RESEARCH LETTER
Arterial Tortuosity in Patients With Filamin A- Associated Vascular Aneurysms Eyal Reinstein,1* Shaine A. Morris,2 David L. Rimoin,3# Stephen P. Robertson,4 and Ronald V. Lacro5 1
Medical Genetics Institute, Rabin Medical Center, Petach-Tikva, Israel
2
Division of Pediatric Cardiology, Texas Children’s Hospital/Baylor College of Medicine, Houston, Texas Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
3 4
Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
5
Department of Cardiology, Children’s Hospital Boston, Boston, Massachusetts
Manuscript Received: 6 January 2014; Manuscript Accepted: 3 July 2014
TO THE EDITOR: Previous reports linked mutations in FLNA to a connective tissue disorder, termed as Ehlers-Danlos syndrome-periventricular heterotopia subtype (EDS-PH), characterized by joint, skin, and vascular abnormalities, primarily dilatation of the thoracic aorta [Sheen et al., 2005; Go´mez-Garre et al., 2006]. We recently reported on the molecular and clinical manifestations in a cohort of 11 patients with X-linked-PH and suggested that EDS-PH is not a separate syndrome from XL-PH, but rather part of the clinical spectrum associated with XL-PH [Reinstein et al., 2013]. Arterial tortuosity of the head and neck vessels, as measured by the Vertebral Artery Tortuosity Index (VTI), was recently demonstrated to be elevated in patients with Loeys-Dietz (LDS) and Marfan syndromes (MS), and correlated with adverse cardiovascular outcomes in those patients [Morris et al., 2011]. We aimed to evaluate the vascular tortuosity in a mother-daughter pair with vascular aneurysms due to a mutation in the FLNA gene. This family is part of the recently published cohort of patients with FLNA mutations [Reinstein et al., 2013]. The proband is a 38-year-old female diagnosed with a 48 mm thoracic aortic aneurysm that was expanded to 57 mm under treatment with a beta-receptor antagonist, necessitating a valve-sparing aortic root repair. A medical genetics consult was requested for evaluation of a possible Marfan syndrome. The patient reported a history of clumsiness, recurrent falls, and joint laxity during childhood, but no dislocations or fractures. She bruises normally and has normal scar formation. Physical examination revealed normal habitus with non-dysmorphic facial features. Oral exam revealed single uvula and normal palate. There was no pectus deformity and a well-healed sternal scar was noted. Joint hypermobility was noted with Beighton score of 6/ 9 while thumb and wrist signs were negative. The skin examination revealed no striae atrophica, normal scars, and soft non-hyperextensible skin. An ophthalmological exam confirmed myopia and excluded lens and retinal abnormalities. FBN1 gene sequencing yielded normal results. The identification of brain gray-matter heterotopias on MRI suggested a diagnosis of XL-PH and sequencing of the FLNA gene revealed an 8-bp deletion in exon 6, c.883_890 that constitutes a null FLNA allele. The patient’s 19-year-old
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Reinstein E, Morris SA, Rimoin DL, Robertson SP, Lacro RV. 2014. Arterial tortuosity in patients with Filamin A- associated vascular aneurysms. Am J Med Genet Part A 164A:2961–2963.
daughter is loose jointed, bruises easily, and has soft skin albeit with normal elasticity. She was found to carry the same FLNA mutation and imaging studies revealed a normal aorta but an aneurysm of the proximal right subclavian artery up to 2.4 cm (Fig. 1), and bilateral widespread neuronal heterotopia, similar to her mother. The subclavian aneurysm has slightly enlarged over last three years to 2.7cm, and surgery is pending. Calculation of arterial tortuosity following magnetic resonance angiography analysis was performed as previously described [Morris et al., 2011]. Briefly, the VTI is a result of the ratio between the actual length to the straight length of the vertebral artery. Actual length was measured by tracing the course of the vessel through 3D space from origin to end. Straight distance was calculated by measuring the linear distance from the origin to the end of the vessel. Distance factor was calculated by the formula: [actual distance/straight line distance1] x100. The VTI was compared to the previously reported cohort of patients with heritable disorders of connective tissue. The VTIs of the mother and daughter were 6 and 5, respectively (Fig. 2A and B compare to 2C – Conflict of interest: none. # Deceased. Correspondence to: Eyal Reinstein, M.D., PhD, Medical Genetics Institute, Rabin Medical Center, Petach-Tikva, Israel. E-mail: [email protected] or [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 14 August 2014 DOI 10.1002/ajmg.a.36717
2961
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FIG. 1. MRA of the neck in the daughter demonstrating an aneurysm of the right subclavian artery (arrow).
