Arteriovenous Malformations In Hereditary Hemorrhagic Telangiectasia Research Articles

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.

A rare case of spinal involvement in hereditary hemorrhagic telangiectasia

IntroductionHere, we describe a rare case of a spinal arteriovenous fistula in a patient with known hereditary hemorrhagic telangiectasia (HHT) and spontaneous intraspinal hemorrhage. Furthermore, we provide a brief review of the literature on the formation of spinal arteriovenous malformations (AVM) in relation to this disease.Case presentationThe case involves a 54-year-old male with known HHT. At the age of 49, the patient experienced recurrent cystitis. Urological evaluation ruled the cause to be neurological and subsequent imaging revealed a thoracic AVM. Four years later, the patient was admitted to A&E with chest pain and loss of function of the lower extremities and right arm, suspicious for ruptured aortic dissection. Trauma-CT excluded this and a final diagnosis of ruptured spinal AVM was made. Seven months post-injury, a spinal angiography was performed confirming the AVM. The remaining AVM was embolized under general anesthesia with acceptable results.DiscussionSpinal involvement in HHT is exceedingly rare but remains an important differential diagnosis, especially when patients present autonomic symptoms as these could potentially progress to life-threatening complications. The literature and the presented case indicate the prudence of closing spinal AVMs in HHT in case of symptoms, including autonomic, such as bladder dysfunction.

Investigation of the Genetic Determinants of Telangiectasia and Solid Organ Arteriovenous Malformation Formation in Hereditary Hemorrhagic Telangiectasia (HHT).

Telangiectases and arteriovenous malformations (AVMs) are the characteristic lesions of Hereditary Hemorrhagic Telangiectasia (HHT). Somatic second-hit loss-of-function variations in the HHT causative genes, ENG and ACVRL1, have been described in dermal telangiectasias. It is unclear if somatic second-hit mutations also cause the formation of AVMs and nasal telangiectasias in HHT. To investigate the genetic mechanism of AVM formation in HHT, we evaluated multiple affected tissues from fourteen individuals. DNA was extracted from fresh/frozen tissue of 15 nasal telangiectasia, 4 dermal telangiectasia, and 9 normal control tissue biopsies, from nine unrelated individuals with HHT. DNA from six formalin-fixed paraffin-embedded (FFPE) AVM tissues (brain, lung, liver, and gallbladder) from five individuals was evaluated. A 736 vascular malformation and cancer gene next-generation sequencing (NGS) panel was used to evaluate these tissues down to 1% somatic mosaicism. Somatic second-hit mutations were identified in three in four AVM biopsies (75%) or half of the FFPE (50%) samples, including the loss of heterozygosity in ENG in one brain AVM sample, in which the germline mutation occurred in a different allele than a nearby somatic mutation (both are loss-of-function mutations). Eight of nine (88.9%) patients in whom telangiectasia tissues were evaluated had a somatic mutation ranging from 0.68 to 1.96% in the same gene with the germline mutation. Six of fifteen (40%) nasal and two of four (50%) dermal telangiectasia had a detectable somatic second hit. Additional low-level somatic mutations in other genes were identified in several telangiectasias. This is the first report that nasal telangiectasias and solid organ AVMs in HHT are caused by very-low-level somatic biallelic second-hit mutations.

Neuropilin-1 deficiency in vascular smooth muscle cells is associated with hereditary hemorrhagic telangiectasia arteriovenous malformations.

