A 32-year-old woman was in her usual state of health until 7 months before presentation, when she developed a productive cough with scant hemoptysis. She also noted dyspnea on exertion and three-pillow orthopnea. She was admitted to a local hospital, where a computed tomography (CT) scan of the chest revealed extensive mediastinal and hilar lymphadenopathy with right hilar calcification. A bronchoscopy and mediastinal lymph node biopsy were performed. The pathologic examination showed reactive hyperplasia.
A transthoracic echocardiogram revealed a flail posterior mitral valve leaflet and severe mitral regurgitation. The estimated pulmonary artery systolic pressure was 44 mm Hg, but her systolic function was preserved. She underwent a sternotomy with mitral valve repair and an annuloplasty at an outside institution. The gross pathology of the native valve was reported as “myxomatous degeneration with no vegetations.” Her postoperative course was uncomplicated, and within a month of discharge the patient had resumed walking 2 miles each day.
Three months after her surgery, the patient developed chest pain, palpitations, and marked dyspnea following stair climbing. She was evaluated by her cardiologist, who noted a new III/VI decrescendo murmur in diastole, heard along the left sternal border. A transthoracic echocardiogram showed severe aortic regurgitation. The patient underwent a transesophageal echocardiogram that revealed a dissection of the sinus of Valsalva into the interventricular septum. The results of 3 sets of blood cultures were negative.
Consequently, the patient underwent another sternotomy, this time with placement of a St. Jude Medical aortic valve. In addition, the aortic annulus was replaced with a bovine pericardial patch. Pathology of the surgical specimen revealed a 3-mm defect in the aortic sinus above the annulus, with tissue loss above the aortic cusp. The valve leaflets were normal.
The patient's recovery from her second surgery was protracted. She developed intermittent left-sided pleurisy and continued to have dyspnea on exertion. However, CT angiogram and echocardiogram performed 1 month after her surgery were normal. Nine weeks after discharge, she developed paroxysms of nonproductive cough that resulted in vomiting and wheezing. Therapy with azithromycin, moxifloxacin, and albuterol for a presumed asthma exacerbation resulted in no improvement. She was also given an empiric trial of omeprazole for reflux, but her respiratory symptoms continued to worsen over the next several weeks. Three months after her second surgical procedure and 6 months after her first, she presented to our institution complaining of dysphagia to solids and hoarseness with decreased phonation.
Past medical history
The patient had been in good health until the onset of the present illness. Her childhood had been marked by intermittent asthma, but she had never required maintenance glucocorticoids nor had she been hospitalized or intubated for an asthma exacerbation. The patient had not undergone dental work before the onset of her cardiac valvular problems. Her medications at the time of admission included warfarin, omeprazole, ibuprofen, alprazolam, and albuterol. She had no known drug allergies.
Social and family history
The patient had to suspend her studies in nursing school because of her health problems over the preceding 6 months. She was divorced, had a 7-year-old daughter, and lived with a roommate. She consumed up to 5 alcoholic drinks a week and had a smoking history of 10 packs per year. She reported having used intranasal cocaine from 1993–1996, but denied intravenous drug use. She was not sexually active. Both of her parents and her daughter were well, and there was no family history of cardiac valvular disease or cardiovascular problems.
Review of systems
The review of systems was remarkable for the absence of fevers, sweats, weight loss, skin lesions, auditory or visual changes, and lower back pain. She reported a 4-year history of generalized fatigue, intermittent arthralgia, and nasal inflammation. In 2002, she had developed relapsing–remitting episodes of nasal swelling. She described episodes of purplish-red discoloration of the skin overlying her nose, accompanied by a burning nasal pain. The episodes generally lasted 3 weeks before resolving spontaneously. In 2003, she developed pain, redness, and swelling of the external helix of her right ear. She was treated with multiple courses of antibiotics for presumed ear infections, without response. Two years before presentation, she saw an allergist and was prescribed piroxicam, a nonsteroidal antiinflammatory drug, which improved her symptoms. The patient also reported frequent aphthous oral ulcers that occurred in groups of 4 or 5 and lasted 2–3 weeks. They healed with residual scarring. Furthermore, she had experienced intermittent episodes of genital ulcers on her labia majora, but recalled testing negative for herpes simplex virus on 2 occasions.
