Beyond Epistaxis: Cascade Screening and Presymptomatic Treatment of Hereditary Hemorrhagic Telangiectasia

Beyond Epistaxis: Cascade Screening and Presymptomatic Treatment of Hereditary Hemorrhagic Telangiectasia | 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 Beyond Epistaxis: Cascade Screening and Presymptomatic Treatment of Hereditary Hemorrhagic Telangiectasia Chen Xiang Ang, Hui-Lin Chin, Shu Zhen Teresa Tan, Denise Li Meng Goh This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7509064/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Jan, 2026 Read the published version in BMC Pediatrics → Version 1 posted 12 You are reading this latest preprint version Abstract Background Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder that may present with recurrent epistaxis, mucocutaneous telangiectasias, or visceral arteriovenous malformations (AVMs), yet its early signs may be overlooked in children. Case Presentation We report a family in which a fifteen-year old boy and his mother presented for genetic evaluation of recurrent epistaxis, after his previously well seven-year-old sister demised suddenly from likely spontaneous atraumatic intracranial hemorrhage, following a brief history of headache and vomiting. She had a background of infrequent nosebleeds and a family history of recurrent epistaxis in multiple maternal relatives. Genetic testing in the mother diagnosed HHT (heterozygous for NM_001114753(ENG):c.1134G>A (p.Ala378=) , an established pathogenic variant). Cascade testing for her two surviving children was done. The fifteen-year-old boy tested positive and was found on subsequent screening to have intracranial vascular malformations which were treated pre-symptomatically with gamma knife surgery. Another son tested negative. Conclusion This case emphasizes the prompt recognition of HHT in children presenting with recurrent epistaxis and highlights the need for thorough family history. Pediatricians play a crucial role in early diagnosis and referral for genetic testing with subsequent surveillance imaging. Early identification can prevent catastrophic outcomes such as intracranial hemorrhage. This case emphasizes the need for heightened awareness of HHT in pediatric practice and supports the value of integrating genetic cascade testing and organ-specific screening in at-risk children, even before symptoms appear. Hereditary Hemorrhagic Telangiectasia Epistaxis Intracranial Hemorrhage Arteriovenous Malformation Genetic Cascade Testing Genogram Figures Figure 1 BACKGROUND Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic condition characterized by the presence of vascular malformations. It is associated with mutations in genes including ENG, ACVRL1, SMAD4, or GDF2 , which are involved in signaling pathway of transforming growth factor-beta (TGF-β) / bone morphogenic protein (BMP) 1 , 2 , 3 . Clinically, this manifests as spontaneous recurrent epistaxis, mucocutaneous telangiectasias, and AVMs in organs including the brain, pulmonary system, and liver 4 , 5 . Early recognition can be challenging in children, as epistaxis and telangiectasia may be absent or subtle, and these signs are expressed in an age-dependent manner 6 . Prompt diagnosis through genetic testing and subsequent surveillance screening is important due to the potential risk of morbidity and mortality that visceral AVMs have. Although HHT is more commonly seen in adults, pediatricians need to be watchful in cases with relevant family history suggesting an autosomal dominant pattern of inheritance. Proactive intervention before the onset of symptoms can be lifesaving. Prompted by the unfortunate passing of his younger sister, we present the clinical journey of a pediatric patient and his mother with HHT, and highlight the importance of genetic cascade testing, multidisciplinary teamwork and pre-symptomatic neurosurgical intervention. CASE PRESENTATION Our patient is a fifteen-year-old boy, reviewed at the Pediatric Genetics Service after the sudden death of his seven-year-old sister from atraumatic intracranial hemorrhage. The boy had a history of recurrent spontaneous epistaxis. This occurred several times a month, and would resolve with manual compression. This was not associated with other bleeding manifestations, symptoms of anemia, or systemic complaints. He was otherwise well thrived. On physical examination, he had visible lip telangiectasias with sparing of the fingers and periungual region. Neurological examination did not reveal any deficits. Vital signs were within normal limits and general examination was unremarkable. His mother, a forty-two-year-old woman, had a history of recurrent spontaneous epistaxis and mucocutaneous telangiectasias. She had been on follow-up with Adult Otolaryngology and Respiratory Medicine Services, and fulfilled two Curaçao criteria for HHT 5 . As such, surveillance imaging had been previously done for her, including magnetic resonance imaging (MRI) of the brain and computed tomography (CT) of the thorax in 2021, which