This 11-year-old boy was well until 2 weeks before admission, when he developed emesis, decreased appetite, and low-grade fever. One week before admission, he was seen by a physician and diagnosed with “stomach flu.” However, a heart murmur was heard, and it was noted that his pulse was 140 bpm, and his blood pressure was 100/60. He had no outpatient testing at that time.
Two days later, he had a normal chest X-ray and an ECG that revealed sinus tachycardia, right atrial enlargement, and possible left ventricular hypertrophy. Echocardiography revealed nonobstructive hypertrophic cardiomyopathy with biventricular hypertrophy.
His past history was remarkable for pneumonia at 4 to 5 months that required hospitalization. Review of systems was unremarkable. In particular, he had no history of palpitations, shortness of breath, chest pain, headaches, syncope, or sweating. The family history was remarkable in that the maternal grandfather had a myocardial infarction at 48 years.
On exam, the patient was an alert, healthy-appearing boy. Initial vital signs were pulse 116, respiratory rate 20, blood pressure 128/43. Weight was in the 40th percentile, height in the 15th percentile. HEENT exam was unremarkable. Neck was supple. There was no thyromegaly. Lungs were clear. S1 was normal. S2 was physiologically split.
There was III/VI systolic murmur heard best along the left sternal board at the apex. There were no gallops. Pulses were 2+ and symmetric. Abdomen was soft, without masses or organomegaly. Extremities were normal. There were no rashes. On initial evaluation, CBC with differential, Chem 14 and chest X-ray were normal.
Robert Listernick, MD, moderator: What’s the differential diagnosis of hypertrophic cardiomyopathy?
Barbara Deal, MD, pediatric cardiologist: Hypertrophic cardiomyopathy is the most common cause of sudden death in athletes. It typically occurs in healthy, young adolescents who have no cardiac findings and who present with a catastrophic outcome. So it’s not surprising that he didn’t have symptoms. Hypertrophic cardiomyopathy may be secondary to a number of conditions, including long-standing hypertension, volume overload, anemia, or the use of drugs, such as anabolic steroids.In addition, there are a number of primary causes, including: inborn errors of metabolism (eg, Pompe disease); malformation syndromes (eg, Noonan syndrome); and a number of autosomal dominant disorders involving numerous different proteins, all leading to familial cases of hypertrophic cardiomyopathy.
Dr. Listernick: Because you brought it up, how do you distinguish between a normally enlarged athlete’s heart and a pathologic condition?
Dr. Deal: Generally, it’s a matter of degree, but the distinction may be difficult. That’s the basis of the reluctance of the athletic associations to perform screening echocardiograms. Our patient had an unequivocally abnormal echocardiogram.
Dr. Listernick: Two hours after admission, his blood pressure was 220/140 and pulse 122 without any symptoms or change in his clinical status.
Donald Zimmerman, MD, pediatric endocrinologist: Clearly, the diagnosis that immediately springs to mind in someone who has episodic severe hypertension is pheochromocytoma. The most reliable tests for diagnosing pheochromocytoma would be to measure metabolites, especially metanephrine and normetanephrine, in the plasma and in a 24-hour urine collection.
Dr. Listernick: Do different tumors secrete different metabolites?
Dr. Zimmerman: Absolutely. Normetanephrines, the metabolites of norepinephrine, are secreted by all sympathetic-derived structures, whereas metanephrine is derived from epinephrine, which is made only in the adrenal cortex. If normetanephrine is elevated but metanephrine is not, the tissues secreting the hormones may or may not be adrenal. However, if only metanephrine is elevated, the tumor is adrenal in origin.
Dr. Listernick: Once the diagnosis became obvious, additional family history was obtained. The child’s biological father and his father’s sister had pheochromocytomas removed. Why they didn’t tell us initially is anybody’s guess. How do pheochromocytomas generally present?
Dr. Zimmerman: Approximately half the time, patients have sustained hypertension yet widely fluctuating blood pressures, even hypotension if the tumor secretes epinephrine. The other half has paroxysmal symptoms, including pounding headache, palpitations, inappropriate sweating, fevers, tremor, weight loss, and anxiety. The first contact with a physician may be with the primary care physician or any number of subspecialists, including a psychiatrist.
Dr. Listernick: Now we have a tentative diagnosis and the urine and serum catecholamine testing was sent. What’s next?
Tamar Ben Ami, MD, pediatric radiologist: While you’re stabilizing the patient, it would be helpful to try to localize the tumor. In our patient, it was fairly easy. The initial study was a cardiac MRI because it was thought that he had a cardiomyopathy before he became hypertensive. A right-sided adrenal mass was identified.
Dr. Listernick: If the cardiac MRI had not been done, what would have been an appropriate initial study?
Dr. Ben Ami: Ultrasonography is an easily performed and noninvasive first step. Almost certainly, the next step would be CT or MRI of the abdomen. The ultrasound revealed a large right suprarenal mass.Although there has been some controversy whether the intravenous contrast used with CT scans might precipitate a hypertensive crisis in an individual who has pheochromocytoma, this doesn’t seem to be the case with the newer agents. Nevertheless, he underwent MRI of the abdomen that showed an additional smaller mass on the left side.
Kathy Barsness, MD, pediatric surgeon: At this point, I decided to perform a metaiodobenzylguanidine (MIBG) scan. Although the lesion on the right was well-localized to the adrenal gland, I couldn’t tell whether the left-sided mass was arising from the adrenal gland or was separate from it. I needed to know whether both adrenal glands needed to be removed.