The patient appeared chronically ill and had paroxysms of nonproductive cough. She was 5 feet 5 inches tall and weighed 65 kg. Her temperature was 36.8°C, her heart rate 72 beats/minute, respiratory rate 20 breaths/minute, and her blood pressure (taken in both arms) was 130/70 mm Hg. Her oxygen saturation on room air was 96%. The patient's skin was clear. There was full range of motion of the joints but no hyperextensibility, chronic joint deformities, or synovitis. She had no external eye abnormalities, but nasal examination revealed a saddle-nose deformity with large, asymmetric nares (Figure 1). Her nasal septum was midline and her nasal passages had no crusting or bleeding, but transillumination of the septum revealed a small perforation. There was bland scarring of the buccal mucosa that the patient attributed to previous aphthous ulcers.
The cardiac examination showed a nondisplaced point of maximal impulse with mechanical heart sounds, but no murmurs, rubs, or gallops. The peripheral pulses were 2+ with the exception of the radial pulses, which were undetectable bilaterally. There were no bruits over the carotid, subclavian, or femoral arteries, or the abdominal aorta. The lung examination revealed diffuse inspiratory wheezing and markedly decreased airway entry over the left lung fields. Her abdomen was soft, nontender, and without organomegaly. The neurologic examination was nonfocal.
The patient's laboratory evaluation at the time of admission is shown in Table 1. In addition to these routine examinations, 3 sets of blood cultures were negative and syphilis serologies (both the rapid plasma reagin and fluorescent treponemal antibody absorption assays) were negative. The erythrocyte sedimentation rate was 94 mm/hour (normal rate <20 mm/hour) and the C-reactive protein level was 51.3 mg/dl (normal level <5 mg/dl). An assay for antinuclear antibodies was positive at a titer of 1:80 in a speckled pattern, but antibodies to extractable nuclear antigens (Ro, La, Sm, RNP) were negative, as were assays for rheumatoid factor, anti–double-stranded DNA (anti-dsDNA) antibodies, and antineutrophil cytoplasmic antibodies (ANCAs). The serum complement components C3 and C4 were 155 mg/dl and 33 mg/dl, respectively (both normal).
A chest CT revealed a large thoracic aneurysm just distal to the left subclavian artery. The aneurysm measured 9 cm in diameter and had a 4-cm neck. The aneurysm was exerting marked compression on the left pulmonary artery and the left main bronchus, and moderate compression on the right pulmonary artery, the right main bronchus, and the esophagus (Figure 2). The patient was also noted incidentally to have an abdominal aneurysm that measured 4 cm in diameter (Figure 2C).
This young woman has sustained multiple cardiac and vascular lesions in the preceding 6 months, including both mitral and aortic regurgitation and aneurysms of her thoracic and abdominal aorta. In addition to the patient's aortic lesions and their impact on her phonation and swallowing, she has a 4-year history of recurrent auricular and nasal inflammation leading to a saddle-nose deformity, and reports aphthous ulcers and genital ulcers. She has undergone open-heart surgery twice during the period of this illness, but remains without a diagnosis.
Part of the patient's chief complaint, hoarseness, is secondary to Ortner's syndrome (1), a cardiovocal syndrome caused by compression of the recurrent laryngeal nerve. In the first case reported in 1897, recurrent laryngeal nerve palsy was caused by a dilated left atrium, secondary to mitral stenosis. Recurrent laryngeal nerve paralyses due to other causes, including pulmonary hypertension, dissecting aneurysms, and expanding thoracic aortic aneurysms, have also been reported (2, 3). The second part of her chief complaint, dysphagia to solids, is caused by a similar mechanism referred to as dysphagia aortica, the result of extrinsic compression of the esophagus by the aortic aneurysm. How does one attempt to link the patient's diverse symptoms, signs, and findings?
In evaluating the diagnosis of cardiac valve failure and aortic aneurysms in a young patient, 3 major categories of disease must be considered: infection, heritable disorders of connective tissue, and systemic inflammatory conditions (Table 2).
Table 2. Disorders associated with cardiac valve dysfunction and/or aortic aneurysm in a young patient*
MAGIC = mouth and genital ulcers with inflamed cartilage.
Heritable disorders of connective tissue
Systemic inflammatory conditions
Likely to cause primary aortitis (with secondary valvular dysfunction)
Likely to cause primary valvular dysfunction
Juvenile idiopathic arthritis
Systemic lupus erythematosus
Hypocomplementemic urticarial vasculitis syndrome
In terms of priority, infections must be excluded first because of the high mortality associated with endovascular infections. It is conceivable that the patient had an intracardiac infection at the time of her mitral valve surgery, leading directly or indirectly to her subsequent cardiovascular issues. However, endocarditis appears unlikely because the patient had no overt risk factors, fevers, cutaneous stigmata, and had negative blood cultures. For the same reasons, a mycotic aneurysm would be an unusual cause of this patient's presentation. Fastidious organisms (e.g., HACEK organisms; Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella) (4) can be associated with infections that are difficult to culture. Such organisms must be considered seriously in the absence of another probable explanation.