Patients with hereditary hemorrhagic telangiectasia (HHT) have arteriovenous malformations (AVMs) with genetic mutations involving the activin-A receptor like type 1 (ACVRL1 or ALK1) and endoglin (ENG). Recent studies have shown that Neuropilin-1 (NRP-1) inhibits ALK1. We investigated the expression of NRP-1 in livers of patients with HHT and found that there was a significant reduction in NRP-1 in perivascular smooth muscle cells (SMCs). We used Nrp1SM22KO mice (Nrp1 was ablated in SMCs) and found hemorrhage, increased immune cell infiltration with a decrease in SMCs, and pericyte lining in lungs and liver in adult mice. Histologic examination revealed lung arteriovenous fistulas (AVFs) with enlarged liver vessels. Evaluation of the retina vessels at P5 from Nrp1SM22KO mice demonstrated dilated capillaries with a reduction of pericytes. In inflow artery of surgical AVFs from the Nrp1SM22KO versus WT mice, there was a significant decrease in Tgfb1, Eng, and Alk1 expression and phosphorylated SMAD1/5/8 (pSMAD1/5/8), with an increase in apoptosis. TGF-β1–stimulated aortic SMCs from Nrp1SM22KO versus WT mice have decreased pSMAD1/5/8 and increased apoptosis. Coimmunoprecipitation experiments revealed that NRP-1 interacts with ALK1 and ENG in SMCs. In summary, NRP-1 deletion in SMCs leads to reduced ALK1, ENG, and pSMAD1/5/8 signaling and reduced cell death associated with AVM formation.

Comparison of Ferumoxytol-enhanced MR Angiography and CT Angiography for the Detection of Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia: Initial Results.

To perform a preliminary comparison of the sensitivity and positive predictive value of ferumoxytol-enhanced MR angiography with those of CT angiography for detection of pulmonary arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT). Institutional review board approval and informed patient consent were obtained. Ten patients with pulmonary AVMs who had undergone CT of the chest within 12 months underwent MRI of the chest and abdomen with ferumoxytol at 3.0 T at a dose of 4 mg per kilogram of body weight. Consensus review of MR and CT images assessed the presence and characteristics of pulmonary AVMs, image quality, vessel visibility, and artifact grade. Forty-three AVMs were detected, 13 native and 30 recanalized. Twenty-one AVMs had a feeding artery diameter of greater than 2 mm, of which detection occurred in 19 (at MRI and CT), in two (at MRI only), and zero (at CT only). Twenty-two AVMs had a feeding artery diameter of less than or equal to 2 mm, of which detection occurred in 16 (at MRI and CT), six (at CT only), and zero (at MRI only). For the entire cohort, the sensitivity of ferumoxytol-enhanced MRI using CT as the reference standard was 85.4% (35 of 41), and the positive predictive value was 100% (35 of 35). No significant difference was found between CT and MRI in AVM size, feeding artery and draining vein diameter, and artifact score (P >.05 for all). Initial results suggest that ferumoxytol-enhanced MRI is a feasible alternative to CT for detection of pulmonary AVM in HHT, while avoiding repeated exposure to radiation, nephrotoxic contrast material, or gadolinium-based contrast agent.© RSNA, 2020.

Diagnostic yield of capsule endoscopy for small bowel arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis.

Background and study aims Small bowel arteriovenous malformations (AVMs) pose a bleeding risk and have traditionally been diagnosed by invasive enteroscopic procedures in patients with hereditary hemorrhagic telangiectasia (HHT). Capsule endoscopy (CE) is emerging as a safe and non-invasive alternative for small intestinal evaluation, but its diagnostic yield and utility in diagnosing small bowel AVMs in HHT patients are understudied. The aim of this study was to meta-analyze the utility of CE for diagnosing AVMs in HHT patients. Methods A meta-analysis and systematic review of the literature on CE in HHT patients identified in the PubMed, EMBASE, Scopus, and Cochrane databases from inception to March 2018 were conducted. Summary effects were estimated using a random effects model. Results After applying exclusion criteria, five studies (n = 124 patients) were eligible for meta-analysis. The pooled diagnostic yield for visualization of small bowel AVMs by CE was 77.0 % (95 % CI 65.8 – 85.4 %, P < 0.001). Conclusions CE has a good diagnostic yield for small bowel AVMs in HHT. It can be regarded as a sufficient, noninvasive diagnostic modality for identifying small bowel AVMs in HHT patients.

