ACVRL1 Mutations Research Articles

Treprostinil Effectiveness in Higher-Risk Pediatric Patients With Idiopathic and Heritable Pulmonary Arterial Hypertension

BackgroundLittle is known about the effectiveness of treprostinil in higher-risk paediatric patients with various pulmonary arterial hypertension genotypes. This study was designed to investigate the prognosis of higher-risk paediatric patients with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH) after treprostinil therapy. MethodsChildren with IPAH/HPAH who were stratified as higher risk and treated with treprostinil in our centre were included as the study cohort. Those who received only oral medications were included as the reference cohort. All patients in the study cohort received PAH-related genotyping. Survival was defined as no death. Event-free survival was defined as no death, Potts shunt, or atrial septostomy. ResultsForty-nine children (median age 7.7 years [interquartile range (IQR) 4.2-11.5 years], 65% female) were included in the study cohort and 48 children were included in the reference cohort; 84% of the study cohort had genetic disorders after genetic testing with a dominance of BMPR2 and ACVRL1 mutations. After a median therapy duration of 5.56 months (IQR 2.66-11.12 months), all patients were alive with significant improvements in clinical characteristics. One-, 2-, and 3-year survival rates were 91%, 84%, and 69%, respectively with a median follow-up duration of 19.17 months (IQR 9.7-29.79 months), which was significantly superior to the reference cohort (P = 0.038). Multivariate Cox regression analysis identified World Health Organisation functional class after therapy as a predictor for survival. There was no significant difference in survival among patients with different genotypes. ConclusionsTreprostinil can significantly improve the prognosis in children with IPAH/HPAH who are at higher risk, despite genetic backgrounds.

A case report of isolated right ventricular noncompaction with mutation of ACVRL1: a new cause of noncompaction of ventricular myocardium?

BackgroundNoncompaction of ventricular myocardium(NVM) is a rare kind of cardiomyopathy associated with genetic mutations and nongenetic factors, among which the isolated right ventricular noncompaction (iRVNC) is the most rare type. ACVRL1 is the pathogenic gene of type 2 hereditary hemorrhagic telangiectasia (HHT2), and there’s no NVM reported to be associated with ACVRL1 mutation.Case presentationThis is a rare case diagnosed as iRVNC and pulmonary hypertention with ACVRL1 mutation detected.ConclusioniRVNC in this case may be due to ACVRL1 mutation, secondary to pulmonary hypertention and right ventricular failure caused by ACVRL1 mutation, or they happened in the same case coincidently.

169 Exome Sequencing Implicates Endothelial Ras Signaling Network in Vein of Galen Aneurysmal Malformation

INTRODUCTION: Early neurovascular development is a complex and intricate process with devastating consequences when impaired. Vein of Galen Aneurysmal Malformations (VGAMs) are the most common and severe neonatal arteriovenous malformation and often present with high-output heart failure, hydrocephalus, neurodevelopmental delay, and brain hemorrhage. Despite their prevalence and severity, little is known regarding their genetic pathomechanism. METHODS: Genetic samples were collected from 114 VGAM probands, including 90 trios, from multiple sites. Collected specimens underwent whole exome sequencing, pathway analysis, and select ACVRL1 and EPHB4 mutations identified via sequencing were then studied in zebrafish models. RESULTS: Exome sequencing revealed a genome-wide significant burden of de novo mutations in Ras suppressor p120 Ras-GAP (RASA1) (enrichment = 324-fold; p = 4.8 x 10-7). Damaging transmitted variants were enriched in p120 Ras-GAP negative regulator Eph-B4 (EPHB4) (odds ratio = 27.4; p = 1.7 x 10-6). Eph-B4 missense variants caused loss of receptor tyrosine kinase activity constitutive Ras activation. Other probands had pathogenic variants in OMIM vascular disease genes PTNPN11, NOTCH1, and ACVRL1; the latter we found mutated in an ultra-rare multi-generational VGAM family. Pathway analysis identified enrichment of rare, damaging de novo and inherited variants in a network of interacting OMIM vascular disease genes involved in axon guidance (FDR = 2.3 x 10-5; enrichment = 3.65-fold). In zebrafish, the functional studies of ACVRL1 and EPHB4 confirmed severe vascular defects in mutant embryos. CONCLUSIONS: These results demonstrate that genetic regulation of a RASA1-centered Ras signaling hub is critical for cerebrovascular development and is impaired in VGAM pathogenesis. This finding has significant implications for the genetic counseling of patient families and the development of targeted therapeutics for VGAM neurovascular disorders.

