interaction remains unclear. In patients with noncardiac cerebral ischemia, a higher frequency of moderate hyperhomocysteinemia has been observed in those with an abnormal increase in lupus anticoagulant 19 . Since both conditions independently elevate the risk of VTE, their coexistence may jointly increase the likelihood of VTE incidence and recurrence at a younger age. Warfarin and other vitamin K antagonists (VKAs) at therapeutic doses are the standard treatment for thrombotic APS 20 . Since antiphospholipid antibodies may contribute to the patient’s VTE as a potential thrombosis risk factor, he was started on a combination of antiplatelet and anticoagulation therapy, including aspirin, warfarin, folic acid, betaine, vitamin B6 and B12 supplementation. This approach, which includes aspirin, warfarin, folic acid and vitamin B6 and B12 supplementation, is designed to manage the immediate thrombotic risk while also addressing the underlying metabolic defect. In conclusion, the etiology of DVT is multifactorial, particularly in cases involving multisystem involvement and recurrent episodes. In patients with unexplained recurrent thrombosis, clinicians should consider the possibility of genetic mutations, as these may significantly impact treatment decisions. This case highlights the importance of thoroughly investigating underlying risk factors for VTE, including APS and hyperhomocysteinemia. Declarations Funding This study was funded by the Beijing Science and Technology Program (Z191100006619110), the China International Medical Exchange Foundation (No. Z-2018-40-2101), and the Research and Development Fund of Peking University People's Hospital (RD 2022-66). Ethics Approval and Consent This case report was conducted in accordance with ethical standards. The authors confirm that all procedures followed in the study were approved by the Ethics Committee of Peking University People’s Hospital. The ethics approval number is 2020PHB427-01. The patient’s parents consented to the publication of his case details in a medical journal, with the understanding that his case could be used for educational and research purposes. No personal identifying information has been included in the report to protect the patient's privacy. Consent to Publish The authors confirm that written informed consent has been obtained from the patient's parent for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of the journal. The patient’s parent understands that his personal information will be anonymized to the extent possible. References Kyrle, P. A. et al. The long‐term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study. Journal of Thrombosis and Haemostasis 14 , 2402-2409, doi:https://doi.org/10.1111/jth.13524 (2016). Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. Jama 288 , 2015-2022, doi:10.1001/jama.288.16.2015 (2002). Awan, Z. et al. Severe hyperhomocysteinemia due to cystathionine β-synthase deficiency, and Factor V Leiden mutation in a patient with recurrent venous thrombosis. Thrombosis Journal 12 , 30, doi:10.1186/s12959-014-0030-0 (2014). Karaca, M. et al. High prevalence of cerebral venous sinus thrombosis (CVST) as presentation of cystathionine beta-synthase deficiency in childhood: Molecular and clinical findings of Turkish probands. Gene 534 , 197-203, doi:https://doi.org/10.1016/j.gene.2013.10.060 (2014). Beard, R. S. & Bearden, S. E. Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research. American Journal of Physiology-Heart and Circulatory Physiology 300 , H13-H26, doi:10.1152/ajpheart.00598.2010 (2010). Muñoz-Moreno, J. M. et al. A 25-Year-Old Woman with a High-Risk Large and Occlusive Pulmonary Embolism, Later Diagnosed with Primary Antiphospholipid Syndrome and Hyperhomocysteinemia: A Case Report. Am J Case Rep 24 , e939078, doi:10.12659/ajcr.939078 (2023). Jiang, H. et al. Clinical characteristics and prognosis of patients with isolated thrombotic vs. obstetric antiphospholipid syndrome: a prospective cohort study. Arthritis Res Ther 23 , 138, doi:10.1186/s13075-021-02515-w (2021). Hua, N. et al. Recurrent dislocation of binocular crystal lenses in a patient with cystathionine beta-synthase deficiency. BMC Ophthalmol 21 , 212, doi:10.1186/s12886-021-01974-8 (2021). Hainsworth, A. H., Yeo, N. E., Weekman, E. M. & Wilcock, D. M. Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID). Biochim Biophys Acta 1862 , 1008-1017, doi:10.1016/j.bbadis.2015.11.015 (2016). Sikora, M., Lewandowska, I., Marczak, Ł., Bretes, E. & Jakubowski, H. Cystathionine β-synthase deficiency: different changes in proteomes of thrombosis-resistant Cbs−/− mice and thrombosis-prone CBS−/− humans. Scientific Reports 10 , 10726, doi:10.1038/s41598-020-67672-5 (2020). Bublil, E. M. & Majtan, T. Classical homocystinuria: From cystathionine beta-synthase deficiency to novel enzyme therapies. Biochimie 173 , 48-56, doi:10.1016/j.biochi.2019.12.007 (2020). Majtan, T. et al. Deciphering pathophysiological mechanisms underlying cystathionine beta-synthase-deficient homocystinuria using targeted metabolomics, liver proteomics, sphingolipidomics and analysis of mitochondrial function. Redox Biology 73 , 103222, doi:https://doi.org/10.1016/j.redox.2024.103222 (2024). Mudd, S. H. et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 37 , 1-31 (1985). Martínez-Gutiérrez, J. D., Mencía-Gutiérrez, E., Gracia-García-Miguel, T., Gutiérrez-Díaz, E. & López-Tizón, E. Classical familial homocystinuria in an adult presenting as an isolated lens subluxation. Int Ophthalmol 31 , 227-232, doi:10.1007/s10792-011-9444-x (2011). Yap, S. et al. Vascular Outcome in Patients With Homocystinuria due to Cystathionine β-Synthase Deficiency Treated Chronically. Arteriosclerosis, Thrombosis, and Vascular Biology 21 , 2080-2085, doi:10.1161/hq1201.100225 (2001). Omorou, M. et al. Cystathionine beta-Synthase in hypoxia and ischemia/reperfusion: A current overview. Arch Biochem Biophys 718 , 109149, doi:10.1016/j.abb.2022.109149 (2022). Jiang, X. et al. CBS and SERPINC1 mutation-induced ischemic stroke and multisystem diseases in a young woman: a case description and literature analysis. Quant Imaging Med Surg 13 , 5423-5429, doi:10.21037/qims-23-255 (2023). Lopez, F. F., Sweeney, J. D., Blair, A. J. & Sikov, W. M. Spontaneous venous thrombosis in a young patient with combined factor V Leiden and lupus anticoagulant. Am J Hematol 62 , 58-60, doi:10.1002/(sici)1096-8652(199909)62:13.0.co;2-0 (1999). Chen, W. H., Lin, H. S., Kao, Y. F., Lan, M. Y. & Liu, J. S. Hyperhomocysteinemia relates to the subtype of antiphospholipid antibodies in non-SLE patients. Clin Appl Thromb Hemost 13 , 398-403, doi:10.1177/1076029607303537 (2007). Sayar, Z., Moll, R., Isenberg, D. & Cohen, H. Thrombotic antiphospholipid syndrome: A practical guide to diagnosis and management. Thrombosis Research 198 , 213-221, doi:https://doi.org/10.1016/j.thromres.2020.10.010 (2021). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 05 Feb, 2026 Read the published version in Thrombosis Journal → Version 1 posted Editorial decision: Revision requested 14 Oct, 2025 Reviews received at journal 23 Sep, 2025 Reviewers agreed at journal 14 Sep, 2025 Reviewers agreed at journal 10 Jun, 2025 Reviewers invited by journal 10 Jun, 2025 Editor assigned by journal 02 Jun, 2025 Submission checks completed at journal 02 Jun, 2025 First submitted to journal 27 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6756359","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":469529036,"identity":"5a8d627d-80bc-41f6-8eed-240e40bc18d4","order_by":0,"name":"Yuebing Wang","email":"","orcid":"","institution":"Peking University People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuebing","middleName":"","lastName":"Wang","suffix":""},{"id":469529037,"identity":"5847b674-bf54-4047-ab90-ecf24c956e9a","order_by":1,"name":"Ru Li","email":"","orcid":"","institution":"Peking University People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ru","middleName":"","lastName":"Li","suffix":""},{"id":469529038,"identity":"918e4d39-c518-407b-962d-8eaf73b904b6","order_by":2,"name":"Chun Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYBACNv7mAwcSDGx42NibDz5IqKghrIVP4ljigQcFaXL8PMeSDR6cOUZYixxDjvHBBx8OG0vOyDGTfNjCTITDGI4lAB12OHHDjbS0isQGNgb+9u4E/FqYwX5JT9xw5vGxG4k7ZBgkzpzdQIwt1okbjqel3Ug8w8ZgIJFLSEuOAVALc+KGAzlmBYltzERrcTaW7MgxYyBOiwTYYZBAlkg4c4yHoF/k+5sPf/zxBxKVH39U1Mjxt/fi14IBeEhTPgpGwSgYBaMAKwAA0BdTK+UalH4AAAAASUVORK5CYII=","orcid":"","institution":"Peking University People’s Hospital","correspondingAuthor":true,"prefix":"","firstName":"Chun","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-05-27 07:08:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6756359/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6756359/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12959-025-00820-x","type":"published","date":"2026-02-05T15:58:15+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84670113,"identity":"00d2d789-0ed2-4df9-b140-b70843b630b4","added_by":"auto","created_at":"2025-06-16 06:35:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":157031,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eContrast-enhanced computed tomography angiography (CTA) performed on April 2, 2024, demonstrating pulmonary thrombosis.