Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs) in internal organs. HHT is caused by inheritance of a loss of function mutation in one of three genes. Although individuals with HHT are haploinsufficient for one of these genes throughout their entire body, rather than exhibiting a systemic vascular phenotype, vascular malformations occur as focal lesions in discrete anatomic locations. The inconsistency between genotype and phenotype has provoked debate over whether haploinsufficiency or a different mechanism gives rise to the vascular malformations. We previously showed that HHT-associated skin telangiectases develop by a two-hit mutation mechanism in an HHT gene. However, somatic mutations were identified in only half of the telangiectases, raising the question whether a second-hit somatic mutation is a necessary (required) event in HHT pathogenesis. Here, we show that another mechanism for the second hit is loss of heterozygosity across the chromosome bearing the germline mutation. Secondly, we investigate the two-hit mutation mechanism for internal organ AVMs, the source of much of the morbidity of HHT. Here, we identified somatic molecular genetic events in eight liver telangiectases, including point mutations and a loss of heterozygosity event. We also identified somatic mutations in one pulmonary AVM and two brain AVMs, confirming that mucocutaneous and internal organ vascular malformations undergo the same molecular mechanisms. Together, these data argue that bi-allelic loss of function in an HHT gene is a required event in the pathogenesis of HHT-associated vascular malformations.

Implementation of 3D modelling to improve understanding and conceptualisation of arteriovenous malformation (AVM) morphology for the execution of safe microsurgical excision of complex paediatric AVMs.

INTRODUCTION: Brain arteriovenous malformations (bAVMs) present complex challenges in neurosurgery, requiring precise pre-surgical planning. In this context, 3D printing technology has emerged as a promising tool to aid in understanding bAVM morphology and enhance surgical outcomes, particularly in pediatric patients. This study aims to assess the feasibility and effectiveness of using 3D AVM models in pediatric bAVM surgery. METHODOLOGY: The study was conducted at Great Ormond Street Hospital, and cases were selected sequentially between October 2021 and February 2023. Eight pediatric bAVM cases with 3D models were compared to eight cases treated before the introduction of 3D printing models. The 3D modelling fidelity and clinical outcomes were assessed and compared between the two cohorts. RESULTS: The study demonstrated excellent fidelity between 3D models and actual operative anatomy, with a median difference of only 0.31 mm. There was no statistically significant difference in angiographic cure rates or complications between the 3D model group and the non-3D model group. Surgical time showed a non-significant increase in cases involving 3D models. Furthermore, the 3D model cohort included higher-grade bAVMs, indicating increased surgical confidence. CONCLUSION: This study demonstrates the feasibility and efficacy of utilizing 3D AVM models in pediatric bAVM surgery. The high fidelity between the models and actual operative anatomy suggests that 3D modelling can enhance pre-surgical planning and intraoperative guidance without significantly increasing surgical times or complications. Further research with larger cohorts is warranted to confirm and refine the application of 3D modelling in clinical practice.

Arteriovenous malformation with hair collar sign.

We report the case of a newborn who was noted at birth to have an occipital scalp nodule presenting with a hair collar sign (HCS). The nodule had enlarged since birth. An MRI revealed a soft tissue mass on the occipital scalp without deep extension or cranial bone involvement. A biopsy of the nodule led to a diagnosis of arteriovenous malformation (AVM). A vascular malformation with HCS has not been reported before in North America. This case highlights the complexity of diagnosing a lesion with a hair collar sign.

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.

Endothelial-to-Mesenchymal Transition in an Hereditary Hemorrhagic Telangiectasia-like Pediatric Case of Multiple Pulmonary Arteriovenous Malformations.

Pulmonary arteriovenous malformations (PAVMs) are vascular anomalies resulting in abnormal connections between pulmonary arteries and veins. In 80% of cases, PAVMs are present from birth, but clinical manifestations are rarely seen in childhood. These congenital malformations are typically associated with Hereditary Hemorrhagic Telangiectasia (HHT), a rare disease that affects 1 in 5000/8000 individuals. HHT disease is frequently caused by mutations in genes involved in the TGF-ß pathway. However, approximately 15% of patients do not have a genetic diagnosis and, among the genetically diagnosed, more than 33% do not meet the Curaçao criteria. This makes clinical diagnosis even more challenging in the pediatric age group. Here, we introduce an 8-year-old patient bearing a severe phenotype of multiple diffuse PAVMs caused by an unknown mutation which ended in lung transplantation. Phenotypically, the case under study follows a molecular pattern which is HHT-like. Therefore, molecular- biological and cellular-functional analyses have been performed in primary endothelial cells (ECs) isolated from the explanted lung. The findings revealed a loss of functionality in lung endothelial tissue and a stimulation of endothelial-to-mesenchymal transition. Understanding the molecular basis of this transition could potentially offer new therapeutic strategies to delay lung transplantation in severe cases.

