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Transforming Growth Factor-Beta Receptor Type II Mutation in a Patient With Bicuspid Aortic Valve Disease and Intraoperative Aortic Dissection

2011; Elsevier BV; Volume: 91; Issue: 5 Linguagem: Inglês

10.1016/j.athoracsur.2010.12.060

1552-6259

Evaldas Girdauskas, Solveig Schulz, Michael A. Borger, Marco Mierzwa, Thomas Kuntze,

Cardiac Valve Diseases and Treatments

We report on a patient with familial bicuspid aortic valve disease operated on for proximal aortic aneurysm. The surgery was complicated by intraoperative aortic dissection. Multi-generational genetic analysis demonstrated a mutation in the transforming growth factor-beta receptor type II gene. This case confirms the clinical hypothesis that the proximal aortic disease has a genetic origin in some bicuspid aortic valve patients. We report on a patient with familial bicuspid aortic valve disease operated on for proximal aortic aneurysm. The surgery was complicated by intraoperative aortic dissection. Multi-generational genetic analysis demonstrated a mutation in the transforming growth factor-beta receptor type II gene. This case confirms the clinical hypothesis that the proximal aortic disease has a genetic origin in some bicuspid aortic valve patients. The bicuspid aortic valve (BAV) is the most common congenital abnormality of the human heart, affecting approximately 1% to 2% of the general population [1Williams D.S. Bicuspid aortic valve.J Insure Med. 2006; 38: 72-74PubMed Google Scholar]. Although there is adequate evidence that BAV is a heritable disorder (ie, autosomal dominant disease with incomplete penetrance) [2Garg V. Muth A.N. Ransom J.F. et al.Mutations in NOTCH1 cause aortic valve disease.Nature. 2005; 437: 270-274Crossref PubMed Scopus (1140) Google Scholar], there is also controversy regarding the pathogenesis of dilatation of the proximal aorta. A 48-year-old woman was referred for elective surgery of a proximal aortic aneurysm measuring 55 mm in diameter. Screening echocardiography performed by the referring cardiologist demonstrated a BAV with mild to moderate aortic valve insufficiency and dilatation of the aortic root and the ascending aorta. The echocardiographic investigation was performed as a consequence of the recent sudden cardiac death of the patient's brother at the age of 42 years, immediately after the onset of excruciating chest pain. Moreover, the patient's father had a history of elective surgical replacement of the aortic valve and supracoronary ascending aorta for BAV stenosis and ascending aortic aneurysm at the age of 72 years. Our patient was completely asymptomatic and her prior cardiovascular history was unremarkable. A detailed physical examination revealed no clinical features of marfanoid disease. In addition, there were no craniofacial deformations or signs of mental retardation that could be predictive of Loeys-Dietz syndrome. Preoperative magnetic resonance imaging demonstrated an aortic aneurysm with a maximal diameter of 56 mm, extending from the aortic annulus to the level of the brachiocephalic trunk, without any evidence of dissection (Fig 1). A multi-slice computed tomographic scan was performed to rule out coronary artery disease. Elective surgery was scheduled using a standard median sternotomy approach. Due to the extension of aneurysmal disease into the proximal aortic arch, cardiopulmonary bypass was instituted using right axillary perfusion and right atrial venous drainage. The distal ascending aorta was cross clamped, and crystalloid cardioplegia was administered through a needle-vent catheter placed in the mid-ascending aorta. After opening the ascending aneurysm, an acute aortic dissection was found, extending from the sinotubular junction to the level of aortic cross clamp. There was no pressure elevation on the arterial perfusion line and the transesophageal echocardiogram showed no dissection in the aortic arch or descending aorta. Core cooling was extended down to the rectal temperature of 23°C using a maximal cardiopulmonary bypass temperature gradient of 6°C. Evaluation of the aortic valve confirmed BAV disease with moderate calcific degeneration of both cusps and a concomitant aortic root aneurysm. Composite aortic root replacement (ie, modified Bentall procedure) using a 25-mm mechanical prosthesis was performed. After reaching a core temperature of 23°C, the systemic circulation was reduced to 10 mL/kg/min and unilateral antegrade cerebral perfusion was implemented. Then the aortic cross clamp was removed, and the aortic arch was carefully evaluated. The dissection process was found to cease at the level of brachiocephalic trunk, with no further extension into the aortic arch. The orifices of supra-aortic vessels were completely intact. Proximal hemi-arch replacement with an open technique was accomplished and re-warming was initiated afterward. The remainder of the procedure was uneventful. The patient was successfully weaned from cardiopulmonary bypass without the need for inotropic support. The patient awoke the day of surgery without any neurologic deficit, and she was extubated and discharged from the intensive care unit. The entire postoperative course was uneventful. Histologic examination of the ascending aorta demonstrated a typical pattern of cystic medial necrosis, which involved the entire circumference of the ascending aorta in a symmetrical pattern. Multi-generational genetic analysis of the family was performed and identified a heterozygous mutation in the transforming growth factor-beta receptor type II gene (TGFBR2) in our patient and her father. The TGFBR2 missense mutation included a sequence alteration in exon 4 (ie, c.1159G > A), which resulted in an amino acid change (ie, p.V387M) and in decreased stability of the mutant TGFBR2 protein [3Matyas G. Arnold E. Carrel T. et al.Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders.Hum Mutat. 2006; 27: 760-769Crossref PubMed Scopus (96) Google Scholar]. Moreover, the family tested negative for mutations in the gene encoding fibrillin-1 (ie, Marfan syndrome). Whether dilatation of the proximal aorta in patients with BAV disease is secondary to hemodynamic effects related to the abnormal aortic valve or a primary manifestation of the genetic disorder remains controversial. It is widely accepted that BAV is a very heterogeneous disease and that the different phenotypes of BAV-associated aortopathy may be caused by unique pathogenetic mechanisms [4Cotrufo M. Della Corte A. The association of bicuspid aortic valve disease with asymmetric dilatation of the tubular ascending aorta: identification of a definite syndrome.J Cardiovasc Med (Hagerstown). 2009; 10: 291-297Crossref PubMed Scopus (55) Google Scholar]. There is a subgroup of young male BAV patients who present with predominant dilatation of the aortic root, which occurs independent of age, body size, and valve function [5Nistri S. Sorbo M.D. Marin M. Scognamiglio R. Thiene G. Aortic root dilatation in young men with normally functioning bicuspid aortic valves.Heart. 1999; 82: 19-22PubMed Google Scholar]. There is some evidence that this "root dilatation phenotype" may illustrate the predominantly genetic form of BAV disease, which is less influenced by hemodynamic factors [6Loscalzo M.L. Goh D.L. Loeys B. Kent K.C. Spevak P.J. Dietz H.C. Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance.Am J Med Genet. 2007; 143: 1960-1967Crossref Scopus (167) Google Scholar]. However, thus far, no genetic defect responsible for the BAV-associated aortopathy has been identified. Mutations in the TGFBR1 and TGFBR2 genes have been recently demonstrated to result in a wide spectrum of Marfan syndrome-related genetic disorders (eg, Loeys-Dietz syndrome, familial thoracic aortic aneurysms, and dissections) [7Loeys B.L. Schwarze U. Holm T. et al.Aneurysm syndromes caused by mutations in the TGF-beta receptor.N Engl J Med. 2006; 355: 788-798Crossref PubMed Scopus (1287) Google Scholar]. However, thus far, mutations in the TGFBR1 and TGFBR2 genes have not been described in patients with the familial and sporadic BAV disease [6Loscalzo M.L. Goh D.L. Loeys B. Kent K.C. Spevak P.J. Dietz H.C. Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance.Am J Med Genet. 2007; 143: 1960-1967Crossref Scopus (167) Google Scholar, 8Arrington C.B. Sower T. Chuckwuk N. et al.Absence of TGFBR1 and TGFBR2 mutations in patients with bicuspid aortic valve and aortic dilation.Am J Cardiol. 2008; 102: 629-631Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. We believe that this is the first clinical report of the mutation in the TGFBR2 gene in a family with the BAV-associated aortopathy. The BAV has been previously described as an associated feature of Loeys-Dietz syndrome [7Loeys B.L. Schwarze U. Holm T. et al.Aneurysm syndromes caused by mutations in the TGF-beta receptor.N Engl J Med. 2006; 355: 788-798Crossref PubMed Scopus (1287) Google Scholar]. However, no clinical signs of this syndrome were found in the affected family in our case. Our described missense mutation in the TGFBR2 gene (ie, c.1159G > A) was first identified by Lücke and coauthors [9Lücke C.D. Philpott A. Metcalfe J.C. et al.Inhibiting mutations in the transforming growth factor beta type 2 receptor in recurrent human breast cancer.Can Res. 2001; 61: 482-485PubMed Google Scholar] in recurrent human breast cancer. Matyas and coauthors [3Matyas G. Arnold E. Carrel T. et al.Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders.Hum Mutat. 2006; 27: 760-769Crossref PubMed Scopus (96) Google Scholar] found the same mutation in patients with Marfan syndrome-like phenotypes who tested negative for mutations in the fibrillin-1 gene. Moreover, these authors clearly demonstrate that this mutation results in destabilization of the protein structure and has a pathogenic effect on TGFBR2 function. Some specific features were indicative of a genetic origin of the BAV-associated aortopathy in our patient. The indices of a Marfan syndrome-like connective tissue disorder were as follows: the strong family history of BAV disease with the involvement of the proximal aorta, the root dilatation phenotype of aortopathy with the marked fragility of the aortic wall (which led to the intraoperative aortic dissection), and the histologic pattern of symmetrical cystic medial necrosis. Our clinical suspicion was confirmed by identifying the TGFBR2 gene mutation in the affected family. In summary, this case report confirms the clinical hypothesis that proximal aortic disease has a genetic origin in some BAV patients. As there are no genetic studies, and detailed surgical reports have focused on the root dilatation phenotype of BAV disease, the true incidence of TGFBR mutations in BAV disease is not known.