Identifying hereditary PGL-PCC syndromes just got easier

Pheochromocytomas (PCCs) are rare tumors of the adrenal medulla; paragangliomas (PGLs) are equally uncommon tumors that arise in the sympathetic and parasympathetic paraganglia. Both pheochromocytomas and sympathetic PGLs secrete catecholamines, which can cause classic symptoms such as headache, sweating, palpitations and, in some patients, hypertension. Tumors that develop along the parasympathetic chain in the head and neck usually don't produce catecholamines but, depending on size and location, may lead to hearing loss or dysphagia.

Pheochromocytomas and paragangliomas are mainly benign — about 13 percent of PCCs and 20 percent of paragangliomas are malignant. Patients with metastatic disease have a poor prognosis, with a five-year survival rate of 40 to 45 percent.

Hereditary PCCs and PGLs

Genetic conditions such as von Hippel-Lindau disease and multiple endocrine neoplasia, type II, have traditionally been associated with an increased risk of pheochromocytoma. More recently, germline DNA mutations in subunits of the succinate dehydrogenase (SDH) gene family — including SDHA, SDHB, SDHC and SDHD — have been identified as causes of hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndromes. Mutations of the succinate dehydrogenase assembly factor 2 (SDHAF2), the transmembrane protein 127 (TMEM127) and the MAX-gene also are associated with PGL-PCC syndromes.

Douglas L. Riegert-Johnson, M.D., a gastroenterologist and medical geneticist at Mayo Clinic in Florida, says SDH gene family mutations should be considered in all patients presenting with PCCs and PGLs, especially those with multiple, bilateral, multifocal or recurrent tumors, early onset (before age 40) or a family history of a pheochromocytoma or paraganglioma.

"It's important to identify patients with hereditary paraganglioma or pheochromocytoma disease for several reasons," he points out. "Treatment for hereditary tumors may be different; some subtypes, particularly SDHB, are more aggressive and require more aggressive treatment and follow-up. Patients who have undergone resection of a pheochromocytoma or paraganglioma in the setting of a hereditary syndrome require lifelong follow-up with MRI and blood and urine testing. And because about 50 percent of children of patients with a hereditary cause will inherit the tumor predisposition, screening of children and other family members can also be important."

In the past, patients had to persist until they found a physician who understood the syndromic presentation or noticed a familial pattern. Diagnosis can be challenging, however, because many people with hereditary PGL-PCC syndrome may present with a single tumor of the head, neck, abdomen or adrenal gland without any family history of the disorder.

Furthermore, family history itself can be complicated. SDHD mutations, for instance, only cause disease when inherited from the father. Children of a woman with these mutations will not have an increased tumor risk, but if she has a son who inherits the mutation, any offspring of his who also inherit it will be at higher risk.

To help identify those people who may have inherited disease, Mayo Clinic physicians are now implementing a screening test — SDHB tumor immunohistochemistry — that will be offered to all patients presenting with pheochromocytomas and paragangliomas. Patients with a positive screening test will be offered confirmatory DNA genetic testing.

Two Mayo Clinic researchers are helping develop the screening test — William F. Young Jr., M.D., in Rochester, Minn., and Kevin J. Wu, M.D., a pathologist in Florida.

"We will be one of the only institutions in the world offering this test, and it will be available before the end of 2014," Dr. Riegert-Johnson notes.