Original Article
Brief Report
Occult Pseudoxanthoma Elasticum in Patients with Premature Cardiovascular Disease
N Engl J Med 1993; 329:1237-1239October 21, 1993
- Article
Pseudoxanthoma elasticum is an inherited disorder of connective tissue that is associated with numerous systemic manifestations, including premature coronary artery disease. Without a serologic marker, the diagnosis relies on clinical features and the histologic demonstration of abnormal, calcified elastic fibers1,2.
The typical patient presents with yellow macules or papules that can become confluent to form plaques and, in severe cases, redundant folds of skin. Cutaneous lesions have been likened to “plucked chicken skin.” In patients whose skin is mildly affected, the condition may be difficult to recognize. Ocular complications occasionally occur without the characteristic skin lesions. The histologic diagnosis of pseudoxanthoma elasticum has been made by biopsy of scars or flexural skin of the neck or axillae in patients who have angioid streaks on funduscopic examination but no visible skin lesions3.
We describe four patients who presented with premature cardiovascular disease and were found to have angioid streaks and histologic evidence of pseudoxanthoma elasticum, despite the absence of characteristic skin lesions.
Case Reports
Patient 1
Patient 1 was a 27-year-old woman with a history of mild angina pectoris for several years. The patient had no history of smoking, hypertension, diabetes, or hyperlipidemia. The family history included angina pectoris in one sister (Patient 2).
The patient was hospitalized with unstable angina two months before she was seen by us. Cardiac catheterization revealed stenosis of the left anterior descending artery, its diagonal branch, and the right coronary artery. The patient underwent four-vessel coronary artery bypass surgery, including anastomosis of the left internal thoracic artery to the left anterior descending artery. Multiple arterial biopsies revealed calcification of the internal elastic laminae of both the coronary and internal thoracic arteries.
On examination, the patient did not have any skin lesions. Funduscopic examination revealed angioid streaks and peau d'orange in the right eye. There were no streaks in the left eye, but pigmentary mottling was present. The blood pressure was 130/88 mm Hg. Cardiac auscultation was normal. Four months after the initial examination progressive angina developed, for which the patient was hospitalized.
Patient 2
Patient 2 was the 39-year-old sister of Patient 1. She had no history of smoking, hypertension, diabetes, hyperlipidemia, or other risk factors for atherosclerosis. She had occasional sternal pressure on exertion. Treadmill exercise testing showed ST-segment depression of 1.5 mm after seven minutes. Cardiac catheterization was not performed. The patient was referred for evaluation after pseudoxanthoma elasticum was diagnosed in her sister.
On examination there were no skin lesions. Funduscopic examination revealed angioid streaks in both eyes (Figure 1Figure 1
Angioid Streaks in the Ocular Fundus of Patient 2.). Cardiac auscultation was normal.Patient 3
Patient 3 was a 59-year-old man who first had angina pectoris in his early 40s. At the age of 47 he underwent single-vessel coronary artery bypass surgery. At the age of 58 he was hospitalized with atrial fibrillation that reverted to sinus rhythm after the administration of digoxin and verapamil. Two months before he was seen by us he had an inferior myocardial infarction. Echocardiography revealed calcification of the mitral and aortic valves. There was no family history of pseudoxanthoma elasticum or atherosclerotic vascular disease. The patient reported no cigarette smoking, diabetes, hypertension, hyperlipidemia, or other risk factors for atherosclerosis. On examination there were no skin lesions. Funduscopic examination revealed angioid streaks in both eyes.
Patient 4
Patient 4 was a 32-year-old woman who had been hospitalized with congestive heart failure for two months before being seen by us. Echocardiography revealed enlargement of all cardiac chambers and diffuse biventricular hypokinesis. Swan-Ganz catheterization revealed elevated filling pressures on the right and left sides of the heart, and radionuclide ventriculography revealed a left ventricular ejection fraction of 0.25. A transudative pleural effusion and other manifestations of heart failure improved after treatment with intravenous furosemide and digoxin. Viral-antibody tests were negative. Left-heart catheterization revealed normal coronary arteries and hemodynamics but diffusely impaired left ventricular function. Endomyocardial biopsy revealed moderate myocytic hypertrophy and patchy interstitial fibrosis without evidence of vessel disease, active myocarditis, or amyloidosis.
The patient acknowledged drinking five cans (1.8 liters) of beer daily for two years but had consumed little alcohol during the four years before her visit. She reported no history of smoking, diabetes, or hyperlipidemia and no family history of cardiac disease. The patient had first been told that she was hypertensive during her recent hospitalization. On examination she was noted to have angioid streaks and was therefore referred for evaluation. There were no skin lesions. Funduscopic examination revealed mottling of the retinal-pigment epithelium and angioid streaks in both eyes. The first and second heart sounds were normal, and a fourth sound was heard. There was a grade 2 systolic murmur, but no S3 gallop.
Methods
Informed consent was obtained from the patients. Four-millimeter punch-biopsy specimens were taken from normal-appearing axillary skin in each of the patients. The specimens were stained with hematoxylin-and-eosin, elastic-tissue (Verhoeff-van Gieson), and calcium (von Kossa) stains.
Results
Verhoeff-van Gieson staining revealed characteristic fragmentation and clumping of elastic tissue in the middle and deep dermis in all the patients. With the von Kossa stain, there was staining of calcified elastic tissue in the middle and deep dermis in all the patients (Figure 2Figure 2
Von Kossa Staining of an Axillary-Skin-Biopsy Specimen from Patient 1.).Discussion
The development of cardiovascular disease in young patients should trigger a search for predisposing factors. In the absence of a marked elevation of the serum cholesterol level or other risk factors, funduscopic examination for angioid streaks is an inexpensive step that requires only brief examination with an ophthalmoscope. In patients who do not have skin lesions typical of pseudoxanthoma elasticum but who have angioid streaks, biopsy of axillary skin or scars should be performed. In our experience, every young patient with angioid streaks who has presented with premature cardiovascular disease has been found to have histologic evidence of pseudoxanthoma elasticum, whether or not skin lesions were present.
