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Background: The location of telangiectases in hereditary hemorrhagic telangiectasia (HHT), as set forth in the consensus diagnostic (Curaçao) criteria, is based primarily on adults.Objective: Document the locations and numbers of telangiectases in a cohort of pediatric patients with HHT.Methods: A retrospective chart review using a standardized data collection form for site and number of telangiectases was performed for pediatric patients with HHT (age, 0-18 years) from 2005 to 2016.Results: Of 90 pediatric patients with HHT, 71% had one or more telangiectases. Of all the telangiectases counted (N = 319), cutaneous telangiectases were more common (73%) than oral telangiectases (27%). The hands were the most frequent site, accounting for 33% of all telangiectases. Adolescents were more likely than children to have cutaneous telangiectases (85% vs 50% [Q = 0.005]). The most frequent sites in children younger than 10 years were the hands excluding the fingers (27%), fingers (25%), and face (23%). Only 23% of subjects (21 of 90) presented with multiple (≥3) telangiectases at locations considered characteristic for the current consensus diagnosis guidelines (lips, oral cavity, and fingers).Limitations: Ascertainment bias based on recruitment.Conclusions: In this pediatric population, telangiectases at sites not included as "characteristic" by the Curaçao diagnostic criteria were common. The Curaçao criteria in regard to both number and location of telangiectases may be inadequate in the pediatric HHT population. [ABSTRACT FROM AUTHOR]

Hereditary hemorrhagic telangiectasia (HHT) is characterized by recurrent spontaneous epistaxis, mucocutaneous telangiectases, and multisystem arteriovenous malformations (AVMs). Brain AVMs typically present at birth and are identified in approximately 10–20% of patients with HHT. A retrospective review was undertaken of all HHT patients with known single or multiple brain AVMs treated at our institution. Thirty-nine patients with brain AVM(s) were diagnosed with HHT. Most patients presented with at least one Curaçao criterion. A total of 78 brain AVMs were identified in 39 patients. Two-thirds of patients had solitary brain AVMs, whereas 33% of patients harbored at least two lesions (range: 2–16). Brain AVMs of the supratentorial cerebral hemispheres comprised 83% of all lesions, whereas infratentorial lesions accounted for only 17%. Of the 55 brain AVMs assigned Spetzler-Martin grading, the majority of patients were Grade 1 (73%), and 23% and 4% were Grades 2 and 3, respectively. Patients were treated with surgery alone (51%), embolization alone (6%), embolization followed by surgery (9%), stereotactic radiosurgery (11%), stereotactic radiosurgery followed by surgery (3%), or observation (20%). Of patients who underwent genetic analysis, 62% possessed mutations in ENG (HHT type 1), whereas 38% had mutations in ACVRL1 (HHT type 2). This robust patient cohort of brain AVMs in 39 patients with HHT advances the collective understanding of this disease’s varied presentation, diagnostic workup, genetic underpinnings, and available treatment options. [ABSTRACT FROM AUTHOR]

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder that causes angiodysplasia and results in mucocutaneous telangiectasias and arteriovenous malformations of organs. Although central nervous system vascular malformations can occur anywhere along the neuraxis, spinal vascular malformations are rare. We present our experience with the presentation and management of spinal vascular malformations in patients with HHT. Of the more than 800 patients with the diagnosis of HHT screened at our institution from 1995 through 2017, four patients with spinal vascular malformations (age range 1 month–77 years; 2 male, 2 female) were identified, three of whom came to clinical attention after significant neurological deterioration from previously unknown malformations. A review of the literature including our patients demonstrated 29 total spinal arteriovenous fistulas (AVFs) in 28 HHT patients (69% male). The lesions were located predominantly in the thoracic spine (65.5%). Three lesions were not treated, 17 were treated with embolization, 6 were surgically resected, and 3 were treated with embolization and surgery. In 14 cases, the patients presented with hemorrhage of the AVF. Overall, 79% of patients achieved complete or near-complete occlusion, with 75% reporting improvement in neurological function. Discovery of spinal lesions often occurs after neurological decline because current screening protocols do not include evaluation of the patient for spinal lesions. Most patients benefit from intervention, which is tailored to the characteristics of the patient and their malformation. Given the often-severe neurological deficit encountered at presentation, we favor a protocol that screens HHT patients for spinal vascular malformations. [ABSTRACT FROM AUTHOR]