345 Structural Cardiac Defects and Vascular Anomalies in Vein of Galen Malformation Patients: A Multi-Institutional Cohort With Genetic Sequencing

INTRODUCTION: Vein of Galen malformations (VOGM) are rare, potentially lethal brain arteriovenous malformations (AVM). The roles of EPHB4, RASA1, and ACVRL1 have been described in VOGM pathogenesis, and previous studies have reported the co-occurrence of VOGM with cardiac and vascular disorders. METHODS: We queried our cross-institutional cohort of 129 VOGM patients with detailed genotypic and phenotypic data. Genetic samples from a subset of 114 VOGM probands, including 90 trios, underwent whole exome sequencing. RESULTS: We found that 9.3% of our patients had structural cardiac defects, as compared to 0.8-1.2% in the general population. Our cohort’s cardiac defects included 3.9% with patent ductus arteriosus, compared to 0.1% in the general population, and 1.6% with atrial septal defect, a congenital condition previously connected to VOGM. 22.5% of our patients had vascular abnormalities, including 16.3% with cutaneous vascular lesions and 4.7% with recurrent epistaxis. One patient presented with VOGM and moyamoya disease. Our whole exome sequencing found that patients with damaging RASA1 mutations presented with significantly more cutaneous vascular lesions relative to the rest of the VOGM cohort (60% vs 16%, p = 0.007) and patients with damaging ACVRL1 mutations had significantly higher rates of recurrent epistaxis (50% vs 5%, p = 0.002). CONCLUSIONS: RASA1 is associated with capillary malformation-arteriovenous malformation syndrome (CM-AVM), and ACVRL1 is associated with hereditary hemorrhagic telangiectasia (HHT); CM-AVM and HHT are neurovascular disorders in which the VOGM phenotype is frequently encountered. Our findings demonstrate the high incidence of cardiac defects and vascular abnormalities in VOGM patients and the value of clinical sequencing of VOGM patients with these co-occurring clinical features.

Germline genetic mutations in pediatric cerebrovascular anomalies: a multidisciplinary approach to screening, testing, and management.

Genetic alterations are increasingly recognized as etiologic factors linked to the pathogenesis and development of cerebrovascular anomalies. Their identification allows for advanced screening and targeted therapeutic approaches. The authors aimed to describe the role of a collaborative approach to care and genetic testing in pediatric patients with neurovascular anomalies, with the objectives of identifying what genetic testing recommendations were made, the yield of genetic testing, and the implications for familial screening and management at present and in the future. The authors performed a descriptive retrospective cohort study examining pediatric patients genetically screened through the Pediatric Neurovascular Program of a single treatment center. Patients 18 years of age and younger with neurovascular anomalies, diagnosed radiographically or histopathologically, were evaluated for germline genetic testing. Patient demographic data and germline genetic testing and recommendation, clinical, treatment, and outcome data were collected and analyzed. Sixty patients were included; 29 (47.5%) were female. The mean age at consultation was 11.0 ± 4.9 years. Diagnoses included cerebral arteriovenous malformations (AVMs) (n = 23), cerebral cavernous malformations (n = 19), non-neurofibromatosis/non-sickle cell moyamoya (n = 8), diffuse cerebral proliferative angiopathy, and megalencephaly-capillary malformation. Of the 56 patients recommended to have genetic testing, 40 completed it. Genetic alterations were found in 13 (23%) patients. Four patients with AVMs had RASA1, GDF2, and ACVRL1 mutations. Four patients with cavernous malformations had Krit1 mutations. One with moyamoya disease had an RNF213 mutation. Three patients with megalencephaly-capillary malformation had PIK3CA mutations, and 1 patient with a cavernous sinus lesion had an MED12 mutation. The majority of AVM patients were treated surgically. Patients with diffuse cerebral proliferative angiopathy were treated medically with sirolimus. At-risk relatives of 3 patients positive for genetic anomalies had also been tested. This study demonstrates a role for exploring genetic alterations in the identification and treatment of pediatric neurovascular disease pathogenesis. Germline genetic mutations were found in almost one-quarter of the patients screened in this study, results that helped to identify medically targeted treatment modalities for some pediatric neurovascular patients. Insight into the genetic etiology of vascular anomalies may provide broader clinical implications for risk assessment, family screening, follow-up surveillance, and medical management.