MicroRNA-135b-5p Is a Pathologic Biomarker in the Endothelial Cells of Arteriovenous Malformations.

Arteriovenous malformations (AVMs) are congenital vascular anomalies with a poor prognosis. AVMs are considered intractable diseases, as there is no established approach for early diagnosis and treatment. Therefore, this study aimed to provide new evidence by analyzing microRNAs (miRNAs) associated with AVM. We present fundamental evidence for the early diagnosis and treatment of AVM by analyzing miRNAs in the endothelial cells of AVMs. This study performed sequencing and validation of miRNAs in endothelial cells from normal and AVM tissues. Five upregulated and two downregulated miRNAs were subsequently analyzed under hypoxia and vascular endothelial growth factor (VEGF) treatment by one-way analysis of variance (ANOVA). Under hypoxic conditions, miR-135b-5p was significantly upregulated in the AVM compared to that under normal conditions, corresponding to increased endothelial activity (p-value = 0.0238). VEGF treatment showed no significant increase in miR-135b-5p under normal conditions, however, a surge in AVM was observed. Under both hypoxia and VEGF treatment, comparison indicated a downregulation of miR-135b-5p in AVM. Therefore, miR-135b-5p was assumed to affect the pathophysiological process of AVM and might play a vital role as a potential biomarker of AVMs for application related to diagnosis and treatment.

Executive summary of the 14th HHT international scientific conference.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by small, dilated clustered vessels (telangiectasias) and by larger visceral arteriovenous malformations (AVMs), which directly connect the feeding arteries with the draining veins. These lesions are fragile, prone to rupture, and lead to recurrent epistaxis and/or internal hemorrhage among other complications. Germline heterozygous loss-of-function (LOF) mutations in Bone Morphogenic Protein 9 (BMP9) and BMP10 signaling pathway genes (endoglin-ENG, activin like kinase 1 ACVRL1 aka ALK1, and SMAD4) cause different subtypes of HHT (HHT1, HHT2 and HHT-juvenile polyposis (JP)) and have a worldwide combined incidence of about 1:5000. Expert clinicians and international scientists gathered in Cascais, Portugal from September 29th to October 2nd, 2022 to present the latest scientific research in the HHT field and novel treatment strategies for people living with HHT. During the largest HHT scientific conference yet, participants included 293 in person and 46 virtually. An impressive 209 abstracts were accepted to the meeting and 59 were selected for oral presentations. The remaining 150 abstracts were presented during judged poster sessions. This review article summarizes the basic and clinical abstracts selected as oral presentations with their new observations and discoveries as well as surrounding discussion and debate. Two discussion-based workshops were also held during the conference, each focusing on mechanisms and clinical perspectives in either AVM formation and progression or current and future therapies for HHT. Our hope is that this paper will represent the current progress and the remaining unanswered questions surrounding HHT, in order to serve as an update for those within the field and an invitation to those scientists and clinicians as yet outside of the field of HHT.

Localized conditional induction of brain arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia.