Cardiac lesions associated with rheumatic heart disease would be atypical in an adult without a history of rheumatic fever as a child, and the patient has no other features of acute rheumatic fever (5). Tertiary syphilis, a classic cause of ascending aortic aneurysms, is caused by destruction of the vasa vasorum by the spirochete (6). Although Treponema pallidum can cause aortic regurgitation as a result of dilatation of the ascending aorta, mitral valve disease is not typical (6). In addition, the fact that the patient has tested negative for syphilis by both rapid plasma reagin and fluorescent treponemal antibody absorption assays excludes a luetic cause of her illness.
Heritable disorders of connective tissue
Heritable disorders of connective tissue can be associated with cardiac valvular failure and/or aortic dysfunction. Marfan's syndrome is an autosomal dominant inherited disorder of connective tissue that involves mutations of the FBN1 gene (7). The clinical spectrum of Marfan's syndrome involves the ocular, cardiovascular, and musculoskeletal systems. The histopathologic findings include noninflammatory cystic disintegration of the aortic media that leads to aneurysmal dilatation, aortic insufficiency, and dissection (8).
Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperelasticity, and tissue and arterial fragility. Up to 11 subtypes of EDS have been described in the past, but recent efforts have simplified the classification scheme into 6 major subtypes and an “other” type (9). The vascular subtype, formerly known as EDS type IV, is characterized by minimal joint laxity, cigarette-paper skin, severe bruisability, and a striking predilection for arterial rupture (10–12). Individuals with vascular EDS are particularly vulnerable to rupture of medium-sized arteries and the descending aorta, generally occurring in the patient's thirties and often leading to sudden death (10). In addition, vessel wall friability often makes surgical repair difficult. Aortic root dilatation has been detected by transthoracic echocardiography in up to 28% of patients in the classic and hypermobile types of EDS (11).
Our patient has no family history of sudden death, nor does she have the arachnodactyly, joint hypermobility, skin hyperelasticity, or poor wound healing that are characteristically seen in these syndromes.
The patient's illness has a number of other features that suggest the possibility of an underlying systemic inflammatory disease. Multiple systemic inflammatory disorders can be associated with cardiac valve dysfunction and/or aortic aneurysm. These include a number of primary arthritides as well as multiple forms of systemic vasculitis.
Rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) can both be associated with aortic valve lesions and aortitis (13, 14). However, when cardiac valve dysfunction (usually aortic regurgitation) occurs, it does so characteristically in the setting of a well-defined, advanced underlying primary condition. For example, when RA is associated with aortitis and valvulitis, the patient invariably has severe, seropositive, nodular, and destructive disease that is often accompanied by other extraarticular manifestations (13). Our patient was rheumatoid factor negative and did not have arthritis or any of the other types of organ system involvement typical of RA or JIA.
The seronegative spondylarthritides include ankylosing spondylitis (AS), reactive arthritis, and arthritis-associated inflammatory bowel disease. AS, a chronic inflammatory disease strongly associated with HLA–B27, was the first rheumatic disease known to be associated with aortitis (15). Its distinctive features include a propensity for axial and peripheral arthritis, enthesitis, and inflammatory back pain in young adults. Aortitis with aortic insufficiency is an uncommon but well-recognized extraarticular manifestation. The incidence of aortic insufficiency in AS, which varies between 3% and 10%, is lowest in the first decade of disease but increases to 10% among patients with >30 years of disease duration (16). Aortic pathology results from obliterating arteritis with focal destruction of the media and thickening of the intima and adventitia (17). Valvular changes in AS have been described as fibrotic, retracted cusps with rolled edges that progress to aortic insufficiency over time (17).
Our patient also developed mitral valve regurgitation, which is not typical of AS (18). Although oral ulcers are seen in association with spondylarthritides, they are often painless. She also lacks the history of inflammatory back pain and has no evidence of axial disease on physical examination.
