Citations

Thoracic aortic aneurysm and dissection (TAAD) encompasses a clinically heterogeneous group of diseases characterized by high morbidity and mortality. Genetic studies over the past two decades have significantly expanded our understanding of the molecular landscape underlying heritable TAAD, revealing contributions from multiple interconnected biological pathways. This review systematically summarizes more than 75 genes implicated in TAAD pathogenesis, categorizing them according to major mechanistic roles including TGF-β signaling, extracellular matrix remodeling, smooth muscle cell contractility and cytoskeletal regulation, cell–matrix and cell–cell adhesion, metabolic processes, ion transport, and transcriptional regulation. Special emphasis is placed on emerging genes with variable or overlapping clinical phenotypes, dual-mechanism candidates, and their implications for personalized clinical management, including surveillance and surgical intervention thresholds. The integration of molecular insights into clinical practice, along with cautious consideration of genes of uncertain significance, promises to enhance diagnostic precision and risk stratification in individuals and families affected by heritable aortic disease.

Bicuspid aortic valve (BAV) and thoracic aortic aneurysms and dissections (TAAD) are recognized in syndromic connective tissue diseases (CTD), but most cases occur sporadically. The extent to which non-syndromic BAV or TAAD predisposes to additional arteriopathies, particularly in younger individuals, remains unclear. We retrospectively analyzed 1438 patients (mean age = 48.0, 67.7% female), excluding those with CTDs. Participants were ≤60 years old and categorized by the presence of BAV and/or TAAD. We examined co-existing arterial pathologies, including fibromuscular dysplasia, spontaneous coronary artery dissection, abdominal aortic aneurysms (AAA), mesenteric, peripheral extremity, and carotid/cerebral arteriopathies. Overall, 44.6% had either BAV or TAAD, and 27.2% had multiple arteriopathies. While vascular diseases were frequently noted, odds ratios demonstrated no significantly increased risk of extra-aortic arteriopathies in the BAV or TAAD cohorts. AAA exhibited a non-significant trend toward higher prevalence in TAAD patients. These findings support current guidelines recommending targeted imaging (transthoracic echocardiography of the aortic root and ascending aorta) over comprehensive “head-to-pelvis” screening for non-syndromic BAV or TAAD patients without additional risk factors. Ongoing genetic analyses may elucidate whether particular variants predispose to multi-site aneurysms or dissections. Consequently, targeted surveillance remains appropriate, with broader imaging reserved for patients with genetic or clinical indicators of higher risk.

ABSTRACT The alpha 1 and 2 chains of type IV collagen, encoded by the COL4A1 (MIM 120130) and COL4A2 (MIM 120090) respectively, play essential roles in the vascular basement membranes. Pathogenic variants in COL4A1 / COL4A2 are associated with autosomal dominant cerebral angiopathies. The clinical manifestations of COL4A1 / COL4A2 ‐related disorders include: aneurysms, intracerebral hemorrhage, polymicrogyria, porencephaly, heterotopia, periventricular leukomalacia, epilepsy, and neurodevelopmental disorders. COL4A1 pathogenic variants that are in exons 24 and 25 have been associated with hereditary angiopathy, nephropathy, aneurysms, and cramps. The multisystemic phenotypes of COL4A1 / COL4A2 ‐related disorders are increasingly being studied. Animal models have suggested that COL4A2 ‐related disorders may also manifest with a variable combination of multisystemic abnormalities affecting the eyes, muscles, and kidneys. Okano and colleagues recently reported a case of recurrent episodes of rhabdomyolysis in a 2‐year‐old with COL4A1 ‐related disorder raising fundamental questions on mechanisms of COL4A1 / COL4A2 variants in muscle homeostasis. To date, rhabdomyolysis has not been associated with COL4A2 ‐related disorder in humans. Rhabdomyolysis is a medical emergency, where there is elevated creatine kinase (CK) level in the blood and increased excretion of myoglobin in urine, due to skeletal muscle damage and release of intracytoplasmic proteins into systemic circulation. Rhabdomyolysis is a serious medical condition. It require intensive care management due to an increased risk of some life‐threatening complications [including disseminated intravascular coagulation, renal failure, and severe hyperkalemia]. Herein, we report a case of rhabdomyolysis in an adult with COL4A2 ‐related structural brain malformations (including polymicrogyria and heterotopia).