BACKGROUND: Longitudinal mouse models of brain arteriovenous malformations (AVMs) are crucial for developing novel therapeutics and pathobiological mechanism discovery underlying brain AVM progression and rupture. The sustainability of existing mouse models is limited by ubiquitous Cre activation, which is associated with lethal hemorrhages resulting from AVM formation in visceral organs. To overcome this condition, we developed a novel experimental mouse model of hereditary hemorrhagic telangiectasia (HHT) with CreER-mediated specific, localized induction of brain AVMs. METHODS: Hydroxytamoxifen (4-OHT) was stereotactically delivered into the striatum, parietal cortex, or cerebellum of R26CreER; Alk12f/2f (Alk1-iKO) littermates. Mice were evaluated for vascular malformations with latex dye perfusion and 3D time-of-flight magnetic resonance angiography (MRA). Immunofluorescence and Prussian blue staining were performed for vascular lesion characterization. RESULTS: Our model produced two types of brain vascular malformations, including nidal AVMs (88%, 38/43) and arteriovenous fistulas (12%, 5/43), with an overall frequency of 73% (43/59). By performing stereotaxic injection of 4-OHT targeting different brain regions, Alk1-iKO mice developed vascular malformations in the striatum (73%, 22/30), in the parietal cortex (76%, 13/17), and in the cerebellum (67%, 8/12). Identical application of the stereotaxic injection protocol in reporter mice confirmed localized Cre activity near the injection site. The 4-week mortality was 3% (2/61). Seven mice were studied longitudinally for a mean (SD; range) duration of 7.2 (3; 2.3-9.5) months and demonstrated nidal stability on sequential MRA. The brain AVMs displayed microhemorrhages and diffuse immune cell invasion. CONCLUSIONS: We present the first HHT mouse model of brain AVMs that produces localized AVMs in the brain. The mouse lesions closely resemble the human lesions for complex nidal angioarchitecture, arteriovenous shunts, microhemorrhages, and inflammation. The model's longitudinal robustness is a powerful discovery resource to advance our pathomechanistic understanding of brain AVMs and identify novel therapeutic targets.

BMP10 functions independently from BMP9 for the development of a proper arteriovenous network.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by the presence of arteriovenous malformation (AVM) in multiple organs. HHT is caused by mutations in genes encoding major constituents for transforming growth factor-ß (TGF-ß) family signaling: endoglin (ENG), activin receptor-like kinase 1 (ALK1), and SMAD4. The identity of physiological ligands for this ENG-ALK1 signaling pertinent to AVM formation has yet to be clearly determined. To investigate whether bone morphogenetic protein 9 (BMP9), BMP10, or both are physiological ligands of ENG-ALK1 signaling involved in arteriovenous network formation, we generated a novel Bmp10 conditional knockout mouse strain. We examined whether global Bmp10-inducible knockout (iKO) mice develop AVMs at neonatal and adult stages in comparison with control, Bmp9-KO, and Bmp9/10-double KO (dKO) mice. Bmp10-iKO and Bmp9/10-dKO mice showed AVMs in developing retina, postnatal brain, and adult wounded skin, while Bmp9-KO did not display any noticeable vascular defects. Bmp10 deficiency resulted in increased proliferation and size of endothelial cells in AVM vessels. The impaired neurovascular integrity in the brain and retina of Bmp10-iKO and Bmp9/10-dKO mice was detected. Bmp9/10-dKO mice exhibited the lethality and vascular malformation similar to Bmp10-iKO mice, but their phenotypes were more pronounced. Administration of BMP10 protein, but not BMP9 protein, prevented retinal AVM in Bmp9/10-dKO and endothelial-specific Eng-iKO mice. These data indicate that BMP10 is indispensable for the development of a proper arteriovenous network, whereas BMP9 has limited compensatory functions for the loss of BMP10. We suggest that BMP10 is the most relevant physiological ligand of the ENG-ALK1 signaling pathway pertinent to HHT pathogenesis.

Resting-state functional alterations in patients with brain arteriovenous malformations involving language areas.

Brain arteriovenous malformations (AVMs) may involve language areas but usually do not lead to aphasia. This study evaluated resting-state functional alterations and investigated the language reorganization mechanism in AVM patients. Thirty-nine patients with AVMs involving language areas and 32 age- and sex-matched healthy controls were prospectively enrolled. The AVM patients were categorized into three subgroups according to lesion location: the frontal (15 patients), temporal (14 patients), and parietal subgroups (10 patients). All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI), and the amplitude of low-frequency fluctuation (ALFF) approach was applied to analyze rs-fMRI data. Language abilities were normal in all participants based on the Western Aphasia Battery. Compared with those of healthy subjects, ALFF values significantly increased (FDR corrected p < .01) in the anterior part of the right putamen in the frontal AVM subgroup, in the posterior part of the right inferior and middle temporal gyrus in the temporal AVM subgroup, and in the inferior lateral part of the left cerebellar hemisphere (lobule VIII) and the right inferior parietal lobule in the parietal AVM subgroup. Functional annotation using Neurosynth indicated that the ALFF t-map was only significantly positively associated with the language-related domain (FDR corrected p < .01). In patients with AVMs involving the language cortex, language network reorganization occurs to maintain normal language abilities. The brain areas recruited into the reorganized language network were located in the right cerebral and left cerebellar hemispheres, both of which are nondominant hemispheres. Differences in lesion location led to distinct reorganization patterns.

