Abstract


V804M mutation in the RET Proto-oncogene has been linked to MEN2A syndrome. This mutation presents with not only medullary thyroid cancer but also papillary thyroid carcinoma. It has rarely been associated with primary hyperparathyroidism, but pheochromocytoma is not a typical finding. To our knowledge, only two cases of pheochromocytoma in this mutation have been described in the literature view more

V804M mutation in the RET Proto-oncogene has been linked to MEN2A syndrome. This mutation presents with not only medullary thyroid cancer but also papillary thyroid carcinoma. It has rarely been associated with primary hyperparathyroidism, but pheochromocytoma is not a typical finding. To our knowledge, only two cases of pheochromocytoma in this mutation have been described in the literature
A 23 year old  presented with tremors, palpitations, headache and anxiety. Her mother was diagnosed with MTC at 28 years and was found to have V804M mutation in the RET proto-oncogene. Patient underwent genetic testing and was confirmed to have V804M mutation.  She underwent thyroidectomy which showed a 0.25 cm focus of PTC, a 0.9 cm focus of C-cell hyperplasia, but no MTC.
Workup for pheochromocytoma showed normal plasma free fractionated metanephrines as well as 24hr urine metanephrines and catecholamines. CT abdomen showed 1.5cm right and 1cm left adrenal nodules, with 70-75% contrast washout at 5 mins
A repeat CT abdomen a year later showed 2.1cm right adrenal nodule with absolute washout of 60%. Biochemical workup showed normal aldosterone, PRA activity and 24hr urine free cortisol. However she was found to have mildly elevated plasma free metanephrines at 124 pg/mL (normal <57).  24hr urine catecholamines continued to be in normal limits.
A year later, patient started experiencing fainting spells and elevated BP readings. Repeat biochemical analysis showed mild elevations in plasma epinephrine (136pg/mL, limit of normal <95) and frank elevation in plasma free metanephrines (2.7, normal <0.5), plasma free normetanephrines (1.2, normal <0.9) as well as 24hr urine epinephrine (123mcg/24hr, normal <20). MRI of abdomen showed a 3.6cm right adrenal mass, with findings concerning for pheochromocytoma as well as a 0.8cm mass in left adrenal gland. MIBG scan showed uptake in right adrenal gland, suggestive of pheochromocytoma and no uptake in left adrenal gland. Repeat biochemical parameters showed progressive elevations and the patient underwent laparoscopic right subtotal adrenalectomy. Final pathology confirmed the diagnosis of pheochromocytoma and patient had normalization of biochemical markers post surgery
We have presented a case of pheochromocytoma in a patient with the V804M mutation. To our knowledge, this is only the third case in the literature. It may be prudent to screen patients with this mutation for pheochromocytoma. Current endocrine society guidelines suggest that in low risk mutations screening may be started at an older age and done less frequently with biochemical testing. However, patients may have an indolent period where the biochemical markers may initially be normal. Hence, if a patient with this mutation is known to have an adrenal mass, vigilant monitoring of the mass with imaging as well as biochemical markers may be necessary to ensure there is no progression requiring intervention.

1. Characterization of V804M-mutated RET proto-oncogene associated with familial medullary thyroid cancer, report of the largest Turkish family. Basaran MN, et al. J Endocrinol Invest. 2015 May;38(5):541-6. doi: 10.1007/s40618-014-0224-0. Epub 2014 Dec 12.2. One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: is this a new syndrome--MEN 2C? Shirfrin AL, et al. Surgery. 2009 Dec;146(6):998-1005. 3. Brandi, Maria Luisa, et al. "Consensus: guidelines for diagnosis and therapy of MEN type 1 and type 2." The Journal of Clinical Endocrinology & Metabolism86.12 (2001): 5658-5671.

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