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is often associated with cardiac valvular lesions, particularly of the mitral valve (19). Libman-Sacks endocarditis, a type of valve lesion peculiar to SLE, is often but not always accompanied by antiphospholipid antibodies (20). Although SLE may induce mitral valve disease and is associated with arthralgia and painful oral lesions, it is unusual for the disease to involve the thoracic aorta. Our patient's tests for anti-dsDNA antibodies and antibodies to extractable nuclear antigens were negative.
Hypocomplementemic urticarial vasculitis syndrome
Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare autoimmune disorder characterized by chronic urticaria and hypocomplementemia, with many systemic features that resemble SLE. It can occur in conjunction with arthritis, glomerulonephritis, uveitis, and recurrent abdominal pain (21). The hallmark laboratory findings include low C3 and C4 levels and a markedly depressed C1q. Skin biopsy results reveal a leukocytoclastic vasculitis with perivascular depositions of immunoglobulins, complements, and fibrin (21).
Jaccoud's arthropathy can be seen in HUVS (22). This group of patients is at increased risk for valvular heart disease. The combination of aortic and mitral valve regurgitation has been described in a case report (22), with features of fibrinoid necrosis and immunoglobulin deposition on the valve surface. Evidence against this diagnosis in our patient was the absence of skin disease.
Several types of large-vessel vasculitis can cause aortic dilatation and aortic aneurysms, leading secondarily to aortic valve insufficiency. These include Takayasu arteritis, idiopathic aortitis, and Cogan's syndrome.
Takayasu arteritis is a chronic vasculitis that affects the aorta and its primary branches in young women. Clinical manifestations range from hypertension to ischemic complications in the region of occluded vessels (23). Physical examination may reveal blood pressure discrepancies (either between the 2 arms or low pressures in both arms compared with the legs), asymmetrical pulses, and bruits. Stenosing lesions are the hallmark of Takayasu disease. Arteriography typically reveals smoothly tapered luminal narrowing or occlusion of the entire aorta or its branches, with areas of dilation (24). In this case, the CT angiogram did not show the classic features of Takayasu arteritis. Although our patient had absent radial pulses, it was suspected that they were a complication of trauma due to arterial line placements from prior surgeries.
Thoracic aortic aneurysms are often the result of cystic medial degeneration due to aging and hypertension (25). However, aortitis is sometimes an unexpected finding in specimens from valvular or aneurysm resection surgery. Idiopathic aortitis should always be considered if chronic inflammation is present on histologic studies of the aorta. In a review of 1,204 surgical aortic specimens from the Cleveland Clinic (26), 4% were found to have inflammatory infiltrates in patients without symptoms of systemic illness. The average age of patients with idiopathic aortitis was 60 years. It is possible that idiopathic aortitis is part of a spectrum of disease that includes giant cell arteritis or Takayasu arteritis. Seventeen percent of untreated patients subsequently developed new aneurysms over a followup of 41 months (26).
Evidence against idiopathic aortitis in our patient includes her young age and the multiple systemic symptoms before the onset of her cardiovascular complications.
Cogan's syndrome is a chronic inflammatory disorder of the young adult characterized by both ocular (typically interstitial keratitis) and acute cochlear dysfunction that mimics Ménière disease. Nonspecific systemic manifestations such as fatigue, weight loss, fever, headache, and arthralgia are commonly present (27). The frequency of vasculitis is estimated at 10%. Aortitis, valvulitis, aortic insufficiency, and coronary artery disease may develop within weeks to years of the initial diagnosis. It may resemble Takayasu arteritis, causing occlusion of the aortic arch vessels or involving smaller arteries such as the testicular and external iliac arteries (27). Recurrent phlebitis and leukocytoclastic vasculitis of smaller vessels have also been reported (27).
Although the age of our patient and her systemic symptoms can be seen in Cogan's syndrome, she does not have the ophthalmologic and otolaryngologic manifestations that are the hallmark findings of this clinical entity.
Among the ANCA-associated vasculitides (Wegener's granulomatosis [WG], microscopic polyangiitis, and Churg-Strauss syndrome), WG is the disorder that causes some of the findings displayed by this patient. In particular, WG is notorious for causing saddle-nose deformities and it can also cause auricular chondritis of the type our patient described. ANCA negativity does not exclude WG, because a minority of patients with this disease do not possess these autoantibodies in their serum. However, many of the patient's other findings, including severe cardiac valvular disease, aortitis leading to aneurysms, and genital ulcers, are highly atypical of WG and point strongly to other diagnoses (28).
Finally, there are 2 additional inflammatory rheumatic disorders that may cause many of the features of this patient's illness: Behçet's disease (BD) and relapsing polychondritis (RP).
