Clinical manifestations of patients with <scp><i>GDF2</i></scp> mutations associated with hereditary hemorrhagic telangiectasia type 5

Farhan, Ahmed; Yuan, Frank; Partan, Elizabeth S.; Weiss, Clifford R.

doi:10.1002/ajmg.a.62522

Cited by 13 publications

(8 citation statements)

References 44 publications

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“…The second of these genes, GDF2, codes for bone morphogenetic protein 9 (BMP9), a ligand in the TGF-β signaling pathways. Mutations in this gene have also been described in patients presenting with symptoms typical for HHT in the few studies which as of now have examined the subject [7,8,9,10].…”

Section: Epidemiology and Geneticsmentioning

confidence: 96%

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Hereditary Hemorrhagic Telangiectasia - a literature review

Stodolak,

Krużel,

Kłos

et al. 2024

J Educ Health Sport

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Introduction and purpose: Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare and complex vascular disorder characterized by abnormal blood vessel formation. It can present significant challenges in diagnosis and management, as it is currently estimated up to 90% of those affected are never diagnosed. Despite its rarity, HHT can carry substantial implications for patients and their families, at times requiring comprehensive medical care and support. This paper aims to provide an in-depth exploration of HHT, encompassing its epidemiology, genetics, clinical manifestations, diagnostic approaches, and current management strategies. Moreover, we hope to point out possible areas in need of future research. Description of the state knowledge: HHT is an autosomal dominant genetic disorder that affects 1 in 5-10,000 people. Its most prominent symptoms include telangiectasia of skin and mucous membranes, recurrent epistaxis, gastrointestinal bleeding and arteriovenous malformations in vital organs. In the vast majority of cases, it is caused by a mutation in one of the following genes: ENG, ACVRL1, SMAD4; however, mutations in other genes have been described to cause a similar or much the same constellation of symptoms. Treatment options are focused on managing symptoms and improving quality of life, but possible new treatment options are being researched that could change the landscape of HHT management. Summary: HHT is a severely underdiagnosed disease that has seen a surge of researchers’ interest in recent years. We firmly believe that, combined with plummeting costs of genetic testing and possible new treatment options, means that HHT will become increasingly important in physicians’ everyday practice.

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Section: Epidemiology and Geneticsmentioning

confidence: 96%

“…However, the genes linked to HHT code for proteins in the TGF-β pathway [4,5,6,7,8,9,10] or related pathways [10,11]. Further research into the genetic basis of HHT may prove useful for developing more effective treatments and creating more reliable management guidelines.…”

Section: What Is Hereditary Hemorrhagic Telangiectasia?mentioning

confidence: 99%

Hereditary Hemorrhagic Telangiectasia - a literature review

Stodolak,

Krużel,

Kłos

et al. 2024

J Educ Health Sport

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“…4 Most recently, a mutation in GDF2 is related to an HHT-like syndrome that shows some overlap with classical HHT but has a distinct clinical manifestation. 5 Recurring epistaxis is present in 95% of patients with HHT, while the prevalence of telangiectatic lesions in the skin and mucosa increases with age. 6 Visceral AVMs are mainly pulmonary (PAVM), hepatic (HAVM), and cerebral (CAVM) and are important to recognize as they can cause serious complications (especially PAVM) that could be prevented with proper treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in SMAD4 are seen in patients with a rare combination of HHT and juvenile polyposis syndrome (OMIM 600993, JP‐HHT) 4 . Most recently, a mutation in GDF2 is related to an HHT‐like syndrome that shows some overlap with classical HHT but has a distinct clinical manifestation 5 …”