Second International Pulmonary Hypertension/Heart Failure Symposium—Structural heart disease, right ventricular dysfunction, and stem cell therapy: The European Pediatric Pulmonary Vascular Disease Network

Second International Pulmonary Hypertension/Heart Failure Symposium—Structural heart disease, right ventricular dysfunction, and stem cell therapy: The European Pediatric Pulmonary Vascular Disease Network

Thrombosis in hereditary hemorrhagic telangiectasia

Thrombosis in hereditary hemorrhagic telangiectasia

Cardiac and Hemodynamic Manifestations of Hereditary Hemorrhagic Telangiectasia.

The autosomal dominant trait hereditary hemorrhagic telangiectasia (HHT) causes multiorgan dysplastic lesions of the vasculature that can activate multiple physiological cascades leading to a broad array of cardiovascular diseases. Up to 78% of patients with HHT develop hepatic arteriovenous malformations (AVMs), which cause a hyperdynamic circulatory state secondary to hepatic/portal shunting. This condition can eventually progress to high-output cardiac failure (HOCF) with continued peripheral tissue hypoxemia. Treatment for HOCF is often limited to supportive measures (diuretics and treatment of anemia); however, recent studies using systemic bevacizumab have shown promise by substantially reducing the cardiac index. In the context of liver AVMs and high cardiac output, the pulmonary vasculature can also experience high flow. Without adequate dilation of pulmonary vessels, post-capillary pulmonary hypertension can develop. Another form of pulmonary hypertension observed in HHT, pulmonary arterial hypertension, is caused by HHT-related mutations in ENG and ACVRL1 causing congestive arteriopathy. Post-capillary pathogenesis is addressed by reducing the high-output state, whereas the pre-capillary state is treated with supportive mechanisms (diuretics, oxygen) and agents targeting pulmonary vasoreactivity: endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors. If either form of pulmonary hypertension is left untreated or proves refractory and progresses, the common hemodynamic complication is right heart failure. Targeted right heart therapies involve similar strategies to those of pulmonary arterial hypertension, with several experimental approaches under study. In this review, we describe in detail the mechanisms of pathogenesis, diagnosis, and treatment of the hemodynamic complications and associated cardiovascular diseases that may arise in patients with HHT.

Neurovascular Manifestations in Pediatric Patients With Hereditary Haemorrhagic Telangiectasia

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a multiorgan vascular dysplasia with limited data regarding its neurovascular manifestations and genotype-phenotype correlation in children. The objective of this study was to describe the neurovascular findings in a large cohort of children with HHT and correlate between phenotype and genotype. MethodsThis retrospective study was conducted on 221 children (<18 years) with a definite or possible diagnosis of HHT based on Curacao criteria, or with positive genetics for the mutated genes of ENG, ACVRL-1, and SMAD-4, who also underwent brain MRI and/or conventional angiography. Demographic and clinical information, imaging findings, and follow up information were gathered. ResultsTwo hundred twenty-one children with HHT (70.6% genetically confirmed, and 99.5% positive family history) were included, with a median age of 7 years (interquartile range: 3 to 11 years) and 58.8% male predominance. Neurovascular lesions were found in 64 of 221 (28.9%), with 3.1% prevalence of intracranial hemorrhage. The most commonly observed vascular malformations were developmental venous anomalies (48.5%) and brain arteriovenous malformations (AVMs) (31.2%), followed by capillary malformations (14.1%). Multiple AVMs were seen in 10.0% of the cohort. We found no instances of de novo AVM (1281.8 patient-years).A significantly higher proportion of patients with ENG mutations (19.7%) had brain AVM than those with ACVRL-1 (4.9%) and SMAD-4 (0%) mutations (P < 0.01). There was no significant difference in the hemorrhagic risk of shunting lesions associated with ENG (35.3%) or ACVRL-1 (33.3%) positivity (P = 0.9). ConclusionsWe describe the neurovascular imaging and genetic findings from a large pediatric cohort of HHT, to enhance clinical awareness and guide management of patients with HHT.

