Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder associated with aortic root enlargement and risk of thoracic aortic dissection (AD). Genetic examination is essential for diagnosis.
The study aimed at analysis of clinical data on cardiovascular involvement and management of LDS patients.
The study included carriers of LDS-associated genetic variants, identified between 2012 and 2022. Assessment of cardiovascular involvement was based on echocardiography and computed tomography angiography with quantitative assessment of arterial tortuosity. Involvement of other systems was also evaluated. We noted major cardiovascular events, including aortic events, defined as AD, elective aortic surgery, or otherwise unexplained sudden death.
Thirty-four patients from 15 families were included, and five identified variants were novel. Probands\' mean age was 41 years. Cardiovascular abnormalities, aortic involvement, aortic tortuosity, and tortuosity of cervical arteries were present in 79%, 71%, 68%, and 100% of carriers, respectively. First aortic events (9 A-type AD, 6 elective thoracic aortic surgeries, and one sudden death) occurred in 16 (47%) patients at a median age of 35 years. The youngest age at AD was 16 years, and 7 years for elective aneurysm repair. Second and third aortic events occurred in 9 and 4 patients, respectively. Eight patients (24%) experienced other major cardiovascular events. Aortic event-free survival was shorter in the presence of skin striae (P = 0.03), tended to be shorter in the presence of Marfanoid features (P = 0.06), and longer with TGFB2 variants (P = 0.06).
LDS is associated with high burden of cardiovascular complications at a young age.

Hughes-Stovin syndrome is a rare disease characterized by thrombophlebitis and multiple pulmonary and/or bronchial aneurysms. The etiology and pathogenesis of HSS are incompletely known. The current consensus is that vasculitis underlies the pathogenic process, and pulmonary thrombosis follows arterial wall inflammation. As such, Hughes-Stovin syndrome may belong to the vascular cluster with lung involvement of Behçet syndrome, although oral aphtae, arthritis, and uveitis are rarely found. Behçet syndrome is a multifactorial polygenic disease with genetic, epigenetic, environmental, and mostly immunological contributors. The different Behçet syndrome phenotypes are presumably based upon different genetic determinants involving more than one pathogenic pathway. Hughes-Stovin syndrome may have common pathways with fibromuscular dysplasias and other diseases evolving with vascular aneurysms. We describe a Hughes-Stovin syndrome case fulfilling the Behçet syndrome criteria. A MYLK variant of unknown significance was detected, along with other heterozygous mutations in genes that may impact angiogenesis pathways. We discuss the possible involvement of these genetic findings, as well as other potential common determinants of Behçet/Hughes-Stovin syndrome and aneurysms in vascular Behçet syndrome. Recent advances in diagnostic techniques, including genetic testing, could help diagnose a specific Behçet syndrome subtype and other associated conditions to personalize the disease management.

暂无摘要。

Thoracic aortic aneurysms and dissections are precarious conditions that often cannot be diagnosed with fatal outcomes. Over the last few years, pathogenic variants in numerous genes have been identified that predispose to heritable presentations of TAAD. An evidence-based strategy for the selection of genes to test in familial TAAD helps inform family screening and intervention to prevent life-threatening events. Using whole-exome sequencing, four members of three unrelated families clinically diagnosed with TAAD were used to identify the genetic origin of the disorder. Variant evaluation was carried out to detect the pathogenic mutation. Our studies suggest that mutations of COL3A1 and ACTA2 are responsible for familial TAAD. In addition, we highlight FBLN5, FBN1, SLC2A10, FBN2, and NOTCH1 as candidate genes. Future studies of crosstalk among the pathways may provide us a step toward understanding the pathogenic mechanism. This finding indicates the necessity of obtaining family medical history and screening of extended relatives of patients with TAAD for the early identification and treatment of TAAD.

Type B aortic dissection (TBAD) is commonly thought of as a sporadic event. However, an increasing body of data has suggested that genetic factors can influence TBAD. Our aim was to determine the prevalence of heritable TBAD, defined as either syndromic TBAD or nonsyndromic familial TBAD and to detail the natural history and long-term clinical outcomes compared with patients with \"sporadic\" TBAD without an identified syndrome or family history.
The clinical records of 389 patients with TBAD who had presented to a single health care system from 1995 to 2017 were reviewed. A family history was obtained by interview and/or medical record review. Syndromic TBAD was defined as TBAD in patients with Marfan, Loeys-Dietz, or vascular Ehlers-Danlos syndrome. Nonsyndromic familial TBAD was defined as a family history of aortic or arterial aneurysm or dissection and/or sudden death in a first- or second-degree relative in the absence of a known syndrome. Patients with syndromic and nonsyndromic familial TBAD were compared with patients with sporadic TBAD in terms of the comorbid conditions, aortic repair, and mortality.
Of 389 patients (71.2% male) with TBAD, the etiology of TBAD was heritable in 27.9% (9.6% syndromic; 18.3% nonsyndromic familial TBAD) and 72.1% sporadic of the cases. Patients with syndromic and nonsyndromic familial TBAD had been more frequently referred in the chronic phase than were the patients with sporadic TBAD (35.5% vs 44.1% vs 25.8%; P = .014) and had presented at a younger age (40.6 ± 10.9 years vs 55.2 ± 11.3 years vs 62 ± 12.9 years; P < .001) and with lower blood pressure at acute TBAD (systolic, 159.2 ± 21 mm Hg vs 178.9 ± 39.3 mm Hg vs 186.1 ± 38.4, P = .01; diastolic, 84.3 ± 17.3 mm Hg vs 91.4 ± 24.1 mm Hg vs 101.6 ± 22.3 mm Hg, P = .001). Among patients with acute TBAD surviving to discharge from the initial hospitalization, thoracic endovascular aortic repair (TEVAR) had been performed in 115 patients, with no significant differences in TEVAR usage in the three groups. However, those with syndromic and nonsyndromic familial TBAD had had a greater incidence of retrograde aortic dissection after TEVAR (33.3% vs 15% vs 3%; P = .006). They had also required a greater number of arch repairs (30% vs 10.5% vs 3.6%; P < .001) and had died at a younger age (47.7 ± 13.1 years vs 65.7 ± 13.7 years vs 72.8 ± 12.7 years; P < .001). Aortic-related mortality was more common among patients with syndromic TBAD (36.7% vs 12.3% vs 17.6%; P = .016).
In our single-institutional experience, heritable TBAD accounted for one in four patients with TBAD. Nonsyndromic familial TBAD was twice as common as syndromic TBAD and appeared to share many clinical features. Identifying these patients early in their disease course and personalizing their care might improve their survival.