AMERICAN JOURNAL OF MEDICAL GENETICS PART A increased VTI in a patient with Loeys-Dietz syndrome due to mutation in the TGFBR2 gene). As per previous studies, the normal observed range was 0–10, it was concluded that the VTI was normal for both patients. We report here on normal VTI measurements but adverse cardiovascular outcome in a family with arterial aneurysms due to mutation in FLNA. During recent years, several syndromes, resulting from abnormalities in the transforming growth factor (TGFb) signaling pathway and involving the thoracic aorta have been identified [Loeys et al., 2005, 2006; Boileau et al., 2012; Doyle et al., 2012; van der Linde et al., 2013]. In some of the disorders, vascular dissection or rupture can occur in the absence of a preceding aneurysm. Thus, the decision about the timing of surgical intervention in these patients that traditionally was based on the diameter of the aortic root and rate of aortic enlargement has to be based now on additional parameters. These include the underlying genetic disorder (and sometimes the type of mutation such as in vascular-type EDS), family history of severe outcomes, and, the histo-pathological abnormalities of collagen and elastin fibers in the aortic wall. The degree of vascular tortuosity has recently been proposed as one of these parameters. Arterial tortuosity is described as a common and distinctive feature of LDS, yet reports on arterial tortuosity are usually based on qualitative observations. Investigation on the association between quantitative degree of tortuosity and cardiovascular outcomes in LDS and other heritable connective tissue disorders suggest that a high degree of tortuosity is a strong indicator of earlier surgery, dissection, and death [Loeys et al., 2005, 2006; Morris et al., 2011]. The spectrum of vascular abnormalities associated with FLNA mutations has recently been delineated in more details [Reinstein et al., 2013]. In addition to dilatation of the aorta, these patients can have diffused arterial disease involving peripheral vessels including the subclavian artery and the pulmonary arterial tree. While histopathology of the aorta in some patients with FLNA mutation shows areas of cystic medial degeneration, a rather nonspecific finding that can be seen in aortic specimens of patients
FIG. 2. Measurement of the actual and straight lengths of the vertebral arteries to calculate the VTI. (A) Mother with FLNA mutation; VTI ¼ 6 (B) Daughter with FLNA mutation; VTI ¼ 5 (C) Patient with Loeys-Dietz syndrome due to mutation in the TGFBR2 gene; VTI ¼ 36.
REINSTEIN ET AL. with MS and LDS, it is not clear yet whether increased incidence of rupture and dissection are common complication of XL-PH. Although the VTI may offer additional helpful surgical decision making and prognostic information in heritable disorders of connective tissue such as MS and LDS, our observation suggests that VTI may not be useful in patients with FLNA-associated vascular aneurysm to predict vascular fragility and need for surgery. Significant expansion of aortic aneurysm was seen in the mother despite normal VTI, culminating in an early aortic replacement surgery. In the daughter, a slight expansion in the size of the subclavian aneurysm has been observed and surgery is pending. Why is VTI normal in our patients? Normal tortuosity seems to be present in multiple other aneurysm disorders including some of the familial Thoracic Aortic Aneurysm and Dissection (TAAD) syndromes. It is known that arteries are able to adapt to diverse genetic defects and sustained alterations in mechanical loading. For example, induced mechanical stress on carotid arteries from a mouse model of MS causes reduced axial stretch relative to wild type controls. In addition, arterial caliber and wall thickness can be controlled by changes in blood flow and pressure. Thus, it is hypothesized that tortuosity represents accelerated/abnormal lengthening of vessels in a fixed space, and this lengthening may be a maladaptive “coping” mechanism to wall stress [Humphrey et al., 2009; Shamszad et al., 2013]. One possibility is that vessels with FLNA mutation “cope” in a different way, such as an increase in the arterial caliber. This is hypothesized to be the case in many forms of congenital heart disease, including tetralogy of Fallot, persistent truncus arteriosus, and transposition of the great arteries. In these disorders, significant aortic dilation is observed, however tortuosity is not usually present. Given this, dissection in these disorders is also extremely rare [Niwa, 2013]. There are several limitations to the current study. First, since previous reports included only small cohort of control individuals, it is unclear how much variance in vascular tortuosity is seen in the normal population. Second, since this study reports the VTI in only two patients, at this point we cannot generalize this observation to the general group of patients with FLNA mutations. Future studies will need to address whether there is a predisposition for aortic dissection and rupture in FLNA-related disorders and to provide the best evidence to guide vascular surveillance in these patients.
