Arterial aneurysm and dissection: toward the evolving phenotype of Tatton-Brown-Rahman syndrome.

BACKGROUND: Tatton-Brown-Rahman syndrome (TBRS) is a rare disorder, caused by DNMT3A heterozygous pathogenic variants, and first described in 2014. TBRS is characterised by overgrowth, intellectual disability, facial dysmorphism, hypotonia and musculoskeletal features, as well as neurological and psychiatric features. Cardiac manifestations have also been reported, mainly congenital malformations such as atrial septal defect, ventricular septal defect and cardiac valvular disease. Aortic dilatation has rarely been described. METHODS: Here we have undertaken a detailed clinical and molecular description of eight previously unreported individuals, who had TBRS and arterial dilatation and/or dissection, mainly thoracic aortic aneurysm (TAA). We have also reviewed the seven previously published cases of TAA in individuals with TBRS to try to better delineate the vascular phenotype and to determine specific follow-up for this condition. RESULTS: We include eight new patients with TBRS who presented with arterial aneurysms mainly involving aorta. Three of these patients presented with dissection that required critical surgery. CONCLUSIONS: Arterial aneurysms and dissections are a potentially lethal, age-dependent manifestation. The prevalence of aortic disease in individuals with TBRS is far in excess of that expected in the general population. This cohort, together with individuals previously published, illustrates the importance to consider dilatation/dissection, mainly in aorta but also in other arteries. Arterial vascular weakness may therefore also be a cardinal feature of TBRS and vascular surveillance is recommended.

A novel NF1 mutation in a pediatric patient with renal artery aneurysm.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome, due to heterozygous pathogenic variants in NF1 gene. The main clinical manifestations are multiple café au lait spots, axillary and inguinal freckling, cutaneous and plexiform neurofibromas, optic glioma, Lisch nodules and osseous lesions, such as sphenoid and tibial dysplasia. Vasculopathy is another feature of NF1; it consists of stenosis, aneurysms, and arteriovenous malformations, frequently involving renal arteries. CASE PRESENTATION: We report on a 9-year-old girl with a novel mutation in NF1 gene and renal artery aneurysm, treated by coil embolization and complicated with hypertension. CONCLUSION: Vasculopathy is a complication of NF1, affecting from 0.4 to 6.4% of patients with NF1. Among the vascular abnormalities, renal artery aneurysm is a rare manifestation, with only a few cases regarding adult patients and no pediatric reports described in current literature. The finding of a vascular abnormality in a specific site requires the evaluation of the entire vascular system because multiple vessels could be involved at the same time.

RNF213 c.14576G>A Is Associated with Intracranial Internal Carotid Artery Saccular Aneurysms.

A mutation in RNF213 (c.14576G>A), a gene associated with moyamoya disease (>80%), plays a role in terminal internal carotid artery (ICA) stenosis (>15%) (ICS). Studies on RNF213 and cerebral aneurysms (AN), which did not focus on the site of origin or morphology, could not elucidate the relationship between the two. However, a report suggested a relationship between RNF213 and AN in French-Canadians. Here, we investigated the relationship between ICA saccular aneurysm (ICA-AN) and RNF213. We analyzed RNF213 expression in subjects with ICA-AN and atherosclerotic ICS. Cases with a family history of moyamoya disease were excluded. AN smaller than 4 mm were confirmed as AN only by surgical or angiographic findings. RNF213 was detected in 12.2% of patients with ICA-AN and 13.6% of patients with ICS; patients with ICA-AN and ICS had a similar risk of RNF213 mutation expression (odds ratio, 0.884; 95% confidence interval, 0.199-3.91; p = 0.871). The relationship between ICA-AN and RNF213 (c.14576G>A) was not correlated with the location of the ICA and bifurcation, presence of rupture, or multiplicity. When the etiology and location of AN were more restricted, the incidence of RNF213 mutations in ICA-AN was higher than that reported in previous studies. Our results suggest that strict maternal vessel selection and pathological selection of AN morphology may reveal an association between genetic mutations and ICA-AN development. The results of this study may form a basis for further research on systemic vascular diseases, in which the RNF213 (c.14576G>A) mutation has been implicated.