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6756359/v1/b079c9dcad6f98f40f092d3c.png"},{"id":84671345,"identity":"00ecfbc2-b6a6-485a-beac-bd49e1acbe66","added_by":"auto","created_at":"2025-06-16 06:43:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":132209,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComputed tomography venography (CTV) demonstrating complete occlusion of the left common iliac vein with extensive thrombosis extending through the left external iliac, femoral, and popliteal veins.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6756359/v1/c3c2415024ad8ad54f641a23.png"},{"id":84670116,"identity":"c15ac250-f260-4893-8b45-2434fb563cef","added_by":"auto","created_at":"2025-06-16 06:35:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":126989,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentation of the CBS gene structure highlighting the patient's mutations. Exons are depicted as orange numbered boxes. The two identified CBS variants are indicated and color-coded according to mutation type.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6756359/v1/994e1389ed7374d25bace2c3.png"},{"id":84671346,"identity":"37cfb6f0-8e59-4f2a-8ed7-7a03df6749e4","added_by":"auto","created_at":"2025-06-16 06:43:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":151342,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComprehensive clinical imaging demonstrating multiple pathological manifestations in the patient.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6756359/v1/9e49d18ee1a2e8957d3f2e9b.png"},{"id":102234765,"identity":"a479b688-6cc2-4308-bf4e-ad183e3e97ad","added_by":"auto","created_at":"2026-02-09 16:13:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1177519,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6756359/v1/b2e5ebe2-2a63-4d84-8893-a2bda6c5fa9d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Recurrent Venous Thrombosis in an Adolescent Male with CBS Mutation and Persistent Antiphospholipid Antibody Positivity: A Case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eVenous thromboembolism (VTE), comprising deep vein thrombosis (DVT) of the lower limb and pulmonary embolism (PE), is a common and clinically significant condition\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Epidemiological evidence has demonstrated an independent association between elevated plasma homocysteine (Hcy) levels and an increased risk of VTE\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, likely mediated through mechanisms such as endothelial dysfunction and impaired thrombolysis\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Genetic polymorphisms play a contributory role in thrombosis predisposition by elevating plasma Hcy concentrations\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Notably, mutations in the cystathionine β-synthase (CBS) gene lead to reduced enzymatic activity, resulting in elevated plasma Hcy levels, a condition known as hyperhomocysteinemia (HHcy)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAntiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by diverse vascular and obstetric manifestations associated with antiphospholipid antibodies (aPLs). Hyperhomocysteinemia is not an uncommon finding in patients with primary APS and has been linked to cerebral microangiopathy, multiple aPL positivity, and the concurrent involvement of various vascular territories\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. However, extremely elevated Hcy is uncommon. In a prospective study at Peking Union Medical College Hospital from 2013 to 2020, the median blood homocysteine levels were 11.20 (9.70\u0026ndash;14.60) \u0026micro;mol/L in patients with isolated thrombotic APS and 9.9 (8.10\u0026ndash;12.10) \u0026micro;mol/L in those with isolated obstetric APS\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. This report describes a 15-year-old male with a history of recurrent severe deep vein thrombosis (DVT) of the lower extremities, congenital lens subluxation, aneurysm-like bone cysts, and persistent aPL positivity. He was found to have elevated homocysteine levels and mutations in the CBS gene.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eIn March 2024, a 15-year-old male presented with left lower abdominal pain, which was partially alleviated by applying pressure to the affected area. The patient also reported intermittent nausea, without accompanying vomiting, diarrhea, or fever, and maintained normal bowel movements. Subsequently, the patient developed gradual swelling of the left lower extremity, accompanied by localized skin temperature elevation, though without systemic fever. Notably, the patient had recently undergone surgical intervention for bilateral congenital lens subluxation.