Nicod et al. (1989) described a family in which 9 members over 2 generations had aortic dissecting aneurysm or aortic or arterial dilatation at a young age. Three died of ruptured aortic dissecting aneurysms at ages 14, 18, ... Nicod et al. (1989) described a family in which 9 members over 2 generations had aortic dissecting aneurysm or aortic or arterial dilatation at a young age. Three died of ruptured aortic dissecting aneurysms at ages 14, 18, and 24 years, respectively. A fourth member of the family died suddenly at age 48 years, a few years after aortic repair for aneurysmal dilatation. One member underwent surgical repair of an ascending aortic dissecting aneurysm at age 18 years and was still living at the time of report. Histologic examination of the aortic wall in 3 patients showed a loss of elastic fibers, deposition of mucopolysaccharide-like material in the media, and cystic medial changes--the typical findings of Erdheim cystic medial necrosis. Collagen of types I (see 120150) and III (see 120180) from cultured fibroblasts appeared to be normal on gel electrophoresis. In view of the phenotypic overlap between the Loeys-Dietz syndrome (LDS) and vascular Ehlers-Danlos syndrome (EDS; 130050), Loeys et al. (2006) screened the TGFBR1 and TGFBR2 genes in 40 probands who had previously received a provisional diagnosis of vascular EDS by a medical geneticist, but in whom the diagnosis had been ruled out by studies of type III collagen (see 120180) biosynthesis. Twelve of these patients carried a heterozygous mutation in one of these genes and were assigned to the LDS type 2 category. Physical findings in these patients included prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, diffuse arterial aneurysms and dissections, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. None of these patients had cleft palate, hypertelorism, or craniosynostosis. Three patients had bifid uvula, and one had a family history of cleft palate. Mean age at the first major vascular event was 29.8 years, versus 24.5 years for LDS type 1 patients. The extent of vascular and skin involvement was similar in the patients with true vascular EDS and in those with LDS2; only joint laxity was significantly more prevalent in those with LDS2 (12 of 12 vs 18 of 28, P = 0.03). Loeys et al. (2006) pointed out that in both LDS and vascular EDS, dissection can occur without marked arterial dilatation. However, incidence of fatal complications during or immediately after vascular surgery is about 45% in vascular EDS but only 4.8% in LDS2, and only 1.7% in LDS overall. Thus, genotyping is beneficial in patients who present with features of vascular EDS. Matyas et al. (2006) screened a cohort of 70 individuals with phenotypes related to Marfan syndrome (154700) without mutations in the FBN1 gene (134797) for mutations in TGFBR1. In a 43-year-old patient with thoracic aortic aneurysm and dissection they found a heterozygous missense mutation (190181.0006). No abnormality of the skeletal system or eyes was described, and family history was negative. Drera et al. (2008) reported a 45-year-old Italian man with LDS2A confirmed by genetic analysis (190181.0008). He had a prominent and narrow nose, thin lips, bifid uvula and cleft palate, hypermobility of small joints, and soft skin. He also had a history of dissection of both internal iliac arteries and the right femoral artery. There was no aortic root dilatation or tortuosity of the great vessels. The phenotype was reminiscent of vascular EDS. Ades (2008) described the evolution of craniofacial features in 7 patients with LDS type 2 and proven mutations in the TGFBR1 or TGFBR2 genes. Most patients had dolichocephaly, a tall broad forehead, frontal bossing, high anterior hairline, hypoplastic supraorbital margins, a 'jowly' appearance in the first 3 years of life, translucent and redundant facial skin that was most pronounced in the periorbital area, prominent upper central incisors in late childhood/adulthood, and an open-mouthed myopathic face. The adult faces appeared prematurely aged. Although not exclusive to the LDS type 2 phenotype, Ades (2008) suggested that recognition of these facial features and their evolution might assist in the differentiation of some cases of LDS type 2 from related clinical entities.
Tran-Fadulu et al. (2009) analyzed the TGFBR1 gene in 150 unrelated families with thoracic aortic aneurysm (AAT) and identified heterozygous missense mutations in 4 families, including a 4-generation family originally described by Nicod et al. (1989) (190181.0007). Tran-Fadulu ... Tran-Fadulu et al. (2009) analyzed the TGFBR1 gene in 150 unrelated families with thoracic aortic aneurysm (AAT) and identified heterozygous missense mutations in 4 families, including a 4-generation family originally described by Nicod et al. (1989) (190181.0007). Tran-Fadulu et al. (2009) compared the clinical features of 30 affected individuals from these 4 families with TGFBR1 mutations to those of 77 patients from 4 families previously reported with mutations in the TGFBR2 gene (Pannu et al., 2005) and found that the average age of onset of vascular disease was significantly younger in the TGFBR1 cohort compared to the TGFBR2 cohort (31.4 vs 45.6 years; p = 0.002). In addition, men in TGFBR1 families presented with vascular disease at a statistically significant younger age compared with affected women (23 vs 39 years; p = 0.019). Thoracic aortic aneurysm was the predominant vascular presentation in both cohorts of patients, but the TGFBR1 patients were twice as likely to present with vascular disease elsewhere (23% vs 8%, respectively; p = 0.039), and vascular disease presentation differed based on gender in the TGFBR1 families: all men but 1 presented with AAT, whereas half of the affected women presented with disease in other vascular beds, including abdominal aortic aneurysms and carotid and coronary artery dissections (p = 0.038). In a combined analysis of the families, there was no difference in overall survival; however, survival was significantly worse in men than in women in TGFBR1 families (p = 0.017) but not in TGFBR2 families. The data also suggested that individuals with TGFBR2 mutations were more likely to dissect at aortic diameters less than 5.0 cm than individuals with TGFBR1 mutations: 3 TGFBR2 patients had dissections with aortic diameters under 5.0 cm, whereas there were no dissections under 5.0 cm in TGFBR1 patients, who often had dramatically enlarged aortic diameters at dissection (6.5 cm to 14.0 cm) or repair (8.5 cm). One TGFBR1 patient who refused repair had been stable for 3 years with an aortic diameter of 5.6 cm.
In 4 patients with LDS2, Loeys et al. (2006) detected heterozygosity for 4 different missense mutations in the TGFBR1 gene. Three of these involved the same codon and occurred at the same codon, arg487 at the C-terminal end ... In 4 patients with LDS2, Loeys et al. (2006) detected heterozygosity for 4 different missense mutations in the TGFBR1 gene. Three of these involved the same codon and occurred at the same codon, arg487 at the C-terminal end of the kinase domain (see 190181.0004). The fourth mutation occurred in exon 4 of the TGFBR1 gene at codon lys232 at the N-terminal end of the kinase domain.