Nonsyndromic genetic predisposition to aortic dissection

CARDIOLOGY/CASE REPORT

Nonsyndromic Genetic Predisposition to Aortic Dissection: A Newly Recognized, Diagnosable, and Preventable Occurrence in Families

Sumera N. Hasham, PhD Matthew R. Lewin, MD, PhD Van T. Tran, MS Hariyadarshi Pannu, PhD Ann Muilenburg, MS Marcia Willing, MD, PhD Dianna M. Milewicz, MD, PhD From the Division of Medical Genetics, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX (Hasham, Tran, Pannu, Milewicz); the Department of Pediatrics, University of Iowa, Iowa City, IA (Willing, Muilenburg); and the Department of Emergency Medicine, University of California–San Francisco, San Francisco, CA (Lewin).

The major diseases affecting the aorta are aortic aneurysms and dissections, with patients with acute dissections often presenting in the emergency department (ED). Recent studies demonstrate a strong genetic predisposition to thoracic aortic aneurysms and dissections, independent of syndromes traditionally considered to predispose to aortic disease (such as Marfan syndrome). Nonsyndromic familial thoracic aortic aneurysms and dissections are inherited in families as an autosomal dominant disorder and a variable age of onset of the aortic disease. The case reported here illustrates the critical importance of obtaining a family history of thoracic aortic aneurysms and dissections, along with unexplained sudden death, when assessing an individual with chest pain in the ED, regardless of age and in the absence of a known genetic syndrome. [Ann Emerg Med. 2004;43:79-82.]

INTRODUCTION

The major diseases affecting the aorta are aortic aneurysms and dissections, with patients with acute aortic dissections often presenting in the emergency department (ED) setting. Thoracic aortic aneurysms and dissections are the major cardiac feature in patients with Marfan syndrome.1 However, up to 19% of individuals with thoracic aortic aneurysms and dissections who do not have Marfan syndrome have a firstdegree relative with aortic aneurysms or dissections, indicating a strong genetic predisposition to this disease.2,3 Within families, thoracic aortic aneurysms and dissections are inherited primarily in an autosomal dominant manner, with decreased penetrance and variable expression.4 The case reported here illustrates the great importance of obtaining a family history of thoracic aortic aneurysms and dissections when assessing an individual with chest pain in the ED, even in the absence of a known genetic syndrome. CASE REPORT

0196-0644/$30.00 Copyright © 2004 by the American College of Emergency Physicians. doi:10.1016/mem.2004.425

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The patient was a 19-year-old man (Figure; IV:12) with a history of seasonal allergies, asthma, and smoking who presented to the ED complaining of sharp, nonradiating, left-sided chest pain that started 20 minutes before arrival. The pain worsened with inspiration and was relieved by rest. The nursing record noted the pain to rate “3 to 4,”

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out of a possible 10. In addition to chest pain, he complained of upper respiratory tract symptoms that had persisted for 2 weeks. He denied difficulty breathing, and except as already noted, his review of systems was unremarkable. His family history was notable for thoracic aortic aneurysms. He was taking cetirizine (Zyrtec) and desloratidine (Clarinex) for his allergy symptoms. His vital signs were blood pressure 137/88 mm Hg, pulse rate 79 beats/min, respiratory rate 20 breaths/min, and temperature 35.6°C (96.0°F; tympanic). Physical examination was notable only for an exudative pharyngitis. An ECG showed nondiagnostic ST-segment abnormalities in the inferior leads; chest radiographs were read as normal by the emergency physician and the radiologist. He was discharged with diagnoses of upper respiratory infection and pleuritic chest pain and with instructions to take ibuprofen and to follow up with his family physician within 2 days. The chest pain persisted, and 2 days later his family physician’s record states he would “look into the aortic aneurysm for his age group to see what the best approach is.” Three days later, the patient returned to the ED with severe “7 of 10” substernal chest pain and pressure,

which increased with coughing and breathing. His vital signs were blood pressure 153/86 mm Hg, pulse rate 66 beats/min, respiratory rate 20 breaths/min, and temperature 36.2°C (97.1°F). His chest was tender to palpation. Chest radiographs were again read as normal, a CBC count and monospot test were normal, and he was discharged with additional medications for pain. Four days later, the patient was robbed but not assaulted. While being interviewed by the police, he collapsed. Resuscitation efforts by the police, emergency medical services, and the ED were unsuccessful. Autopsy revealed a tear in the base of the aorta at the attachment to the heart and hemorrhage into the soft tissue around the tear and hemopericardium. No skeletal features of Marfan syndrome were noted. Microscopic examination of the aorta revealed cystic medial necrosis and no evidence of coronary artery occlusion. Blood immunoassays for drugs of abuse and alcohol were negative. The patient had a family history of aortic dissection, with his paternal uncle (III:16) dying at the age of 38 years of aortic dissection and his father (III:11) undergoing surgical repair of an aortic dissection at the age of 42 years (Figure). The patient was a member of a large

Figure.