De Novo Germline and Somatic Variants Convergently Promote Endothelial-to-Mesenchymal Transition in Simplex Brain Arteriovenous Malformation.

[Figure: see text].

Impairment and Plasticity of Language-Related White Matter in Patients With Brain Arteriovenous Malformations.

BACKGROUND: Language dysfunction is rarely seen in patients with unruptured brain arteriovenous malformation (AVM) albeit the AVM nidus involving language areas, which provides a unique disease model to study language reorganization. The objective of this study was to investigate the impairment and reorganization patterns and characteristics of language-related white matter in AVMs located at different brain areas. METHODS: Thirty-three patients with AVMs involving language areas were prospectively enrolled. Patients were categorized into 3 groups according to the lesion locations: the frontal (14 patients), temporal (15 patients), and parietal groups (4 patients). Thirty age- and sex-matched healthy controls were enrolled as comparison. All participants underwent diffusion tensor imaging scans, and automated fiber quantification method was applied to quantitatively study the difference of segmented language-related white matter connectivity between 3 AVM groups and control group. RESULTS: Language functions were normal in all subjects according to Western Aphasia Battery test. In the frontal group, fractional anisotropy (FA) value decreased in the left arcuate fascicle and increased in left superior longitudinal fasciculus and uncinate fascicle; in the temporal group, FA values decreased in left inferior fronto-occipital fascicle and inferior longitudinal fascicle and increased in right anterior thalamic radiation and uncinate fascicle; in the parietal group, FA values decreased in left arcuate fascicle and inferior longitudinal fascicle and increased in bilateral anterior thalamic radiations and uncinate fascicles and right inferior fronto-occipital fascicle. In fascicles with decreased FA values, the increase of radial diffusivity was common, and fascicles with increased FA values usually presented along with increased axial diffusivity values. CONCLUSIONS: Remodeling of language-related white matter occurs when traditional language areas are involved by AVM nidus, and its reorganization patterns vary with locations of AVM nidus. Fascicle impairment is mainly caused by the myelin deficits, and its plasticity may be dominated by the axon remodeling procedure.

Loss of Endothelial Endoglin Promotes High-Output Heart Failure Through Peripheral Arteriovenous Shunting Driven by VEGF Signaling.

RATIONALE: ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and is strongly expressed in endothelial cells. Mutations in ENG lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood. OBJECTIVE: The goal of the work was to determine how ENG maintains vessel caliber in adult life to prevent AVM formation and thereby protect heart function. METHODS AND RESULTS: Genetic depletion of endothelial Eng in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of hemorrhage, anemia, or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis-a noncapsulated cartilage with a naturally high endogenous expression of VEGF (vascular endothelial growth factor). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure. Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells leads to increased sensitivity to VEGF and a hyperproliferative response. Development of AVMs and associated progression to high-output heart failure in the absence of endothelial ENG was attenuated by targeting VEGF signaling with an anti-VEGFR2 (VEGF receptor 2) antibody. CONCLUSIONS: ENG promotes the normal balance of VEGF signaling in quiescent endothelial cells to maintain vessel caliber-an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG, increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function.

Capillary Malformation-arteriovenous Malformation Type 2: A Case Report and Review.

Capillary malformation-arteriovenous malformation syndrome is a rare genodermatosis with cutaneous capillary malformations and a risk of associated fast-flow malformations. We describe here a four-generation family with a novel heterozygous pathogenic variant in the EPHB4 gene (NM_004444.5 (EPHB4): c.2224G>C, p.(Ala742Pro)). A review of the literature retrieved 127 patients with capillary malformation-arteriovenous malformation syndrome and confirmed variants in EPHB4. Multiple capillary malformations were present in 114 (89.76%) patients, and 12 (9.44%) patients had a solitary capillary malformation. Arteriovenous malformations/fistulas were present in 23 (18.1%) patients, and were located within the central nervous system in 5 (3.9%) patients. Not all papers included description of epistaxis. Telangiectasias were reported in 28 (22%) patients, and Bier spots were described in 20 (15.7%) patients. The clinical characteristics of capillary malformation-arteriovenous malformation syndrome are diverse and often discrete, which can make it difficult to distinguish capillary malformation-arteriovenous malformation syndrome from hereditary haemorrhagic telangiectasia.