were negative for AVMs. Family history showed an autosomal dominant pattern of inheritance (Fig. 1 ). Relatives across three generations on the maternal side had a history of recurrent spontaneous epistaxis. There was no family history of prior stroke or intracranial bleeds. No formal diagnosis or genetic testing had been performed in the family. The patient had two siblings: a twelve-year-old brother and seven-year-old sister. The younger brother was asymptomatic while the younger sister had a history of infrequent epistaxis. In March 2022, the younger sister passed away from spontaneous atraumatic intracranial hemorrhage. She had presented to a General Practitioner’s clinic with a one-day history of vomiting and lethargy. While awaiting evaluation, she experienced a cardiac arrest. Prompt resuscitation was initiated, and she was transferred expediently to the nearest tertiary hospital, however, there was no return of spontaneous circulation. History and clinical findings of raised intracranial pressure were consistent with a diagnosis of likely atraumatic intracranial hemorrhage. Unfortunately, confirmatory postmortem brain imaging was not available. Apart from having a past medical history of Kawasaki disease at age three years old with discharge from follow-up, our patient’s sister was well prior to the event. In view of the mother’s clinical history and the sibling’s demise from likely intracranial hemorrhage, the family sought genetic evaluation. Genetic testing (gene panel at a clinically-accredited commercial laboratory) was performed on the mother which showed that she was heterozygous for NM_001114753(ENG):c.1134G > A (p.Ala378=) , an established pathogenic variant 8 , confirming the diagnosis of HHT. Cascade testing was then performed on the surviving children. Her twelve-year-old son tested negative for the familial variant and was discharged from follow-up. Our fifteen-year old patient tested positive for the same pathogenic variant. Following the diagnosis, he underwent baseline screening for visceral AVMs. Pulse oximetry and chest radiography were normal. He was referred to the Otolaryngology Service for follow-up of his epistaxis and was additionally diagnosed with allergic rhinitis. Magnetic resonance imaging (MRI) and Magnetic Resonance Angiography (MRA) of the brain showed focal prominent vessels and nodular foci in the right occipital lobe, without definite nidus or abnormal flow signals on MRA. There was focal hemosiderin staining in the right occipital cortex is likely related to prior hemorrhage. Digital subtraction angiography (DSA) was then performed and which revealed small vascular malformations at the vertex from the left internal carotid artery, along with additional small vascular formations in the posterior circulation. A multidisciplinary team review concluded that the lesions were not amenable to embolization or surgical resection due to their small size, multiple number, and location being peripheral in nature. Gamma Knife Stereotactic radiosurgery was recommended as the treatment modality. Intraoperatively, four AVM nidus sites were identified and treated with a prescription dose of 25 Gray successfully. Immediate postoperative brain MRI was unremarkable. At follow-up, the patient remained neurologically intact and continued to have only infrequent, self-limiting episodes of epistaxis. He had no evidence of anemia, gastrointestinal bleeding, or other systemic involvement. He remains under follow-up with Genetics, Neurosurgery, and Otolaryngology Services. DISCUSSION AND CONCLUSION AVMs that remain undetected and untreated in visceral organs have high morbidity and mortality risk 9 . Targeted screening can prevent these outcomes. Pediatricians need to take a detailed family history and construct a genogram when evaluating children with symptomatic family members. In our patient, recognition of an autosomal dominant inheritance pattern in the maternal lineage prompted timely screening that diagnosed HHT. Pre-symptomatic treatment of his brain AVMs likely averted a potentially catastrophic intracranial bleed. This case raises the question: if genetic testing had been initiated earlier for this family, would this have triggered timely screening for AVMs, and possibly allowed for preventive management in the proband's younger sister? Our experience supports initiating family discussions about genetic testing as soon as the diagnosis of HHT is suspected. Since the first International HHT Guidelines, genetic testing has been recommended for first degree relatives of individuals with a confirmed diagnosis of HHT 10 . Pathogenic variants in ENG (HHT1), ACVRL1 (HHT2) , and SMAD4 (JP-HHT) account for 97% of patients with definite HHT 4 , 5 , 6 . Pediatricians and General Practitioners play a crucial role in picking up subtle clinical signs and initiating referrals for genetic counseling and testing when the family history is suggestive. This case underscores the importance of proactive identification, counselling, and