Genetic Conditions Associated With Pheochromocytomas

Pheochromocytomas are usually sporadic. However, at least 10% are hereditary and may occur as part of

Figure 9-7. Positron emission tomographic scan showing metastatic pheochromocytomas.

certain familial syndromes. MEN type II is an autosomal dominant disorder with two distinct subtypes: MEN type IIA (Sipple's syndrome): medullary thyroid carcinoma, hyperparathyroidism, pheochromo-cytoma, or adrenal medullary hyperplasia, lichen planus amyloidosis, and Hirschsprung's disease; MEN type IIB: mucosal neuromas, intestinal ganglioneuromas, thick corneal nerves, marfanoid habitus, medullary thyroid carcinoma, and pheochromo-cytoma or adrenal medullary hyperplasia.45

In patients with a MEN type IIA genetic defect, the ultimate occurrence of medullary thyroid carcinoma is nearly 100%. However, the incidence of pheochromocytoma varies in different kindreds, ranging from 6 to 100% (average 40%), depending on the kindred. Pheochromocytomas tend to present in middle age, often without hypertension. The incidence of hyperparathyroidism has also varied, averaging 35%.46,47 Pheochromocytomas that arise in patients with MEN type IIA or IIB are usually located in the adrenal glands; extra-adrenal paragan-gliomas are rare. Individuals who belong to kindreds with MEN type IIA (Figure 9-8) or IIB (Figure 9-9) should have RET proto-oncogene mutation analysis prior to age 6 years for MEN type IIA and at diagnosis in suspected MEN type IIB to determine if they carry the autosomal dominant trait and require thy-roidectomy and close surveillance for these tumors. Each specific type of mutation in the RET gene determines each kindred's idiosyncrasies, such as the age of onset and aggressiveness of medullary thyroid carcinoma.52 Patients with the 634-point mutation are more prone to pheochromocytoma and hyperparathyroidism.48 Plasma concentrations of metanephrine are elevated early in most patients with pheochromocytoma associated with MEN type II.49 About 1% of patients with von Recklinghausen's neurofibromatosis ultimately develop pheochromo-cytomas. These tend to be at an older age. However, such patients are prone to develop vascular anomalies such as coarctation of the aorta and renal artery stenosis, which can also produce hypertension and mimic pheochromocytoma. Patients usually have areas of café au lait skin pigmentation.

In VHL disease, a mutation of the tumor suppressor VHL gene causes an autosomal dominant predisposition to hemangioblastomas in the cerebellum,

Figure 9-8. Abdominal computed tomographic scan in a 30-year-old woman with multiple endocrine neoplasia type IIA showing a left adrenal pheochromocytoma (arrow) with characteristic central necrosis. Courtesy of Quan-Yang Duh, MD.

spinal cord, and retina. About 10 to 20% of patients with VHL ultimately manifest a pheochromocytoma; such patients are usually those with VHL gene missense mutations rather than those with deletion or frame-shift mutations. Pancreatic cysts, kidney cysts, and renal cell carcinoma also occur. In a series of 36 French patients with pheochromocytoma and VHL disease, pheochromocytoma was the presenting tumor in 53%. Pheochromocytomas were bilateral in

Figure 9-9. A 26-year-old woman had severe constipation and developed multisystem failure. She was found to have a thyroid nodule and cervical lymphadenopathy. Abdominal computed tomographic scan showed bilateral adrenal tumors (arrows). Biochemical workup was consistent with pheochromocytoma, and the patient underwent open bilateral adrenal resection for pheochromocytomas followed by thyroidectomy for medullary thyroid cancer. Genetic study confirmed the clinical diagnosis of multiple endocrine neopla-sia type IIB. Courtesy of Quan-Yang Duh, MD.

Figure 9-9. A 26-year-old woman had severe constipation and developed multisystem failure. She was found to have a thyroid nodule and cervical lymphadenopathy. Abdominal computed tomographic scan showed bilateral adrenal tumors (arrows). Biochemical workup was consistent with pheochromocytoma, and the patient underwent open bilateral adrenal resection for pheochromocytomas followed by thyroidectomy for medullary thyroid cancer. Genetic study confirmed the clinical diagnosis of multiple endocrine neopla-sia type IIB. Courtesy of Quan-Yang Duh, MD.

42% and concurrent paragangliomas were present in 11%. Three had malignant pheochromocytoma. In 18%, pheochromocytoma was the only manifestation of the disease.50 Plasma normetanephrine levels are usually elevated when patients with VHL disease develop a pheochromocytoma.49

Pheochromocytomas may also occur as an isolated familial genetic syndrome. Pheochromocy-tomas occurring as part of any familial syndrome are more likely to be bilateral or associated with adrenal medullary hyperplasia than are those occurring sporadically. Hereditary paragangliomas have been attributed to mutations in three genes (SDHB, SDHC, SDHD). Individuals with such genetic proclivity require frequent clinical and biochemical screening for pheochromocytoma.49

Carney's triad generally presents in women under age 40. It consists of the triad of multicentric para-gangliomas, gastric leiomyosarcomas, and pulmonary chondromas.

Genetic screening is indicated for all patients with a family history of pheochromocytomas or paragangliomas, bilateral pheochromocytomas, or other manifestations of the genetic syndromes noted above. Such screening can be done for MEN type II RET proto-oncogene mutations, VHL mutations, and SDHB, SDHC, and SDHD mutations.51

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