ALK1 Research Articles

The influence of interleukin-4 on transendothelial transport of low-density lipoproteins

BACKGROUND: Cytokines are important participants in the atherosclerotic process. The product of T-helpers and mast cells, interleukin-4, causes activation of endothelial cells and induces polarization of macrophages into anti-inflammatory M2 phenotype. AIM: The aim was to study the influence of interleukin-4 on the activation of transendothelial transport of low-density lipoproteins. MATERIALS AND METHODS: Low-density lipoproteins transendothelial transport was evaluated in a two-chamber model on a monolayer of human endothelial cell line EA.hy926. For that, 200 mkg/ml of low-density lipoproteins, and 1, or 10, or 100 ng/ml of interleukin-4, or 10, or 50 ng/ml of interleukin-6, or 50 ng/ml of tumor necrosis factor, or 10 ng/ml of interleukin-4 and 50 ng/ml of tumor necrosis factor, or a phosphate buffer saline were added to the cells on 24 h. The integrity of endothelial monolayer was controlled by the passage through 1 mkg/ml of fluorescein Na. The levels of mRNA and proteins in the cells were determined by reverse transcription polymerase chain reaction and Western blotting, the activity of matrix metalloproteinases-1, -2 and -9 in the culture medium — by zymography, interleukin-6 and -8 concentrations — by enzyme-linked immunosorbent assay. RESULTS: Interleukin-4 had no effect on the passage of low-density lipoproteins through the monolayer of endothelial cells in basal and tumor necrosis factor stimulation conditions. At the same time, interleukin-4 suppressed interleukin-8 secretion by cells and increased their production of interleukin-6. The latter also did not cause the changes in the permeability of endothelial monolayer. In addition, interleukin-4 did not affect the expression of CAV, SCARB1, ACVRL1 genes, encoding proteins involved in low-density lipoproteins transendothelial transport. An addition of interleukin-4 or -6 to the cells did not change the activity of the matrix metalloproteinases. CONCLUSIONS: Interleukin-4 does not affect the transendothelial transport of low-density lipoproteins, while modulating the production of other cytokines by endothelial cells. In the future, it is necessary to establish the effect of a wider range of cytokines produced by intimal cells on low-density lipoproteins transendothelial transport, as well as to clarify the molecular mechanisms of influence of tumor necrosis factor on this process in order to identify new targets for atherosclerosis therapy.

Arteriovenous Malformations in Osler-Weber-Rendu Syndrome: Pathophysiology, Clinical Manifestations, and Advances in Management

Osler-Weber-Rendu Syndrome, or Hereditary Hemorrhagic Telangiectasia (HHT), is a rare genetic disorder marked by the development of arteriovenous malformations (AVMs) throughout the body. These abnormal vascular connections bypass the capillary network, leading to significant clinical challenges. This article reviews the pathophysiology, clinical manifestations, and advances in the management of AVMs in HHT. The genetic basis of HHT involves mutations in the ENG, ACVRL1, and SMAD4 genes, which play critical roles in the TGF-β signaling pathway. These mutations result in endothelial dysfunction, contributing to the formation of AVMs. The clinical impact of AVMs is significant, particularly when they occur in the brain, lungs, liver, or gastrointestinal tract, where they can lead to life-threatening complications. This review also explores current diagnostic and management strategies, emphasizing the importance of a multidisciplinary approach. Interventional techniques such as embolization, stereotactic radiosurgery, and microsurgical resection are discussed, alongside emerging therapies like anti-angiogenic drugs and gene therapy. These advancements have led to more personalized and effective treatment plans for patients. As a result, the management of AVMs in HHT has seen significant progress, with a growing emphasis on individualized care. Continued research and the development of specialized treatment centers are crucial for further improving patient outcomes in this complex condition.

