Genetic variants and clinical phenotypes in Korean patients with hereditary hemorrhagic telangiectasia

Clinical and Experimental Otorhinolaryngology ◽

10.21053/ceo.2020.02124 ◽

2021 ◽

Author(s):

Young Jae Lee ◽

Joo-hyun Jung ◽

Bo Gyeong Kim ◽

Mi-Jung Kim ◽

Eun Hyue Moon ◽

...

Keyword(s):

Genetic Variants ◽

Genetic Screening ◽

Hereditary Hemorrhagic Telangiectasia ◽

Diagnostic Screening ◽

Pathogenic Variants ◽

Recurrent Epistaxis ◽

Common Clinical Presentation ◽

History Of ◽

Standards And Guidelines

Objectives. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by recurrent epistaxis, telangiectasias, and visceral arteriovenous malformations (AVMs). Activin A receptor-like type 1 (ACVRL1/ALK1) and Endoglin (ENG) are the principal genes whose mutations cause HHT. A multicenter study to investigate the correlation between genetic variations and clinical outcomes in Korean HHT patients has been lacking.Methods. Seventy-two members from 40 families suspected of HHT based on symptoms were genetically screened for pathogenic variants in ACVRL1 and ENG. Patients with genetically diagnosed HHT were also evaluated.Results. In the HHT genetic screening, 42 patients from 24 of the 40 families had genetic variants that met the pathogenic criteria (pathogenic very strong, pathogenic strong, pathogenic moderate, or pathogenic supporting) based on ACMG Standards and Guidelines in either ENG or ACVRL1; 26 from 12 families (50%) in ENG, and 16 from 12 families (50%) in ACVRL1. The diagnostic screening of 42 genetically positive HHT patients based on the Curaçao criteria revealed that 24 patients (57%) were in the definite group, 17 patients (41%) were in the probable group, and 1 patient (2%) was in the unlikely group. Epistaxis was the most common clinical presentation (38/42, 90%), followed by visceral AVMs (24/42, 57%), and telangiectasia (21/42, 50%). Five patients (12%) did not have a family history of HHT clinical symptoms.Conclusion. Among patients having ACVRL1 or ENG genetic variants, only about half of them could be clinically diagnosed as definite HHT, suggesting that genetic screening is important to confirm the diagnosis.

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Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia

BMC Medical Genomics ◽

10.1186/s12920-021-01139-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kana Kitayama ◽

Tomoya Ishiguro ◽

Masaki Komiyama ◽

Takayuki Morisaki ◽

Hiroko Morisaki ◽

...

Keyword(s):

Hereditary Hemorrhagic Telangiectasia ◽

Clinical Information ◽

Japanese Patients ◽

Kinase Domain ◽

Single Family ◽

Serine Threonine Kinase ◽

Blood Leukocytes ◽

Pathogenic Variants ◽

Japanese Cohort ◽

Recurrent Epistaxis

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder characterized by recurrent epistaxis, skin/mucocutaneous telangiectasia, and organ/visceral arteriovenous malformations (AVM). HHT is mostly caused by mutations either in the ENG or ACVRL1 genes, and there are regional differences in the breakdown of causative genes. The clinical presentation is also variable between populations suggesting the influence of environmental or genetic backgrounds. In this study, we report the largest series of mutational and clinical analyses for East Asians. Methods Using DNAs derived from peripheral blood leukocytes of 281 Japanese HHT patients from 150 families, all exons and exon–intron boundaries of the ENG, ACVRL1, and SMAD4 genes were sequenced either by Sanger sequencing or by the next-generation sequencing. Deletions/amplifications were analyzed by the multiplex ligation-dependent probe amplification analyses. Clinical information was obtained by chart review. Results In total, 80 and 59 pathogenic/likely pathogenic variants were identified in the ENG and ACVRL1 genes, respectively. No pathogenic variants were identified in the SMAD4 gene. In the ENG gene, the majority (60/80) of the pathogenic variants were private mutations unique to a single family, and the variants were widely distributed without any distinct hot spots. In the ACVRL1 gene, the variants were more commonly found in exons 5–10 which encompasses the serine/threonine kinase domain. Of these, 25/59 variants were unique to a single family while those in exons 8–10 tended to be shared by multiple (2–7) families. Pulmonary and cerebral AVMs were more commonly found in ENG-HHT (69.1 vs. 14.4%, 34.0 vs. 5.2%) while hepatic AVM was more common in ACVRL1-HHT (31.5 vs. 73.2%). Notable differences include an increased incidence of cerebral (34.0% in ENG-HHT and 5.2% in ACVRL1-HHT), spinal (2.5% in ENG-HHT and 1.0% in ACVL1-HHT), and gastric AVM (13.0% in ENG-HHT, 26.8% in ACVRL1-HHT) in our cohort. Intrafamilial phenotypic heterogeneity not related to the age of examination was observed in 71.4% and 24.1% of ENG- and ACVRL1-HHT, respectively. Conclusions In a large Japanese cohort, ENG-HHT was 1.35 times more common than ACVRL1-HHT. The phenotypic presentations were similar to the previous reports although the cerebral, spinal, and gastric AVMs were more common.