REFERENCES Boileau C, Guo DC, Hanna N, Regalado ES, Detaint D, Gong L, Varret M, Prakash SK, Li AH, d’Indy H, Braverman AC, Grandchamp B, Kwartler CS, Gouya L, Santos-Cortez RL, Abifadel M, Leal SM, Muti C, Shendure J, Gross MS, Rieder MJ, Vahanian A, Nickerson DA, Michel JB, National Heart, Lung, and Blood Institute (NHLBI) Go Exome Sequencing Project, Jondeau G, Milewicz DM. 2012. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet 44:916–921.
2963 Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, Schepers D, Gillis E, Mortier G, Homfray T, Sauls K, Norris RA, Huso ND, Leahy D, Mohr DW, Caulfield MJ, Scott AF, Destre´e A, Hennekam RC, Arn PH, Curry CJ, Van Laer L, McCallion AS, Loeys BL, Dietz HC. 2012. Mutations in the TGF-b repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet 44:1249–1254. Go´mez-Garre P1, Seijo M, Gutie´rrez-Delicado E, Castro del Rı´o M, de la Torre C, Go´mez-Abad C, Morales-Corraliza J, Puig M, Serratosa JM. 2006. Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation. J Med Genet 43:232– 237. Humphrey JD, Eberth JF, Dye WW, Gleason RL. 2009. Fundamental role of axial stress in compensatory adaptations by arteries. J Biomech 42:1–8. Loeys BL1, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. 2005. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37:275– 281. Loeys BL1, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA, Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, De Paepe AM, Dietz HC. 2006. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 355:788– 798. Morris SA, Orbach DB, Geva T, Singh MN, Gauvreau K, Lacro RV. 2011. Increased vertebral artery tortuosity index is associated with adverse outcomes in children and young adults with connective tissue disorders. Circulation 124:388–396. Niwa K. 2013. Aortopathy in congenital heart disease in adults: Aortic dilatation with decreased aortic elasticity that impacts negatively on left ventricular function. Korean Circ J 43:215–220. Reinstein E, Frentz S, Morgan T, Garcı´a-Min˜au´r S, Leventer RJ, McGillivray G, Pariani M, van der Steen A, Pope M, Holder-Espinasse M, Scott R, Thompson EM, Robertson T, Coppin B, Siegel R, Bret Zurita M, Rodrı´guez JI, Morales C, Rodrigues Y, Arcas J, Saggar A, Horton M, Zackai E, Graham JM, Rimoin DL, Robertson SP. 2013. Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A. Eur J Hum Genet 21:494–502. Shamszad P, Barnes JN, Morris SA. 2013. Aortic dissection in hospitalized children and young adults: A multi institutional study. Congenit Heart Dis 9:54–62. Sheen VL, Jansen A, Chen MH, Parrini E, Morgan T, Ravenscroft R, Ganesh V, Underwood T, Wiley J, Leventer R, Vaid RR, Ruiz DE, Hutchins GM, Menasha J, Willner J, Geng Y, Gripp KW, Nicholson L, Berry-Kravis E, Bodell A, Apse K, Hill RS, Dubeau F, Andermann F, Barkovich J, Andermann E, Shugart YY, Thomas P, Viri M, Veggiotti P, Robertson S, Guerrini R, Walsh CA. 2005. Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome. Neurology 64:254–262. van der Linde D1, Bekkers JA, Mattace-Raso FU, van de Laar IM, Moelker A, van den Bosch AE, van Dalen BM, Timmermans J, Bertoli-Avella AM, Wessels MW, Bogers AJ, Roos-Hesselink JW. 2013. Progression rate and early surgical experience in the new aggressive aneurysms-osteoarthritis syndrome. Ann Thorac Surg 95:563–569.