Specifications of the ACMG/AMP Variant Curation Guidelines for Hereditary Hemorrhagic Telangiectasia Genes—ENG and ACVRL1

The 2015 ACMG/AMP standards and guidelines for interpretation of sequence variants are widely used by laboratories, including for variant curation of the hereditary hemorrhagic telangiectasia (HHT) genes. However, the need for gene- and disease-specific modifications and specifications of these general guidelines to optimize and standardize variant classification was recognized at the time of publication. With this goal, the ClinGen HHT variant curation expert panel was formed. Here, we describe our recommended HHT-specific variant classification criteria and the outcomes from pilot testing of 30 variants of the ENG and ACVRL1 genes. Eight of the original ACMG/AMP rules were determined to not be applicable for ENG- or ACVRL1-related HHT or were previously recommended by ClinGen for removal, two rules were unmodified, and the remaining 18 rules were modified according to HHT specifications or previous ClinGen general recommendations. This study demonstrates the importance of HHT-specific criteria in the optimization and standardization of HHT variant classification and conflicting classification resolution.

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 with Recurrent Epistaxis, Telangiectasia, Hepatic Arteriovenous Malformation, and a Poorly Developed Middle Cerebral Artery in a Patient with a Novel Mutation in the ACVRL1 Gene.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder characterized by intractable epistaxis, mucocutaneous telangiectasias, and arteriovenous malformations (AVMs) in multiple organs, including the lungs, liver, gastrointestinal tract, brain, and spinal cord. We herein report a 50-year-old Japanese man with HHT who experienced recurrent epistaxis, telangiectasia in the cornea, apex of the tongue and fingers; hepatic AVM; and a poorly developed main arterial trunk in the right middle cerebral artery. A genetic analysis revealed a novel heterozygous mutation in the activin A receptor-like type 1 gene, with a frameshift mutation in NM_000020.3:c.826_836del (p.Ile276ProfsTer112).

The Influence of Adiponectin on Transport of Low-Density Lipoproteins through Human Endothelial Cell Monolayer In Vitro.

The influence of adiponectin, a protein secreted by adipocytes, on the activation of transendothelial LDL transport, the initial event of atherogenesis, was studied. The addition of adiponectin to the cultured endothelial hybridoma EA.hy926 cells did not affect both basal and TNF-stimulated transendothelial transport of LDL. In addition, adiponectin affects neither expression levels of CAV1, SCARB1, and ACVRL1 genes encoding proteins involved in transendothelial LDL transport, nor the MMP secretion by the EA.hy926cells. At the same time, adiponectin suppressed the TNF-stimulated IL-8 production and expression of the adhesion molecule gene ICAM1 in these cells. Thus, adiponectin reduces proinflammatory activation of EA.hy926 cells, which is not accompanied by changes in the transendothelial LDL transport. We speculate that anti-inflammatory action of adiponectin is the base for the influence of this adipokine on atherogenesis.

Generation of a Syngeneic Heterozygous ACVRL1(wt/mut) Knockout iPS Cell Line for the In Vitro Study of HHT2-Associated Angiogenesis

Hereditary hemorrhagic telangiectasia (HHT) type 2 is an autosomal dominant disease in which one allele of the ACVRL1 gene is mutated. Patients exhibit disturbances in TGF-beta/BMP-dependent angiogenesis and, clinically, often present with severe nosebleeds as well as a reduced quality of life. The aim of our study was to use CRISPR/Cas9 to knockout ACVRL1 in normal induced pluripotent stem cells (iPSCs) and evaluate the effects on TGF-beta- and BMP-related gene expression as well as angiogenesis. The CRISPR/Cas9 knockout of the ACVRL1 gene was carried out in previously characterized wild-type (ACVRL1wt/wt) iPSCs. An HHT type 2 iPS cell line was generated via a single-allele knockout (ACVRL1wt/mut) in wild-type (ACVRL1wt/wt) iPSCs, resulting in a heterozygous 17 bp frameshift deletion in the ACVRL1 gene [NG_009549.1:g.13707_13723del; NM_000020.3:c.1137_1153del]. After the generation of embryoid bodies (EBs), endothelial differentiation was induced via adding 4 ng/mL BMP4, 2% B27, and 10 ng/mL VEGF. Endothelial differentiation was monitored via immunocytochemistry. An analysis of 151 TGF-beta/BMP-related genes was performed via RT-qPCR through the use of mRNA derived from single iPS cell cultures as well as endothelial cells derived from EBs after endothelial differentiation. Differential TGF-beta/BMP gene expression was observed between ACVRL1wt/wt and ACVRL1wt/mut iPSCs as well as endothelial cells. EBs derived from CRISPR/Cas9-designed ACVRL1 mutant HHT type 2 iPSCs, together with their isogenic wild-type iPSC counterparts, can serve as valuable resources for HHT type 2 in vitro studies.