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Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria

European Journal of Human Genetics ◽

10.1038/s41431-021-00858-1 ◽

2021 ◽

Author(s):

Judy Savige ◽

Helen Storey ◽

Elizabeth Watson ◽

Jens Michael Hertz ◽

Constantinos Deltas ◽

...

Keyword(s):

Renal Failure ◽

Alport Syndrome ◽

Pathogenic Variants ◽

Persistent Proteinuria ◽

Mutational Hotspots ◽

Splicing Variants ◽

History Of ◽

Standards And Guidelines ◽

Reference Databases ◽

End Stage

AbstractThe recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common ‘incidental’ findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.

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Resveratrol As a Novel Treatment for Recurrent Epistaxis in SMAD4+ Hereditary Hemorrhagic Telangiectasia

Blood ◽

10.1182/blood-2021-149800 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1048-1048

Author(s):

Shahbegh Gill ◽

Shadi Swaidani ◽

Joseph Parambil ◽

Keith R. McCrae

Keyword(s):

Quality Of Life ◽

Hereditary Hemorrhagic Telangiectasia ◽

Autosomal Dominant ◽

Deficiency Anemia ◽

Severe Bleeding ◽

Autosomal Dominant Disorder ◽

Severity Scores ◽

Recurrent Epistaxis ◽

History Of

Abstract Introduction Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by the development of arteriovenous malformations or telangiectasias that may affect any organ system, but are most prevalent in the nose and gastrointestinal tract. Nasal telangiectasia account for epistaxis, the most frequent manifestation of HHT, which may be frequent, debilitating and lead to decreased quality of life. Epistaxis is quantified by the Epistaxis Severity Scores (ESS), which ranges from 1-10 with higher scores associated with more severe bleeding. The diagnosis of HHT is based on clinical criteria and requires three or more of the following features: epistaxis, mucocutaneous telangiectasis, visceral AVMs, and/or a family history of HHT. HHT is associated with several mutations that may involve ENG, ACVRL1, or SMAD4; the latter occurs in only ~2% of HHT patients, which is also associated with the Juvenile Polyposis Syndrome (JPS), another autosomal dominant disorder associated with an increased risk for colorectal, stomach, small intestine, and pancreatic cancers. Methods Case report with serial ESS scores, hemoglobin and hematocrit monitoring. Results A 25-year-old male was diagnosed with JPS/HHT and a c.1081C>T mutation in SMAD4 leading to an R361C missense mutation was diagnosed in 2013. The patient had a longstanding history of frequent epistaxis leading to severe iron deficiency anemia and requiring at least two 750 mg iron infusions annually (total of 14), and did not improve with oral iron supplements. In December 2020, the patient initiated a 1 g daily dose of resveratrol for general anti-aging and health benefits. His epistaxis improved immediately, and his ESS decreased from 6 (consistent with severe bleeding) to 1 (no bleeding) over a two week period. The frequency, severity and duration of epistaxis all improved dramatically (Figure). No additional iron therapy has been required since initiation of resveratrol. Recent serum iron and ferritin values (6/2021) were both within normal limits. Of interest, in parallel with the resolution of epistaxis, the patient also had a dramatic reduction in colonic polyposis after starting resveratrol. Conclusions There are no approved therapies for the treatment of HHT, and patients with this disorder may suffer from a markedly reduced quality of life due to unpredictable epistaxis and other manifestations. While a responses to bevacizumab have been reported in 60-70% of patients, treatment is expensive and may be associated with thromboembolic events, and patients may become refractory over time. Invasive approaches such as sclerotherapy may be initially, but only temporarily effective. Thus, there is an urgent need for better HHT therapies. Figure 1 Figure 1. Disclosures McCrae: Sanofi, Novartis, Alexion, and Johnson & Johnson: Consultancy, Honoraria; Dova, Novartis, Rigel, and Sanofi Genzyme: Consultancy.