surveillance of at-risk children to prevent life-threatening complications and improve long-term outcomes. PATIENT PERSPECTIVE HHT is a rare disease that has been in my family generation for years which we were unaware of. Our elders would typically dismiss the occasional nose bleeds as a normal symptom for body heatiness and imparted this knowledge down the family line. The passing of our beloved daughter has been a tragic loss that was unexpected and sudden. I hope doctors and medical practitioners can work together towards sharing more information about the HHT disease in order to create more awareness. Early intervention or preventative measures can be taken so that no family should go through such an ordeal as mine. Abbreviations HHT hereditary hemorrhagic telangiectasia AVM arteriovenous malformation MRI magnetic resonance imaging CT computered tomography TGF-β Transforming Growth Factor-Beta BMP Bone Morphogenic Protein MRA magnetic resonance angiography DSA Digital subtraction angiography Declarations Ethics approval and consent to participate: Not applicable Consent for publication: Written and signed consent to publish the information from the patients and their guardians have been obtained . Availability of data and materials: Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. Competing interests: All authors have no conflicts of interest to disclose. Funding: No funding was secured for this study. Authors' contributions: CX Ang and HL Chin were responsible for conceptualization, data curation, formal analysis, writing the original draft and reviewing the submission. DLM Goh and SZT Tan were responsible for reviewing and editing the submission. All authors read and approved the final manuscript. Acknowledgements: The authors acknowledge the patient and his family for allowing us to write about their story. During the writing stage, the patient’s mother provided perspectives on the medical journey and diagnostic odyssey that her family went through. During the review stage, the patient and his mother also provided feedback and comments to the writing of this publication. Clinical trial number: Not applicable References Danesino C, Cantarini C, Olivieri C. Hereditary hemorrhagic telangiectasia in pediatric age: focus on genetics and diagnosis. Child (Basel). 2023;15(1):11. 10.3390/children15010011 . McAllister KA, Grogg KM, Johnson DW, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8(4):345–51. 10.1038/ng1294-345 . Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996;13(2):189–95. 10.1038/ng0696-189 . McDonald J, Stevenson DA et al. Hereditary hemorrhagic telangiectasia. In: Adam MP, Feldman J, Mirzaa GM, editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–. Updated 2021 Nov 24 [cited 2025 Aug 3]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1351/ Faughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48(2):73–87. 10.1136/jmg.2009.069013 . Porteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet. 1992;29(8):527–30. 10.1136/jmg.29.8.527 . McDonald J, Wooderchak-Donahue W, VanSant Webb C, et al. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet. 2015;6:1. 10.3389/fgene.2015.00001 . National Center for Biotechnology Information. ClinVar; VCV000458328.31 [Internet]. Bethesda (MD): National Library of Medicine (US); c2025 [cited 2025 Aug 14]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000458328.31 Giordano P, Nigro A, Del Vecchio GC, Sabbà C, De Mattia D. HHT in childhood: screening for special patients. Curr Pharm Des. 2006;12(10):1217–20. 10.2174/138161206775474362 . Faughnan ME, Mager JJ, Hetts SW, et al. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann Intern Med. 2020;173(12):989–1001. 10.7326/M20-1443 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 23 Jan, 2026 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 19 Sep, 2025 Reviews received at journal 19 Sep, 2025 Reviews received at journal 17 Sep, 2025 Reviewers agreed at journal 17 Sep, 2025 Reviews received at journal 16 Sep, 2025 Reviewers agreed at journal 15 Sep, 2025 Reviewers agreed at journal 13 Sep, 2025 Reviewers invited by journal 12 Sep, 2025 Editor invited by journal 09 Sep, 2025 Editor assigned by journal 09 Sep, 2025 Submission checks completed at journal 09 Sep, 2025 First submitted to journal 01 Sep, 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. 