A theory for polymicrogyria and brain arteriovenous malformations in HHT.

Hereditary hemorrhagic telangiectasia (HHT) is generally considered a disorder of endothelial dysfunction, characterized by the development of multiple systemic arteriovenous malformations (AVMs), including within the brain. However, there have recently been a number of reports correlating HHT with malformations of cortical development, of which polymicrogyria is the most common type. Here we present 7 new cases demonstrating polymicrogyria in HHT, 6 of which demonstrate a brain AVM (bAVM) in close spatial proximity, with the aim of providing a common origin for the association. Upon reviewing patient genetics and imaging data and comparing with previously reported findings, we form 2 new conclusions: (1) polymicrogyria in HHT appears exclusively associated with a subset of mutations in the transmembrane protein endoglin that is involved with blood flow-related mechanotransduction signaling during angiogenesis and (2) the polymicrogyria is characteristically unilateral, typically focal, and correlates with vascular regions experiencing low fluid shear stress during corticogenesis in utero. Integrating these with findings in the literature from genetics and molecular biology experiments, we propose a theory suggesting haploinsufficient endoglin mutations, especially those that are dominant-negative, may predispose focal, aberrant hypersprouting angiogenesis during corticogenesis that leads to the production of polymicrogyria. This hypoxic insult may further serve as the revealing trigger for later development of a spatially coincident bAVM. This hypothesis suggests an essential role for endoglin-mediated hemodynamic mechanotransduction in normal corticogenesis.

Abstract W P417: A Common Variant in a TGFβ Modifier Locus Is Associated with Intracranial Hemorrhage Presentation of Brain Arteriovenous Malformation in Hereditary Hemorrhagic Telangiectasia

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ALK1. HHT patients have arteriovenous malformations (AVM) in brain, lung and liver, leading to severe complications including intracranial hemorrhage (ICH) from brain AVM. ICH presentation of brain AVM in HHT is a marker of high ICH risk. The clinical heterogeneity of HHT suggests a potential role for genetic modifier effects. Common genetic variants in loci that modify phenotype severity in Tgfb knockout mice have been reported to be associated with pulmonary AVM in HHT. We sought to replicate these associations and investigate whether these variants are also associated with brain AVM and ICH presentation of brain AVM in HHT patients. Methods: We genotyped 3 variants (PTPN14 rs2936018, USH2A rs700024 and ADAM17 rs10495565) in 665 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium (BVMC). Association of genotype with pulmonary AVM, brain AVM and ICH presentation was evaluated by multivariate logistic regression adjusted for age, gender and family clustering, and also stratified by HHT mutation (ALK1 or ENG). Results: Of 665 Caucasian HHT patients analyzed, 51% had pulmonary AVM and 20% had brain AVM, of whom 17% presented with ICH. None of the 3 SNPs was significantly associated with pulmonary or brain AVM. Among 130 brain AVM patients, USH2A rs700024 was associated with ICH presentation (OR=3.34, 95% CI=1.22-9.15, p=0.019). The effect size was similar in HHT patients with ALK1 and ENG mutations, but only reached statistical significance among the latter (OR=6.77, p=0.014). Conclusions: A common variant in USH2A, rs700024, previously reported to be associated with pulmonary AVM in HHT, was associated with ICH presentation of brain AVM, but not with brain or pulmonary AVM, in the BVMC HHT cohort. Association of the same USH2A variant with different HHT severity phenotypes in different cohorts suggests that it may act as a genetic modifier of HHT phenotype severity in concert with other genetic and environmental factors. Once validated, such genetic modifiers may improve our understanding of the phenotypic heterogeneity of HHT and aid in ICH risk prediction in HHT brain AVM.