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Hereditary Hemorrhagic Telangiectasia: A Genetic Disorder with Oral Manifestations

International Journal of Experimental Dental Science ◽

10.5005/jp-journals-10029-1069 ◽

2014 ◽

Vol 3 (1) ◽

pp. 49-52

Author(s):

Apollonia Desiate ◽

Stefania Cantore ◽

Andrea Ballini

Keyword(s):

Family History ◽

Hereditary Hemorrhagic Telangiectasia ◽

Arteriovenous Malformations ◽

Autosomal Dominant ◽

Genetic Disorder ◽

Oral Manifestations ◽

Systemic Diseases ◽

Recurrent Epistaxis ◽

History Of ◽

Broad Understanding

ABSTRACT The case of a 74-year-old man who was diagnosed as having hereditary hemorrhagic telangiectasia (HHT), with telangiectasies localized in oral district is presented. This condition is an autosomal dominant mucocutaneous and visceral fibrovascular dysplasia in which telangiectasia, arteriovenous malformations and aneurysms may be widely distributed throughout the cardiovascular system. It is usually recognized as a ‘triad’ of telangiectasia, recurrent epistaxis and a family history of the disorder. The nature of the practice of dentistry necessitates a broad understanding of the systemic diseases reflected in the oral cavity. Hereditary hemorrhagic telangiectasia is one such disease. How to cite this article Ballini A, Cantore S, Desiate A. Hereditary Hemorrhagic Telangiectasia: A Genetic Disorder with Oral Manifestations. Int J Experiment Dent Sci 2014; 3(1): 49-52.

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Splenic Involvement in Hereditary Hemorrhagic Telangiectasia

Case Reports in Medicine ◽

10.1155/2016/3212947 ◽

2016 ◽

Vol 2016 ◽

pp. 1-4

Author(s):

Susumu Takamatsu ◽

Kota Sato ◽

Shunsuke Kato ◽

Hiroto Nagano ◽

Shunro Ohtsukasa ◽

...

Keyword(s):

Computed Tomography ◽

Hereditary Hemorrhagic Telangiectasia ◽

Epigastric Pain ◽

Liver Parenchyma ◽

Pathological Examination ◽

Resected Specimen ◽

Recurrent Epistaxis ◽

Rare Manifestation ◽

Splenic Involvement ◽

History Of

A 33-year-old man who presented with prolonged epigastric pain was referred to our hospital. He had experienced recurrent epistaxis and had a family history of hereditary hemorrhagic telangiectasia. Computed tomography and magnetic resonance imaging revealed splenomegaly and a 9 cm hypervascular mass in his spleen. Computed tomography also showed a pulmonary arteriovenous malformation and heterogeneous enhancement of the liver parenchyma, suggesting the presence of arteriosystemic shunts and telangiectases. Based on these findings, the patient was definitely diagnosed with hereditary hemorrhagic telangiectasia according to Curaçao criteria. He underwent splenectomy, and his symptoms disappeared after surgery. Pathological examination of the resected specimen revealed that the hypervascular lesion of the spleen was not a tumor but was composed of abnormal vessels associated with hereditary hemorrhagic telangiectasia. Symptomatic splenic involvement may be a rare manifestation of hereditary hemorrhagic telangiectasia but can be revealed by imaging modalities.

