Boileau et al. (1990) described a large French family in which multiple members in an autosomal dominant pedigree pattern exhibited some of the skeletal and cardiovascular features of the Marfan syndrome (154700) but lacked ocular abnormalities. Boileau et ... Boileau et al. (1990) described a large French family in which multiple members in an autosomal dominant pedigree pattern exhibited some of the skeletal and cardiovascular features of the Marfan syndrome (154700) but lacked ocular abnormalities. Boileau et al. (1993) considered that the patients fulfilled criteria for the MASS (mitral valve, aortic, skeleton, and skin) phenotype (see 157700), but might represent a distinct clinical entity. The proband was a man who died at age 39 years from aortic dissection. Necropsy showed dilatation of the ascending aorta at the level of the sinuses of Valsalva. Other members demonstrated aortic dilatation on echocardiograms as well as mitral valve prolapse. The father of one of these patients died suddenly at the age of 35 years. Another member of the family died suddenly of aortic dissection at age 29 years. One girl died at the age of 9 years after complaining of chest pain. Dietz et al. (1995) felt that the clinical presentation of the family described by Boileau et al. (1993) failed to meet the diagnostic criteria for Marfan syndrome and that the assignment of 'affected' status was sometimes arbitrary. The salient phenotype in the French family was that of ascending aortic dissection affecting individuals in their mid-thirties. Most of these individuals were deceased and no tissue was available for study. Only 1 person with a dissection contributed a sample, but no further phenotypic description was provided. No individual in this pedigree had documented involvement of the skin, eye, lung, or dura; only the skeletal and cardiovascular systems were involved. Boileau et al. (1995) defended their case-by-case phenotype determination on the basis of reexamination and clinical developments. See also comment of Gilchrist (1994). Hasham et al. (2003) described a 4-generation family of Swiss-German heritage in which multiple members had thoracic aortic aneurysms and dissection but no ocular or skeletal features of Marfan syndrome. Pannu et al. (2005) described 4 unrelated families with thoracic aortic aneurysms leading to type A dissections who also had descending aortic disease and aneurysms of other arteries. One of these families was the one reported by Hasham et al. (2003). Disabella et al. (2006) reported 3 probands with a phenotype comprising cardioskeletal anomalies but without major ocular signs described as 'Marfan syndrome type II.' One proband was a 27-year-old man with aortic dilation, mitral valve prolapse, severe pectus excavatum, pes planus, arachnodactyly, scoliosis, and left lumbar gibbus. The ocular and nervous systems did not show major signs, although he had mild myopia. His affected father had died at age 40 from aortic dissection. The second proband was a 24-year-old woman with aortic root dilation, mitral valve prolapse, scoliosis, spondylolisthesis, arachnodactyly, pectus excavatum, pes cavus, joint hypermobility, and high-arched palate with crowded teeth. Her ocular system was not involved. Family history revealed that her father and a paternal aunt both died from aortic root dissection at age 37 and 45, respectively. The aunt reportedly had ocular involvement. The third proband was a 4-year-old girl with aortic root dilation, aortic valve incompetence, pulmonary dilation, and mitral valve prolapse immediately after birth. The skeletal habitus was suggestive of Marfan syndrome. The ocular system was not involved. Loeys et al. (2006) commented that 'prior studies have suggested that some TGFBR2 mutations are present in families whose members have classic Marfan's syndrome ... or familial thoracic aortic aneurysm and dissection. Many of these families had findings that were atypical for these diagnoses, including cervical-spine instability, dysmorphic facies, patent ductus arteriosus, and cardiac septal defects in patients designated as having Marfan's syndrome, and clinically significant skeletal abnormalities and aneurysms with primary dissections distant from the thoracic aorta in those designated as having familial thoracic aortic aneurysm and dissection. All these features have been associated with the Loeys-Dietz syndrome phenotype. In our experience, all patients with TGFBR mutations have had clinical features that can be used to discriminate the Loeys-Dietz syndrome from Marfan's syndrome or from familial thoracic aortic aneurysm and dissection. Some features of both types are subtle and may have been overlooked (e.g., bifid uvula and skin findings) or missed in the absence of specialized imaging (e.g., arterial tortuosity) on examination of the families described as having Marfan's syndrome or familial thoracic aortic aneurysm and dissection. A reevaluation of these families might shed light on this important issue.' 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) compared the clinical features of 30 affected individuals from 4 TAAD families with TGFBR1 mutations to those of 77 patients from 4 families previously reported with mutations in the TGFBR2 gene (Pannu et al., ... Tran-Fadulu et al. (2009) compared the clinical features of 30 affected individuals from 4 TAAD 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); the difference was not statistically significant in the TGFBR2 cohort (42 vs 50 years). 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). 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.
Identification of a 3p24.1 chromosomal breakpoint disrupting the gene encoding TGF-beta receptor-2 (TGFBR2; 190182) in a Japanese individual with a diagnosis of Marfan syndrome led Mizuguchi et al. (2004) to consider TGFBR2 as the gene underlying the phenotype ... Identification of a 3p24.1 chromosomal breakpoint disrupting the gene encoding TGF-beta receptor-2 (TGFBR2; 190182) in a Japanese individual with a diagnosis of Marfan syndrome led Mizuguchi et al. (2004) to consider TGFBR2 as the gene underlying the phenotype in the French family reported by Boileau et al. (1993). In affected members of this family, Mizuguchi et al. (2004) identified a 1524G-A mutation in TGFBR2 causing a synonymous amino acid substitution (Q508Q; 190182.0004) resulting in abnormal splicing. In 4 unrelated probands, Mizuguchi et al. (2004) identified 3 other missense mutations in TGFBR2 that led to loss of function of TGF-beta signaling activity on extracellular matrix formation. These results showed that heterozygous mutations in TGFBR2, a putative tumor-suppressive gene implicated in several malignancies, are also associated with inherited connective tissue disorders. Pannu et al. (2005) sequenced 8 coding exons of the TGFBR2 gene using genomic DNA from 80 unrelated familial cases with TAAD. They found 2 TGFBR2 missense mutations (190182.0014, 190182.0015) in 4 unrelated families. Affected family members also had descending aortic disease and aneurysms of other arteries. Strikingly, both mutations affected an arginine residue at position 460 in the intracellular domain, suggesting a mutation 'hotspot.' Assessment of linked polymorphisms suggested that these families were not distantly related. Structural analysis of the TGFBR2 serine/threonine kinase domain revealed that R460 is strategically located within a highly conserved region of this domain and that the amino acid substitutions resulting from these mutations will interfere with the receptor's ability to transduce signals. They estimated that germline TGFBR2 mutations are responsible for the inherited predisposition to familial TAAD in 5% of cases. The 3 probands reported by Disabella et al. (2006) carried 3 distinct heterozygous missense mutations in the TGFBR2 gene. All 3 mutations, in exon 5, affected evolutionarily conserved residues of the serine/threonine kinase domain (e.g., 190182.0015). One of the mutations occurred at residue R460.