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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-7509064","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":517148767,"identity":"dc4db840-79a7-4a26-ba5a-0625190cb9d7","order_by":0,"name":"Chen Xiang Ang","email":"","orcid":"","institution":"Khoo Teck Puat – National University Children's Medical Institute, National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chen","middleName":"Xiang","lastName":"Ang","suffix":""},{"id":517148771,"identity":"968400b1-fa98-43f3-8fb1-5f2d82825eb8","order_by":1,"name":"Hui-Lin 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02:29:32","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":43126,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7509064/v1/c211ad6d6fdcc5768ade0a9b.html"},{"id":91931329,"identity":"757d92e1-018a-44f8-8805-b38bbf5a0b98","added_by":"auto","created_at":"2025-09-23 02:29:32","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":473887,"visible":true,"origin":"","legend":"\u003cp\u003eGenogram of Family with HHT, consistent with an autosomal dominant pattern of inheritance. The proband, labeled with arrow, a fifteen-year old boy and his mother presented with recurrent spontaneous epistaxis and telangiectasia, and genetic testing was heterozygous for NM_001114753(ENG):c.1134G\u0026gt;A (p.Ala378=), an established pathogenic variant. His seven-year old sister demised from likely spontaneous atraumatic intracranial hemorrhage. Solid black symbols represent confirmed HHT on genetic testing, hatched symbols represent presumed HHT based on clinical features, and open symbols represent unaffected individuals.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7509064/v1/3eff66b923fc135a096c063d.jpeg"},{"id":101151716,"identity":"9e9d444c-c5d3-490a-9e5d-34265242fcb8","added_by":"auto","created_at":"2026-01-26 16:02:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":861317,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7509064/v1/ccad825d-fcf0-4f23-9355-983f1a8f564b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Beyond Epistaxis: Cascade Screening and Presymptomatic Treatment of Hereditary Hemorrhagic Telangiectasia","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eHereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic condition characterized by the presence of vascular malformations. It is associated with mutations in genes including \u003cem\u003eENG, ACVRL1, SMAD4, or GDF2\u003c/em\u003e, which are involved in signaling pathway of transforming growth factor-beta (TGF-β) / bone morphogenic protein (BMP)\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Clinically, this manifests as spontaneous recurrent epistaxis, mucocutaneous telangiectasias, and AVMs in organs including the brain, pulmonary system, and liver\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Early recognition can be challenging in children, as epistaxis and telangiectasia may be absent or subtle, and these signs are expressed in an age-dependent manner\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Prompt diagnosis through genetic testing and subsequent surveillance screening is important due to the potential risk of morbidity and mortality that visceral AVMs have.\u003c/p\u003e\u003cp\u003eAlthough HHT is more commonly seen in adults, pediatricians need to be watchful in cases with relevant family history suggesting an autosomal dominant pattern of inheritance. Proactive intervention before the onset of symptoms can be lifesaving. Prompted by the unfortunate passing of his younger sister, we present the clinical journey of a pediatric patient and his mother with HHT, and highlight the importance of genetic cascade testing, multidisciplinary teamwork and pre-symptomatic neurosurgical intervention.\u003c/p\u003e"},{"header":"CASE PRESENTATION","content":"\u003cp\u003eOur patient is a fifteen-year-old boy, reviewed at the Pediatric Genetics Service after the sudden death of his seven-year-old sister from atraumatic intracranial hemorrhage. The boy had a history of recurrent spontaneous epistaxis. This occurred several times a month, and would resolve with manual compression. This was not associated with other bleeding manifestations, symptoms of anemia, or systemic complaints. He was otherwise well thrived. On physical examination, he had visible lip telangiectasias with sparing of the fingers and periungual region. Neurological examination did not reveal any deficits. Vital signs were within normal limits and general examination was unremarkable.\u003c/p\u003e\u003cp\u003eHis mother, a forty-two-year-old woman, had a history of recurrent spontaneous epistaxis and mucocutaneous telangiectasias. She had been on follow-up with Adult Otolaryngology and Respiratory Medicine Services, and fulfilled two Curaçao criteria for HHT\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. As such, surveillance imaging had been previously done for her, including magnetic resonance imaging (MRI) of the brain and computed tomography (CT) of the thorax in 2021, which were negative for AVMs. Family history showed an autosomal dominant pattern of inheritance (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Relatives across three generations on the maternal side had a history of recurrent spontaneous epistaxis. There was no family history of prior stroke or intracranial bleeds. No formal diagnosis or genetic testing had been performed in the family.