Acroangiodermatitis presenting as unilateral hypertrophic verrucous plaques.

Acroangiodermatitis (AAD)[KL1] is a rare vasoproliferative disorder often involving the extremities that has been classified into two variants. Mali-type AAD is more common and associated with chronic venous stasis. Stewart-Bluefarb syndrome[KL2], the other variant, is associated with underlying arteriovenous abnormalities. Mali-type AAD is a relatively benign diagnosis but it may mimic more harmful etiologies such as Kaposi sarcoma both clinically and histologically. A 67-year-old woman with a history of varicose veins, deep vein thrombosis, stroke, and obesity presented to our outpatient clinic with verrucous red-brown papules and plaques on her right lower extremity worsening for three years. Biopsy was consistent with a diagnosis of Mali-type AAD. Providers should be aware of AAD and its variants to accurately differentiate it from more harmful entities.

Oscillatory shear stress promotes angiogenic effects in arteriovenous malformations endothelial cells.

BACKGROUND: Vascular endothelial cells (ECs) are subject to continuous shear stress due to blood circulation. Mechanical stress due to high shear flow can also cause arteriovenous malformation (AVM) when ECs respond hyper-sensitively to shear flow. This study was conducted to test the hypothesis that angiogenesis could be promoted in response to mechanical stress via regulation of pro-angiogenic factors in AVM cells. METHODS: ECs were extracted from the tissue samples from six AVM patients and six normal patients. Shear stress at 7 dynes/cm2 were applied for 24 h. Before and after application of shear stress to each group, RT-PCR was performed to access the expression levels of angiopoietin2(AGP2), aquaporin1(AQP1) and TGFßR1. Immunofluorescences was also performed to evaluate the level of protein expressions. RESULTS: In both normal and AVM tissues, AGP2 and TGFßR1 under the shear stress showed increased expression in the ECs compared to the non-sheared samples. When AVMs and normal arterial vasculature were compared, the expression levels of both AGP2 and TGFßR1 in AVMs were higher when compared to normal arterial vasculature with or without shear stress. Immunofluorescence-based protein analysis also confirmed shear-induced AGP2 and TGFßR1 in both samples of normal and AVM patients. CONCLUSIONS: AVMs exhibited higher sensitivity to shear stress by producing higher expressions of some marked genes and proteins that regulate the endothelial functions upon exposure to shear stress. While the physiological mechanism for AVMs remain elusive, our study shows the plausibility of physical stress imposed by the shearing flow can cause the occurrence of AVMs.

Impaired SMAD1/5 Mechanotransduction and Cx37 (Connexin37) Expression Enable Pathological Vessel Enlargement and Shunting.

OBJECTIVE: Impaired ALK1 (activin receptor-like kinase-1)/Endoglin/BMP9 (bone morphogenetic protein 9) signaling predisposes to arteriovenous malformations (AVMs). Activation of SMAD1/5 signaling can be enhanced by shear stress. In the genetic disease hereditary hemorrhagic telangiectasia, which is characterized by arteriovenous malformations, the affected receptors are those involved in the activation of mechanosensitive SMAD1/5 signaling. To elucidate how genetic and mechanical signals interact in AVM development, we sought to identify targets differentially regulated by BMP9 and shear stress. Approach and Results: We identify Cx37 (Connexin37) as a differentially regulated target of ligand-induced and mechanotransduced SMAD1/5 signaling. We show that stimulation of endothelial cells with BMP9 upregulated Cx37, whereas shear stress inhibited this expression. This signaling was SMAD1/5-dependent, and in the absence of SMAD1/5, there was an inversion of the expression pattern. Ablated SMAD1/5 signaling alone caused AVM-like vascular malformations directly connecting the dorsal aorta to the inlet of the heart. In yolk sacs of mouse embryos with an endothelial-specific compound heterozygosity for SMAD1/5, addition of TNFα (tumor necrosis factor-α), which downregulates Cx37, induced development of these direct connections bypassing the yolk sac capillary bed. In wild-type embryos undergoing vascular remodeling, Cx37 was globally expressed by endothelial cells but was absent in regions of enlarging vessels. TNFα and endothelial-specific compound heterozygosity for SMAD1/5 caused ectopic regions lacking Cx37 expression, which correlated to areas of vascular malformations. Mechanistically, loss of Cx37 impairs correct directional migration under flow conditions. CONCLUSIONS: Our data demonstrate that Cx37 expression is differentially regulated by shear stress and SMAD1/5 signaling, and that reduced Cx37 expression is permissive for capillary enlargement into shunts.