Brain arteriovenous malformation in hereditary hemorrhagic telangiectasia: Recent advances in cellular and molecular mechanisms.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by vessel dilatation, such as telangiectasia in skin and mucosa and arteriovenous malformations (AVM) in internal organs such as the gastrointestinal tract, lungs, and brain. AVMs are fragile and tortuous vascular anomalies that directly connect arteries and veins, bypassing healthy capillaries. Mutations in transforming growth factor β (TGFβ) signaling pathway components, such as ENG (ENDOGLIN), ACVRL1 (ALK1), and SMAD4 (SMAD4) genes, account for most of HHT cases. 10-20% of HHT patients develop brain AVMs (bAVMs), which can lead to vessel wall rupture and intracranial hemorrhages. Though the main mutations are known, mechanisms leading to AVM formation are unclear, partially due to lack of animal models. Recent mouse models allowed significant advances in our understanding of AVMs. Endothelial-specific deletion of either Acvrl1, Eng or Smad4 is sufficient to induce AVMs, identifying endothelial cells (ECs) as primary targets of BMP signaling to promote vascular integrity. Loss of ALK1/ENG/SMAD4 signaling is associated with NOTCH signaling defects and abnormal arteriovenous EC differentiation. Moreover, cumulative evidence suggests that AVMs originate from venous ECs with defective flow-migration coupling and excessive proliferation. Mutant ECs show an increase of PI3K/AKT signaling and inhibitors of this signaling pathway rescue AVMs in HHT mouse models, revealing new therapeutic avenues. In this review, we will summarize recent advances and current knowledge of mechanisms controlling the pathogenesis of bAVMs, and discuss unresolved questions.

First genetic characteristics of Polish patients with idiopathic pulmonary arterial hypertension

Abstract Introduction Pulmonary arterial hypertension (PAH) is a rare, severe disorder of multifactorial origin. Genetic alterations in BMP/SMAD pathways were previously associated with disease development, however the exact role of other genetic factors from BMP/SMAD signalling is still unclear. Purpose We aimed to search for known PAH-associated mutations and potential novel variants responsible for disease onset in Polish PAH patients. Methods We prospectively recruited 93 consecutive idiopathic PAH patients from a single pulmonary hypertension reference centre between years 2009 and 2020. Eligible patients had pre-capillary pulmonary hypertension with pulmonary vascular resistance >3 Wood units in the absence of other causes of pre-capillary pulmonary hypertension. The presence of large gene rearrangements was analyzed by the Multiplex Ligation-dependent Probe Amplification (MLPA) reactions in the ENG, ACVRL1 and BMPR2 genes (SALSA MLPA Kit, MRC-Holland). We have further sequenced a panel of selected 48 genes from BMP/SMAD and related pathways using next-generation sequencing (SureSelect XT library preparation Kit, Agilent; NextSeq 500 sequencer, Illumina) and assessed causative potential of rare variants (minor allele frequency in non-finish Europeans below 1%) with Mutation Taster web-based tool. Results We identified at least one likely-causative variant of investigated genes in 51 (54.8%) subjects. Large genomic rearrangements were found by MLPA in 2 patients in ENG and ACVRL1 (ALK1) genes. We have found mutations in BMPR2 gene in 12 patients (12.5%) from our cohort with most variants present in one sample and 3 variants present in 2 samples. Mutations were located mostly in protein kinase domain (6 variants) and Activin type I and II receptor domain (2 variants). We have found 5 likely pathogenic variants in 6 patients in genes previously associated with PAH other than BMPR2 (SMAD9, KCNA5, KCNK3, EIF2AK4). In total, potentially disease causing mutations in literature-known genes, were present in 18 patients, which accounted for 18.75% of tested cohort. Medium impact variants were also present in KCNA5, TGFBR2, AQP7, BMP6, EIF2AK4, FBP1, NOTCH1, NOTCH3, SMAD7, TBX4, TGFB2, TOPBP1, GDF5, IL6, PPARA, RXRA, KCNK3, KLF4, BMPR1B, ILK, TGFBR1, SMAD9, PPARD and TGFB3 genes. Additionally, in one patient with clinical diagnosis of pulmonary venoocclusive disease we identified an unknown homozygous frameshift variant (p.Phe1523fs/c.4567_4570delTTTG) in exon 35 of EIF2AK4 gene. Conclusions We found potentially disease causing mutations in 18,75% Polish patients diagnosed with IPAH most of them were present in BMPR2 gene which is in line with data from other European cohorts. Additionally we found an unknown mutation in the EIF2AK4 gene. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Narodowe Centrum Nauki - National Science Centre