\u003c/p\u003e \u003cp\u003eThe patient initially presented to the General Surgery Department, where acute abdominal pathology was ruled out. Subsequently, color Doppler ultrasonography of the deep veins in both lower extremities was performed, revealing thrombosis in the left common femoral vein, great saphenous vein, upper femoral vein, and deep femoral vein. Additional color Doppler ultrasonography of the iliac veins indicated thrombosis in the left common iliac vein, the proximal segment of the internal iliac vein, and the external iliac vein. A pulmonary CT angiography (CTA) showed that he had pulmonary embolism (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eLaboratory investigations revealed that the patient's white blood cell, red blood cell, and platelet counts, as well as liver and kidney functions, electrolytes, and routine urine and stool analyses, were within normal limits. Coagulation studies showed a prothrombin time of 17.0 seconds (reference range: 11.5\u0026ndash;14.5 seconds), with normal prothrombin activity. The prothrombin international normalized ratio (INR) was 1.35 (reference range: 0.8\u0026ndash;1.2), and the D-dimer level was elevated at 0.76 mg/L FEU (reference range: 0\u0026ndash;0.5). Further testing of coagulation factor activities and plasma coagulation-related proteins revealed: plasma protein C activity at 81.0% (reference range: 70\u0026ndash;140%), plasma protein S activity at 76.3% (reference range: 63.5\u0026ndash;149%), and plasma antithrombin activity at 40.0% (reference range: 83\u0026ndash;128%).\u003c/p\u003e \u003cp\u003eThe patient was diagnosed with venous thrombosis of the lower extremities, common iliac vein compression syndrome (Cockett's syndrome), left common iliac vein occlusion, and left external iliac vein occlusion. On March 31, 2024, the patient underwent inferior vena cava (IVC) filter placement, followed by percutaneous iliac vein balloon dilatation and percutaneous perforation of the inferior vena cava for thrombolysis on the subsequent day. The patient also had a history of pathologic fracture, and on April 8, 2024, an aspiration biopsy of a lesion in the left distal femur confirmed the diagnosis of a benign bone tumor\u0026mdash;aneurysm-like bone cyst in the left distal femur. As a result, the patient underwent surgical intervention for the bone tumor on May 13, 2024.\u003c/p\u003e \u003cp\u003eThe patient was readmitted on May 27 for lower extremity deep vein thrombosis, experiencing intermittent swelling and pain. Ultrasound and CTV confirmed thrombosis and occlusion in multiple veins (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). On May 30, the patient underwent angiography, IVC filter removal, and iliac vein balloon dilatation under local anesthesia. Post-procedure, anticoagulation therapy of edoxaban was initiated. On June 27, the patient was readmitted to the Vascular Surgery Unit with left lower extremity swelling and pain. CTV revealed filling defects in multiple veins, indicating common iliac vein compression syndrome. On July 1, balloon dilatation and stent implantation were performed via left lateral percutaneous puncture. Postoperatively, symptoms significantly improved.\u003c/p\u003e \u003cp\u003eFurther laboratory tests revealed an elevated lupus anticoagulant screening ratio (dRVVT), along with elevated anticardiolipin antibody IgG levels of 1.31 (reference range: \u0026lt;1.2) and 57.80 U/mL (reference range: 0\u0026ndash;20), respectively. The Anti-nuclear antibody was negative. Complement C3 was mildly reduced at 0.74 g/L (reference range: 0.79\u0026ndash;1.52 g/L). Notably, the patient's blood homocysteine level was significantly elevated at 180.7 \u0026micro;mol/L.\u003c/p\u003e \u003cp\u003eOn September 12, the patient's anti-beta2 glycoprotein I antibody testing was negative, while anti-cardiolipin antibody IgG was markedly elevated at 74 CU. Whole exome sequencing was performed on the patient's blood samples to screen for inherited disorders. The results identified two single nucleotide variants in the CBS gene that may be associated with the patient's clinical phenotype (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The first variant, c.1499C\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Ser500), is a nonsense mutation in the CBS gene that could lead to loss of normal protein function via nonsense-mediated mRNA decay (NMD) or premature