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Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections.

Bertoli-Avella AM, Gillis E, Morisaki H, Verhagen JM, de Graaf BM, van de Beek G, Gallo E, Kruithof BP, Venselaar H, Myers LA, Laga S, Doyle AJ, Oswald G, van Cappellen GW, Yamanaka I, van der Helm RM, Beverloo B, de Klein A, Pardo L, Lammens M, Evers C, Devriendt K, Dumoulein M, Timmermans J, Bruggenwirth HT, Verheijen F, Rodrigus I, Baynam G, Kempers M, Saenen J, Van Craenenbroeck EM, Minatoya K, Matsukawa R, Tsukube T, Kubo N, Hofstra R, Goumans MJ, Bekkers JA, Roos-Hesselink JW, van de Laar IM, Dietz HC, Van Laer L, Morisaki T, Wessels MW, Loeys BL - J. Am. Coll. Cardiol. (2015)

Bottom Line: Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture.In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-β signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-β signaling in association with up-regulation of the expression of TGF-β ligands.Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium; Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: a.bertoliavella@erasmusmc.nl.

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Phenotypic Characteristics of Patients With a TGFB3 MutationObserved clinical features include: long face (1-III:11, 5-II:1, 7-II:1, 8-II:1); pectus carinatum (1-IV:2); hypertelorism (2-III:7, 2-IV:2, 2-IV:3, 7-II:1, 8-II:1); bifid uvula (2-III:7, 2-IV:3, 7-II:1); joint hypermobility (2-IV:2); arachnodactyly (5-II:1); and metatarsus adductus (8-III:1). All affected individuals or parents gave permission to publish these photographs.
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fig3: Phenotypic Characteristics of Patients With a TGFB3 MutationObserved clinical features include: long face (1-III:11, 5-II:1, 7-II:1, 8-II:1); pectus carinatum (1-IV:2); hypertelorism (2-III:7, 2-IV:2, 2-IV:3, 7-II:1, 8-II:1); bifid uvula (2-III:7, 2-IV:3, 7-II:1); joint hypermobility (2-IV:2); arachnodactyly (5-II:1); and metatarsus adductus (8-III:1). All affected individuals or parents gave permission to publish these photographs.

Mentions: We studied a large Dutch family (family 1) with clinical features overlapping with MFS and LDS consistent with an autosomal dominant inheritance pattern. Seven family members, between 40 and 68 years of age, presented with aneurysms and dissections, mainly involving the descending thoracic and abdominal aorta (Figure 1, Online Table 2). Three patients died from aortic dissection and rupture of the descending thoracic or abdominal aorta (1-II:4, II:5, and II:7) (Figure 1), confirmed by autopsy in 2 cases (1-II:4, age 57 years and II:5, 56 years). In addition, 4 members had mitral valve abnormalities, ranging from mild prolapse to severe regurgitation requiring surgical intervention. Craniofacial abnormalities were rather subtle, including a long face, high-arched palate, and retrognathia (Figure 2). Pectus deformity and scoliosis were frequently observed (Figure 2). Other recurrent findings included velvety skin, varices, and hiatal hernia. Several family members presented with autoimmune features including (HLA-B27 positive) spondyloarthritis, Graves' disease, and celiac disease.


Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections.

Bertoli-Avella AM, Gillis E, Morisaki H, Verhagen JM, de Graaf BM, van de Beek G, Gallo E, Kruithof BP, Venselaar H, Myers LA, Laga S, Doyle AJ, Oswald G, van Cappellen GW, Yamanaka I, van der Helm RM, Beverloo B, de Klein A, Pardo L, Lammens M, Evers C, Devriendt K, Dumoulein M, Timmermans J, Bruggenwirth HT, Verheijen F, Rodrigus I, Baynam G, Kempers M, Saenen J, Van Craenenbroeck EM, Minatoya K, Matsukawa R, Tsukube T, Kubo N, Hofstra R, Goumans MJ, Bekkers JA, Roos-Hesselink JW, van de Laar IM, Dietz HC, Van Laer L, Morisaki T, Wessels MW, Loeys BL - J. Am. Coll. Cardiol. (2015)

Phenotypic Characteristics of Patients With a TGFB3 MutationObserved clinical features include: long face (1-III:11, 5-II:1, 7-II:1, 8-II:1); pectus carinatum (1-IV:2); hypertelorism (2-III:7, 2-IV:2, 2-IV:3, 7-II:1, 8-II:1); bifid uvula (2-III:7, 2-IV:3, 7-II:1); joint hypermobility (2-IV:2); arachnodactyly (5-II:1); and metatarsus adductus (8-III:1). All affected individuals or parents gave permission to publish these photographs.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4380321&req=5

fig3: Phenotypic Characteristics of Patients With a TGFB3 MutationObserved clinical features include: long face (1-III:11, 5-II:1, 7-II:1, 8-II:1); pectus carinatum (1-IV:2); hypertelorism (2-III:7, 2-IV:2, 2-IV:3, 7-II:1, 8-II:1); bifid uvula (2-III:7, 2-IV:3, 7-II:1); joint hypermobility (2-IV:2); arachnodactyly (5-II:1); and metatarsus adductus (8-III:1). All affected individuals or parents gave permission to publish these photographs.
Mentions: We studied a large Dutch family (family 1) with clinical features overlapping with MFS and LDS consistent with an autosomal dominant inheritance pattern. Seven family members, between 40 and 68 years of age, presented with aneurysms and dissections, mainly involving the descending thoracic and abdominal aorta (Figure 1, Online Table 2). Three patients died from aortic dissection and rupture of the descending thoracic or abdominal aorta (1-II:4, II:5, and II:7) (Figure 1), confirmed by autopsy in 2 cases (1-II:4, age 57 years and II:5, 56 years). In addition, 4 members had mitral valve abnormalities, ranging from mild prolapse to severe regurgitation requiring surgical intervention. Craniofacial abnormalities were rather subtle, including a long face, high-arched palate, and retrognathia (Figure 2). Pectus deformity and scoliosis were frequently observed (Figure 2). Other recurrent findings included velvety skin, varices, and hiatal hernia. Several family members presented with autoimmune features including (HLA-B27 positive) spondyloarthritis, Graves' disease, and celiac disease.

Bottom Line: Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture.In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-β signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-β signaling in association with up-regulation of the expression of TGF-β ligands.Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium; Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: a.bertoliavella@erasmusmc.nl.

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Related in: MedlinePlus