The patients described above had a number of clinical features in common. In all of them the presenting symptoms were those of cardiovascular disease; all had angioid streaks and were found to have histologic evidence of pseudoxanthoma elasticum, but the disorder was first recognized up to 15 years after the onset of cardiac symptoms.
Angioid streaks are present in the majority of patients with pseudoxanthoma elasticum. The only other conditions that are regularly associated with angioid streaks are sickle cell anemia and Paget's disease of bone,4,5 but they have also occasionally been seen in patients with hyperphosphatemia, Ehlers-Danlos syndrome, lead poisoning, trauma, pituitary disorders, and intracranial disorders. When patients are examined closely, however, the majority are found to have pseudoxanthoma elasticum. Although the diagnosis of pseudoxanthoma elasticum is straightforward in patients with extensive cutaneous lesions, it may be difficult to make in those with mild skin lesions. Angioid streaks should suggest the diagnosis.
The pattern of inheritance of pseudoxanthoma elasticum has been controversial. In one survey of patients, two autosomal dominant and two autosomal recessive patterns of inheritance were described. Autosomal dominant inheritance was found in 53 percent of the patients6. In a more recent series of patients, however, sporadic or autosomal recessive inheritance was found in more than 90 percent5. The genetic character of this disorder has become even more unclear with the recognition of histologically proved pseudoxanthoma elasticum in patients with angioid streaks who do not have skin lesions3. Since the diagnosis can be missed in family members with minimal skin lesions, an autosomal dominant pattern of inheritance may be overlooked.
Patients 3 and 4 had the sporadic form of the disease, with no family history of pseudoxanthoma elasticum. Patients 1 and 2 were sisters and had three brothers and a third sister without angioid streaks or cutaneous signs of pseudoxanthoma elasticum. A 41-year-old brother was subsequently found to have angioid streaks. Their mother was in good health, and their father, who died at the age of 69, had a history of retinal hemorrhage.
In the absence of clear-cut cutaneous lesions of pseudoxanthoma elasticum, some would consider the patients we describe to be heterozygous carriers of a recessive pseudoxanthoma elasticum gene. In the setting of heart disease, angioid streaks, and histologic evidence of pseudoxanthoma elasticum, however, it is likely that these patients have pseudoxanthoma elasticum with mild cutaneous expression. Whether the patients have dominant or recessive forms of the disorder cannot be definitively determined, however.
The first three patients presented with features typical of atherosclerotic coronary disease. In the absence of cardiac risk factors, patients presenting with myocardial infarction or other signs of atherosclerotic vascular disease at an early age should be investigated for pseudoxanthoma elasticum. The importance of establishing a diagnosis of pseudoxanthoma elasticum is demonstrated by the case of Patient 1, who underwent coronary artery bypass surgery. Unfortunately, one of the grafts selected was the internal thoracic artery, which proved to have a calcified internal elastic lamina. The patient subsequently had progressively increasing chest pain, which may have resulted from a narrowing of this graft.
Patient 4 presented with congestive heart failure caused by a dilated cardiomyopathy. Although a restrictive cardiomyopathy due to the deposition of calcified elastic tissue in the endocardium has been described,7 echocardiography revealed dilated cardiomyopathy in this patient, and there was no angiographic evidence of coronary artery disease. Pseudoxanthoma elasticum may have been coincidental; alternatively, the cardiomyopathy may have been related to hypertension, although left ventricular hypertrophy was not documented.
A number of cardiac abnormalities are associated with pseudoxanthoma elasticum, including mitral-valve prolapse8 and restrictive cardiomyopathy7. The most serious cardiac complication is a condition that resembles accelerated atherosclerosis. This has resulted in myocardial infarctions at an early age in patients with no other risk factors for atherosclerotic vascular disease9. Accelerated cardiovascular disease in patients with pseudoxanthoma elasticum has been attributed to calcification of the internal elastic laminae of arteries, including the coronary arteries. Calcification of peripheral arteries can occasionally be seen on x-ray films and results in diminished peripheral pulses. Intermittent claudication affects up to a third of patients, and hypertension has been reported as a result of renal-artery calcification1,5.
Noncardiac complications of pseudoxanthoma elasticum include loss of vision and a bleeding diathesis. There are numerous reports of gastrointestinal and uterine bleeding. Nasal bleeding and bleeding into the bladder, joints, and other organs can occur1,5. Diagnosing pseudoxanthoma elasticum is important, because some of the complications can be prevented by avoiding platelet inhibitors such as aspirin.
In summary, this report describes four patients who presented with cardiovascular disease at an early age despite the absence of cardiac risk factors. All four patients were found to have angioid streaks and histologic proof of pseudoxanthoma elasticum on skin biopsy. We suggest that a diagnosis of pseudoxanthoma elasticum be considered in any patient presenting with signs of accelerated atherosclerosis at an early age in the absence of known risk factors. Finally, arterial grafts should not be used for coronary artery bypass surgery in patients with pseudoxanthoma elasticum because of possible calcification of the internal elastic laminae.
Source Information
From the Departments of Dermatology (M.L., R.G.P.) and Pathology (R.G.P.) and the Division of Cardiology, Department of Internal Medicine (J.H.), Mount Sinai Medical Center, New York.
Address reprint requests to Dr. Lebwohl at Mount Sinai Medical Center, 5 E. 98th St., Box 1048, New York, NY 10029-6574.
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