Loeys et al. (2005) described 10 families with an aortic aneurysm syndrome characterized by hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity with ascending aortic aneurysm and dissection. Other findings included craniosynostosis, structural brain abnormalities, mental ... Loeys et al. (2005) described 10 families with an aortic aneurysm syndrome characterized by hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity with ascending aortic aneurysm and dissection. Other findings included craniosynostosis, structural brain abnormalities, mental retardation, congenital heart disease, and aneurysms with dissection throughout the arterial tree. The syndrome showed variable clinical expression. Loeys et al. (2006) assigned patients with 'typical' craniofacial manifestations of LDS, including those from the 10 families described in the report of Loeys et al. (2005), to the type 1 category. Watanabe et al. (2008) evaluated the parents of a patient with LDS1B associated with a heterozygous mutation in the TGFBR2 gene. Analysis of the paternal DNA indicated that the father was somatic mosaic for the mutation, with the mutation detected in 52%, 25%, 0%, and 35% of leukocytes, buccal cells, hair root cells, and nails, respectively. Clinical examination of the father did not reveal any features of LDS1B, including bifid uvula, narrow palate, micrognathia, marfanoid habitus, or arachnodactyly, and echocardiography in the father was normal. The information was useful for genetic counseling in this family. Kirmani et al. (2010) reported 2 male patients with Loeys-Dietz syndrome, age 17 years and 26 years, respectively, who had a significant history of low bone mineral density and multiple low-impact fractures. Kirmani et al. (2010) noted that 4 of 40 patients reported by Loeys et al. (2006) had 'osteoporosis with multiple fractures at a young age,' and suggested that skeletal fragility and increased fracture risk might be features of LDS.
Attias et al. (2009) compared clinical features and outcomes of 71 patients with TGFBR2 mutations to those of 243 patients with FBN1 mutations. Aortic dilation was present in a similar proportion of patients in both the TGFBR2 and ... Attias et al. (2009) compared clinical features and outcomes of 71 patients with TGFBR2 mutations to those of 243 patients with FBN1 mutations. Aortic dilation was present in a similar proportion of patients in both the TGFBR2 and FBN1 groups (78% and 79%, respectively) but was highly variable; the incidence and average age for thoracic aortic surgery and aortic dissection were also similar in the 2 groups. Mitral valve involvement was less frequent in the TGFBR2 than in the FBN1 group (p less than 0.05 for myxomatous valve, prolapse, or mitral regurgitation). Aortic dilation, dissection, or sudden death was the index event leading to genetic diagnosis in 65% of families with TGFBR2 mutations, versus 32% with FBN1 mutations (p = 0.002). The rate of death was greater in TGFBR2 families before diagnosis, but similar once the disease was recognized. Most pregnancies were uneventful in both groups. Seven (10%) of the 71 patients with TGFBR2 mutations fulfilled the Ghent criteria for Marfan syndrome, including 2 with ectopia lentis, compared with 140 (58%) of 243 patients in the FBN1 group (p less than 0.0001); 3 patients in the TGFBR2 group fulfilled the diagnostic criteria for both Loeys-Dietz and Marfan syndromes. Noting that clinical outcomes were similar between treated patients from both groups, Attias et al. (2009) concluded that prognosis depends on clinical disease expression and treatment rather than simply the presence of a TGFBR2 mutation.
Loeys et al. (2005) considered TGFBR2 as a candidate gene for LDS because TGF-beta signaling has a prominent role in vascular and craniofacial development in mouse models (Azhar et al., 2003, Sanford et al., 1997) and because conditional ... Loeys et al. (2005) considered TGFBR2 as a candidate gene for LDS because TGF-beta signaling has a prominent role in vascular and craniofacial development in mouse models (Azhar et al., 2003, Sanford et al., 1997) and because conditional knockout of TGFBR2 in neural crest cells caused cleft palate and calvaria defects (Ito et al., 2003). Loeys et al. (2005) sequenced all exons of the TGFBR2 gene and identified heterozygous mutations (190182.0008-190182.0013) in 6 of 10 families with LDS. Of these 10 patients, 8 showed hypertelorism, 2 cleft palate, and 2 craniosynostosis. No mutations in TGFBR2 were found in the 4 other families with a clinically indistinguishable phenotype. Therefore, Loeys et al. (2005) sequenced all exons of the TGFBR1 gene (190181) and found a unique missense mutation in each family. Loeys et al. (2006) identified a total of 52 families with LDS, including the 10 described by Loeys et al. (2005). Loeys et al. (2006) found mutations in TGFBR2 in 27 probands with LDS type 1. The other 13 probands with LDS1 had mutations in TGFBR1 (190181). Overall, they found 29 mutations in TGFBR2 and 13 in TGFBR1. Of the 30 new probands whose phenotype was consistent with LDS type 1, 21 had mutations in TGFBR2. In a Japanese boy with clinical findings reported as Shprintzen-Goldberg syndrome (SGS; 182212), Kosaki et al. (2006) identified heterozygosity for a splice site mutation in the TGFBR2 gene (190182.0016). Because the patient had a bifid uvula and sigmoid configuration of the brachycephalic left common carotid and left subclavian arteries, Robinson et al. (2006) suggested that the diagnosis of Loeys-Dietz syndrome would also be appropriate for this patient. In 2 male patients with LDS who had a significant history of low bone mineral density and multiple low-impact fractures, Kirmani et al. (2010) identified 2 different heterozygous mutations in the TGFBR2 gene, respectively (see, e.g., 190182.0005).