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Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer

Cancers ◽

10.3390/cancers12103046 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3046

Author(s):

Marina Pavanello ◽

Isaac HY Chan ◽

Amir Ariff ◽

Paul DP Pharoah ◽

Simon A. Gayther ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Genetic Variants ◽

Susceptibility Genes ◽

Low Grade ◽

Brca1 And Brca2 ◽

Pathogenic Variants ◽

History Of ◽

Rare Genetic Variants ◽

Repair Genes

A family history of ovarian or breast cancer is the strongest risk factor for epithelial ovarian cancer (EOC). Germline deleterious variants in the BRCA1 and BRCA2 genes confer EOC risks by age 80, of 44% and 17% respectively. The mismatch repair genes, particularly MSH2 and MSH6, are also EOC susceptibility genes. Several other DNA repair genes, BRIP1, RAD51C, RAD51D, and PALB2, have been identified as moderate risk EOC genes. EOC has five main histotypes; high-grade serous (HGS), low-grade serous (LGS), clear cell (CCC), endometrioid (END), and mucinous (MUC). This review examines the current understanding of the contribution of rare genetic variants to EOC, focussing on providing frequency data for each histotype. We provide an overview of frequency and risk for pathogenic variants in the known susceptibility genes as well as other proposed genes. We also describe the progress to-date to understand the role of missense variants and the different breast and ovarian cancer risks for each gene. Identification of susceptibility genes have clinical impact by reducing disease-associated mortality through improving risk prediction, with the possibility of prevention strategies, and developing new targeted treatments and these clinical implications are also discussed.

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Familial Hypercholesterolemia: Update and Review

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530321666210208212148 ◽

2021 ◽

Vol 21 ◽

Author(s):

Oscar Francisco Chacón Camacho ◽

Glustein Pozo Molina ◽

Claudia Fabiola Méndez Catalá ◽

Julia Reyes Reali ◽

René Méndez Cruz ◽

...

Keyword(s):

Metabolic Disease ◽

Familial Hypercholesterolemia ◽

Genetic Screening ◽

Population Studies ◽

Premature Coronary Artery Disease ◽

Ribonucleic Acids ◽

Pathogenic Variants ◽

The World ◽

History Of ◽

Artery Disease

Abstract: Knowledge of epidemiology, genetic etiopathogenesis, diagnostic criteria, and management of familial hypercholesterolemia have increased in the last two decades. Several population studies have shown that familial hypercholesterolemia is more frequent than previously thought, making this entity the most common metabolic disease with monogenic inheritence in the world. Identification of causal heterozygous pathogenic variants in LDLR, APOB, and PCSK9 genes have increased diagnostic accuracy of classical criteria (extreme hypercholesterolemia, personal / family history of premature coronary artery disease or other cardiovascular disease). Genetic screening has been recently introduced in many European countries to detect patients with familial hypercholesterolemia, mainly affected pediatric subjects, asymptomatic or those at the beggining of their disease, with the purpose of increasing surveillance and avoiding complications such as cardiovascular diseases. Cholesterol-lowering drugs should be started as soon as the diagnosis is made. Various combinations between drugs can be used when the goal is not achieved. New therapies, including small interference ribonucleic acids (siRNA) are being tested in different clinical trials.

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A 2-Year-Old Child with Bilateral Ectopis Lentis and a Novel FBN1 Gene Variant Cys129Ser

Journal of Pediatric Genetics ◽

10.1055/s-0037-1612592 ◽

2017 ◽

Vol 07 (02) ◽

pp. 083-085 ◽

Cited By ~ 1

Author(s):

Ahmed Mohammad ◽

Paldeep Atwal

Keyword(s):

Genetic Analysis ◽

Marfan Syndrome ◽

Pathogenic Variant ◽

Gene Variant ◽

Ectopia Lentis ◽

Fbn1 Gene ◽

Pathogenic Variants ◽

Syndrome Diagnosis ◽

History Of

AbstractMarfan syndrome and dominant ectopia lentis are part of type 1 fibrillinopathies that are caused by FBN1 pathogenic variants. Making a diagnosis could be challenging due to the clinical overlap between these disorders. The revised Ghent criteria used for Marfan syndrome diagnosis helped in resolving some of the confusion, especially in younger children. We report on a case of bilateral ectopia lentis in a 2-year-old child with a normal echocardiogram. FBN1 sequencing revealed a novel likely pathogenic variant described as c.385T > A (p.Cys129Ser). The patient's father also has a history of bilateral ectopia lentis and his genetic analysis detected the same FBN1 variant as the proband.

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