Paraganglioma and Pheochromocytoma Syndrome with Rare Genetic Mutation

Bilateral pheochromocytoma and paragangliomas are often associated with genetic syndromes and rarely have been associated with MSH2 mutations.

Case Description:

A 63-year-old female presented with anxiety elevated blood pressures, fatigue, and incidental findings of bilateral adrenal masses over several years. She has a history of type 2 diabetes, primary hypothyroidism, obesity, tobacco use, and weight gain. She had a history of hyperparathyroidism status post-surgical resection. Medications included lisinopril, Jardiance, Zoloft, Ozempic and pitavastatin, Tresiba and levothyroxine. She had a cortisol of 1.3 mcg/dL after 1-mg dexamethasone. DHEA-S was 34 (9.7 - 159 mcg/dL), Aldosterone of 11 (< =21 ng/dL), renin was 34 ng/mL/h. 24-hour urine normetanephrines were elevated at 1688 (138-521 normotensive) and norepinephrine at 261 (15 - 80 mcg/24 h). 24-hour total metanephrines were 1884 (171-616 mcg/24 h). Computerized tomography (CT) of the abdomen and pelvis showed bilateral adrenal gland nodules, measuring 1.8 cm on the right with a non-contrast Hounsfield (HU) of 27; a 2 cm on the left with a HU of 32; and an additional 1.7 cm left nodule with a HU of 25. She also had a pedunculated 2.6 x 1.2 cm right bladder wall mass and was incidentally noted to have thickened endometrium and a 3 cm pelvic cystic lesion. DOTATATE positron emission tomography (PET) showed hyperenhancement of the bladder mass (standardized uptake value (SUV) 250), bilateral adrenals (SUV 96.6 on the right and 81.3 on the left). No other findings seen elsewhere. With structural and biochemical concern for pheochromocytoma/paraganglioma (PPGL) as well as history of hyperparathyroidism, genetic testing was performed, which only revealed a MSH2 mutation. Patient was started on alpha blockade and beta blockade with doxazosin and metoprolol, but also required amlodipine. She is scheduled for surgery with right sided cortical-sparing adrenalectomy, left-sided adrenalectomy, intra-operative cystoscopy followed by open surgical bladder resection, and endometrial biopsy with hysterectomy.

Discussion:

Paraganglioma and pheochromocytoma syndromes are exceedingly rare. 35-40% of PPGL harbor germline mutations, hence all patients should be considered for genetic testing. The hereditary conditions most commonly involved include multiple endocrine neoplasia types 2a and 2b, von Hippel-Lindau disease, and neurofibromatosis. Genetic testing includes SDHx (AF2, A, B, C, D), RET, NF1, VHL, MAX, or TMEM127. Hereditary syndromes can be associated with other tumors including gastrointestinal stromal tumors (GIST) tumors, renal cell carcinoma, pulmonary chrondromas and other tumors. MSH2 is a tumor suppressor gene and mutations of this gene are most often associated with Lynch syndrome though it has been reported in adrenocortical carcinoma. This mutation has rarely been associated with PPGL. There are an increasing number of cases reporting coexistence of Lynch Syndrome and neuroendocrine tumors, though not necessarily PPGL. Further study is needed to determine the significance of an association with Lynch and PPGL and whether the MSH2 mutation drives PPGL progression.