SUN-286 Medullary Thyroid Cancer and Bilateral Pheochromocytomas in a MEN2A Patient with Biallelic Germline RET K666N Variant

Abstract Disclosure: M. Trieu: None. J.O. Culver: None. Y. Cardona: None. A.N. Lim: None. M.S. Swanson: None. T.E. Angell: None. Background: Multiple endocrine neoplasia 2A (MEN2A) is a hereditary syndrome associated with an increased risk of medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPTH) and is caused by pathogenic germline variants in the RET proto-oncogene. Many such RET variants cause MEN2A, with most affected individuals being heterozygous (i.e. monoallelic). Here, we report a rare presentation of MTC and bilateral PHEO due to the presence of homozygous pathogenic RET variants (i.e. biallelic), specifically, RET K666N, illustrating the phenotype-genotype correlation of this condition and highlighting the value of genetic testing and counseling. Case: A 62-year-old woman was incidentally found to have bilateral adrenal nodules on CT measuring 3.7 x 3.3 cm and 2.1 x 1.7 cm on the right and left, respectively. Workup revealed 24-hour urinary metanephrine of 2972 mcg (90-315 mcg/24 hr) and normetanephrine of 579 mcg (122-676 mcg/24 hr) suggestive of PHEO. Thyroid nodule fine needle aspiration cytology was suspicious for MTC. Serum calcitonin was 1780 pg/mL (<5 pg/mL). The diagnosis of both PHEO and MTC strongly suggested MEN2A. Parathyroid hormone and calcium concentrations were normal. After adequate preoperative preparation, bilateral laparoscopic adrenalectomy was performed confirming PHEO, and total thyroidectomy and neck dissection confirmed MTC. Germline testing found biallelic presence of the RET K666N variant. The patient was treated with hydrocortisone, fludrocortisone, and levothyroxine. She has no PHPTH, has had no recurrence of PHEO, and while serum calcitonin has remained elevated between 100-300 pg/mL, there has been no identifiable structural disease 5 years after initial surgeries. Because all of her children are obligate carriers of RET K666N, genetic counseling was recommended. Discussion: Patients who are heterogeneous for RET K666N present almost exclusively with MTC without PHEO or PHPTH, suggestive of familial MTC (FMTC). However, patients who are homozygous for RET K666N have rarely been reported. One previous case reported a 59-year-old woman homozygous for RET K666N who similarly presented with MTC and PHEO. The 24-hour urinary normetanephrine in that case was elevated, whereas here, the urinary normetanephrine level was within normal limits, adding to the understanding of how biallelic RET K666N MEN2A may present. Conclusion: Clinicians should recognize that patients with MEN2A presenting with MTC and PHEO may be homozygous for germline RET K666N despite presenting at an older age. Recognition of this with genetic testing is important because family members may be obligate heterozygotes, for which appropriate counseling and familial screening should be performed. Presentation: Sunday, July 13, 2025