Background: As early life interventions for congenital heart disease improve, more patients are living to adulthood and are considering pregnancy. Scoring and classification systems predict the maternal cardiovascular risk of pregnancy in the context of congenital heart disease, but these scoring systems do not assess the potential subsequent risks following pregnancy. Data on the long-term cardiac outcomes after pregnancy are unknown for most lesion types. This limits the ability of healthcare practitioners to thoroughly counsel patients who are considering pregnancy in the setting of congenital heart disease.Objective: We aimed to evaluate the association between pregnancy and the subsequent long-term cardiovascular health of individuals with congenital heart disease.Study Design: This was a retrospective longitudinal cohort study of individuals identifying as female who were receiving care in two adult congenital heart disease centers from 2014 to 2019. Patient data were abstracted longitudinally from a patient age of 15 years (or from the time of entry into the healthcare system) to the conclusion of the study, death, or exit from the healthcare system. The primary endpoint, a composite adverse cardiac outcome (death, stroke, heart failure, unanticipated cardiac surgery, or a requirement for a catheterized procedure), was compared between parous (at least one pregnancy >20 weeks' gestation) and nulliparous individuals. By accounting for differences in the follow-up, the effect of pregnancy was estimated based on the time to the composite adverse outcome in a proportional hazards regression model adjusted for the World Health Organization class, baseline cardiac medications, and number of previous sternotomies. Participants were also categorized according to their lesion type, including septal defects (ventricular septal defects, atrial septal defects, atrioventricular septal defects, or atrioventricular canal defects), right-sided valvular lesions, left-sided valvular lesions, complex cardiac anomalies, and aortopathies, to evaluate if there is a differential effect of pregnancy on the primary outcome when adjusting for lesion type in a sensitivity analysis.Results: Overall, 711 individuals were eligible for inclusion; 209 were parous and 502 nulliparous. People were classified according to the World Health Organization classification system with 86 (12.3%) being classified as class I, 76 (10.9%) being classified as class II, 272 (38.9%) being classified as class II to III, 155 (22.1%) being classified as class III, and 26 (3.7%) being classified as class IV. Aortic stenosis, bicuspid aortic valve, dilated ascending aorta or aortic root, aortic regurgitation, and pulmonary insufficiency were more common in parous individuals, whereas dextro-transposition of the great arteries, Turner syndrome, hypoplastic right heart, left superior vena cava, and other cardiac diagnoses were more common in nulliparous individuals. In multivariable modeling, pregnancy was associated with the composite adverse cardiac outcome (36.4%% vs 26.1%%; hazard ratio, 1.83; 95% confidence interval, 1.25-2.66). Parous individuals were more likely to have unanticipated cardiac surgery (28.2% vs 18.1%; P=.003). No other individual components of the primary outcome were statistically different between parous and nulliparous individuals in cross-sectional comparisons. The association between pregnancy and the primary outcome was similar in a sensitivity analysis that adjusted for cardiac lesion type (hazard ratio, 1.61; 95% confidence interval, 1.10-2.36).Conclusion: Among individuals with congenital heart disease, pregnancy was associated with an increase in subsequent long-term adverse cardiac outcomes. These data may inform counseling of individuals with congenital heart disease who are considering pregnancy. [ABSTRACT FROM AUTHOR]

Approximately 10% of people with hereditary hemorrhagic telangiectasia (HHT) have brain vascular malformations (VMs). Few reports describe de novo brain VM formation. International HHT Guidelines recommend initial brain VM screening upon HHT diagnosis in children but do not address rescreening. We aimed to confirm whether brain VMs can form de novo in patients with HHT. The Brain Vascular Malformation Consortium HHT project is a 17-center longitudinal study enrolling patients since 2010. We analyzed the database for de novo VMs defined as those detected (1) on follow-up neuroimaging in a patient without previous brain VMs or (2) in a location distinct from previously identified brain VMs and reported those in whom a de novo VM could be confirmed on central neuroimaging review. Of 1909 patients enrolled, 409 (21%) had brain VMs. Seven patients were recorded as having de novo brain VMs, and imaging was available for central review in four. We confirmed that three (0.7% of individuals with brain VMs) had de novo brain VMs (two capillary malformations, one brain arteriovenous malformation) with intervals of six, nine, and 13 years from initial imaging. Two with de novo brain VMs were <18 years. The fourth patient, a child, did not have a de novo brain VM but had a radiologically confirmed increase in size of an existing brain arteriovenous malformation. Brain VMs can, albeit rarely, form de novo in patients with HHT. Given the potential risk of hemorrhage from brain VMs, regular rescreening in patients with HHT may be warranted. [ABSTRACT FROM AUTHOR]