Symptomatic Liver Involvement in Neonatal Hereditary Hemorrhagic Telangiectasia

High-flow hepatic vascular anomalies with arteriovenous shunting commonly manifest during the neonatal period with signs and symptoms of congestive heart failure, but to our knowledge, they have never been described in patients with hereditary hemorrhagic telangiectasia (HHT). We report here our experience with 3 patients with hepatic arteriovenous malformations (AVMs) who presented with symptoms of high-output congestive heart failure during the neonatal period and were subsequently diagnosed with HHT. Imaging showed large hypervascular lesions and multiple hepatic arteriovenous shunts that differentiated these lesions from liver hemangiomas. Transcatheter embolization was performed in all cases. One infant died of sepsis shortly after embolization; follow-up at the age of 2.5 years of the surviving infants revealed involution of the vascular lesions and no evidence of symptom recurrence. We conclude that severe symptoms related to hepatic AVMs in HHT can occur in the neonatal period and that HHT should therefore be included in the differential diagnosis of symptomatic neonatal hepatic vascular malformations. Imaging plays a key role in differentiating hepatic AVMs from hemangiomas, because the latter require additional pharmacologic treatments. Early transcatheter embolization seems to be effective, but long-term outcomes still need to be assessed.

Endovascular coil embolization of pulmonary AV malformations in a patient with hereditary hemorrhagic telangiectasia

An asymptomatic Caucasian woman was diagnosed at 22 years of age with bilateral lung ‘masses’ during work-up for knee surgery. CT angiography (CTA) confirmed AV malformations (AVM), for which she underwent left lower lobectomy. Afterwards, she had recurrent epistaxis and bleeding from her tongue; she noticed several pinhead-sized bright-red spots on her tongue, lips and finger nails (Panels A and B). She was subsequently diagnosed with an asymptomatic cerebral AVM by CT angiogram. Her mother and two sisters also had systemic AVMs. At age 38, the patient was diagnosed with a second AVM in the right lung. Owing to the previous lobectomy, endovascular treatment was elected. The right pulmonary trunk was selectively engaged with a 7-French guide catheter and the lower lobar AVM was successfully embolized with MRI compatible coils (Panel C). Hereditary hemorrhagic telangiectasia (HHT) is a vascular anomaly transmitted by an autosomal dominant trait of varying penetrance and has an incidence of 1 in 5000–8000.1 First described by Osler, Weber and Hanes in early 19th century, HHT usually presents in childhood with anemia, epistaxis from mucosal AVMs, and mucocutaneous telangiectases. 2 Arteriovenous malformations in HHT can also involve the lungs (20–30%), liver (30%), and brain (10–20%). 3,4 There is an increased incidence of neurological symptoms among patients with HHT. 3 Owing to late penetrance, there is no age cut-off at which offspring of patients with HHT may present, unless tested negative for endoglin or ALK-1 gene mutations. Management is usually by a multidisciplinary approach. Regardless of symptomatology, patients with mucocutaneous telangiectases should be screened for pulmonary and cerebral AVMs to avert risks of visceral bleeding, paradoxical embolism and stroke. Family genetic counseling and screening are essential. Because of their multilocation and recurrent nature, all visceral AVMs are preferably treated endovascularly.

Acute paraplegia due to spinal arteriovenous fistula in two patients with hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by recurrent epistaxis, cutaneous telangiectasia, and visceral arteriovenous malformations (AVM). Of these, spinal AVM is a rare manifestation that concerns mainly children. In this report, we describe two cases of spinal AVM revealed by acute paraparesis due to subarachnoid hemorrhage in children with HHT and reviewed the literature on spinal arteriovenous malformations in HHT. In most of the cases reported, the clinical presentation was acute in the pediatric population and insidious during adulthood. The prognosis of spinal AVM mainly depends on the presence or not of medullar signs and symptoms and on the delay before treatment. In conclusion, any child with a family history of HHT should be considered at risk for spinal AVM in order to improve management of such complications and to decrease the risk of neurological sequellae.