Section: Introductionmentioning

confidence: 99%

Skin and mucosal telangiectatic lesions in hereditary hemorrhagic telangiectasia patients

et al. 2022

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Background The diagnostic criteria for hereditary hemorrhagic telangiectasia (HHT) include the presence of telangiectatic lesions in common sites (nose, fingers, oral cavity, and lips). Telangiectatic lesions are described as red spots in the skin, but this description is inadequate. Few studies have investigated the characteristics of telangiectatic lesions in HHT, and we aimed to describe the distribution and morphology of telangiectatic lesions in HHT patients. Methods We reviewed the telangiectatic lesions in 34 adult HHT patients seen at our HHT center. Photo documentation was used to describe the morphology and distribution of the lesions. ResultsThe telangiectatic lesions in both HHT1 and HHT2 patients were predominantly round and either flat or slightly elevated. However, elongated flat lesions and larger round, elevated lesions were also observed. Patients with HHT1 had more lesions in the mucosa (tongue and oral cavity) compared with HHT2 patients. There was no difference between HHT1 and HHT2 patients in the total number of lesions in the skin and mucosa. Conclusions The typical round, flat telangiectatic lesion is the most common lesion in HHT, but it is very often accompanied by elevated or elongated lesions. The total number of lesions did not vary between gender, but women had significantly more lesions in the mucosa (p = 0.027). The presentation of telangiectatic lesions may vary a little between HHT1 and HHT2 patients but not in such a way that allows the morphology and location of the lesions to predict the HHT subtype.

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“…In the majority (>90%) of patients with HHT, it is possible to detect a causal heterozygous pathogenic variant (PV) in mainly ENG (HHT1) and ACVRL1 (HHT2), while approximately 3%–5% have a PV in SMAD4 2. Rarely GDF2 variants have been reported 4–6. Improvement in genetic technologies with next-generation sequencing (NGS) has allowed for broader use of genetic testing in patients with symptoms of HHT and/or juvenile polyps.…”

Section: Introductionmentioning

confidence: 99%

Hereditary haemorrhagic telangiectasia in Danish patients with pathogenic variants inSMAD4:a nationwide study

et al. 2022

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Background and aimsHereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition characterised by recurrent epistaxis, telangiectatic lesions in the skin and mucosal membranes, and arteriovenous malformations (AVMs) in various organs. In 3%–5% of patients, HHT is caused by pathogenic germline variants (PVs) in SMAD4, and these patients often have additional symptoms of juvenile polyposis syndrome and thoracic aneurysms. The phenotypic spectrum of SMAD4-associated HHT is less known, including the penetrance and severity of HHT. We aimed to investigate the phenotypic spectrum of HHT manifestations in Danish patients with PVs in SMAD4 and compare the findings with current literature.MethodsThe study is a retrospective nationwide study with all known Danish patients with PVs in SMAD4. In total, 35 patients were included. The patients were identified by collecting data from genetic laboratories, various databases and clinical genetic departments across the country. Clinical information was mainly collected from the Danish HHT-Centre at Odense University Hospital.ResultsTwenty-nine patients with PVs in SMAD4 (83%) were seen at the HHT-Centre. Seventy-six per cent of these fulfilled the Curaçao criteria, 86% experienced recurrent epistaxis and 83% presented with telangiectatic lesions at different anatomical localisations. Almost 60% had AVMs, mainly pulmonary and hepatic, while none was found to have cerebral AVMs. Fifteen per cent had thoracic aortic abnormalities.ConclusionWe present a nationwide study of one of the largest populations of patients with PVs in SMAD4 that has systematically been examined for HHT manifestations. The patients presented the full spectrum of HHT-related manifestations and the majority fulfilled the Curaçao criteria.

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Clinical manifestations of patients with GDF2 mutations associated with hereditary hemorrhagic telangiectasia type 5

Cited by 13 publications

References 44 publications

Hereditary Hemorrhagic Telangiectasia - a literature review

Hereditary Hemorrhagic Telangiectasia - a literature review

Skin and mucosal telangiectatic lesions in hereditary hemorrhagic telangiectasia patients

Hereditary haemorrhagic telangiectasia in Danish patients with pathogenic variants inSMAD4:a nationwide study

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