Pivotal models and biomarkers related to the prognosis of breast cancer based on the immune cell interaction network

The effect of breast cancer heterogeneity on prognosis of patients is still unclear, especially the role of immune cells in prognosis of breast cancer. In this study, single cell transcriptome sequencing data of breast cancer were used to analyze the relationship between breast cancer heterogeneity and prognosis. In this study, 14 cell clusters were identified in two single-cell datasets (GSE75688 and G118389). Proportion analysis of immune cells showed that NK cells were significantly aggregated in triple negative breast cancer, and the proportion of macrophages was significantly increased in primary breast cancer, while B cells, T cells, and neutrophils may be involved in the metastasis of breast cancer. The results of ligand receptor interaction network revealed that macrophages and DC cells were the most frequently interacting cells with other cells in breast cancer. The results of WGCNA analysis suggested that the MEblue module is most relevant to the overall survival time of triple negative breast cancer. Twenty-four prognostic genes in the blue module were identified by univariate Cox regression analysis and KM survival analysis. Multivariate regression analysis combined with risk analysis was used to analyze 24 prognostic genes to construct a prognostic model. The verification result of our prognostic model showed that there were significant differences in the expression of PCDH12, SLIT3, ACVRL1, and DLL4 genes between the high-risk group and the low-risk group, which can be used as prognostic biomarkers.

Novel experimental model of brain arteriovenous malformations using conditional Alk1 gene deletion in transgenic mice.

Hereditary hemorrhagic telangiectasia is the only condition associated with multiple inherited brain arteriovenous malformations (AVMs). Therefore, a mouse model was developed with a genetics-based approach that conditionally deleted the causative activin receptor-like kinase 1 (Acvrl1 or Alk1) gene. Radiographic and histopathological findings were correlated, and AVM stability and hemorrhagic behavior over time were examined. Alk1-floxed mice were crossed with deleter mice to generate offspring in which both copies of the Alk1 gene were deleted by Tagln-Cre to form brain AVMs in the mice. AVMs were characterized using MRI, MRA, and DSA. Brain AVMs were characterized histopathologically with latex dye perfusion, immunofluorescence, and Prussian blue staining. Brains of 55 Tagln-Cre+;Alk12f/2f mutant mice were categorized into three groups: no detectable vascular lesions (group 1; 23 of 55, 42%), arteriovenous fistulas (AVFs) with no nidus (group 2; 10 of 55, 18%), and nidal AVMs (group 3; 22 of 55, 40%). Microhemorrhage was observed on MRI or MRA in 11 AVMs (50%). AVMs had the angiographic hallmarks of early nidus opacification, a tangle of arteries and dilated draining veins, and rapid shunting of blood flow. Latex dye perfusion confirmed arteriovenous shunting in all AVMs and AVFs. Microhemorrhages were detected adjacent to AVFs and AVMs, visualized by iron deposition, Prussian blue staining, and macrophage infiltration using CD68 immunostaining. Brain AVMs were stable on serial MRI and MRA in group 3 mice (mean age at initial imaging 2.9 months; mean age at last imaging 9.5 months). Approximately 40% of transgenic mice satisfied the requirements of a stable experimental AVM model by replicating nidal anatomy, arteriovenous hemodynamics, and microhemorrhagic behavior. Transgenic mice with AVFs had a recognizable phenotype of hereditary hemorrhagic telangiectasia but were less suitable for experimental modeling. AVM pathogenesis can be understood as the combination of conditional Alk1 gene deletion during embryogenesis and angiogenesis that is hyperactive in developing and newborn mice, which translates to a congenital origin in most patients but an acquired condition in patients with a confluence of genetic and angiogenic events later in life. This study offers a novel experimental brain AVM model for future studies of AVM pathophysiology, growth, rupture, and therapeutic regression.