Dr. Ben Ami: MIBG is structurally similar to norepinephrine and is incorporated into the neurosecretory granules of pheochromocytoma. Whereas CT scans might miss a small extra-adrenal pheochromocytoma, MIBG scans allow for whole body scanning. MIBG scans are excellent for detecting extra-adrenal tumors or metastatic and recurrent disease.There are very few false-positive scans, although MIBG will also be taken up by neuroblastoma and carcinoid tumors. It is probably best used in patients in whom pheochromocytoma is suspected but catecholamine testing is negative. Both the masses in our patient brightly lit up.
Dr. Listernick: So now we know that he needs surgery. What are the issues regarding his preoperative management?
Babette Horn, MD, pediatric anesthesiologist: The operative mortality of anesthetizing a patient with an untreated or unprepared pheochromocytoma verges on 50%. These patients have to be carefully prepared for surgery. You need to establish blockade of the autonomic nervous system from the effects of circulating epinephrine and norepinephrine.However, the order you establish this blockade is critical. Alpha blockade should be established first; if you start with beta blockade, the patient will develop severe hypertension from unopposed alpha activity. Alpha blockade should be considered successful when the blood pressure improves and the circulating plasma volume increases because of a relaxed peripheral vascular system as evidenced by a drop in the hematocrit. When this occurs, beta blockade can be started.
Dr. Listernick: What pharmacologic agents did you use?
Dr. Horn: We started with doxazosin, which is a competitive selective alpha-1 blocker. In the past, phenoxybenzamine, a non-selective alpha-blocker, had been used, but the incidence of side effects was much greater.In addition, phenoxybenzamine is a very long-acting agent; its effects, and the resultant hypotension, are difficult to control postoperatively. Once alpha blockade was accomplished, beta blockade was initiated with propranolol. He was in the intensive care unit for 2 weeks before he was adequately prepared for surgery. The general rule of thumb is that the blood pressure should not be higher than 140/90 to 150/90 for 24 hours before surgery.
Dr. Listernick: Tell us about the surgery.
Dr. Barsness: The traditional teaching is to make a very large incision so that the surgeon is able to manipulate the tumor as little as possible. Anytime you touch the tumor you run the risk of “squeezing out” catecholamines, creating a hypertensive crisis.In addition, we’re taught to ligate the feeding vein first to decrease blood flow from the tumor. In theory that’s great, but the vein is approximately 4 mm in diameter and often difficult to manipulate.As a minimally invasive surgeon, I approached the right tumor in the retroperitoneum laparoscopically. The larger 7-cm tumor was easily seen, but one part of it was extremely sensitive to touch and his blood pressure intermittently skyrocketed.Ultimately, we were able to remove the tumor. However, the left-sided 3-cm tumor was 0.5 cm from the superior mesenteric artery and was overlying the renal vein and completely wrapped around the aorta. Despite mobilizing the colon and working on the tumor for more than 1 hour, it was so densely adherent to the local structures that we finally decided to perform an open procedure.So, both adrenal glands were removed. I was concerned that the smaller tumor might be malignant because it was so adherent locally, and that it was actually a lymph node metastasis from the adrenal gland.
Dr. Listernick: How did you manage the blood pressure intraoperatively?
Dr. Horn: The blood pressure would suddenly rise dramatically, then bottom out. We needed to use very short-acting agents that could immediately respond to these changes. For lowering the blood pressure, we used a nitroprusside infusion as well as esmolol. The hypotension responded to administration of intravenous boluses of fluid.Once the tumors were removed, the patient had “vasomotor paralysis” and required continuous infusions of dopamine, epinephrine, and norepinephrine to maintain his blood pressure. We also gave him dextrose-containing fluids because there is a risk of profound hypoglycemia once the tumors are removed.
Dr. Listernick: Can we see the pathology?
Elaine Cham, MD, pediatric pathologist: Pheochromocytomas are tumors arising from the chromaffin cells of the adrenal medulla. We cannot distinguish histologically between benign and malignant tumors; perhaps in the future, molecular testing will help with that distinction.The right adrenal mass had a classic appearance of pheochromocytoma within which there were areas of hemorrhage. The left paraspinal mass was extra-adrenal, pushing up on the adrenal cortex; this represented a paraganglioma. Paragangliomas are tumors arising from the neuroendocrine ganglia distributed in the paraspinal tissues. Tumors arising from sympathetic ganglia generally secrete catecholamines, whereas those arising from parasympathetic ganglia are usually nonsecretory.
Dr. Listernick: How do we account for the family history?
Dr. Zimmerman: There are several familial syndromes in which pheochromocytomas arise. First, Von Hippel-Lindau disease, an autosomal dominant tumor suppressor syndrome, is characterized by the presence of pheochromocytomas, hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts. Hereditary paraganglioma-pheochromocytoma syndrome is caused by an autosomal dominant mutation in one of four genes responsible for the mitochondrial enzyme succinate dehydrogenase.Finally, pheochromocytomas can be seen in multiple endocrine neoplasia 2A and multiple endocrine neoplasia 2B, caused by activating mutations in the ret proto-oncogene. Given the lack of any other tumors in this family, we suspected that they had hereditary paraganglioma-pheochromocytoma syndrome.
Dr. Listernick: Let’s not forget about neurofibromatosis-1, although pheochromocytoma is almost unheard of in these children. Genetic testing of this child is pending. How will you follow this child?
Dr. Zimmerman: Assuming we identify a mutation in one of the genes responsible for succinate dehydrogenase, we’ll perform yearly metanephrines and ultrasonography, as well as MRI scans of the chest and abdomen at least every 3 years. Of course, all the other first-degree relatives of the father should be tested for the mutation if one is identified.
Dr. Listernick: Thank you, everyone.