Telangiectasias, recurrent epistaxis and a strong family history-a case of Osler- Weber-Rendu Syndrome in Pakistan.

Osler-Weber-Rendu syndrome or Hereditary Haemorrhagic Telangiectasia (HHT) is a rare condition, with very few reported cases, especially in Pakistan. As healthcare workers, we encounter multiple cases of recurrent epistaxis in the emergency as well as outpatient departments. However, patients are usually treated symptomatically without a thorough workup. HHT should be considered among the differentials for recurrent epistaxis, as a clinical diagnosis can be made with detailed family history and physical examination. Here is the case of a 58-year-old male who presented to the Gastroenterology OPD, Combined Military Hospital, Lahore, in November 2021, with complaints of generalised weakness and blood in stools. He had a history of recurrent epistaxis and telangiectasias, and further inquiry revealed a strong family history of similar symptoms. He was diagnosed as a case of Osler-Weber- Rendu Syndrome. Informed consent was taken from the patient prior to the writing of the manuscript.

Outcomes of patients with Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia caused by pathogenic SMAD4 variants in a pan-Scotland cohort.

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme.

The ENG/VEGFα Pathway Is Likely Affected by a Nonsense Variant of Endoglin (ENG)/CD105, Causing Hereditary Hemorrhagic Telangiectasia Type 1 (HHT1) in a Chinese Family.

Hereditary hemorrhagic telangiectasia (HHT), also called Rendu-Osler syndrome, is a group of rare genetic diseases characterized by autosomal dominance, multisystemic vascular dysplasia, and age-related penetrance. This includes arteriovenous malformations (AVMs) in the skin, brain, lung, liver, and mucous membranes. The correlations between the phenotype and genotype for HHT are not clear. An HHT Chinese pedigree was recruited. Whole exome sequencing (WES) analysis, Sanger verification, and co-segregation were conducted. Western blotting was performed for monitoring ENG/VEGFα signaling. As a result, a nonsense, heterozygous variant for ENG/CD105: c.G1169A:p. Trp390Ter of the proband with hereditary hemorrhagic telangiectasia type 1 (HHT1) was identified, which co-segregated with the disease in the M666 pedigree. Western blotting found that, compared with the normal levels associated with non-carrier family members, the ENG protein levels in the proband showed approximately a one-half decrease (47.4% decrease), while levels of the VEGFα protein, in the proband, showed approximately a one-quarter decrease (25.6% decrease), implying that ENG haploinsufficiency, displayed in the carrier of this variant, may affect VEGFα expression downregulation. Pearson and Spearman correlation analyses further supported TGFß/ENG/VEGFα signaling, implying ENG regulation in the blood vessels. Thus, next-generation sequencing including WES should provide an accurate strategy for gene diagnosis, therapy, genetic counseling, and clinical management for rare genetic diseases including that in HHT1 patients.

Pulmonary vascular phenotype identified in patients with GDF2 (BMP9) or BMP10 variants: an international multicentre study.

BACKGROUND: Bone morphogenetic proteins 9 and 10 (BMP9 and BMP10), encoded by GDF2 and BMP10, respectively, play a pivotal role in pulmonary vascular regulation. GDF2 variants have been reported in pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). However, the phenotype of GDF2 and BMP10 carriers remains largely unexplored. METHODS: We report the characteristics and outcomes of PAH patients in GDF2 and BMP10 carriers from the French and Dutch pulmonary hypertension registries. A literature review explored the phenotypic spectrum of these patients. RESULTS: 26 PAH patients were identified: 20 harbouring heterozygous GDF2 variants, one homozygous GDF2 variant, four heterozygous BMP10 variants, and one with both GDF2 and BMP10 variants. The prevalence of GDF2 and BMP10 variants was 1.3% and 0.4%, respectively. Median age at PAH diagnosis was 30 years, with a female/male ratio of 1.9. Congenital heart disease (CHD) was present in 15.4% of the patients. At diagnosis, most of the patients (61.5%) were in New York Heart Association Functional Class III or IV with severe haemodynamic compromise (median (range) pulmonary vascular resistance 9.0 (3.3-40.6) WU). Haemoptysis was reported in four patients; none met the HHT criteria. Two patients carrying BMP10 variants underwent lung transplantation, revealing typical PAH histopathology. The literature analysis showed that 7.6% of GDF2 carriers developed isolated HHT, and identified cardiomyopathy and developmental disorders in BMP10 carriers. CONCLUSIONS: GDF2 and BMP10 pathogenic variants are rare among PAH patients, and occasionally associated with CHD. HHT cases among GDF2 carriers are limited according to the literature. BMP10 full phenotypic ramifications warrant further investigation.

Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT.

ABSTRACT: For monogenic diseases caused by pathogenic loss-of-function DNA variants, attention focuses on dysregulated gene-specific pathways, usually considering molecular subtypes together within causal genes. To better understand phenotypic variability in hereditary hemorrhagic telangiectasia (HHT), we subcategorized pathogenic DNA variants in ENG/endoglin, ACVRL1/ALK1, and SMAD4 if they generated premature termination codons (PTCs) subject to nonsense-mediated decay. In 3 patient cohorts, a PTC-based classification system explained some previously puzzling hemorrhage variability. In blood outgrowth endothelial cells (BOECs) derived from patients with ACVRL1+/PTC, ENG+/PTC, and SMAD4+/PTC genotypes, PTC-containing RNA transcripts persisted at low levels (8%-23% expected, varying between replicate cultures); genes differentially expressed to Bonferroni P < .05 in HHT+/PTC BOECs clustered significantly only to generic protein terms (isopeptide-bond/ubiquitin-like conjugation) and pulse-chase experiments detected subtle protein maturation differences but no evidence for PTC-truncated protein. BOECs displaying highest PTC persistence were discriminated in unsupervised hierarchical clustering of near-invariant housekeeper genes, with patterns compatible with higher cellular stress in BOECs with >11% PTC persistence. To test directionality, we used a HeLa reporter system to detect induction of activating transcription factor 4 (ATF4), which controls expression of stress-adaptive genes, and showed that ENG Q436X but not ENG R93X directly induced ATF4. AlphaFold accurately modeled relevant ENG domains, with AlphaMissense suggesting that readthrough substitutions would be benign for ENG R93X and other less rare ENG nonsense variants but more damaging for Q436X. We conclude that PTCs should be distinguished from other loss-of-function variants, PTC transcript levels increase in stressed cells, and readthrough proteins and mechanisms provide promising research avenues.

Genome sequencing identify chromosome 9 inversions disrupting ENG in 2 unrelated HHT families.

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the ENG and ACVRL1 genes are responsible for most cases of HHT. Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH). In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the ENG gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients. This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified.

Hereditary hemorrhagic telangiectasia: from signaling insights to therapeutic advances.

Hereditary hemorrhagic telangiectsia (HHT) is an inherited vascular disorder with highly variable expressivity, affecting up to 1 in 5,000 individuals. This disease is characterized by small arteriovenous malformations (AVMs) in mucocutaneous areas (telangiectases) and larger visceral AVMs in the lungs, liver, and brain. HHT is caused by loss-of-function mutations in the BMP9-10/ENG/ALK1/SMAD4 signaling pathway. This Review presents up-to-date insights on this mutated signaling pathway and its crosstalk with proangiogenic pathways, in particular the VEGF pathway, that has allowed the repurposing of new drugs for HHT treatment. However, despite the substantial benefits of these new treatments in terms of alleviating symptom severity, this not-so-uncommon bleeding disorder still currently lacks any FDA- or European Medicines Agency-approved (EMA-approved) therapies.

Shear Stress and Sub-Femtomolar Levels of Ligand Synergize to Activate ALK1 Signaling in Endothelial Cells.

Endothelial cells (ECs) respond to concurrent stimulation by biochemical factors and wall shear stress (SS) exerted by blood flow. Disruptions in flow-induced responses can result in remodeling issues and cardiovascular diseases, but the detailed mechanisms linking flow-mechanical cues and biochemical signaling remain unclear. Activin receptor-like kinase 1 (ALK1) integrates SS and ALK1-ligand cues in ECs; ALK1 mutations cause hereditary hemorrhagic telangiectasia (HHT), marked by arteriovenous malformation (AVM) development. However, the mechanistic underpinnings of ALK1 signaling modulation by fluid flow and the link to AVMs remain uncertain. We recorded EC responses under varying SS magnitudes and ALK1 ligand concentrations by assaying pSMAD1/5/9 nuclear localization using a custom multi-SS microfluidic device and a custom image analysis pipeline. We extended the previously reported synergy between SS and BMP9 to include BMP10 and BMP9/10. Moreover, we demonstrated that this synergy is effective even at extremely low SS magnitudes (0.4 dyn/cm2) and ALK1 ligand range (femtogram/mL). The synergistic response to ALK1 ligands and SS requires the kinase activity of ALK1. Moreover, ALK1's basal activity and response to minimal ligand levels depend on endocytosis, distinct from cell-cell junctions, cytoskeleton-mediated mechanosensing, or cholesterol-enriched microdomains. However, an in-depth analysis of ALK1 receptor trafficking's molecular mechanisms requires further investigation.