termination of the coding amino acid sequence. The second variant, c.502G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Val168Met), is a missense mutation in the CBS gene (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This variant, which has been identified in two heterozygous cases in the large-scale population frequency database gnomAD, has not been previously reported in pure heterozygotes. It has been documented in patients with cystathionine beta-synthase-deficient hyperhomocystinuria in a compound heterozygous state\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. The patient was started on a regimen of oral aspirin (75 mg daily) and warfarin (4.5 mg daily) for anticoagulation therapy, along with hydroxychloroquine. To manage hyperhomocysteinemia, oral folic acid, betaine, vitamins B12 and B6 were prescribed to support homocysteine metabolism. By February 2025, his blood homocysteine levels had decreased to 10.5 \u0026micro;mol/L, demonstrating the treatment's effectiveness.\u003c/p\u003e \u003cp\u003eOur patient presented with extensive venous thrombosis involving the left iliac and femoral veins and underwent multiple interventions, including inferior vena cava (IVC) filter placement and iliac vein stenting. Blood analysis revealed markedly elevated homocysteine (Hcy) levels (180.7 \u0026micro;mol/L). According to recent guidelines, mild-to-moderate hyperhomocysteinemia (HHcy) is characterized by Hcy concentrations between 10 and 100 \u0026micro;M, while severe HHcy is defined as levels exceeding 100 \u0026micro;M, the latter often associated with genetic mutations in the CBS or MTHFR genes\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The patient\u0026rsquo;s significantly elevated Hcy levels warranted further genetic analysis, which identified CBS gene mutations, including one nonsense mutation and one missense mutation.\u003c/p\u003e \u003cp\u003eThe patient's medical history includes multisystem involvement, with recurrent severe DVT of the lower extremities, congenital lens subluxation, aneurysm-like bone cyst (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). CBS deficiency, a rare inborn error of metabolism resulting from mutations in the CBS gene, is characterized by severely elevated levels of the sulfur-amino acid homocysteine and its metabolites\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Classical homocystinuria, primarily caused by pathogenic missense mutations in CBS, is an autosomal recessive disorder and represents the most common cause of hyperhomocysteinemia. It can affect three major systems: the vasculature, connective tissue, and nervous system. Clinical manifestations include thromboembolism, myopia, lens ectopia, osteoporosis, lateral spine shift, intellectual disability, and seizures\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Ectopia lentis, a hallmark feature of CBS deficiency, occurs due to abnormalities in the structural proteins of the lens zonules, which disrupt the microfibrillar components and cause lens dislocation\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe prevalence of thrombotic complications among patients with CBS deficiency has been reported to range between 25% and 42%\u003csup\u003e15\u003c/sup\u003e. Elevated homocysteine levels contribute to disease pathogenesis through mechanisms such as smooth muscle proliferation, promoting vascular sclerosis, LDL cholesterol oxidation, and exacerbation of atherosclerosis. Additionally, homocysteine induces endoplasmic reticulum stress, impairs protein function, causes endothelial dysfunction, and inhibits anticoagulant protein activity, increasing the risk of thrombosis and vascular disease\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. In conclusion, the pathological mechanisms of homocystinuria-associated thrombotic disorders include vascular sclerosis and hypercoagulability.\u003c/p\u003e \u003cp\u003eThe coexistence of multiple thrombophilic defects significantly increases the risk of thrombosis. Lopez et al. were the first to report a case of a 28-year-old man with extensive spontaneous deep vein thrombosis, attributed to a heterozygous factor V Leiden mutation along with the presence of lupus anticoagulant (LA) and elevated IgM anticardiolipin antibodies (ACA)\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. More recently, Mu\u0026ntilde;oz-Moreno et al. described a 25-year-old woman who presented with a high-risk, large, occlusive pulmonary embolism and was later diagnosed with primary antiphospholipid syndrome and hyperhomocysteinemia\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Similarly, our patient exhibited persistent positivity for antiphospholipid antibodies. Although both antiphospholipid antibodies and elevated homocysteine levels have overlapping effects on hemostasis, their precise interaction remains unclear. In patients with noncardiac cerebral ischemia, a higher frequency of moderate hyperhomocysteinemia has been observed in those with an abnormal increase in lupus anticoagulant\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Since both conditions independently elevate the risk of VTE, their coexistence may jointly increase the likelihood of VTE incidence and recurrence at a younger age.