Hereditary hemorrhagic telangiectasia complicated by aortic sinus aneurysm caused by a pathogenic mutation in the ACVRL1 gene： a family survey

Hereditary hemorrhagic telangiectasia complicated by aortic sinus aneurysm caused by a pathogenic mutation in the ACVRL1 gene： a family survey

Establishment of a human induced pluripotent stem cell line, KMUGMCi001-A, from a patient bearing a heterozygous c.772 + 3_772 + 4dup mutation in the ACVRL1 gene leading Telangiectasia, hereditary hemorrhagic, type 2 (HHT2)

Telangiectasia, hereditary hemorrhagic, type 2 (HHT2) is a rare autosomal dominant disease caused by a mutated ACVRL1 gene (Letteboer et al., 2005). The peripheral blood mononuclear cells (PBMCs) from a patient carrying a heterozygous 2 bp duplication in intron 6 of the ACVRL1 gene, NG_009549.1(NM_000020.2):c.772 + 3_772 + 4dup, were reprogrammed using episomal vectors. The inserted mutation in ACVRL1 will causes the abnormal splicing, which will be associated with HHT2. The cell line will enable proper in vitro disease modelling of HHT2(Roman and Hinck, 2017).

Clinical genetic analysis and diagnosis of a family with hereditary hemorrhagic telangiectasia

Objective: To explore the diagnostic significance of the combination of clinical and genetic detection of hereditary hemorrhagic telangiectasia (HHT) by analyzing the clinical and genetic diagnosis of a family with HHT. Methods: Medical history data of the probands and their family members were collected, and the sequence analyses of coding regions of ENG, ACVRL1, SMAD4 and GDF2 genes were performed by PCR-sequencing method, and a comprehensive diagnosis was made based on the clinical features and gene detection results. After the pathogenic gene variation was identified, 11 members of 3 generations of the family were tested for pathogenic gene mutation. Results: There was an ACVRL1 c.715_716delAG mutation in the proband and 9 other family members, which caused p.S239C. Based on the clinical and genetic findings, the 7 suspected were diagnosed and 2 asymptomatic patients were found to carry the mutation site. Conclusion: The combination of clinical features and gene detection can determine the etiology and classification of HHT, which is convenient for the early diagnosis and prevention of the disease.

Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia

BackgroundHereditary 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.MethodsUsing 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.ResultsIn 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.ConclusionsIn 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.

Cyanosis in a Previously Well Child.

Cyanosis in a Previously Well Child.

S2747 Hereditary Hemorrhagic Telangiectasia: A Rare Disease Diagnosed From Incidental Liver Lesions

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant syndrome characterized by mucocutaneous telangiectasias and AVMs. Epistaxis and GI bleeding are the most common presenting features. HHT-related visceral AVMs have also been well-described and when identified without a prior diagnosis of HHT can present a significant diagnostic challenge. Case Description/Methods: A 60-year-old male with prior history of prior tobacco and alcohol use was referred to GI clinic for two years of chronic diarrhea and dyspepsia. No unintentional weight loss although he reported intermittent episodes of epistaxis every 2-3 months for past 40 years. Physical examination and family history was unremarkable. CT A/P showed a heterogeneous liver with innumerable liver lesions. (Figure 1) An EGD was performed for dyspepsia which revealed an 8mm gastric body ulcer and biopsy negative for H.pylori. The patient’s diarrhea resolved with probiotics and changes to diet. Hepatology recommended a liver biopsy which was suggestive of an arteriovenous or vascular malformation with scarring. Follow up EGD revealed a healed stomach ulcer and a 5mm gastric AVM. Chart review revealed a prior CT chest with a small pulmonary vascular malformation. The patient was referred to genetics for evaluation of HHT. A HHT genetic panel was positive for a pathogenic heterozygous variant in the ACVRL1 gene and the diagnosis of HHT was confirmed. Discussion: HHT is a clinically heterogenous disorder and diagnosis requires at least three of the following Curaçao criteria: epistaxis, mucocutaneous telangiectasias, visceral AVMs and family history of HHT. HHT-related AVMs can involve the brain, lung or liver. Hepatic involvement is common ranging from 32% up to 95%. Hepatic AVMs, are rarely symptomatic and routine screening is not recommended. Symptomatic hepatic AVMs can present with three distinct clinical presentations – high output heart failure from AV shunting, portal hypertension from arterioportal shunting and biliary disease from chronic ischemia. In the absence of routine screening, follow-up of these patients requires close attention to the development of these complications. In these cases, multi-phasic CT may be the preferred imaging modality. In conclusion, hepatic AVMs should be included in the differential for hepatic lesions and genetic evaluation should be considered with concomitant history of epistaxis, GI bleeding and/or evidence of other visceral AVMs.Figure 1.: CT abdomen and pelvis without contrast revealed several liver lesions, largest lesion 3.3cm in diameter.