Arterial Tortuosity in Patients With Filamin A- Associated Vascular Aneurysms Eyal Reinstein,1* Shaine A. Morris,2 David L. Rimoin,3# Stephen P. Robertson,4 and Ronald V. Lacro5 1
Medical Genetics Institute, Rabin Medical Center, Petach-Tikva, Israel
2
Division of Pediatric Cardiology, Texas Children’s Hospital/Baylor College of Medicine, Houston, Texas Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
3 4
Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
5
Department of Cardiology, Children’s Hospital Boston, Boston, Massachusetts
Manuscript Received: 6 January 2014; Manuscript Accepted: 3 July 2014
TO THE EDITOR: Previous reports linked mutations in FLNA to a connective tissue disorder, termed as Ehlers-Danlos syndrome-periventricular heterotopia subtype (EDS-PH), characterized by joint, skin, and vascular abnormalities, primarily dilatation of the thoracic aorta [Sheen et al., 2005; Go´mez-Garre et al., 2006]. We recently reported on the molecular and clinical manifestations in a cohort of 11 patients with X-linked-PH and suggested that EDS-PH is not a separate syndrome from XL-PH, but rather part of the clinical spectrum associated with XL-PH [Reinstein et al., 2013]. Arterial tortuosity of the head and neck vessels, as measured by the Vertebral Artery Tortuosity Index (VTI), was recently demonstrated to be elevated in patients with Loeys-Dietz (LDS) and Marfan syndromes (MS), and correlated with adverse cardiovascular outcomes in those patients [Morris et al., 2011]. We aimed to evaluate the vascular tortuosity in a mother-daughter pair with vascular aneurysms due to a mutation in the FLNA gene. This family is part of the recently published cohort of patients with FLNA mutations [Reinstein et al., 2013]. The proband is a 38-year-old female diagnosed with a 48 mm thoracic aortic aneurysm that was expanded to 57 mm under treatment with a beta-receptor antagonist, necessitating a valve-sparing aortic root repair. A medical genetics consult was requested for evaluation of a possible Marfan syndrome. The patient reported a history of clumsiness, recurrent falls, and joint laxity during childhood, but no dislocations or fractures. She bruises normally and has normal scar formation. Physical examination revealed normal habitus with non-dysmorphic facial features. Oral exam revealed single uvula and normal palate. There was no pectus deformity and a well-healed sternal scar was noted. Joint hypermobility was noted with Beighton score of 6/ 9 while thumb and wrist signs were negative. The skin examination revealed no striae atrophica, normal scars, and soft non-hyperextensible skin. An ophthalmological exam confirmed myopia and excluded lens and retinal abnormalities. FBN1 gene sequencing yielded normal results. The identification of brain gray-matter heterotopias on MRI suggested a diagnosis of XL-PH and sequencing of the FLNA gene revealed an 8-bp deletion in exon 6, c.883_890 that constitutes a null FLNA allele. The patient’s 19-year-old
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Reinstein E, Morris SA, Rimoin DL, Robertson SP, Lacro RV. 2014. Arterial tortuosity in patients with Filamin A- associated vascular aneurysms. Am J Med Genet Part A 164A:2961–2963.
daughter is loose jointed, bruises easily, and has soft skin albeit with normal elasticity. She was found to carry the same FLNA mutation and imaging studies revealed a normal aorta but an aneurysm of the proximal right subclavian artery up to 2.4 cm (Fig. 1), and bilateral widespread neuronal heterotopia, similar to her mother. The subclavian aneurysm has slightly enlarged over last three years to 2.7cm, and surgery is pending. Calculation of arterial tortuosity following magnetic resonance angiography analysis was performed as previously described [Morris et al., 2011]. Briefly, the VTI is a result of the ratio between the actual length to the straight length of the vertebral artery. Actual length was measured by tracing the course of the vessel through 3D space from origin to end. Straight distance was calculated by measuring the linear distance from the origin to the end of the vessel. Distance factor was calculated by the formula: [actual distance/straight line distance1] x100. The VTI was compared to the previously reported cohort of patients with heritable disorders of connective tissue. The VTIs of the mother and daughter were 6 and 5, respectively (Fig. 2A and B compare to 2C – Conflict of interest: none. # Deceased. Correspondence to: Eyal Reinstein, M.D., PhD, Medical Genetics Institute, Rabin Medical Center, Petach-Tikva, Israel. E-mail: [email protected] or [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 14 August 2014 DOI 10.1002/ajmg.a.36717
2961
2962
FIG. 1. MRA of the neck in the daughter demonstrating an aneurysm of the right subclavian artery (arrow).