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe patient had two siblings: a twelve-year-old brother and seven-year-old sister. The younger brother was asymptomatic while the younger sister had a history of infrequent epistaxis. In March 2022, the younger sister passed away from spontaneous atraumatic intracranial hemorrhage. She had presented to a General Practitioner’s clinic with a one-day history of vomiting and lethargy. While awaiting evaluation, she experienced a cardiac arrest. Prompt resuscitation was initiated, and she was transferred expediently to the nearest tertiary hospital, however, there was no return of spontaneous circulation. History and clinical findings of raised intracranial pressure were consistent with a diagnosis of likely atraumatic intracranial hemorrhage. Unfortunately, confirmatory postmortem brain imaging was not available. Apart from having a past medical history of Kawasaki disease at age three years old with discharge from follow-up, our patient’s sister was well prior to the event.\u003c/p\u003e\u003cp\u003eIn view of the mother’s clinical history and the sibling’s demise from likely intracranial hemorrhage, the family sought genetic evaluation. Genetic testing (gene panel at a clinically-accredited commercial laboratory) was performed on the mother which showed that she was heterozygous for \u003cem\u003eNM_001114753(ENG):c.1134G \u0026gt; A (p.Ala378=)\u003c/em\u003e, an established pathogenic variant\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, confirming the diagnosis of HHT. Cascade testing was then performed on the surviving children. Her twelve-year-old son tested negative for the familial variant and was discharged from follow-up.\u003c/p\u003e\u003cp\u003eOur fifteen-year old patient tested positive for the same pathogenic variant. Following the diagnosis, he underwent baseline screening for visceral AVMs. Pulse oximetry and chest radiography were normal. He was referred to the Otolaryngology Service for follow-up of his epistaxis and was additionally diagnosed with allergic rhinitis. Magnetic resonance imaging (MRI) and Magnetic Resonance Angiography (MRA) of the brain showed focal prominent vessels and nodular foci in the right occipital lobe, without definite nidus or abnormal flow signals on MRA. There was focal hemosiderin staining in the right occipital cortex is likely related to prior hemorrhage. Digital subtraction angiography (DSA) was then performed and which revealed small vascular malformations at the vertex from the left internal carotid artery, along with additional small vascular formations in the posterior circulation.\u003c/p\u003e\u003cp\u003eA multidisciplinary team review concluded that the lesions were not amenable to embolization or surgical resection due to their small size, multiple number, and location being peripheral in nature. Gamma Knife Stereotactic radiosurgery was recommended as the treatment modality. Intraoperatively, four AVM nidus sites were identified and treated with a prescription dose of 25 Gray successfully. Immediate postoperative brain MRI was unremarkable.\u003c/p\u003e\u003cp\u003eAt follow-up, the patient remained neurologically intact and continued to have only infrequent, self-limiting episodes of epistaxis. He had no evidence of anemia, gastrointestinal bleeding, or other systemic involvement. He remains under follow-up with Genetics, Neurosurgery, and Otolaryngology Services.\u003c/p\u003e"},{"header":"DISCUSSION AND CONCLUSION","content":"\u003cp\u003eAVMs that remain undetected and untreated in visceral organs have high morbidity and mortality risk\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Targeted screening can prevent these outcomes. Pediatricians need to take a detailed family history and construct a genogram when evaluating children with symptomatic family members. In our patient, recognition of an autosomal dominant inheritance pattern in the maternal lineage prompted timely screening that diagnosed HHT. Pre-symptomatic treatment of his brain AVMs likely averted a potentially catastrophic intracranial bleed.\u003c/p\u003e\u003cp\u003eThis case raises the question: if genetic testing had been initiated earlier for this family, would this have triggered timely screening for AVMs, and possibly allowed for preventive management in the proband's younger sister? Our experience supports initiating family discussions about genetic testing as soon as the diagnosis of HHT is suspected. Since the first International HHT Guidelines, genetic testing has been recommended for first degree relatives of individuals with a confirmed diagnosis of HHT\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Pathogenic variants in \u003cem\u003eENG (HHT1), ACVRL1 (HHT2)\u003c/em\u003e, and \u003cem\u003eSMAD4 (JP-HHT)\u003c/em\u003e account for 97% of patients with definite HHT\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003ePediatricians and General Practitioners play a crucial role in picking up subtle clinical signs and initiating referrals for genetic counseling and testing when the family history is suggestive. This case underscores the importance of proactive identification, counselling, and surveillance of at-risk children to prevent life-threatening complications and improve long-term outcomes.