Prevalence of and Factors Associated with Arterial Aneurysms in Patients with Hereditary Hemorrhagic Telangiectasia: 17-Year Retrospective Series of 418 Patients.

PURPOSE: To estimate the prevalence of and identify characteristics associated with the presence of aneurysms in a cohort of patients with hereditary hemorrhagic telangiectasia (HHT). MATERIALS AND METHODS: In the study institution's HHT database, 418 patients with a definite HHT diagnosis were identified based on the clinical Curaçao criteria and/or an HHT-associated genetic mutation. Regression modeling was used to evaluate the association between arterial aneurysms and older age, male sex, smoking, alcohol consumption, hypertension, hyperlipidemia, genetic mutations, the presence of arteriovenous malformations (AVMs) unrelated to the aneurysms, and HHT-related genetic mutations. RESULTS: Forty-three (10.3%) patients had at least 1 aneurysm. Sixteen (3.8%) patients had multiple aneurysms. Of the variables analyzed, older age (odds ratio [OR] = 1.02; 95% confidence interval [CI]: 1.0-1.1), the presence of anatomically and flow-unrelated AVMs (OR = 3.2; 95% CI: 1.3-8.0), and the presence of activin A receptor type II-like 1 (ACVRL1) mutation (OR = 4.0; 95% CI: 1.5-10) were associated with the presence of at least 1 aneurysm. CONCLUSIONS: In this cohort of patients with HHT, the prevalence of intracranial and visceral arterial aneurysms was estimated to be 10.3%. Older age, the presence of unrelated AVMs, and the presence of the ACVRL1 mutation were associated with the presence of arterial aneurysms. Further study is required to assess the clinical importance and risk of rupture of aneurysms in patients with HHT.

Segmental overgrowth and aneurysms due to mosaic PDGFRB p.(Tyr562Cys).

Activating variants in the platelet-derived growth factor receptor ß gene (PDGFRB) have been associated with Kosaki overgrowth syndrome, infantile myofibromatosis, and Penttinen premature aging syndrome. A recently described phenotype with fusiform aneurysm has been associated with mosaic PDGFRB c.1685A > G p.(Tyr562Cys) variant. Few reports however have examined the vascular phenotypes and mosaic effects of PDGFRB variants. We describe clinical characteristics of two patients with a recurrent mosaic PDGFRB p.(Tyr562Cys) variant identified via next-generation sequencing-based genetic testing. We observed intracranial fusiform aneurysm in one patient and found an additional eight patients with aneurysms and phenotypes associated with PDGFRB-activating variants through literature search. The conditions caused by PDGFRB-activating variants share overlapping features including overgrowth, premature aged skin, and vascular malformations including aneurysms. Aneurysms are progressive and can result in morbidities and mortalities in the absence of successful intervention. Germline and/or somatic testing for PDGFRB gene should be obtained when PDGFRB activating variant-related phenotypes are present. Whole-body imaging of the arterial tree and echocardiography are recommended after diagnosis. Repeating the imaging study within a 6- to 12-month period after detection is reasonable. Finally, further evaluation for the effectiveness and safety profile of kinase inhibitors in this patient population is warranted.

Progressive cerebral and coronary aneurysms in the original two patients with Kosaki overgrowth syndrome.