Introduction/Background: Loeys-Dietz syndrome (LDS) is a rare autosomal dominant aortic aneurysm syndrome characterized by arterial tortuosity resulting in arterial aneurysms and dissections, with unique craniofacial and skeletal features including bifid uvula, cleft palate and hypertelorism. While the presence of atrial fibrillation (Afib) and arrhythmias have been reported in LDS patients, limited investigation has been completed regarding the associated risk and severity of vascular complications in relationship to these arrhythmias1,2. Research Questions/Hypothesis: Are there any differences in vascular outcomes in patients with LDS when experiencing various forms of tachyarrhythmia? Goals/Aims: To evaluate the relationship between various types of arrhythmias and vascular outcomes in patients with LDS, including arterial dissection, stroke, revascularization, and death. Methods/Approach: A large sample of LDS patients (n=436) from a single tertiary referral center was assessed for ICD-10 diagnoses of arrhythmia and outcomes of interest. Arrhythmias assessed included Afib, atrial flutter (AFL), premature ventricular contractions (PVCs), and supraventricular tachycardia (SVT). Outcomes were arterial dissection, hemorrhagic and ischemic stroke, revascularization, and all-cause mortality. Results/Data: Our cohort (n=436) had an average age of 47 and was 57.8% female. A total of 26 patients had a documented history of tachyarrhythmia: 16 (3.4%) Afib, 2 (0.5%) AFL, 6 (1.4%) SVT, and 2 (0.5%) PVC. LDS patients with Afib were at significantly higher risk of arterial dissection (25% vs 6.0%, OR: 5.3, p<0.01), revascularization (18.8% vs 3.3%, OR: 8.1, p<0.01), stroke (25% vs 3.6%, OR: 9.0, p<0.001), and death (25% vs 4.3%, OR: 7.4, p<0.01) compared to those without a documented history of arrhythmia. Other arrhythmia types evaluated were not significant. Predictors of any arrhythmia type included hypertension (78% vs 31%, OR: 1.5, p<0.001) and heart failure (39% vs 5.0%, OR: 2.3, p<0.001). Conclusion: Although rare, Afib in LDS patients is associated with adverse vascular outcomes and mortality compared to those without a history of arrhythmia. Furthermore, the magnitude of increased risk is striking. Early identification and management of Afib in LDS patients may be critical in mitigating the risk of potential vascular complications.

Introduction/Background: Fibromuscular Dysplasia (FMD) is a non-atherosclerotic vascular disease that primarily affects medium-sized arteries and is characterized by abnormal cell development in the artery walls. Recent studies have suggested that various connective tissue features may be prevalent in patients with FMD, however the clinical significance of these findings on the disease course are uncertain. Research Questions/Hypothesis: We hypothesized that the presence of connective tissue features in patients with FMD might indicate a more severe disease course, potentially associated with increased severity of vascular complications. Goals/Aims: To evaluate the association between connective tissue features and the severity of vascular complications in FMD patients on outcomes including dissections and stroke. Methods/Approach: This cross-sectional study involved 2,454 patients diagnosed with FMD at a tertiary referral center. Patients were classified into two groups based on the presence (n=324) or absence (n=2130) of connective tissue features (pectus deformity of any kind, scoliosis, pneumothorax, inguinal hernia, uterine rupture, bowel perforation, Achilles tendon rupture). We evaluated the incidence of dissections and ischemic or hemorrhagic strokes using odds ratios and chi-squared tests. Results/Data: The cohort consisted of 2,454 participants with an average age of 64.8 years, of whom 89.1% were female and 92.4% identified as White. When comparing groups with and without connective tissue features, there were no significant differences in the prevalence of aneurysms at any site. Among the subgroup of FMD patients with connective tissue features (n=234), prevalent conditions included pectus (12.35%), scoliosis (47.22%), pneumothorax (16.67%), inguinal hernia (13.58%), uterine rupture (16.36%), bowel perforation (6.48%), and Achilles tendon rupture (1.85%). Vascular outcome analysis showed significant differences: the odds of experiencing a stroke were higher in patients with these features (odds ratio: 1.60; P-value: <0.01), whereas the odds of experiencing dissections were lower (odds ratio: 0.77; P-value: 0.03). Conclusion: The presence of connective tissue features in patients with FMD is associated with 60% higher odds of experiencing a stroke, equivalent to a 1.6-fold increase, compared to those without these features. This association may represent a novel finding in the literature, warranting further investigation.

Abstract With the increasing opportunities for medical management of von Hippel–Lindau (VHL)-related lesions, fundamental questions are arising regarding the possibilities of the FDA-approved medication (Belzutifan) to delay the progression of other non-VHL-related tumors that are not requiring urgent surgical interventions. We present a follow-up report on a VHL patient, with a co-morbid history of pulmonary mucosa-associated lymphoid tissue lymphoma, who was initially described in the clinical scientific literature ~10 years ago. This patient’s case highlights some of the challenges for some VHL patients with comorbid non-VHL-related tumors and potential opportunities for targeted support.

Abstract Chromosome 4p16.3 microdeletions are known to cause Wolf–Hirschhorn syndrome (WHS), which is characterized by a distinct craniofacial gestalt and multiple congenital malformations. The 4p16.3 region encompasses WHS critical region 1 (WHSCR1) and 2 (WHSCR2). The WHSCR contains several genes that have been implicated in the WHS phenotype including: WHS candidate 1 [WHSC1(aka NSD2, OMIM 602952)], WHS candidate 2 [WHSC2 (aka NELFA, OMIM 606026)], and LETM1 (OMIM 604407). Although several patients harboring 4p16.3 microdeletions that are associated with WHS phenotypes have been reported, the precise molecular underpinnings of WHS are subjects of active investigations. The potential role(s) of genes within the 4p16.3 are increasingly being investigated. Here we report the first documented case of 4p16.3 terminal microdeletion that is not associated with the characteristic WHS phenotype. We studied Individual A (7-months-old female) and her father, Individual B (27-year-old), who both carry a terminal 4p16.3 microdeletion (about 555kb) that is distal to the WHSCR [(WHSCR1) and (WHSCR2)], and does not include WHSC1, WHSC2, or LETM1. Overall, our findings expand the phenotypic spectrum associated with 4p16.3 microdeletions and suggest that, in some individuals, microdeletions within 4p16.3 region may not be sufficient to cause WHS.