\u003c/p\u003e \u003cp\u003eWarfarin and other vitamin K antagonists (VKAs) at therapeutic doses are the standard treatment for thrombotic APS\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Since antiphospholipid antibodies may contribute to the patient\u0026rsquo;s VTE as a potential thrombosis risk factor, he was started on a combination of antiplatelet and anticoagulation therapy, including aspirin, warfarin, folic acid, betaine, vitamin B6 and B12 supplementation. This approach, which includes aspirin, warfarin, folic acid and vitamin B6 and B12 supplementation, is designed to manage the immediate thrombotic risk while also addressing the underlying metabolic defect.\u003c/p\u003e \u003cp\u003eIn conclusion, the etiology of DVT is multifactorial, particularly in cases involving multisystem involvement and recurrent episodes. In patients with unexplained recurrent thrombosis, clinicians should consider the possibility of genetic mutations, as these may significantly impact treatment decisions. This case highlights the importance of thoroughly investigating underlying risk factors for VTE, including APS and hyperhomocysteinemia.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the Beijing Science and Technology Program (Z191100006619110), the China International Medical Exchange Foundation (No. Z-2018-40-2101), and the Research and Development Fund of Peking University People\u0026apos;s Hospital (RD 2022-66).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eEthics Approval and Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case report was conducted in accordance with ethical standards. The authors confirm that all procedures followed in the study were approved by the Ethics Committee of Peking University People\u0026rsquo;s Hospital. The ethics approval number is 2020PHB427-01.\u003c/p\u003e\n\u003cp\u003eThe patient\u0026rsquo;s parents consented to the publication of his case details in a medical journal, with the understanding that his case could be used for educational and research purposes. No personal identifying information has been included in the report to protect the patient\u0026apos;s privacy.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eConsent to Publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that written informed consent has been obtained from the patient\u0026apos;s parent for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of the journal. The patient\u0026rsquo;s parent understands that his personal information will be anonymized to the extent possible.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKyrle, P. A.\u003cem\u003e et al.\u003c/em\u003e The long‐term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study. \u003cem\u003eJournal of Thrombosis and Haemostasis\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 2402-2409, doi:https://doi.org/10.1111/jth.13524 (2016).\u003c/li\u003e\n\u003cli\u003eHomocysteine and risk of ischemic heart disease and stroke: a meta-analysis. \u003cem\u003eJama\u003c/em\u003e \u003cstrong\u003e288\u003c/strong\u003e, 2015-2022, doi:10.1001/jama.288.16.2015 (2002).\u003c/li\u003e\n\u003cli\u003eAwan, Z.\u003cem\u003e et al.\u003c/em\u003e Severe hyperhomocysteinemia due to cystathionine \u0026beta;-synthase deficiency, and Factor V Leiden mutation in a patient with recurrent venous thrombosis. \u003cem\u003eThrombosis Journal\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 30, doi:10.1186/s12959-014-0030-0 (2014).\u003c/li\u003e\n\u003cli\u003eKaraca, M.\u003cem\u003e et al.\u003c/em\u003e High prevalence of cerebral venous sinus thrombosis (CVST) as presentation of cystathionine beta-synthase deficiency in childhood: Molecular and clinical findings of Turkish probands. \u003cem\u003eGene\u003c/em\u003e \u003cstrong\u003e534\u003c/strong\u003e, 197-203, doi:https://doi.org/10.1016/j.gene.2013.10.060 (2014).