PH Professional Network: Genetic Counseling and Pulmonary Arterial Hypertension

PH Professional Network: Genetic Counseling and Pulmonary Arterial Hypertension

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

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant fibrovascular dysplasia caused by mutations in ENG, ACVRL1, and SMAD4. Increasingly, there has been an appreciation for vascular conditions with phenotypic overlap to HHT but which have distinct clinical manifestations and arise from novel or uncharacterized gene variants. This study reported on a cohort of four unrelated probands who were diagnosed with a rare form of GDF2-related HHT5, for which only five prior cases have been described. Two patients harbored heterozygous missense variants not previously annotated as pathogenic (p.Val403Ile; p.Glu355Gln). Clinically, these patients had features resembling HHT1, including cerebrovascular involvement of their disease (first report documenting cerebral involvement of HHT5), but with earlier onset of epistaxis and a unique anatomic distribution of dermal capillary lesions that involved the upper forelimbs, trunk, and head. The other two patients harbored interstitial deletions larger than five megabases between 10q11.22 and 10q11.23 that included GDF2. To our knowledge, this is the first report detailing large genomic deletions leading to HHT5. These patients also demonstrated mucocutaneous capillary dysplasias, including intranasal vascular lesions complicated by childhood-onset epistasis, with a number of extravascular findings related to their 10q11.21q11.23 deletion. In conclusion, patients with GDF2-related HHT may present with a number of unique characteristics that differ from classically reported features of HHT.

Peliosis Hepatis with Chylous Ascites in a Dog

A 6-year-old spayed female Toy Poodle dog was referred to the Hokkaido University Veterinary Teaching Hospital for abdominal distension. Abdominocentesis yielded ascitic fluid that had a mildly increased total protein concentration and a 2.7-fold higher triglyceride concentration than plasma, and was interpreted as chylous ascites. The patient had an enlarged liver, which contained multiple, small, nodular masses and cyst-like structures. Microscopically, these lesions were multifocal dilated spaces containing lymphocytes, endothelial cells, fibrin and islands of hepatocytes. Increased α-smooth muscle actin-positive cells were observed in hepatic sinusoids. Based on these findings, we diagnosed peliosis hepatis with chylous ascites, which is likely to have been due to lymphangiectasia and disrupted hepatic sinusoids. Neither Bartonella spp DNA nor mutations in ACVRL1 and MTM1 genes were detected, although there was a 47-fold increase in hepatic ACVRL1 expression compared with age-matched control liver. To the authors' knowledge, this is the first report of chylous ascites resulting from peliosis hepatis in any species.

Founder Effects in Hereditary Hemorrhagic Telangiectasia.

A founder effect can result from the establishment of a new population by individuals from a larger population or bottleneck events. Certain alleles may be found at much higher frequencies because of genetic drift immediately after the founder event. We provide a systematic literature review of the sporadically reported founder effects in hereditary hemorrhagic telangiectasia (HHT). All publications from the ACVRL1, ENG and SMAD4 Mutation Databases and publications searched for terms “hereditary hemorrhagic telangiectasia” and “founder” in PubMed and Scopus, respectively, were extracted. Following duplicate removal, 141 publications were searched for the terms “founder” and “founding” and the etymon “ancest”. Finally, 67 publications between 1992 and 2020 were reviewed. Founder effects were graded upon shared area of ancestry/residence, shared core haplotypes, genealogy and prevalence. Twenty-six ACVRL1 and 12 ENG variants with a potential founder effect were identified. The bigger the cluster of families with a founder mutation, the more remarkable is its influence to the populational ACVRL1/ENG ratio, affecting HHT phenotype. Being aware of founder effects might simplify the diagnosis of HHT by establishing local genetic algorithms. Families sharing a common core haplotype might serve as a basis to study potential second-hits in the etiology of HHT.