Pedigree of family with multiple members with thoracic aortic aneurysms and dissections. Round symbols indicate females; square symbols indicate males. Symbols with a line crossed through it symbolize a deceased person. Blackened symbols indicate affected individuals (affected status was assigned to individuals with aortic aneurysms/dissections, aortic surgical repair, or aortic dissection reported in autopsy report). Open symbols indicate normal ascending aortic size at the sinus of Valsalva. “//” symbolize a divorce. The “X” symbol over an individual indicated a suicide. An autosomal dominant pattern of inheritance is observed for the disease in the family. Variable age of onset is exemplified by individuals II:2 and IV:11 (age of onset 69 and 21 years, respectively). Skipping of generations as seen in individuals II:5 (affected), III:20 (unaffected), and IV:18 (affected) indicates the decreased penetrance. The asterisk indicates the individual who presented with aortic dissection as described in the case report. The arrow indicates the proband. Adapted with permission from Hasham S, Willing M, Guo D, et al. Mapping a locus for familial thoracic aortic aneurysms and dissections (TAAD2) to 3p24-25. Circulation. 2003;107:3184-3190.5

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family with autosomal dominant inheritance of thoracic aortic aneurysms and dissections, and samples from this family’s members have been used to map a novel locus for familial thoracic aortic aneurysms and dissections.5 DISCUSSION

Thoracic aortic aneurysms and dissections are often asymptomatic until a catastrophic event occurs,4 which could be prevented if family members were cautioned about the hereditability of aortic aneurysms and dissections. Aortic aneurysms and dissections are associated with a high degree of morbidity, mortality, and medical expenditure, despite continued improvements in diagnostic and surgical techniques.6 Ascending aortic aneurysms typically enlarge over time until a type A aortic dissection is imminent. Type A aortic dissections can also occur in the absence of dilatation of the aorta, and chest radiograph results can be completely normal.7 In most cases of thoracic aortic aneurysms and dissections, an initial ECG is normal and not helpful. However, any unexpected ECG abnormalities should heighten clinical suspicion for an aortic dissection.8 Ascending thoracic aortic aneurysms and type A dissections are associated primarily with the poorly understood pathologic process termed cystic medial necrosis, or medial degeneration. Medial degeneration occurs as part of the normal aging of the aorta but is accelerated by other conditions, including hypertension and genetic alterations that predispose individuals to aortic disease. Studies are beginning to elucidate the genetic factors that predispose an individual to these aortic diseases in the absence of a known genetic syndrome. Familial aggregation studies have indicated that 11% to 19% of patients with thoracic aortic aneurysms and dissections who are referred for surgical repair of aortic disease have other affected family members, supporting the hypothesis that genetic factors predispose an individual to these aortic diseases.2,3 Families with multiple members with thoracic aortic aneurysms and dissections have been reported, and these pedigrees indicate that in most families the condition is inherited in an autosomaldominant manner.4 The type of aortic disease can vary within a family, with one individual undergoing prophylactic repair of an ascending aortic aneurysm and another individual in the same family presenting with a type A aortic dissection without evidence of dilatation of the ascending aorta (an example of variable expression of the defective gene within the family). In addi-

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tion, the condition demonstrates a variable age of onset of the aortic disease, with individuals presenting with aortic disease ranging from 14 to 76 years of age.5 In some cases, an individual can inherit the defective gene but never have aortic disease (ie, decreased penetrance). Therefore, the condition may appear to skip generations within a family (Figure). The mapping of the first gene for familial thoracic aortic aneurysms and dissections was recently achieved. By use of families with multiple members with the disorder, the locus was mapped to the long arm of chromosome 5 (5q13-14), termed the TAAD1 locus.9 The fact that more than one gene can cause this clinical condition (genetic heterogeneity) was indicated by the fact that only one half of the identified families mapped to this locus. Genetic heterogeneity for the condition was confirmed by mapping another gene causing aortic aneurysms to the long arm of chromosome 11, 11q2324, using 1 large family (termed the FAAl locus).10 In contrast to the TAAD1 locus, the disease in this family is characterized by aneurysms that not only affect the ascending thoracic aorta but also involve other segments of the aorta and other arteries. We have mapped another locus for thoracic aortic aneurysms and dissections to 3p24-25, termed the TAAD2 locus, by using this large family with multiple affected members (Figure).5 The individual presented in this case report was a member of the family used for this study and is indicated in the Figure with an asterisk. Identification of these defective genes at these loci causing thoracic aortic aneurysms and dissections in the future will allow for the timely diagnosis of individuals at risk for these life-threatening conditions, and emergency physicians are in a good position to identify and initiate life-saving treatments while informing families of these genetic links. The prognosis of patients with aortic rupture and dissection markedly improves with early recognition and treatment. Although thoracic aortic aneurysms and dissections occur as a major manifestation of connective tissue disorders like Marfan syndrome and EhlersDanlos syndromes, along with aneuploidy syndromes such as Turner syndrome,11-13 most cases occur in individuals who do not have these conditions. In the absence of associated features, cardiovascular complications are the only marker for those who have inherited the defective gene. Therefore, if an individual gives a family history of aortic aneurysms or dissections, one should consider that the aortic disease is inherited within the family, even in the absence of other genetic syndromes. Prompt investigation using advanced imag-