Capillary malformation-arteriovenous malformation syndrome: a multicentre study.

BACKGROUND: Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a rare syndrome with characteristic skin lesions that are associated with fast-flow vascular malformations (FFVMs) in one-third of patients. Few case series have been described, and none in Spain. AIM: To identify the prevalence of dermatological parameters, FFVMs and associated features in a large series of patients with CM-AVM. METHODS: We conducted an observational study of patients with CM-AVM syndrome diagnosed in 15 Spanish hospitals over 3 years. The main clinical, radiological, genetic findings and associated diseases were analysed. RESULTS: In total, 64 patients were assessed. In 26.5% of cases, the diagnosis was incidental. In 75% of patients, there was one significantly larger macule, which we termed the 'herald patch'. FFVMs were detected in 34% of the patients, with 30% located on the skin, 7.8% in the brain and in 1.5% in the spine. There was a positive family history in 65% of the 64 patients. Genetic analysis was performed for RASA1 mutations in 57 patients, of whom 42 (73%) had a positive result. All 4 patients tested for EPHB4 mutations had a positive result. No tumour lesions were detected in the series, except for five infantile haemangiomas. CONCLUSIONS: Our data on clinical lesions, associated FFVM, family history and genetics are similar to those previously published in the literature. An extensive data analysis failed to demonstrate any statistically significant association between the presence of an FFVM and any clinical, familial or genetic parameter that could predict its onset, although a link between the presence of a herald patch on the midline face and the presence of a brain FFVM was observed. We did not detect any genotype-phenotype correlation.

Massive haemorrhagic complications of ruptured pulmonary arteriovenous malformations: outcomes from a 12 years' retrospective study.

BACKGROUND: The life-threatening haemorrhagic complications of pulmonary arteriovenous malformations (PAVMs) are extremely rare, and only described in isolated cases. This study was designed to comprehensively investigate management of ruptured PAVMs. METHODS: We retrospectively assessed clinical and imaging data of ruptured PAVMs to summarize incidence, clinical characteristics, and outcomes following embolisation between January 2008 and January 2021. RESULTS: Eighteen of 406 (4.4%) patients with PAVMs developed haemorrhagic complications. Twelve of 18 patients were clinically diagnosed with hereditary haemorrhagic telangiectasia (HHT). Haemorrhagic complications occurred with no clear trigger in all cases. Eight of 18 patients (44.4%) were initially misdiagnosed or had undergone early ineffective treatment. 28 lesions were detected, with 89.3% of them located in peripheral lung. Computed tomography angiography (CTA) showed indirect signs to indicate ruptured PAVMs in all cases. Lower haemoglobin concentrations were associated with the diameter of afferent arteries in the ruptured lesions. Successful embolotherapy was achieved in all cases. After embolotherapy, arterial oxygen saturation improved and bleeding was controlled (P < 0.05). The mean follow-up time was 3.2 ± 2.5 years (range, 7 months to 10 years). CONCLUSIONS: Life threatening haemorrhagic complications of PAVMs are rare, they usually occur without a trigger and can be easily misdiagnosed. HHT and larger size of afferent arteries are major risk factors of these complications. CTA is a useful tool for diagnosis and therapeutic guidance for ruptured PAVMs. Embolotherapy is an effective therapy for this life-threatening complication.

Multifocal capillary malformation with segmental distribution and central atrophy: A case in a 12-year-old girl.

We present a 12-year-old girl with multiple geographic capillary malformations in a segmental distribution over the left trunk and arm that were present at birth and evolved over years with ulceration, atrophy, and subsequent scarring. Our case is clinically consistent with the recently described entity "multifocal capillary malformation with segmental distribution and central atrophy." To our knowledge, our patient is the oldest reported to date.