Predictors of mortality in patients with hereditary hemorrhagic telangiectasia

BackgroundRetrospective questionnaire and healthcare administrative data suggest reduced life expectancy in untreated hereditary hemorrhagic telangiectasia (HHT). Prospective data suggests similar mortality, to the general population, in Denmark’s centre-treated HHT patients. However, clinical phenotypes vary widely in HHT, likely affecting mortality. We aimed to measure predictors of mortality among centre-treated HHT patients. HHT patients were recruited at 14 HHT centres of the Brain Vascular Malformation Consortium (BVMC) since 2010 and followed annually. Vital status, organ vascular malformations (VMs) and clinical symptoms data were collected at baseline and during follow-up (N = 1286). We tested whether organ VMs, HHT symptoms and HHT genes were associated with increased mortality using Cox regression analysis, adjusting for patient age, sex, and smoking status.Results59 deaths occurred over average follow-up time of 3.4 years (max 8.6 years). A history of anemia was associated with increased mortality (HR = 2.93, 95% CI 1.37–6.26, p = 0.006), as were gastro-intestinal (GI) bleeding (HR = 2.63, 95% CI 1.46–4.74, p = 0.001), and symptomatic liver VMs (HR = 2.10, 95% CI 1.15–3.84, p = 0.015). Brain VMs and pulmonary arteriovenous malformations (AVMs) were not associated with mortality (p > 0.05). Patients with SMAD4 mutation had significantly higher mortality (HR = 18.36, 95% CI 5.60–60.20, p < 0.001) compared to patients with ACVRL1 or ENG mutation, but this estimate is imprecise given the rarity of SMAD4 patients (n = 33, 4 deaths).ConclusionsChronic GI bleeding, anemia and symptomatic liver VMs are associated with increased mortality in HHT patients, independent of age, and in keeping with the limited treatment options for these aspects of HHT. Conversely, mortality does not appear to be associated with pulmonary AVMs or brain VMs, for which patients are routinely screened and treated preventatively at HHT Centres. This demonstrates the need for development of new therapies to treat chronic anemia, GI bleeding, and symptomatic liver VMs in order to reduce mortality among HHT patients.

Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs such as lungs, liver, and brain. Mutations in ENG (endoglin), ACVRL1 (ALK1), and MADH4 (Smad4) genes account for over 95% of HHT. Localized telangiectases and AVMs are present in different organs, with frequencies which differ among affected individuals. By itself, HHT gene heterozygosity does not account for the focal nature and varying presentation of the vascular lesions leading to the hypothesis of a “second-hit” that triggers the lesions. Accumulating research has identified a variety of triggers that may synergize with HHT gene heterozygosity to generate the vascular lesions. Among the postulated second-hits are: mechanical trauma, light, inflammation, vascular injury, angiogenic stimuli, shear stress, modifier genes, and somatic mutations in the wildtype HHT gene allele. The aim of this review is to summarize these triggers, as well as the functional mechanisms involved.

Integration of clinical parameters, genotype and epistaxis severity score to guide treatment for hereditary hemorrhagic telangiectasia associated bleeding

BackgroundHereditary Hemorrhagic Telangiectasia (HHT) is a rare inherited disorder characterized by development of mucocutaneous telangiectases and visceral organ arteriovenous malformations, which can lead to recurrent, spontaneous bleeding and development of iron deficiency anemia. The primary objective of this study was to ascertain the relationship between epistaxis severity scores (ESS), laboratory values, genotype, and phenotype in HHT. Our secondary objective was to assess efficacy of systemic antifibrinolytic therapy in reducing ESS in HHT.MethodologyWe conducted a retrospective review of patients seen at the UNC HHT Center from January 1, 2009 to February 28, 2015. ESS, demographics, and results of genetic testing were abstracted from the medical record. Response to antifibrinolytic therapy was evaluated by comparing pre-post ESS.ResultsOne hundred and forty nine patients were eligible with 116 having genetic testing and 33 without. Age, hemoglobin and ferritin levels were predictive of ESS. Of the 116 patients that underwent genetic testing: 63 had an ACVRL1 mutation, 40 had an ENG mutation, 2 had a SMAD4 mutation, and 11 patients had no pathologic HHT genetic variation detected. Compared to patients without a detectable HHT-associated genetic variation, patients with a HHT-associated genetic variation had higher ESS scores (p < 0.05). Neither ESS nor genotype was predictive of pulmonary or brain AVMs. Twenty-four HHT patients with ESS > 4 were started on antifibrinolytic therapy (tranexamic acid or aminocaproic acid) and had a post-treatment ESS recorded. All patients had a decrease in ESS of > 0.71 (minimal meaningful difference), but patients taking antifibrinolytics displayed larger decreases. No patients on antifibrinolytics experienced a VTE with median follow up of 13 months.ConclusionsWe demonstrate that the ESS correlates with age, hemoglobin and ferritin. Additionally, we demonstrate that HHT patients with genetic mutations have higher ESS scores. Our data demonstrate that antifibrinolytics are effective in decreasing epistaxis severity and safe with long-term use in HHT patients.