BACKGROUND: Thoracic aortic aneurysms and dissections (TAAD) are rare in children and often associated with underlying genetic disorders accompanied with other systemic manifestations, including connective or osteo-articular tissue diseases.
METHODS: We report the case of a 10-year-old girl with a novel nonsense SMAD3 mutation, p.Glu102X, who presented with familial TAAD without any signs of osteoarthritis. Histological analysis of aorta fragments from the patient with TAAD obtained during surgery revealed elastin degradation and inflammatory infiltration of T cells with dense CD31 + microvessels, which is consistent with previous findings. Interestingly, the family members with the SMAD3 mutation developed IgA nephropathy.
CONCLUSIONS: Because the TGF-β/Smad signalling pathway plays an important role in the primary pathogenesis of IgA nephropathy and TAAD, we presume that IgA nephropathy could be a novel clinical phenotype of SMAD3 deficiency. Further accumulation of genetically proven cases with SMAD3 deficiency is needed to more accurately characterize phenotypic variability and elucidate a wide spectrum of TGF-β-associated disorders.

Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD.
Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed.
Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant.
This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.

We report on a 44-year-old woman with coincidence of two genetic disorders: Andersen-Tawil syndrome and Marfan syndrome. In both, life-threatening arrhythmias could occur. A 44-year-old woman presented acute ascending aortic dissection with aortic arch involvement and chronic thoracic descending and abdominal aortic dissection. Clinical and genetic examination confirmed Marfan syndrome (MFS) diagnosis. Due to repolarization disorder in ECG and premature ventricular contractions in Holter ECG, the sequencing data were analyzed again and mutation in KCNJ2 gene was identified. The case showed that coincidence of Andersen-Tawil syndrome (ATS) and MFS did not provoke life-threatening arrhythmias. Complication was rather caused by expression of FBN1 mutation.

Since the identification of the fibrillin-1 gene as the causal gene for Marfan syndrome, our knowledge of molecular genetics and the applicability of genetic testing in clinical practice have expanded dramatically. Several new syndromes related to thoracic aortic aneurysms and dissections (TAAD) have been described and the list of underlying genes in syndromal and nonsyndromal TAAD already includes more than 10 different genes and is rapidly expanding. Based on this knowledge, our insights into the underlying pathophysiology of TAAD have improved significantly, and new opportunities for targeted treatment have emerged. Clinicians involved in the care of TAAD patients require a basic knowledge of the disease entities and need to be informed on the applicability of genetic testing in their patients and families. Gene-tailored treatment and management is indeed no science fiction anymore and should now be considered as part of good clinical practice. We provide a systematic overview of genetic TAAD entities and practical recommendations for genetic testing and patient management.

BACKGROUND: In this study, patients suspected of having a clinical diagnosis of Marfan Syndrome (MFS), Loeys-Dietz Syndrome (LDS) and Thoracic Aortic Aneurysms and Dissections (TAAD) were referred for genetic testing and examined for mutations in the FBN1, TGFβR1, TGFβR2 and ACTA2 genes.
METHODS: We examined 594 samples from unrelated individuals and different combinations of genes were sequenced, including one or more of the following: FBN1, TGFβR1, TGFβR2, ACTA2, and, in some cases, FBN1 was analyzed by MLPA to detect large deletions.
RESULTS: A total of 112 patients had a positive result. Of those, 61 had a clinical diagnosis of MFS, eight had LDS, three had TAAD and 40 patients had clinical features with no specific diagnosis provided. A total of 44 patients had an inconclusive result; of these, 12 patients were referred with a clinical diagnosis of MFS, 4 with LDS and 9 with TAAD and 19 had no clinical diagnosis. A total of 89 mutations were novel.
CONCLUSIONS: This study reveals the rate of detection of variants in several genes associated with MFS, LDS and TAAD. The evaluation of patients by individuals with expertise in the field may decrease the likelihood of ordering unnecessary molecular testing. Nevertheless, genetic testing supports the diagnosis of MFS, LDS and TAAD.