AMERICAN JOURNAL OF MEDICAL GENETICS PART A increased VTI in a patient with Loeys-Dietz syndrome due to mutation in the TGFBR2 gene). As per previous studies, the normal observed range was 0–10, it was concluded that the VTI was normal for both patients. We report here on normal VTI measurements but adverse cardiovascular outcome in a family with arterial aneurysms due to mutation in FLNA. During recent years, several syndromes, resulting from abnormalities in the transforming growth factor (TGFb) signaling pathway and involving the thoracic aorta have been identified [Loeys et al., 2005, 2006; Boileau et al., 2012; Doyle et al., 2012; van der Linde et al., 2013]. In some of the disorders, vascular dissection or rupture can occur in the absence of a preceding aneurysm. Thus, the decision about the timing of surgical intervention in these patients that traditionally was based on the diameter of the aortic root and rate of aortic enlargement has to be based now on additional parameters. These include the underlying genetic disorder (and sometimes the type of mutation such as in vascular-type EDS), family history of severe outcomes, and, the histo-pathological abnormalities of collagen and elastin fibers in the aortic wall. The degree of vascular tortuosity has recently been proposed as one of these parameters. Arterial tortuosity is described as a common and distinctive feature of LDS, yet reports on arterial tortuosity are usually based on qualitative observations. Investigation on the association between quantitative degree of tortuosity and cardiovascular outcomes in LDS and other heritable connective tissue disorders suggest that a high degree of tortuosity is a strong indicator of earlier surgery, dissection, and death [Loeys et al., 2005, 2006; Morris et al., 2011]. The spectrum of vascular abnormalities associated with FLNA mutations has recently been delineated in more details [Reinstein et al., 2013]. In addition to dilatation of the aorta, these patients can have diffused arterial disease involving peripheral vessels including the subclavian artery and the pulmonary arterial tree. While histopathology of the aorta in some patients with FLNA mutation shows areas of cystic medial degeneration, a rather nonspecific finding that can be seen in aortic specimens of patients
FIG. 2. Measurement of the actual and straight lengths of the vertebral arteries to calculate the VTI. (A) Mother with FLNA mutation; VTI ¼ 6 (B) Daughter with FLNA mutation; VTI ¼ 5 (C) Patient with Loeys-Dietz syndrome due to mutation in the TGFBR2 gene; VTI ¼ 36.
REINSTEIN ET AL. with MS and LDS, it is not clear yet whether increased incidence of rupture and dissection are common complication of XL-PH. Although the VTI may offer additional helpful surgical decision making and prognostic information in heritable disorders of connective tissue such as MS and LDS, our observation suggests that VTI may not be useful in patients with FLNA-associated vascular aneurysm to predict vascular fragility and need for surgery. Significant expansion of aortic aneurysm was seen in the mother despite normal VTI, culminating in an early aortic replacement surgery. In the daughter, a slight expansion in the size of the subclavian aneurysm has been observed and surgery is pending. Why is VTI normal in our patients? Normal tortuosity seems to be present in multiple other aneurysm disorders including some of the familial Thoracic Aortic Aneurysm and Dissection (TAAD) syndromes. It is known that arteries are able to adapt to diverse genetic defects and sustained alterations in mechanical loading. For example, induced mechanical stress on carotid arteries from a mouse model of MS causes reduced axial stretch relative to wild type controls. In addition, arterial caliber and wall thickness can be controlled by changes in blood flow and pressure. Thus, it is hypothesized that tortuosity represents accelerated/abnormal lengthening of vessels in a fixed space, and this lengthening may be a maladaptive “coping” mechanism to wall stress [Humphrey et al., 2009; Shamszad et al., 2013]. One possibility is that vessels with FLNA mutation “cope” in a different way, such as an increase in the arterial caliber. This is hypothesized to be the case in many forms of congenital heart disease, including tetralogy of Fallot, persistent truncus arteriosus, and transposition of the great arteries. In these disorders, significant aortic dilation is observed, however tortuosity is not usually present. Given this, dissection in these disorders is also extremely rare [Niwa, 2013]. There are several limitations to the current study. First, since previous reports included only small cohort of control individuals, it is unclear how much variance in vascular tortuosity is seen in the normal population. Second, since this study reports the VTI in only two patients, at this point we cannot generalize this observation to the general group of patients with FLNA mutations. Future studies will need to address whether there is a predisposition for aortic dissection and rupture in FLNA-related disorders and to provide the best evidence to guide vascular surveillance in these patients.