3:00 PM Abstract No. 91 Association of hereditary hemorrhagic telangiectasia with cerebral and extracerebral arterial aneurysms: experience from a single center of hereditary hemorrhagic telangiectasia excellence

Arterial aneurysms are increasingly recognized as part of the hereditary hemorrhagic telangiectasia (HHT) phenotype, however, literature on this association is limited. This retrospective study describes the incidence of known intra- and extracranial aneurysms in a large cohort of patients with HHT or HHT-associated genetic mutation and identifies factors predictive of aneurysm presence. Institutional review board approval was obtained. In our institution’s HHT database, patients with either definite HHT by clinical criteria (Curacao score of 3 or 4) and/or HHT-associated mutation (ENG, ACVRL1, SMAD4, or GDF2) were identified. 401 patients were included (mean age, 47 years; range, 3-99 years); 244 (61%) were female. 365 had a Curacao score of 3 (n = 201) or 4 (n = 164). Electronic medical records were reviewed for imaging/clinical characteristics of arterial aneurysms. Statistical analysis was performed using IBM SPSS v25. 49/401 patients (12.2%) had at least one aneurysm. 17 (4.2%) were intracranial, of which 10 were treated. 21 (5.2%) had a visceral aneurysm, including splenic (n = 14, 3 treated), renal (n = 3), hepatic (n = 2), and pancreatic (n = 2). 10 (2.5%) had a cardiac/aortic aneurysm, and 7 (1.7%) had a pulmonary aneurysm. 16 patients (4.0%) had more than one aneurysm; 80 aneurysms total were documented in this cohort. 17 patients with aneurysm had an HHT-associated mutation, distributed as follows: ACVRL1 (n = 10), ENG (n = 5), GDF2 (n = 1), and SMAD4 (n = 1). Binomial logistic regression was performed to ascertain the effects of Curacao score, age, gender and genetic mutation on the likelihood that participants have at least one arterial aneurysm. Of the seven predictor variables, Curacao score, age, ACVRL1 and GDF2 were statistically significant (P = 0.007, 0.002, 0.007, and 0.014, respectively). Furthermore, ACVRL1 mutation was associated with a higher number of aneurysms in any one individual (P = 0.017) In this cohort of patients with HHT and/or HHT-associated mutation, higher Curacao score, age, ACVRL1, and GDF2 are associated with presence of at least one aneurysm in patients with HHT. ACVRL1 mutation is associated with a higher number of aneurysms in any one individual.

BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder characterized by development of high-flow arteriovenous malformations (AVMs) that can lead to stroke or high-output heart failure. HHT2 is caused by heterozygous mutations in ACVRL1, which encodes an endothelial cell bone morphogenetic protein (BMP) receptor, ALK1. BMP9 and BMP10 are established ALK1 ligands. However, the unique and overlapping roles of these ligands remain poorly understood. To define the physiologically relevant ALK1 ligand(s) required for vascular development and maintenance, we generated zebrafish harboring mutations in bmp9 and duplicate BMP10 paralogs, bmp10 and bmp10-like. bmp9 mutants survive to adulthood with no overt phenotype. In contrast, combined loss of bmp10 and bmp10-like results in embryonic lethal cranial AVMs indistinguishable from acvrl1 mutants. However, despite embryonic functional redundancy of bmp10 and bmp10-like, bmp10 encodes the only required Alk1 ligand in the juvenile-to-adult period. bmp10 mutants exhibit blood vessel abnormalities in anterior skin and liver, heart dysmorphology, and premature death, and vascular defects correlate with increased cardiac output. Together, our findings support a unique role for Bmp10 as a non-redundant Alk1 ligand required to maintain the post-embryonic vasculature and establish zebrafish bmp10 mutants as a model for AVM-associated high-output heart failure, which is an increasingly recognized complication of severe liver involvement in HHT2.