: PurposeTo review the clinical features and results of surgical treatment of keratoacanthoma of the eyelids.: DesignRetrospective, interventional case series.: ParticipantsTen patients.: MethodsChart review of all eyelid keratoacanthomas treated between 1992 and 2001.: Main outcome measuresAdequate excision, recurrence rate, and complications.: ResultsPatient ages ranged from 27 to 78 years, with a mean age of 59 years. Six patients were male and four were female. The lesion was found on the lower lid in five patients, upper lid in two, medial canthus in two, and lateral canthus in one. The maximum diameter of the lesion varied from 2 to 25 mm, with a mean of 7.2 mm. All lesions were treated by surgical excision, with frozen-section control of margins in five cases. All lesions were excised completely with clear resection margins, and there were no cases of recurrence. The only complication was a minor wound infection in one patient. Mean follow-up was 34.5 months.: ConclusionsBecause of the aggressive nature and uncertain relationship to squamous cell carcinoma, we recommend excision of periocular keratoacanthoma. Surgical excision of eyelid keratoacanthoma provides good results and a very low risk of recurrence. Frozen-section control of margins should be used in selected cases to ensure complete excision. [Copyright &y& Elsevier]

Cerebrovascular malformations occur in both sporadic and inherited patterns. This paper reviews imaging and clinical features of cerebrovascular malformations with a genetic basis. Genetic diseases such as familial cerebral cavernous malformations and hereditary hemorrhagic telangiectasia often have manifestations in bone, skin, eyes, and visceral organs, which should be recognized. Genetic and molecular mechanisms underlying the inherited disorders are becoming better understood, and treatments are likely to follow. An interaction between the intestinal microbiome and formation of cerebral cavernous malformations has emerged, with possible treatment implications. Two-hit mechanisms are involved in these disorders, and additional triggering mechanisms are part of the development of malformations. Hereditary hemorrhagic telangiectasia encompasses a variety of vascular malformations, with widely varying risks, and a more recently recognized association with cortical malformations. Somatic mutations are implicated in the genesis of some sporadic malformations, which means that discoveries related to inherited disorders may aid treatment of sporadic cases. This paper summarizes the current state of knowledge of these conditions, salient features regarding mechanisms of development, and treatment prospects. • Radiologists improve diagnosis and assessment of these diseases by recognizing systemic manifestations. • Features suspicious for CCM or HHT in the CNS or elsewhere in the body should lead to optimized imaging for each. • Understanding genetic and molecular mechanisms underlying these diseases will likely lead to new treatment options. • Molecular mechanisms in these diseases may be relevant to sporadic vascular malformations involving somatic mutations. [ABSTRACT FROM AUTHOR]

Summary The cerebral cavernous malformation (CCM) pathway is required in endothelial cells for normal cardiovascular development and to prevent postnatal vascular malformations, but its molecular effectors are not well defined. Here we show that loss of CCM signaling in endocardial cells results in mid-gestation heart failure associated with premature degradation of cardiac jelly. CCM deficiency dramatically alters endocardial and endothelial gene expression, including increased expression of the Klf2 and Klf4 transcription factors and the Adamts4 and Adamts5 proteases that degrade cardiac jelly. These changes in gene expression result from increased activity of MEKK3, a mitogen-activated protein kinase that binds CCM2 in endothelial cells. MEKK3 is both necessary and sufficient for expression of these genes, and partial loss of MEKK3 rescues cardiac defects in CCM-deficient embryos. These findings reveal a molecular mechanism by which CCM signaling controls endothelial gene expression during cardiovascular development that may also underlie CCM formation. [ABSTRACT FROM AUTHOR]

Objectives: This study investigates alterations in myocardial microvasculature, fibrosis, and hypertrophy before and after mechanical unloading of the failing human heart. Background: Recent studies demonstrated the pathophysiologic importance and significant mechanistic links among microvasculature, fibrosis, and hypertrophy during the cardiac remodeling process. The effect of left ventricular assist device (LVAD) unloading on cardiac endothelium and microvasculature is unknown, and its influence on fibrosis and hypertrophy regression to the point of atrophy is controversial. Methods: Hemodynamic data and left ventricular tissue were collected from patients with chronic heart failure at LVAD implant and explant (n = 15) and from normal donors (n = 8). New advances in digital microscopy provided a unique opportunity for comprehensive whole-field, endocardium-to-epicardium evaluation for microvascular density, fibrosis, cardiomyocyte size, and glycogen content. Ultrastructural assessment was done with electron microscopy. Results: Hemodynamic data revealed significant pressure unloading with LVAD. This was accompanied by a 33% increase in microvascular density (p = 0.001) and a 36% decrease in microvascular lumen area (p = 0.028). We also identified, in agreement with these findings, ultrastructural and immunohistochemical evidence of endothelial cell activation. In addition, LVAD unloading significantly increased interstitial and total collagen content without any associated structural, ultrastructural, or metabolic cardiomyocyte changes suggestive of hypertrophy regression to the point of atrophy and degeneration. Conclusions: The LVAD unloading resulted in increased microvascular density accompanied by increased fibrosis and no evidence of cardiomyocyte atrophy. These new insights into the effects of LVAD unloading on microvasculature and associated key remodeling features might guide future studies of unloading-induced reverse remodeling of the failing human heart. [Copyright &y& Elsevier]