REFERENCES Boileau C, Guo DC, Hanna N, Regalado ES, Detaint D, Gong L, Varret M, Prakash SK, Li AH, d’Indy H, Braverman AC, Grandchamp B, Kwartler CS, Gouya L, Santos-Cortez RL, Abifadel M, Leal SM, Muti C, Shendure J, Gross MS, Rieder MJ, Vahanian A, Nickerson DA, Michel JB, National Heart, Lung, and Blood Institute (NHLBI) Go Exome Sequencing Project, Jondeau G, Milewicz DM. 2012. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet 44:916–921.
2963 Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, Schepers D, Gillis E, Mortier G, Homfray T, Sauls K, Norris RA, Huso ND, Leahy D, Mohr DW, Caulfield MJ, Scott AF, Destre´e A, Hennekam RC, Arn PH, Curry CJ, Van Laer L, McCallion AS, Loeys BL, Dietz HC. 2012. Mutations in the TGF-b repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet 44:1249–1254. Go´mez-Garre P1, Seijo M, Gutie´rrez-Delicado E, Castro del Rı´o M, de la Torre C, Go´mez-Abad C, Morales-Corraliza J, Puig M, Serratosa JM. 2006. Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation. J Med Genet 43:232– 237. Humphrey JD, Eberth JF, Dye WW, Gleason RL. 2009. Fundamental role of axial stress in compensatory adaptations by arteries. J Biomech 42:1–8. Loeys BL1, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. 2005. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37:275– 281. Loeys BL1, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA, Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, De Paepe AM, Dietz HC. 2006. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 355:788– 798. Morris SA, Orbach DB, Geva T, Singh MN, Gauvreau K, Lacro RV. 2011. Increased vertebral artery tortuosity index is associated with adverse outcomes in children and young adults with connective tissue disorders. Circulation 124:388–396. Niwa K. 2013. Aortopathy in congenital heart disease in adults: Aortic dilatation with decreased aortic elasticity that impacts negatively on left ventricular function. Korean Circ J 43:215–220. Reinstein E, Frentz S, Morgan T, Garcı´a-Min˜au´r S, Leventer RJ, McGillivray G, Pariani M, van der Steen A, Pope M, Holder-Espinasse M, Scott R, Thompson EM, Robertson T, Coppin B, Siegel R, Bret Zurita M, Rodrı´guez JI, Morales C, Rodrigues Y, Arcas J, Saggar A, Horton M, Zackai E, Graham JM, Rimoin DL, Robertson SP. 2013. Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A. Eur J Hum Genet 21:494–502. Shamszad P, Barnes JN, Morris SA. 2013. Aortic dissection in hospitalized children and young adults: A multi institutional study. Congenit Heart Dis 9:54–62. Sheen VL, Jansen A, Chen MH, Parrini E, Morgan T, Ravenscroft R, Ganesh V, Underwood T, Wiley J, Leventer R, Vaid RR, Ruiz DE, Hutchins GM, Menasha J, Willner J, Geng Y, Gripp KW, Nicholson L, Berry-Kravis E, Bodell A, Apse K, Hill RS, Dubeau F, Andermann F, Barkovich J, Andermann E, Shugart YY, Thomas P, Viri M, Veggiotti P, Robertson S, Guerrini R, Walsh CA. 2005. Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome. Neurology 64:254–262. van der Linde D1, Bekkers JA, Mattace-Raso FU, van de Laar IM, Moelker A, van den Bosch AE, van Dalen BM, Timmermans J, Bertoli-Avella AM, Wessels MW, Bogers AJ, Roos-Hesselink JW. 2013. Progression rate and early surgical experience in the new aggressive aneurysms-osteoarthritis syndrome. Ann Thorac Surg 95:563–569.