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ing techniques such as contrast computed tomography, magnetic resonance imaging, or transesophageal echocardiography should be initiated because approximately 35% of patients with dissection will die within the first 24 hours and 80% within the first 2 weeks of presentation.14,15 These nonsyndromic cases are often asymptomatic until a life-threatening event such as aortic dissection occurs.4 In light of the recent data showing the genetic predisposition to nonsyndromic thoracic aortic aneurysms and dissections, emergency physicians should take a family history of all individuals who present with chest pain, independent of the diagnosis of associated syndromes or falsely reassuring diagnostic studies such as ECG and chest radiographs. A familial history of thoracic aortic aneurysms and dissections in first-degree relatives but also more distant relatives may be indicative of a familial predisposition to thoracic aortic aneurysms and dissections and should lead to a consideration of advanced imaging and surgical consultation to evaluate for aortic dissection.

10. Vaughan CJ, Casey M, He J, et al. Identification of a chromosome 11q23.2-q24 locus for familial aortic aneurysm disease, a genetically heterogeneous disorder. Circulation. 2001;103:2469-2475. 11. Pyeritz RE, McKusick VA. The Marfan syndrome: diagnosis and management. N Engl J Med. 1979;300:772-777. 12. Milewicz DM, Seidman CE. Genetics of cardiovascular disease 4. Circulation. 2000;102:IV103-IV111. 13. Hasham SN, Guo DC, Milewicz DM. Genetic basis of thoracic aortic aneurysms and dissections. Curr Opin Cardiol. 2002;17:677-683. 14. Kouchoukos NT, Dougenis D. Surgery of the thoracic aorta. N Engl J Med. 1997;336:1876-1888. 15. Hagan PG, Nienaber CA, Isselbacher EM, et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA. 2000;283:897-903.

We appreciate the continued participation and interest of the family in our studies. Received for publication April 30, 2003. Revision received July 18, 2003. Accepted for publication August 8, 2003. Supported by National Institutes of Health grants R01-HL-62594 and M01-RR-02558. Dr. Milewicz is a Doris Duke Distinguished Clinical Scientist. Reprints not available from the authors. Address for correspondence: Dianna M. Milewicz, MD, PhD, 6431 Fannin, MSB 1.614, Houston, TX 77030; 713-500-6727, fax 713-500-6556; E-mail [email protected].

REFERENCES 1. McKusick VA. The Marfan Syndrome. In: Beighton P, ed. Heritable Disorders of Connective Tissue. St. Louis, MO: Mosby; 1993;51-135. 2. Biddinger A, Rocklin M, Coselli J, et al. Familial thoracic aortic dilatations and dissections: a case control study. J Vasc Surg. 1997;25:506-511. 3. Coady MA, Davies RR, Roberts M, et al. Familial patterns of thoracic aortic aneurysms. Arch Surg. 1999;134:361-367. 4. Milewicz DM, Chen H, Park ES, et al. Reduced penetrance and variable expressivity of familial thoracic aortic aneurysms/dissections. Am J Cardiol. 1998;82:474-479. 5. Hasham S, Willing M, Guo D, et al. Mapping a locus for familial thoracic aortic aneurysms and dissections (TAAD2) to 3p24-25. Circulation. 2003;107:3184-3190. 6. Lilienfeld DE, Gunderson PD, Sprafka JM, et al. Epidemiology of aortic aneurysms, I: mortality trends in the United States, 1951 to 1981. Arteriosclerosis. 1987;7:637-643. 7. Klompas M. Does this patient have an acute thoracic aortic dissection? JAMA. 2002;287:2262-2272. 8. Hirata K, Kyushima M, Asato H. Electrocardiographic abnormalities in patients with acute aortic dissection. Am J Cardiol. 1995;76:1207-1212. 9. Guo D, Hasham S, Kuang SQ, et al. Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13-14. Circulation. 2001;103:2461-2468.

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