A 32‐year‐old nursing student with hoarseness and dysphagia to solids

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. 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. 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. 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. Saddle nose deformity due to years of chronic inflammation. 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). A, Three-dimensional reconstruction of the chest computed tomography (CT) with angiogram, demonstrating a large thoracic aneurysm measuring 9 cm in diameter. B, CT angiogram of the chest reveals a large thoracic aneurysm (ANE) causing moderate compression of the right pulmonary artery (*), right main stem bronchus (arrow head), and the esophagus (arrow). The left pulmonary artery, which arises from the main pulmonary artery at this level, is not visible due to marked compression by the aneurysm. The left main stem bronchus is collapsed and is not visible due to compression by the aneurysm. PA = main pulmonary artery. C, CT angiogram reconstruction showing a large thoracic aneurysm and a smaller saccular abdominal aortic aneurysm just before its bifurcation. 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). 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 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 (SLE) is often associated with cardiac valvular lesions, particularly of the mitral valve (19). Libman-Sacks a type of valve to is often but not accompanied by antibodies Although mitral valve disease and is associated with and oral lesions, it is unusual for the disease to the thoracic aorta. Our patient's for antibodies and antibodies to extractable nuclear antigens were negative. syndrome is a disorder characterized by chronic and with systemic features that It can in with arthritis, and recurrent abdominal pain The laboratory findings include C3 and C4 and a markedly biopsy results a with of and can be seen in This group of patients is at risk for valvular heart disease. The of aortic and mitral valve regurgitation has been described in a case with features of and on the valve this diagnosis in our patient was the absence of skin disease. types of can cause aortic dilatation and aortic aneurysms, leading to aortic valve These include idiopathic and arteritis is a chronic that the and its primary in young manifestations range from to in the of examination blood pressure between the 2 or in both with the pulses, and lesions are the of disease. reveals or of the or its with of In this the CT angiogram did not the classic features of Although our patient had radial pulses, it was that they were a of due to arterial from aortic aneurysms are often the result of cystic degeneration due to and However, aortitis is an in from valvular or aneurysm aortitis be considered chronic inflammation is present on studies of the aorta. In a review of surgical aortic from the were to have inflammatory in patients without symptoms of systemic illness. The of patients with idiopathic aortitis was It is that idiopathic aortitis is part of a spectrum of disease that arteritis or of patients developed new aneurysms over a of months idiopathic aortitis in our patient her young and the multiple systemic symptoms before the onset of her cardiovascular syndrome is a chronic inflammatory disorder of the young adult characterized by both and acute dysfunction that disease. systemic manifestations as fatigue, weight loss, and are present The of is estimated at valvulitis, aortic insufficiency, and artery disease within weeks to years of the diagnosis. It causing of the aortic or smaller arteries as the and external arteries Recurrent and of smaller have also been reported Although the of our patient and her systemic symptoms can be seen in she does not have the and manifestations that are the findings of this clinical the and is the disorder that of the findings by this In is for causing saddle-nose and it can also cause auricular of the type our patient does not because a of patients with this disease not these in their However, of the patient's other including severe cardiac valvular aortitis leading to aneurysms, and genital are atypical of and point strongly to other there are 2 inflammatory rheumatic disorders that cause of the features of this patient's disease and This patient has a history of both oral and genital which are classic features of clinical features of are due to which the arterial or the of the and inflammatory aortitis is well described in this disorder large and medium-sized including the and the and arteries, have been described The incidence of aortic aneurysms from and varies to studies aneurysms and at and of surgical of an endovascular as an has been with of surgery and of and is an inflammatory disease of the including the nose, peripheral and The can also as a of characterized by of the vasa by Aortic and mitral valve which in of can within months of the onset of symptoms or be for The aortic is aortic insufficiency which as a result of aortic root dilatation primary involvement of the valve. Aortic aneurysm to the ascending aorta, but be and can the abdominal of and aneurysm but inflammation can to in up to of patients within the first 4 years This patient has disease features of both and but diagnosis in and of of her disease In and described 5 patients with features of both and They the which for and genital ulcers with The at onset of patients in this from that genital are often to and inflammation of the is for the 5 patients developed a of symptoms that are for both disease In addition, of these patients also had and which were considered to be lesions that can be seen in both and lesions including inflammatory eye and system disease were also of syndrome have been reported its of these had symptoms for in which oral and genital ulcers developed first, by onset of inflammation months patients had symptoms by of oral and genital ulcers and/or of these were associated with aortic aneurysm and 2 with secondary aortic insufficiency The vascular histopathologic features of the 2 inflammatory are with that the vasa vasorum and the The between the clinical and pathologic manifestations of both disease suggest a The of patients with syndrome is often on clinical is to symptoms and involves is often required when cardiovascular as aortic insufficiency or aortic aneurysm The patient underwent endovascular of both thoracic and abdominal aortic These surgical were performed in 2 The first of a right to left to subclavian This procedure was performed because the used to repair her was to the of the left artery. The second procedure the thoracic with the of a (Figure 3). The abdominal aneurysm was also with a tomography angiogram reconstruction after endovascular and aortic = right = left = left subclavian = thoracic aortic to the rapid and of valvular and inflammatory aneurysm in this patient, glucocorticoids and was The patient also for she has 5 of with the of a of 6 and to for CT of the at 2 months and 4 months postoperative did not any recurrent aneurysms or of the and peripheral arteries is The are to for efforts in in the of this