Skeletal overgrowth accompanied by de novo heterozygous activating mutations in PDGFRB (platelet-derived growth factor receptor beta), that is, p.Pro584Arg and p.Trp566Arg, defines Kosaki overgrowth syndrome (OMIM #616592). Emerging evidence suggests a role of PDGFRB in the genesis of cerebral aneurysms. The delineation of the range and progression of the vascular phenotype of Kosaki overgrowth syndrome is urgently needed. Herein, we conducted subsequent analyses of serial neurovascular imaging studies of two original patients with a de novo heterozygous mutation in PDGFRB, that is, p.Pro584Arg. The analysis showed the progressive dilation of basilar and vertebral arteries and coronary arteries commencing during the teenage years and early 20s. The radiographic appearance of the basilar vertebral aneurysms showed signs of arterial wall dilation, compatible with the known vascular pathology of vascular-type Ehlers-Danlos syndrome and Loeys-Dietz syndrome. The dolichoectasia in cerebrovascular arteries can lead to fatal complications, even with neurosurgical interventions. To prevent the progression of artery dilation, preventative and therapeutic medical measures using tyrosine kinase inhibitors may be necessary in addition to optimal control of the systemic blood pressure. Kosaki overgrowth syndrome is a clinically recognizable syndrome that can exhibit progressive dilatory and tortuous vascular changes in basilar/vertebral and coronary arteries as early as in the teenage years. We recommend careful counseling regarding the risk of future vascular complications, optimal blood pressure control, and regular systemic vascular screening during follow-up examinations.

MiR-17-5p promotes the endothelialization of endothelial progenitor cells to facilitate the vascular repair of aneurysm by regulating PTEN-mediated PI3K/AKT/VEGFA pathway.

The endothelialization of endothelial progenitor cells (EPCs) was proven to facilitate the vascular repair of aneurysm. MiR-17-5p regulated angiogenesis in various cancers. This research focused on exploring the effect of miR-17-5p on EPCs and the vascular repair of aneurysm. In vivo study: the aneurysm rat model was established and treated with AgomiR-17-5p; the histopathology of aneurysm tissues was examined by hematoxylin-eosin staining; and the level of EPCs in the aneurysm tissues and peripheral blood of rats were evaluated by immunofluorescence and flow cytometry, respectively. In vitro study: EPCs were cultured and identified using flow cytometry; the target of miR-17-5p was proven by dual-luciferase reporter assay; after transfection, the viability, migration, and tube formation of the EPCs were detected by MTT, wound healing, and tube formation assays, respectively; the expressions of VEGFA and factors related to PTEN-mediated PI3K/AKT pathway were detected by ELISA, qPCR, or Western blot as needed. In vivo study: miR-17-5p overexpression promoted the vascular repair in aneurysm rats and increased the level of EPCs in the aneurysm tissues and peripheral blood of the rats. In vitro study: miR-17-5p overexpression promoted the viability, migration, and tube formation of EPCs, up-regulated the expressions of VEGFA, p-PI3K, and p-AKT, and down-regulated the PTEN expression in EPCs; miR-17-5p silencing did the opposite; PTEN was targeted by miR-17-3p and further abrogated the effects of miR-17-5p overexpression on EPCs. MiR-17-5p promoted the endothelialization of EPCs to facilitate the vascular repair of aneurysm by regulating PTEN-mediated PI3K/AKT/VEGFA pathway.

GSK3 modulation in acute lung injury, myocarditis and polycystic kidney disease-related aneurysm.

GSK3 are involved in different physical and pathological conditions and inflammatory regulated by macrophages contribute to significant mechanism. Infection stimuli may modulate GSK3 activity and influence host cell adaption, immune cells infiltration or cytokine expressions. To further address the role of GSK3 modulation in macrophages, the signal transduction of three major organs challenged by endotoxin, virus and genetic inherited factors are briefly introduced (lung injury, myocarditis and autosomal dominant polycystic kidney disease). As a result of pro-inflammatory and anti-inflammatory functions of GSK3 in different microenvironments and stages of macrophages (M1/M2), the rational resolution should be considered by adequately GSK3.

Activating variants in PDGFRB result in a spectrum of disorders responsive to imatinib monotherapy.

More than 50 individuals with activating variants in the receptor tyrosine kinase PDGFRB have been reported, separated based on clinical features into solitary myofibromas, infantile myofibromatosis, Penttinen syndrome with premature aging and osteopenia, Kosaki overgrowth syndrome, and fusiform aneurysms. Despite their descriptions as distinct clinical entities, review of previous reports demonstrates substantial phenotypic overlap. We present a case series of 12 patients with activating variants in PDGFRB and review of the literature. We describe five patients with PDGFRB activating variants whose clinical features overlap multiple diagnostic entities. Seven additional patients from a large family had variable expressivity and late-onset disease, including adult onset features and two individuals with sudden death. Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy and one with a recurrent p.Val665Ala (Penttinen) variant. Along with previously reported individuals, our cohort suggests infants and young children had few abnormal features, while older individuals had multiple additional features, several of which appeared to worsen with advancing age. Our analysis supports a diagnostic entity of a spectrum disorders due to activating variants in PDGFRB. Differences in reported phenotypes can be dramatic and correlate with advancing age, genotype, and to mosaicism in some individuals.