\u003c/p\u003e"},{"header":"PATIENT PERSPECTIVE","content":"\u003cp\u003eHHT is a rare disease that has been in my family generation for years which we were unaware of. Our elders would typically dismiss the occasional nose bleeds as a normal symptom for body heatiness and imparted this knowledge down the family line. The passing of our beloved daughter has been a tragic loss that was unexpected and sudden. I hope doctors and medical practitioners can work together towards sharing more information about the HHT disease in order to create more awareness. Early intervention or preventative measures can be taken so that no family should go through such an ordeal as mine.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHHT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ehereditary hemorrhagic telangiectasia\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAVM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003earteriovenous malformation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emagnetic resonance imaging\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecomputered tomography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTGF-β\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTransforming Growth Factor-Beta\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBMP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBone Morphogenic Protein\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMRA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emagnetic resonance angiography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDSA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDigital subtraction angiography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eWritten and signed consent to publish the information from the patients and their guardians have been obtained\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eData sharing is not applicable to this article as no datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eAll authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNo funding was secured for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCX Ang and HL Chin were responsible for conceptualization, data curation, formal analysis, writing the original draft and reviewing the submission. DLM Goh and SZT Tan were responsible for reviewing and editing the submission.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge the patient and his family for allowing us to write about their story. During the writing stage, the patient’s mother provided perspectives on the medical journey and diagnostic odyssey that her family went through. During the review stage, the patient and his mother also provided feedback and comments to the writing of this publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDanesino C, Cantarini C, Olivieri C. Hereditary hemorrhagic telangiectasia in pediatric age: focus on genetics and diagnosis. Child (Basel). 2023;15(1):11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/children15010011\u003c/span\u003e\u003cspan address=\"10.3390/children15010011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcAllister KA, Grogg KM, Johnson DW, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8(4):345\u0026ndash;51. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/ng1294-345\u003c/span\u003e\u003cspan address=\"10.1038/ng1294-345\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJohnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996;13(2):189\u0026ndash;95. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/ng0696-189\u003c/span\u003e\u003cspan address=\"10.1038/ng0696-189\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcDonald J, Stevenson DA et al. Hereditary hemorrhagic telangiectasia. In: Adam MP, Feldman J, Mirzaa GM, editors. GeneReviews\u0026reg;. Seattle (WA): University of Washington, Seattle; 1993\u0026ndash;. Updated 2021 Nov 24 [cited 2025 Aug 3]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/books/NBK1351/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/books/NBK1351/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFaughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48(2):73\u0026ndash;87. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/jmg.2009.069013\u003c/span\u003e\u003cspan address=\"10.1136/jmg.2009.069013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePorteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet. 1992;29(8):527\u0026ndash;30. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/jmg.29.8.527\u003c/span\u003e\u003cspan address=\"10.1136/jmg.29.8.527\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcDonald J, Wooderchak-Donahue W, VanSant Webb C, et al. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet. 2015;6:1. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fgene.2015.00001\u003c/span\u003e\u003cspan address=\"10.3389/fgene.2015.00001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNational Center for Biotechnology Information. ClinVar; VCV000458328.31 [Internet]. Bethesda (MD): National Library of Medicine (US); c2025 [cited 2025 Aug 14]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000458328.31\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000458328.31\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGiordano P, Nigro A, Del Vecchio GC, Sabb\u0026agrave; C, De Mattia D. HHT in childhood: screening for special patients. Curr Pharm Des. 2006;12(10):1217\u0026ndash;20. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2174/138161206775474362\u003c/span\u003e\u003cspan address=\"10.2174/138161206775474362\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFaughnan ME, Mager JJ, Hetts SW, et al. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann Intern Med. 2020;173(12):989\u0026ndash;1001. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7326/M20-1443\u003c/span\u003e\u003cspan address=\"10.7326/M20-1443\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\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":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hereditary Hemorrhagic Telangiectasia, Epistaxis, Intracranial Hemorrhage, Arteriovenous Malformation, Genetic Cascade Testing, Genogram","lastPublishedDoi":"10.21203/rs.3.rs-7509064/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7509064/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder that may present with recurrent epistaxis, mucocutaneous telangiectasias, or visceral arteriovenous malformations (AVMs), yet its early signs may be overlooked in children.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe report a family in which a fifteen-year old boy and his mother presented for genetic evaluation of recurrent epistaxis, after his previously well seven-year-old sister demised suddenly from likely spontaneous atraumatic intracranial hemorrhage, following a brief history of headache and vomiting. She had a background of infrequent nosebleeds and a family history of recurrent epistaxis in multiple maternal relatives. Genetic testing in the mother diagnosed HHT (heterozygous for \u003cem\u003eNM_001114753(ENG):c.1134G\u0026gt;A (p.Ala378=)\u003c/em\u003e, an established pathogenic variant). Cascade testing for her two surviving children was done. The fifteen-year-old boy tested positive and was found on subsequent screening to have intracranial vascular malformations which were treated pre-symptomatically with gamma knife surgery. Another son tested negative.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case emphasizes the prompt recognition of HHT in children presenting with recurrent epistaxis and highlights the need for thorough family history. Pediatricians play a crucial role in early diagnosis and referral for genetic testing with subsequent surveillance imaging. Early identification can prevent catastrophic outcomes such as intracranial hemorrhage. This case emphasizes the need for heightened awareness of HHT in pediatric practice and supports the value of integrating genetic cascade testing and organ-specific screening in at-risk children, even before symptoms appear.\u003c/p\u003e","manuscriptTitle":"Beyond Epistaxis: Cascade Screening and Presymptomatic Treatment of Hereditary Hemorrhagic Telangiectasia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 02:29:27","doi":"10.21203/rs.3.rs-7509064/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-19T07:18:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-19T06:42:10+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-17T10:39:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"188740027194798570669651941843568329972","date":"2025-09-17T10:27:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-16T17:53:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9814095046498463887449973506977275927","date":"2025-09-15T08:22:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"329511719487372344886033794660402536762","date":"2025-09-13T04:00:02+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-12T11:45:03+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-09T05:54:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-09T04:53:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-09T04:52:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-09-01T13:26:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5d266345-b521-4e51-9ee8-e66e6c28fb19","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-26T16:00:15+00:00","versionOfRecord":{"articleIdentity":"rs-7509064","link":"https://doi.org/10.1186/s12887-025-06376-z","journal":{"identity":"bmc-pediatrics","isVorOnly":false,"title":"BMC Pediatrics"},"publishedOn":"2026-01-23 15:57:26","publishedOnDateReadable":"January 23rd, 2026"},"versionCreatedAt":"2025-09-23 02:29:27","video":"","vorDoi":"10.1186/s12887-025-06376-z","vorDoiUrl":"https://doi.org/10.1186/s12887-025-06376-z","workflowStages":[]},"version":"v1","identity":"rs-7509064","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7509064","identity":"rs-7509064","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}