\u003c/li\u003e\n\u003cli\u003eBeard, R. S. \u0026amp; Bearden, S. E. Vascular complications of cystathionine \u0026beta;-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research. \u003cem\u003eAmerican Journal of Physiology-Heart and Circulatory Physiology\u003c/em\u003e \u003cstrong\u003e300\u003c/strong\u003e, H13-H26, doi:10.1152/ajpheart.00598.2010 (2010).\u003c/li\u003e\n\u003cli\u003eMu\u0026ntilde;oz-Moreno, J. M.\u003cem\u003e et al.\u003c/em\u003e A 25-Year-Old Woman with a High-Risk Large and Occlusive Pulmonary Embolism, Later Diagnosed with Primary Antiphospholipid Syndrome and Hyperhomocysteinemia: A Case Report. \u003cem\u003eAm J Case Rep\u003c/em\u003e \u003cstrong\u003e24\u003c/strong\u003e, e939078, doi:10.12659/ajcr.939078 (2023).\u003c/li\u003e\n\u003cli\u003eJiang, H.\u003cem\u003e et al.\u003c/em\u003e Clinical characteristics and prognosis of patients with isolated thrombotic vs. obstetric antiphospholipid syndrome: a prospective cohort study. \u003cem\u003eArthritis Res Ther\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 138, doi:10.1186/s13075-021-02515-w (2021).\u003c/li\u003e\n\u003cli\u003eHua, N.\u003cem\u003e et al.\u003c/em\u003e Recurrent dislocation of binocular crystal lenses in a patient with cystathionine beta-synthase deficiency. \u003cem\u003eBMC Ophthalmol\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e, 212, doi:10.1186/s12886-021-01974-8 (2021).\u003c/li\u003e\n\u003cli\u003eHainsworth, A. H., Yeo, N. E., Weekman, E. M. \u0026amp; Wilcock, D. M. Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID). \u003cem\u003eBiochim Biophys Acta\u003c/em\u003e \u003cstrong\u003e1862\u003c/strong\u003e, 1008-1017, doi:10.1016/j.bbadis.2015.11.015 (2016).\u003c/li\u003e\n\u003cli\u003eSikora, M., Lewandowska, I., Marczak, Ł., Bretes, E. \u0026amp; Jakubowski, H. Cystathionine \u0026beta;-synthase deficiency: different changes in proteomes of thrombosis-resistant Cbs\u0026minus;/\u0026minus; mice and thrombosis-prone CBS\u0026minus;/\u0026minus; humans. \u003cem\u003eScientific Reports\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 10726, doi:10.1038/s41598-020-67672-5 (2020).\u003c/li\u003e\n\u003cli\u003eBublil, E. M. \u0026amp; Majtan, T. Classical homocystinuria: From cystathionine beta-synthase deficiency to novel enzyme therapies. \u003cem\u003eBiochimie\u003c/em\u003e \u003cstrong\u003e173\u003c/strong\u003e, 48-56, doi:10.1016/j.biochi.2019.12.007 (2020).\u003c/li\u003e\n\u003cli\u003eMajtan, T.\u003cem\u003e et al.\u003c/em\u003e Deciphering pathophysiological mechanisms underlying cystathionine beta-synthase-deficient homocystinuria using targeted metabolomics, liver proteomics, sphingolipidomics and analysis of mitochondrial function. \u003cem\u003eRedox Biology\u003c/em\u003e \u003cstrong\u003e73\u003c/strong\u003e, 103222, doi:https://doi.org/10.1016/j.redox.2024.103222 (2024).\u003c/li\u003e\n\u003cli\u003eMudd, S. H.\u003cem\u003e et al.\u003c/em\u003e The natural history of homocystinuria due to cystathionine beta-synthase deficiency. \u003cem\u003eAm J Hum Genet\u003c/em\u003e \u003cstrong\u003e37\u003c/strong\u003e, 1-31 (1985).\u003c/li\u003e\n\u003cli\u003eMart\u0026iacute;nez-Guti\u0026eacute;rrez, J. D., Menc\u0026iacute;a-Guti\u0026eacute;rrez, E., Gracia-Garc\u0026iacute;a-Miguel, T., Guti\u0026eacute;rrez-D\u0026iacute;az, E. \u0026amp; L\u0026oacute;pez-Tiz\u0026oacute;n, E. Classical familial homocystinuria in an adult presenting as an isolated lens subluxation. \u003cem\u003eInt Ophthalmol\u003c/em\u003e \u003cstrong\u003e31\u003c/strong\u003e, 227-232, doi:10.1007/s10792-011-9444-x (2011).\u003c/li\u003e\n\u003cli\u003eYap, S.\u003cem\u003e et al.\u003c/em\u003e Vascular Outcome in Patients With Homocystinuria due to Cystathionine \u0026beta;-Synthase Deficiency Treated Chronically. \u003cem\u003eArteriosclerosis, Thrombosis, and Vascular Biology\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e, 2080-2085, doi:10.1161/hq1201.100225 (2001).\u003c/li\u003e\n\u003cli\u003eOmorou, M.\u003cem\u003e et al.\u003c/em\u003e Cystathionine beta-Synthase in hypoxia and ischemia/reperfusion: A current overview. \u003cem\u003eArch Biochem Biophys\u003c/em\u003e \u003cstrong\u003e718\u003c/strong\u003e, 109149, doi:10.1016/j.abb.2022.109149 (2022).\u003c/li\u003e\n\u003cli\u003eJiang, X.\u003cem\u003e et al.\u003c/em\u003e CBS and SERPINC1 mutation-induced ischemic stroke and multisystem diseases in a young woman: a case description and literature analysis. \u003cem\u003eQuant Imaging Med Surg\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 5423-5429, doi:10.21037/qims-23-255 (2023).