Current Status of Clinical Diagnosis and Genetic Analysis of Hereditary Hemorrhagic Telangiectasia in South Korea: Multicenter Case Series and a Systematic Review.

PurposeHereditary hemorrhagic telangiectasia (HHT), a rare genetic vascular disorder, has been rarely reported in South Korea. We investigated the current prevalence and presenting patterns of genetically confirmed HHT in South Korea.Materials and MethodsWe defined HHT patients as those with proven mutations on known HHT-related genes (ENG, ACVRL1, SMAD4, and GDF2) or those fulfilling 3 or 4 of the Curaçao criteria. A computerized systematic search was performed in PubMed and KoreaMed using the following search term: (“hereditary hemorrhagic telangiectasia” AND “Korea”) OR (“Osler-Weber-Rendu” AND “Korea”). We also collected government health insurance data. HHT genetic testing results were collected from three tertiary hospitals in which the genetic tests were performed. We integrated patient data by analyzing each case to obtain the prevalence and presenting pattern of HHT in South Korea.ResultsWe extracted 90 cases from 52 relevant articles from PubMed and KoreaMed. An additional 22 cases were identified from the three Korean tertiary hospitals after excluding seven cases that overlapped with those in the published articles. Finally, 112 HHT patients were identified (41 males and 71 females, aged 4–82 years [mean±standard deviation, 45.3±20.6 years]). The prevalence of HHT in South Korea is about 1 in 500,000, with an almost equal prevalence among men and women. Forty-nine patients underwent genetic testing, of whom 28 had HHT1 (ENG mutation) and 19 had HHT2 (ACVRL1 mutation); the other two patients were negative for ENG, ACVRL1, and SMAD4 mutations.ConclusionThe prevalence of HHT is underestimated in Korea. The rate of phenotypic presentation seems to be similar to that found worldwide. Korean health insurance coverage is limited to representative genetic analysis to detect ENG and ACVRL1 mutations. Further genetic analyses to detect HHT3, HHT4, and other forms of HHT should be implemented.

Genotypes and Phenotypes of Chinese Pediatric Patients With Idiopathic and Heritable Pulmonary Arterial Hypertension—A Single-Center Study

BackgroundThe relationship between clinical outcomes and gene mutations in Chinese pediatric patients with idiopathic and heritable pulmonary arterial hypertension (PAH) is unclear. MethodsWe retrospectively studied the clinical characteristics and outcomes of pediatric patients who visited Beijing Anzhen Hospital from September 2008 to December 2018. ResultsEighty-two pediatric patients were included. Forty-two gene mutations were identified in 41 patients (50%), including 25 mutations in BMPR2, 5 mutations in ACVRL1, 3 mutations each in ABCA3 and NOTCH3, 2 mutations each in KCNK3 and HTR2B, 1 mutation in ENG, and 1 mutation in EIF2AK4. The mean age at diagnosis of PAH was 86.4 ± 55.1 months. Forty-eight patients (twenty-eight mutation carriers) underwent cardiac catheterization examinations, with acute vasodilator testing performed simultaneously. Results showed that mutation carriers demonstrated a higher pulmonary vascular resistance index (P = 0.037). Patients with gene mutations responded poorly to vasodilators (P = 0.001). The 1-, 2-, and 3-year survival rates of mutation noncarriers were 95.1%, 87.8%, and 82.5% respectively; while for mutation carriers, the proportions were 86.6% (P = 0.216), 63.8% (P = 0.021), and 52.2% (P = 0.010), respectively. Cardiac index was an independent predictor of death (P = 0.005; odds ratio [OR] 2.16, 95% confidence interval [CI] 1.258-3.704), as well as RAP (P = 0.01; OR 1.26, 95% CI 1.056-1.503). ConclusionsIn our cohort of Chinese pediatric patients, those with an identified gene mutation demonstrated worse clinical outcomes. Therefore, early gene screening for pediatric patients with idiopathic and heritable PAH is recommended, and more aggressive treatment for mutation carriers may be advisable.