Case-matched Comparison of Cardiovascular Outcome in Loeys-Dietz Syndrome versus Marfan Syndrome

Abstract

Background: Pathogenic variants in TGFBR1, TGFBR2 and SMAD3 genes cause Loeys-Dietz syndrome, and pathogenic variants in FBN1 cause Marfan syndrome. Despite their similar phenotypes, both syndromes may have different cardiovascular outcomes. Methods: Three expert centers performed a case-matched comparison of cardiovascular outcomes. The Loeys-Dietz group comprised 43 men and 40 women with a mean age of 34 ± 18 years. Twenty-six individuals had pathogenic variants in TGFBR1, 40 in TGFBR2, and 17 in SMAD3. For case-matched comparison we used 83 age and sex-frequency matched individuals with Marfan syndrome. Results: In Loeys-Dietz compared to Marfan syndrome, a patent ductus arteriosus (p = 0.014) was more prevalent, the craniofacial score was higher (p < 0.001), the systemic score lower (p < 0.001), and mitral valve prolapse less frequent (p = 0.003). Mean survival for Loeys-Dietz and Marfan syndrome was similar (75 ± 3 versus 73 ± 2 years; p = 0.811). Cardiovascular outcome was comparable between Loeys-Dietz and Marfan syndrome, including mean freedom from proximal aortic surgery (53 ± 4 versus 48 ± 3 years; p = 0.589), distal aortic repair (72 ± 3 versus 67 ± 2 years; p = 0.777), mitral valve surgery (75 ± 4 versus 65 ± 3 years; p = 0.108), and reintervention (20 ± 3 versus 14 ± 2 years; p = 0.112). In Loeys-Dietz syndrome, lower age at initial presentation predicted proximal aortic surgery (HR = 0.748; p < 0.001), where receiver operating characteristic analysis identified ≤33.5 years with increased risk. In addition, increased aortic sinus diameters (HR = 6.502; p = 0.001), and higher systemic score points at least marginally (HR = 1.175; p = 0.065) related to proximal aortic surgery in Loeys-Dietz syndrome. Conclusions: Cardiovascular outcome of Loeys-Dietz syndrome was comparable to Marfan syndrome, but the severity of systemic manifestations was a predictor of proximal aortic surgery.

Clinical features and complications of Loeys-Dietz syndrome: A systematic review

“…Amongst individual case reports, the most frequently reported physical characteristics include: aortic aneurysms, abnormal uvula, arterial tortuosity, pectus deformity and arachnodactyly (Table 2). In cohort studies of patients with LDS type 1 (1,2,(12)(13)(14)(15), ranging from 12 to 176 individuals (Supplementary Table 3), the most frequently reported characteristics include: joint laxity (68%), arachnodactyly (62%), pectus deformity (51%), aneurysms of vessels other than the aorta (50%), arterial tortuosity (50%) and retrognathia (50%; Table 3). The presence of aortic aneurysms varied significantly between studies ranging from 17 to 100% and aortic dissections ranged from 17 to 25%.…”

“…The most frequently reported physical characteristics include: aortic aneurysms, hypertelorism, abnormal uvula, joint laxity, pectus deformity, scoliosis, arterial tortuosity, arachnodactyly (Table 2). In cohort studies of patients with LDS type 2 (1,2,12,(14)(15)(16), ranging from 12 to 265 patients (Supplementary Table 4), the most frequently reported features include: velvety skin (82%), malar hypoplasia (75%), easy bruising (67%), aneurysms of vessels other than the aorta (59%), arterial tortuosity (49%), high arched palate (48%) and pectus deformity (47%; Table 3). The prevalence of aortic aneurysm ranged from 23 to 75% as did a history of aortic dissection 16-35%.…”

Genotype–Phenotype Correlation in Children: The Impact of FBN1 Variants on Pediatric Marfan Care

“…High-throughput NGS data were generated on an Illumina sequencing platform. ROI sequences were aligned to the human reference genome (hg19) and visualized and evaluated by using the Sequence Pilot module SeqNext (JSI Medical Systems) [14,15].…”

Clinically relevant variants in a large cohort of Indian patients with Marfan syndrome and related disorders identified by next-generation sequencing

“…Typical cardiovascular features in LDS are dilatation of the aortic root at the level of the sinus of Valsalva, aneurysms affecting thoracic and abdominal aorta and arterial branches, as well as arterial tortuosity 1 , 5 . Cardiovascular manifestations tend to be more severe in LDS than in MFS 6 , however, a multi-center study has recently demonstrated a comparable cardiovascular outcome in individuals with MFS and LDS 7 . Heterozygous pathogenic variants in six genes cause LDS type 1–6: TGFBR1 , TGFBR2 , SMAD3 , TGFB2 , TGFB3 , and SMAD2 8 – 13 .…”