Aneurysmal Dilatation of Ductus Arteriosus and Pulmonary Artery in Association With ACTA2 Mutation.

Actin α2 (ACTA2) is a protein crucial for proper functioning of contractile apparatus in smooth muscles. A specific mutation resulting in substitution of arginine at position 179 by histidine (p.R179 H) in ACTA2 has been shown to be associated with multisystemic smooth muscle dysfunction syndrome. Characteristic features include aneurysmal arterial disease. Due to rarity of this disease, we report a nine-year-old girl with this rare genetic variant in whom cardiovascular manifestations were identified in fetal life and who needed neonatal cardiac surgical intervention.

A multi-institutional experience in the aortic and arterial pathology in individuals with genetically confirmed vascular Ehlers-Danlos syndrome.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder owing to pathogenic variants in COL3A1 that lead to impaired type III collagen production. We aim to describe the contemporary multi-institutional experience of aortic and arterial pathology in individuals with vEDS, to evaluate disease patterns and refine management recommendations. METHODS: This cross-sectional, retrospective study of individuals with genetically confirmed vEDS was conducted between 2000 and 2015 at multiple institutions participating in the Vascular Low Frequency Disease Consortium. Aortic and arterial events including aneurysms, pseudoaneurysms, dissections, fistulae, or ruptures were studied. Demographics, COL3A1 variants, management, and outcomes data were collected and analyzed. Individuals with and without arterial events were compared. RESULTS: Eleven institutions identified 86 individuals with pathogenic variants in COL3A1 (47.7% male, 86% Caucasian; median age, 41 years; interquartile range [IQR], 31.0-49.5 years; 65.1% missense COL3A1 variants). The median follow-up from the time of vEDS diagnosis was 7.5 years (IQR, 3.5-12.0 years). A total of 139 aortic/arterial pathologies were diagnosed in 53 individuals (61.6%; 50.9% male; 88.5% Caucasian; median age, 33 years; IQR, 25.0-42.3 years). The aortic/arterial events presented as an emergency in 52 cases (37.4%). The most commonly affected arteries were the mesenteric arteries (31.7%), followed by cerebrovascular (16.5%), iliac (16.5%), and renal arteries (12.2%). The most common management was medical management. When undertaken, the predominant endovascular interventions were arterial embolization of medium sized arteries (13.4%), followed by stenting (2.5%). Aortic pathology was noted in 17 individuals (32%; 58.8% male; 94.1% Caucasian; median age, 38.5 years; IQR, 30.8-44.7 years). Most notably, four individuals underwent successful abdominal aortic aneurysm repair with excellent results on follow-up. Individuals with missense mutations, in which glycine was substituted with a large amino acid, had an earlier onset of aortic/arterial pathology (median age, 30 years; IQR, 23.5-37 years) compared with the other pathogenic COL3A1 variants (median age, 36 years; IQR, 29.5-44.8 years; P = .065). There were 12 deaths (22.6%) at a median age of 36 years (IQR, 28-51 years). CONCLUSIONS: Most of the vEDS arterial manifestations were managed medically in this cohort. When intervention is required for an enlarging aneurysm or rupture, embolization, and less frequently stenting, seem to be well-tolerated. Open repair of abdominal aortic aneurysm seems to be as well-tolerated as in those without vEDS; vEDS should not be a deterrent to offering an operation. Future work to elucidate the role of surgical interventions and refine management recommendations in the context of patient centered outcomes is warranted.

Femoral Artery Aneurysm Repair in a Patient With a Fibrillin-2 Mutation.