Functional characterization of variants found in Japanese patients with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant form of vascular dysplasia. Genetic diagnosis is made by identifying loss-of-function variants in genes, such as ENG and ACVRL1. However, the causal mechanisms of various variants of unknown significance remains unclear. In this study, we analyzed 12 Japanese patients from 11 families who were clinically diagnosed with HHT. Sequencing analysis identified 11 distinct variants in ACVRL1 and ENG. Three of the 11 were truncating variants, leading to a definitive diagnosis, whereas the remaining eight were splice-site and missense variants that required functional analyses. In silico splicing analyses demonstrated that three variants, c.526-3C > G and c.598C > G in ACVRL1, and c.690-1G > A in ENG, caused aberrant splicing, as confirmed by a minigene assay. The five remaining missense variants were p.Arg67Gln, p.Ile256Asn, p.Leu285Pro, and p.Pro424Leu in ACVRL and p.Pro165His in ENG. Nanoluciferase-based bioluminescence analyses demonstrated that these ACVRL1 variants impaired cell membrane trafficking, resulting in the loss of bone morphogenetic protein 9 (BMP9) signal transduction. In contrast, the ENG mutation impaired BMP9 signaling despite normal cell membrane expression. The updated functional analysis methods performed in this study will facilitate effective genetic testing and appropriate medical care for patients with HHT.

Impact of heterozygous ALK1 mutations on the transcriptomic response to BMP9 and BMP10 in endothelial cells from hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension donors.

Heterozygous activin receptor-like kinase 1 (ALK1) mutations are associated with two vascular diseases: hereditary hemorrhagic telangiectasia (HHT) and more rarely pulmonary arterial hypertension (PAH). Here, we aimed to understand the impact of ALK1 mutations on BMP9 and BMP10 transcriptomic responses in endothelial cells. Endothelial colony-forming cells (ECFCs) and microvascular endothelial cells (HMVECs) carrying loss of function ALK1 mutations were isolated from newborn HHT and adult PAH donors, respectively. RNA-sequencing was performed on each type of cells compared to controls following an 18 h stimulation with BMP9 or BMP10. In control ECFCs, BMP9 and BMP10 stimulations induced similar transcriptomic responses with around 800 differentially expressed genes (DEGs). ALK1-mutated ECFCs unexpectedly revealed highly similar transcriptomic profiles to controls, both at the baseline and upon stimulation, and normal activation of Smad1/5 that could not be explained by a compensation in cell-surface ALK1 level. Conversely, PAH HMVECs revealed strong transcriptional dysregulations compared to controls with > 1200 DEGs at the baseline. Consequently, because our study involved two variables, ALK1 genotype and BMP stimulation, we performed two-factor differential expression analysis and identified 44 BMP9-dysregulated genes in mutated HMVECs, but none in ECFCs. Yet, the impaired regulation of at least one hit, namely lunatic fringe (LFNG), was validated by RT-qPCR in three different ALK1-mutated endothelial models. In conclusion, ALK1 heterozygosity only modified the BMP9/BMP10 regulation of few genes, including LFNG involved in NOTCH signaling. Future studies will uncover whether dysregulations in such hits are enough to promote HHT/PAH pathogenesis, making them potential therapeutic targets, or if second hits are necessary.