This patient has a longstanding history of both oral and genital ulcers, which are classic features of BD. Most clinical features of BD are due to vasculitis, which may involve either the arterial or the venous side of the circulation, and inflammatory aortitis is well described in this disorder (29). Aneurysms involving large and medium-sized vessels, including the aorta and the femoral, pulmonary, iliac, and popliteal arteries, have all been described (30). The incidence of aortic aneurysms ranges from 5–20% and varies according to different studies (29, 30). False aneurysms and thromboses, notably at anastomoses and sites of trauma, further complicate surgical management. Implantation of an endovascular stent graft as an alternative modality has been successful with benefits of avoiding open surgery and prevention of pseudoaneurysms and thrombosis (31).
RP is an episodic inflammatory disease of the cartilaginous structures including the ear, nose, peripheral joints, trachea, and bronchial tree (32). The aorta can also serve as a target of autoimmunity characterized by lymphocytic infiltration of the vasa vasorum, followed by fibrous replacement (33). Aortic and mitral valve disease, which occurs in ∼10% of patients, can appear within months of the onset of symptoms or be delayed for decades. The most common aortic lesion is aortic insufficiency (4–9%), which occurs as a result of aortic root dilatation rather than primary involvement of the valve. Aortic aneurysm tends to affect the ascending aorta, but may be multiple, and can involve the abdominal aorta (34). Surgical treatment consists of valvuloplasty and aneurysm resection, but inflammation can recur adjacent to grafts, requiring reoperation in up to 25% of patients within the first 4 years (35).
This patient has disease features of both BD and RP, but neither diagnosis in and of itself explains all of her disease manifestations. In 1985, Firestein and colleagues described 5 patients with features of both RP and BD. They proposed the term MAGIC syndrome, which stands for “mouth and genital ulcers with inflamed cartilage” (36). The age at onset of patients in this index series varied from 10–59 years.
Firestein et al identified that although genital ulcerations are often unique to BD and inflammation of the cartilage is specific for RP, the 5 patients developed a combination of symptoms that are highly specific for both disease entities. In addition, some of these patients also had large-vessel arteritis, thrombosis, and audiovestibular disease, which were considered to be relatively specific lesions that can be seen in both BD and RP. Less specific lesions including migratory arthropathy, dermatologic disease, inflammatory eye disease, and central nervous system disease were also seen.
Eleven additional cases of MAGIC syndrome have been reported since its coining (37–45). Most of these cases had symptoms specific for BD, in which oral and genital ulcers developed first, followed by onset of cartilage inflammation months later. Fewer patients had RP symptoms initially followed by development of oral and genital ulcers and/or erythema nodosum. Four of these cases were associated with aortic aneurysm and 2 with secondary aortic insufficiency (38–40). The vascular histopathologic features of the 2 inflammatory entities are similar, with lymphohistiocytic infiltrates that affect the vasa vasorum and the media. The similarities between the clinical and pathologic manifestations of both disease entities suggest a common pathogenetic pathway. The prognosis of patients with MAGIC syndrome is variable, often depending on clinical severity. Treatment is targeted to symptoms and involves aggressive immunosuppressive therapy. Surgical management is often required when cardiovascular complications such as aortic insufficiency or aortic aneurysm ensue.
THE PATIENT'S COURSE
The patient underwent endovascular graft repairs of both thoracic and abdominal aortic aneurysms. These surgical repairs were performed in 2 separate procedures. The first consisted of a right carotid to left carotid to subclavian bypass. This procedure was performed because the endograft used to repair her aorta was expected to exclude the origin of the left common carotid artery. The second procedure repaired the thoracic aorta with the intravascular deployment of a 1-piece endograft (Figure 3). The abdominal aneurysm was also repaired with a single tube graft.
Due to the rapid and progressive nature of valvular damage and inflammatory aneurysm formation in this patient, aggressive immunosuppressive treatment using pulse glucocorticoids and monthly cyclophosphamide was undertaken. The patient also received prophylactic treatment for Pneumocystis jiroveci infection. To date, she has received 5 cycles of cyclophosphamide, with the intention of administering a total of 6 cycles and then switching to azathioprine for remission maintenance. Repeat CT angiographies of the aorta at 2 months and 4 months postoperative did not reveal any recurrent aneurysms or leakage. Periodic imaging of the aorta and peripheral arteries is planned.
The MAGIC syndrome.
We are gratefully indebted to Dr. John Stone for his efforts in editorial assistance in the preparation of this manuscript.