Degenerative femoral artery aneurysms are uncommon and often associated with aneurysm in other distributions. We report a case of a 68-year-old man with multianeurysmal disease involving the aorta, iliac, femoral, and popliteal arteries managed interdisciplinary by stent-graft placement and open surgical repair. Genetic testing revealed a variant in the FBN2 gene encoding fibrillin-2, an important component of microfibrils. We detail arterial reconstruction of the femoral artery and discuss incidence, diagnosis, and therapy of femoral artery aneurysms.

Apolipoprotein E polymorphism and the risk of aneurysmal subarachnoid hemorrhage in a South Indian population.

BACKGROUND: The rupture of a brain aneurysm causes bleeding in the subarachnoid space. This is known as aneurysmal subarachnoid hemorrhage (aSAH). We evaluated the association of apolipoprotein E (APOE) polymorphism and the risk of aSAH in a South Indian population. METHODS: The study was performed on 200 subjects with aSAH and 253 healthy control subjects. Blood samples (5 ml) were used to isolate DNA and genotyping was performed for rs7412 and rs429358 using a Taqman allelic discrimination assay. Statistical software R.3.0.11 was used to statistically analyze the data and a p value < 0.05 was considered as statistically significant. RESULTS: We found a significant association with the risk of aSAH in ε3/ ε4 genetic model (OR = 1.91, 95% CI = 1.16-3.14, p = 0.01). However, in the other genetic models and allele frequency, there was no significant association with the risk of aSAH. In subtyping, we found a significant association of ε2 allele frequency with posterior communicating artery (PCOM) aneurysm (OR = 3.59, 95% CI = 1.11-11.64, p = 0.03). CONCLUSION: Our results suggest that APOE polymorphism has an influence on the risk of aSAH in this South Indian population, specifically in the PCOM subtype.

Differentiation and Application of Induced Pluripotent Stem Cell-Derived Vascular Smooth Muscle Cells.

Vascular smooth muscle cells (VSMCs) play a role in the development of vascular disease, for example, neointimal formation, arterial aneurysm, and Marfan syndrome caused by genetic mutations in VSMCs, but little is known about the mechanisms of the disease process. Advances in induced pluripotent stem cell technology have now made it possible to derive VSMCs from several different somatic cells using a selection of protocols. As such, researchers have set out to delineate key signaling processes involved in triggering VSMC gene expression to grasp the extent of gene regulatory networks involved in phenotype commitment. This technology has also paved the way for investigations into diseases affecting VSMC behavior and function, which may be treatable once an identifiable culprit molecule or gene has been repaired. Moreover, induced pluripotent stem cell-derived VSMCs are also being considered for their use in tissue-engineered blood vessels as they may prove more beneficial than using autologous vessels. Finally, while several issues remains to be clarified before induced pluripotent stem cell-derived VSMCs can become used in regenerative medicine, they do offer both clinicians and researchers hope for both treating and understanding vascular disease. In this review, we aim to update the recent progress on VSMC generation from stem cells and the underlying molecular mechanisms of VSMC differentiation. We will also explore how the use of induced pluripotent stem cell-derived VSMCs has changed the game for regenerative medicine by offering new therapeutic avenues to clinicians, as well as providing researchers with a new platform for modeling of vascular disease.

Endovascular Repair of Internal Mammary Artery Aneurysms in 2 Sisters with SMAD3 Mutation.

True aneurysms of the internal mammary artery are rare and have been described in association with vasculitis or connective tissue disorders. Herein, we describe 2 cases of familial internal mammary artery aneurysms (IMAs) in 2 sisters with SMAD3 mutation. The older sister presented at the age of 54 years with an incidental diagnosis of a multilobed right IMA and the younger sister presented several years earlier with a ruptured left IMA aneurysm at the age of 49 years. Both sisters had Debakey type I aortic dissections prior to the IMA aneurysm presentation. To our knowledge, this is the first time IMA aneurysms have been described in siblings with SMAD3 mutation. In our experience, endovascular repair is a feasible and safe treatment option. An assessment of the entire arterial tree is recommended in patients diagnosed with SMAD3 mutations.