\u003c/li\u003e\n\u003cli\u003eLopez, F. F., Sweeney, J. D., Blair, A. J. \u0026amp; Sikov, W. M. Spontaneous venous thrombosis in a young patient with combined factor V Leiden and lupus anticoagulant. \u003cem\u003eAm J Hematol\u003c/em\u003e \u003cstrong\u003e62\u003c/strong\u003e, 58-60, doi:10.1002/(sici)1096-8652(199909)62:1\u0026lt;58::aid-ajh11\u0026gt;3.0.co;2-0 (1999).\u003c/li\u003e\n\u003cli\u003eChen, W. H., Lin, H. S., Kao, Y. F., Lan, M. Y. \u0026amp; Liu, J. S. Hyperhomocysteinemia relates to the subtype of antiphospholipid antibodies in non-SLE patients. \u003cem\u003eClin Appl Thromb Hemost\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 398-403, doi:10.1177/1076029607303537 (2007).\u003c/li\u003e\n\u003cli\u003eSayar, Z., Moll, R., Isenberg, D. \u0026amp; Cohen, H. Thrombotic antiphospholipid syndrome: A practical guide to diagnosis and management. \u003cem\u003eThrombosis Research\u003c/em\u003e \u003cstrong\u003e198\u003c/strong\u003e, 213-221, doi:https://doi.org/10.1016/j.thromres.2020.10.010 (2021).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"thrombosis-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thrj","sideBox":"Learn more about [Thrombosis Journal](http://thrombosisjournal.biomedcentral.com/)","snPcode":"12959","submissionUrl":"https://submission.nature.com/new-submission/12959/3","title":"Thrombosis Journal","twitterHandle":"@Thrombosis_J","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Antiphospholipid Syndrome, Hyperhomocysteinemia, Cystathionine beta synthase (CBS), Venous Thromboembolism","lastPublishedDoi":"10.21203/rs.3.rs-6756359/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6756359/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHomocysteine (Hcy) contributes to endothelial dysfunction and impaired thrombolysis, and genetic polymorphisms that elevate plasma Hcy concentrations have been linked to an increased risk of thrombosis. Notably, mutations in the cystathionine β-synthase (CBS) gene, which reduce enzymatic activity, are a well-established cause of hyperhomocysteinemia (HHcy). This case report presents a 15-year-old male with recurrent, severe deep vein thrombosis (DVT) of the lower extremities, accompanied by persistent positivity for antiphospholipid antibodies. Laboratory evaluation revealed elevated homocysteine levels and mutations in the CBS gene, highlighting an underlying genetic predisposition. The persistent presence of antiphospholipid antibodies further underscores the multifactorial nature of his thrombophilic condition, involving genetic, metabolic, and autoimmune mechanisms.\u003c/p\u003e","manuscriptTitle":"Recurrent Venous Thrombosis in an Adolescent Male with CBS Mutation and Persistent Antiphospholipid Antibody Positivity: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-16 06:35:30","doi":"10.21203/rs.3.rs-6756359/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-14T06:52:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-23T08:33:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"229136479508015104036347368473270000767","date":"2025-09-14T16:57:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"168946579661927509856806124189993508625","date":"2025-06-10T14:01:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-10T13:00:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-02T09:37:39+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-02T09:35:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"Thrombosis Journal","date":"2025-05-27T07:01:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"thrombosis-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thrj","sideBox":"Learn more about [Thrombosis Journal](http://thrombosisjournal.biomedcentral.com/)","snPcode":"12959","submissionUrl":"https://submission.nature.com/new-submission/12959/3","title":"Thrombosis Journal","twitterHandle":"@Thrombosis_J","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fefda5ea-cde6-4bc0-9b73-ab75bd70ca9a","owner":[],"postedDate":"June 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T16:08:51+00:00","versionOfRecord":{"articleIdentity":"rs-6756359","link":"https://doi.org/10.1186/s12959-025-00820-x","journal":{"identity":"thrombosis-journal","isVorOnly":false,"title":"Thrombosis Journal"},"publishedOn":"2026-02-05 15:58:15","publishedOnDateReadable":"February 5th, 2026"},"versionCreatedAt":"2025-06-16 06:35:30","video":"","vorDoi":"10.1186/s12959-025-00820-x","vorDoiUrl":"https://doi.org/10.1186/s12959-025-00820-x","workflowStages":[]},"version":"v1","identity":"rs-6756359","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6756359","identity":"rs-6756359","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}