SIX INCIDENTALLY DISCOVERED IDIOPATHIC PULMONARY ARTERIOVENOUS MALFORMATIONS

TOPIC: Procedures TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pulmonary arteriovenous malformations (PAVMs) are rare vascular abnormalities in which arterioles connect directly to venules without passing through a capillary bed. Up to 95% of all PAVMs are associated with hereditary hemorrhagic telangiectasia (HHT). HHT is an autosomal dominant disease characterized by AVMs most notably affecting the pulmonary, hepatic, and cerebral circulations. Idiopathic PAVMs have a greater propensity to present as solitary malformations. We present the case of a patient with six incidentally discovered PAVMs. Further evaluation, including genetic testing not consistent with HHT, made this an unusual case of multiple presumed idiopathic PAVMs. CASE PRESENTATION: A 34-year-old female with a history of recent left ankle fracture was referred to the pulmonary clinic after an emergency department evaluation revealed six PAVMs on CT pulmonary angiogram following the diagnosis of a left lower extremity deep vein thrombosis. The largest PAVM (2.4 cm) was located in the right upper lobe and was classified as complex, having multiple segmental feeding arteries with a dominant draining vein. The remaining five were classified as simple AVMs, having a single feeding artery and draining vein. She endorsed a history of epistaxis, family history of stroke, and persistent borderline hypoxemia. An anatomic shunt study was performed with arterial blood gas measurements on room air and while breathing 100% oxygen with a calculated shunt fraction of 28%. Transthoracic echocardiogram showed normal pulmonary and central venous pressures. MRI brain revealed multiple punctate foci of enhancement most consistent with small vascular malformations. She underwent genetic testing for HHT (including ACVRL1, ENG, EPHB4, GDF2, RASA1, and SMAD4 genes) which was negative. The patient was referred to Interventional Radiology for coil embolization of the two largest PAVMs given her clinically significant right-to-left shunt. DISCUSSION: PAVMs cause impairment in gas exchange, filtration, and processing of systemic venous blood with a spectrum of clinical manifestations including life-threatening hemorrhage and paradoxical embolism. Although PAVMs are commonly asymptomatic, their unique complications include hypoxemia, dyspnea, hemoptysis, pulmonary hypertension, brain abscess, seizure, and stroke. There is evidence to suggest that idiopathic PAVMs act similarly to HHT-related PAVMs with comparable symptoms and plausible clinical complications. CONCLUSIONS: Clinical presentation may vary widely, however, PAVMs are important to recognize and evaluate for need for intervention, even if asymptomatic, given their potential for serious sequelae if left untreated. REFERENCE #1: Shovlin, CL. Pulmonary Arteriovenous Malformations. Am J Respir Crit Care Med 2014; 190 (11): 1217-28. REFERENCE #2: Wong HH, Chan RP, Klatt R, Faughnan ME: Idiopathic pulmonary arteriovenous malformations: clinical and imaging characteristics. Eur Respir J 2011; 38: 368-75. REFERENCE #3: Kroon S, van den Heuvel DAF, Vos JA, et al. Idiopathic and hereditary haemorrhagic telangiectasia associated pulmonary arteriovenous malformations: comparison of clinical and radiographic characteristics. Clin Radiol. 2021;76(5):394. DISCLOSURES: No relevant relationships by Sarah Kemp, source=Web Response No relevant relationships by Patrick Kicker, source=Web Response

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.

A Novel Variaiton in the ACVRL1 Gene in a patient with Cirrhosis and Hereditary Hemorrhagic Telangiectasia

A Novel Variaiton in the ACVRL1 Gene in a patient with Cirrhosis and Hereditary Hemorrhagic Telangiectasia