Endoglin mutants retained in the endoplasmic reticulum exacerbate loss of function in hereditary hemorrhagic telangiectasia type 1 (HHT1) by exerting dominant negative effects on the wild type allele.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder affecting 1 in 5000-8000 individuals. Hereditary hemorrhagic telangiectasia type 1 (HHT1) is the most common HHT and manifests as diverse vascular malformations ranging from mild symptoms such as epistaxis and mucosal and cutaneous telangiectases to severe arteriovenous malformations (AVMs) in the lungs, brain or liver. HHT1 is caused by heterozygous mutations in the ENG gene, which encodes endoglin, the TGFß homodimeric co-receptor. It was previously shown that some endoglin HHT1-causing variants failed to traffic to the plasma membrane due to their retention in the endoplasmic reticulum (ER) and consequent degradation by ER-associated degradation (ERAD). Endoglin is a homodimer formed in the ER, and we therefore hypothesized that mixed heterodimers might form between ER-retained variants and WT protein, thus hampering its maturation and trafficking to the plasma membrane causing dominant negative effects. Indeed, HA-tagged ER-retained mutants formed heterodimers with Myc-tagged WT endoglin. Moreover, variants L32R, V105D, P165L, I271N and C363Y adversely affected the trafficking of WT endoglin by reducing its maturation and plasma membrane localization. These results strongly suggest dominant negative effects exerted by these ER-retained variants aggravating endoglin loss of function in patients expressing them in the heterozygous state with the WT allele. Moreover, this study may help explain some of the variability observed among HHT1 patients due to the additional loss of function exerted by the dominant negative effects in addition to that due to haploinsufficiency. These findings might also have implications for some of the many conditions impacted by ERAD.

A novel frameshift mutation of the endoglin(ENG) gene causes hereditary hemorrhagic telangiectasia in a Chinese family.

PURPOSE: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited disorder that involves epistaxis, mucocutaneous telangiectases, and visceral arteriovenous malformations (AVMs). This study aims to investigate the genetic causes in a Chinese family with HHT. METHODS: HHT was confirmed according to Curaçao's diagnostic criteria. Three patients diagnosed with HHT and healthy members were recruited. Whole-exome sequencing (WES) and sanger sequencing were performed to define the patient's genetically pathogenic factor. RESULTS: The proband presented with recurrent epistaxis, hepatopulmonary arteriovenous malformation, and adenocarcinoma. A novel frameshift mutation (c.1376_1377delAC, p.H459Lfs*41) of the ENG gene was revealed in affected individuals by WES. There was no report of this variant and predicted to be highly damaging by causing truncation of the ENG protein. CONCLUSION: We report a novel variant in the ENG gene in Chinese that extends the mutational and phenotypic spectra of the ENG gene, and also demonstrates the feasibility of WES in the application of genetic diagnosis of HHT.

New genetic drivers in hemorrhagic hereditary telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease inherited in an autosomal dominant manner. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in around 90% of the patients; also 2% of patients harbor pathogenic variants at SMAD4 and GDF2. Importantly, the genetic cause of 8% of patients with clinical HHT remains unknown. Here, we present new putative genetic drivers of HHT. METHODS: To identify new HHT genetic drivers, we performed exome sequencing of 19 HHT patients and relatives with unknown HHT genetic etiology. We applied a multistep filtration strategy to catalog deleterious variants and prioritize gene candidates based on their known relevance in endothelial cell biology. Additionally, we performed in vitro validation of one of the identified variants. RESULTS: We identified variants in the INHA, HIF1A, JAK2, DNM2, POSTN, ANGPTL4, FOXO1 and SMAD6 genes as putative drivers in HHT. We have identified the SMAD6 p.(Glu407Lys) variant in one of the families; this is a loss-of-function variant leading to the activation of the BMP/TGFß signaling in endothelial cells. CONCLUSIONS: Variants in these genes should be considered for genetic testing in patients with HHT phenotype and negative for ACVRL1/ENG mutations.

Understanding hereditary hemorrhagic telangiectasia: From genetic anomalies to systemic manifestations, quality of life, and epistaxis management-Exploring the otolaryngologist's integral role.

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Rendu-Weber syndrome, is a rare autosomal dominant disorder characterized by vascular malformations. This comprehensive review aimed to provide an overview and summarize various aspects of HHT, including the genetic abnormalities, complications associated with visceral arteriovenous malformations (AVMs), prognosis of HHT, quality of life (QOL), and treatment of epistaxis. In addition, this review highlights the challenges in diagnosing HHT and emphasizes the critical role of otolaryngologists in the early detection of HHT. Otolaryngologists can refer patients with refractory epistaxis for AVM screening to expedite intervention. Mutation of the genes involved in the transforming growth factor-ß signaling pathway leads to the incidence of HHT, resulting in the formation of abnormal blood vessel formation. These vascular malformations commonly manifest as telangiectasia on the skin and mucous membranes; however, epistaxis remains the hallmark symptom of HHT. The impact of HHT goes beyond the visible symptoms and often includes the formation of life-threatening visceral AVMs in the lungs, liver, and brain. The prognosis of patients with HHT is closely related to the development of these complications, necessitating timely diagnosis and intervention. Refractory epistaxis diminishes the QOL of patients with HHT. The management of epistaxis ranges from conservative measures to advanced interventions such as prevention, conservative treatments, ablation, surgical procedures, and the administration of anti-angiogenic agents. However, effective management requires a multidisciplinary approach. The diagnosis of HHT remains challenging due to its variable presentation and lack of awareness among physicians. This review highlights the importance of reducing the duration between symptom onset and diagnosis. Otolaryngologists who are experienced in the management of refractory epistaxis can aid in identifying potential cases of HHT. They can facilitate the initiation of screening for visceral AVMs via prompt recognition of the signs and symptoms of HHT, contributing to improved patient outcomes. Early detection and intervention through screening can extend the life expectancy of patients with HHT to levels comparable with that of the general population. In conclusion, this review provides insight into various aspects of HHT and emphasizes the importance of timely diagnosis and intervention in the mitigation of the potentially life-threatening complications associated with this disorder. Otolaryngologists play a critical role in this process, serving as gatekeepers to the identification of cases of HHT and implementation of appropriate screening and management pathways, thereby improving the life expectancy and QOL of patients.

