Poster number MON 146 A Cough with an Adrenal Surprise First Case Report of Codon C609Y Presenting with Pheochromocytoma Inga Harbuz-Miller, MD1; Jennifer Woods, RN2; Robert Zitsch, MD3 and Camila Manrique, MD1; 1. Division of Endocrinology, Dept of Medicine; 2. Multidisciplinary Thyroid and Parathyroid Clinic; 3. Dept of Otolaryngology; University of Missouri, Columbia, Missouri

RET proto-oncogene Germline mutations of RET proto-oncogene are associated with the pathogenesis of multiple endocrine neoplasia syndromes (MEN2A, MEN2B), Hirschsprung disease, and familial medullary thyroid carcinoma. It contains more than 60kb of genomic DNA and is located on chromosome 10q11.2. It is a “gain of function” mutation – regulating differentiation, proliferation, migration and survival in the cells derived from neural crest, branchial arches, neural cells, and urogenital system. Codon C609Y mutation has been reported in the literature to be associated with late onset medullary thyroid carcinoma (MTC). There are no reports to date on pheochromocytoma as initial presentation associated with C609Y mutation.

Case presentation A 67-year-old woman with a history of hyperlipidemia, type 2 diabetes, coronary artery disease, COPD and osteoarthritis, presented with persistent cough and left-sided chest pain. A computed tomography (CT) of the chest revealed a left upper lobe consolidation consistent with pneumonia and the incidental finding of a right adrenal mass measuring 5.6 x 7.8 cm.

Fig. 1. Abdominal CT, transverse view, Right adrenal mass (arrow) Fig. 2. Abdominal CT, coronal view Right adrenal mass (arrow)

Patient denied complaints of diaphoresis, headache, palpitations and reported no history of paroxysmal elevation of blood pressure. She was not on antihypertensives. Her medication list included acetaminophen for pain, tiotropium and albuterol inhalers for COPD, metformin and glimepiride for diabetes and pravastatin for hyperlipidemia.

Preoperative biochemical evaluation revealed: Preoperative biochemical evaluation revealed: - a normal metabolic panel including calcium corrected to albumin - elevated plasma and urine metanephrines as in Figure 1. Table 1. Pre-op biochemical profile

Treatment and follow up Patient was treated with 10 mg of prazosin twice daily pre-op. She underwent total right adrenalectomy with a 10 x 9.5 x 5.5 cm pheochromocytoma, staged P2NxM0 Due to financial constraints, she declined genetic counseling at the time of diagnosis. She returned three years later after several nieces were diagnosed with MEN2A Genetic testing that detected a mutation of RET proto-oncogene p.C609Y: amino acid change: (Cys609Tyr), DNA change: c.1826G>A (g.43609070).

Fig. 3. Family pedigree with C609Y codon RET protooncogene mutation

Why is RET gene mutation clinically important? Identifies disease phenotypes associated with specific RET mutations Guides therapy and follow up planning ATA guidelines for the management of MTC risk stratifies the mutations as: highest risk category - RET codon M918T mutations,   high-risk category - RET C634 and A883F mutations, moderate risk category – all the other RET mutations C609Y is a moderate risk mutation

Discussion Codon C609Y mutation has not been describes previously with pheochromocytoma as the initial presentation and this is the first case report. Frank-Raue K, et al. described a population of four families in Europe with eight carriers of the mutation C609Y: seven females and one male. The median age at diagnosis of MTC was 33 years old (21-49) and zero pheochromocytomas were identified In the United States, Quayle, et al. described a cohort of 323 patients with RET mutation. The expression of pheochromocytoma varied by amino-acid substitution. None of 23 patients with MEN2A and carrier of codon C609Y had pheochromocytoma.

Conclusions Our patient remains asymptomatic. She has a persistently mild elevation of plasma free metanephrines Metastatic workup remains negative (CT chest/abdomen/pelvis and MIBG). Neck ultrasound without thyroid masses and normal calcitonin level. Due to C609Y association with moderate risk MTC we will continue active biochemical (calcitonin and metanephrines - yearly) and radiological surveillance. Genetic counseling has been offered to her first-degree relatives.

References and Acknowledgements Frank-Raue K, Rybicki LA, Erlic Z, et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat. 2011;32(1):51-8. doi: 10.1002/humu.21385 Calva D, O’Dorisio TM, Sue O’Dorisio M, et al. When Is Prophylactic Thyroidectomy Indicated for Patients with the RET Codon 609 Mutation? Ann Surg Oncol. 2009;16(8):2237-44. doi: 10.1245/s10434-009-0524-3 Wells SA, Asa SL, Dralle H, et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma: The American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Thyroid. 2015;25(6):567-610. doi:10.1089/thy.2014.0335.  Melmed S, Polonsky K, Larsen PR, et al. Chapter 39. In: Williams Textbook of Endocrinology. 13th ed. Elsevier; 2011. Quayle FJ, Fialkowski EA, Benveniste R, Moley JF., Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery. 2007 Dec;142(6):800-5; discussion 805.e1. Erratum in: Surgery. 2008 Feb;143(2):301. Acknowledgements : This work was supported by National Institutes of Health funding through the K08HL129074-01 to CM Thanks to Brenda Hunter and Meg Duffy for editorial and printing assistance

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