Induced Endothelial Cell Cycle Arrest Prevents Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Distinct endothelial cell cycle states (early G1 versus late G1) provide different "windows of opportunity" to enable the differential expression of genes that regulate venous versus arterial specification, respectively. Endothelial cell cycle control and arteriovenous identities are disrupted in vascular malformations including arteriovenous shunts, the hallmark of hereditary hemorrhagic telangiectasia (HHT). To date, the mechanistic link between endothelial cell cycle regulation and the development of arteriovenous malformations (AVMs) in HHT is not known. METHODS: We used BMP (bone morphogenetic protein) 9/10 blocking antibodies and endothelial-specific deletion of activin A receptor like type 1 (Alk1) to induce HHT in Fucci (fluorescent ubiquitination-based cell cycle indicator) 2 mice to assess endothelial cell cycle states in AVMs. We also assessed the therapeutic potential of inducing endothelial cell cycle G1 state in HHT to prevent AVMs by repurposing the Food and Drug Administration-approved CDK (cyclin-dependent kinase) 4/6 inhibitor (CDK4/6i) palbociclib. RESULTS: We found that endothelial cell cycle state and associated gene expressions are dysregulated during the pathogenesis of vascular malformations in HHT. We also showed that palbociclib treatment prevented AVM development induced by BMP9/10 inhibition and Alk1 genetic deletion. Mechanistically, endothelial cell late G1 state induced by palbociclib modulates the expression of genes regulating arteriovenous identity, endothelial cell migration, metabolism, and VEGF-A (vascular endothelial growth factor A) and BMP9 signaling that collectively contribute to the prevention of vascular malformations. CONCLUSIONS: This study provides new insights into molecular mechanisms leading to HHT by defining how endothelial cell cycle is dysregulated in AVMs because of BMP9/10 and Alk1 signaling deficiencies, and how restoration of endothelial cell cycle control may be used to treat AVMs in patients with HHT.

Pro-angiogenic changes of T-helper lymphocytes in hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a rare inherited disease due to heterozygous loss-of-function mutations on the BMP9/10 pathway (ENG, ACVRL1 or MADH4 mainly). HHT endothelial cells are prone to lose their quiescence, leading to progressive appearance of numerous telangiectases on skin and mucosa (complicated by epistaxis and anemia), and to larger arteriovenous malformations in lungs, liver and brain. HHT is also associated with T lymphocyte abnormalities, which are currently poorly understood. We quantified by flow-cytometry the main T lymphocyte circulating subsets in 40 HHT patients and 20 matched healthy controls. Immunostaining was done on 2 HHT skin telangiectases. Disruptions in T lymphocyte homeostasis was observed, characterized by increases in subsets known to promote angiogenesis: Th2 (1.38% vs 1.15%, p=0.021), Th17 (0.32% vs 0.22%, p=0.019 2) and Treg (4.94% vs 3.51%, p= 0.027). T angiogenic lymphocytes (Tang), defined as CD3+CD31+CXCR4+ T cells, were at similar levels in both groups, but the proportion of VEGF-A+ Tang after stimulation was higher in the HHT group compared to controls (68.2% vs 44.9%, p=0.012). The global HHT T lymphopenia predominantly affected the effector memory T-helper cells (200 vs 270 cells/mm3, p=0.017), and the lymphocytic infiltrate around HHT telangiectases consisted of memory T-helper cells. The Th17 circulating subset was positively correlated with the monthly epistaxis duration (r coefficient: +0,431, p=0.042), prospectively assessed. HHT T-helper lymphocytes are affected by several pro-angiogenic changes, potentially resulting from their recruitment by abnormal endothelial cells. They could constitute a biologically relevant source of VEGF-A and a valuable therapeutic target in HHT.

[Prevalencia de la Telangiectasia Hemorrágica Hereditaria: estudio de base poblacional en la Comunitat Valenciana (España).] / Prevalence of Hereditary Hemorrhagic Telangiectasia: a population-based study in the Valencian region (Spain).

OBJECTIVE: The Hereditary Haemorrhagic Telangiectasia (HHT) is a low prevalence disease which presents heterogeneous signs and symptoms and just few population-based epidemiological studies are available. The aims of this paper were to describe the sociodemographic characteristics of people affected by HHT in the Valencian Region (VR), to determine its prevalence and mortality rate, and to analyse the sources of recruitment and verification tests used by the Rare Diseases Information System of the VR (SIER-CV). METHODS: Cross-sectional observational epidemiological study of HHT prevalent cases between 2010-2019 in SIER-CV was performed. The distribution of sociodemographic and clinical characteristics were determined, the prevalence and mortality rates, and the sources of recruitment and verification tests used by SIER-CV were analysed. Statistical analysis was performed using Stata (version 16.1) and Microsoft Excel Office. RESULTS: During 2010-2019, two hundred cases were identified, 55.5% were female. The mean ages were: 56.8 years at recruitment and 50.9 years at diagnosis. 48.4% of cases were diagnosed between thirty-six/sixty-four years of age. 25.5% died, with a mean age of 76.6 years, identifying statistically significant differences above the age of 64. The prevalence was 39.6/1,000,000 inhabitants and the crude mortality rate was 10.1/1,000,000 inhabitants. 95.5% of cases were recruited from the Hospital discharges database and the most frequent verification test was the clinical basis (45.7%). CONCLUSIONS: The increasing trend in prevalence coincides with a better knowledge of HHT, which favours its detection, and also with dying at older ages. To describe the situation of HHT in the VR facilitates its health management and contributes to the establishment of the relevant health policies for the HHT. The need to promote genetic diagnosis and to incorporate the Primary Care Clinical History as a source of recruitment in the population-based registries has been shown.

OBJECTIVE: La Telangiectasia Hemorrágica Hereditaria (THH) es una enfermedad de baja prevalencia, que se presenta con signos y síntomas muy heterogéneos y de la que apenas se dispone de estudios epidemiológicos de base poblacional. Los objetivos de este estudio fueron describir las características sociodemográficas de las personas afectadas por THH en la Comunitat Valenciana (CV), determinar su prevalencia y mortalidad, y analizar las fuentes de captación y pruebas de verificación utilizadas por el Sistema de Información de Enfermedades Raras de la CV (SIER-CV). METHODS: Se realizó un estudio epidemiológico observacional transversal de casos prevalentes de THH durante 2010-2019 en el SIER-CV. Se determinó la distribución de las características sociodemográficas y clínicas, la prevalencia y mortalidad, y se analizaron las fuentes de captación y pruebas de verificación utilizadas por SIER-CV. El análisis estadístico de los datos se realizó mediante el programa Stata (versión 16.1) y Microsoft Excel Office. RESULTS: Durante 2010-2019 se identificaron doscientos casos, de los que el 55,5% eran mujeres. Las edades medias fueron: de captación 56,8 años, y de diagnóstico 50,9 años. El 48,4% fueron diagnosticados entre los treinta y seis, y los sesenta y cuatro años. Fallecieron el 25,5%, con 76,6 años de edad media, identificándose diferencias estadísticamente significativas en mayores de sesenta y cuatro años. La prevalencia fue 39,6 por cada millón de habitantes y la tasa cruda de mortalidad de 10,1 por cada millón de habitantes. El 95,5% se captaron por el Conjunto Mínimo Básico de Datos y la prueba de verificación más frecuente fue la base clínica (45,7%). CONCLUSIONS: La tendencia ascendente de la prevalencia coincide con un mejor conocimiento de la THH, que facilita la detección de casos, y también con fallecimientos en edades avanzadas. Describir la situación de la THH en la CV facilita su manejo sanitario y contribuye al establecimiento de las políticas sanitarias correspondientes. Se muestra la necesidad de favorecer el diagnóstico genético e incorporar la Historia de Atención Primaria como fuente de captación en los registros poblacionales.