Abstract
Background: MEN type 2B is rare and most commonly due to a germline methionine-to-threonine substitution at codon 918 (M918T) of the RET proto-oncogene. Medullary thyroid cancer (MTC) occurs in 100% of the patients affected with the mutation. This mutation is considered the highest risk and is typically associated with aggressive disease and worse overall survival. We describe a case of a late diagnosis of MEN 2B in a patient and his son, both with a relatively indolent presentation of MTC. Clinical Case: A 39-year-old man presented to an outside institution with difficult to control hypertension, headaches and anxiety and was found to have bilateral pheochromocytomas (left, 5.8 x 5.5 x 3.8 cm and right, 9 x 5.2 x 7.3 cm). Upon presentation to our institution, he was noted to have classic phenotypic features of MEN 2B with a marfanoid habitus and multiple mucosal neuromas. Genetic testing confirmed RET M918T mutation. His family history was negative for similar features in his parents and siblings. However, one of his three children, age 12, had similar phenotypic features and was found to have the same mutation. The patient subsequently underwent a successful bilateral adrenalectomy and pathology confirmed pheochromocytomas. Thyroid ultrasound showed multiple nodules with calcifications but no lateral nodal metastases. Calcitonin and carcinoembryonic antigen (CEA) levels were elevated (170 pg/mL, normal ≤10, and 180.4 ug/L, normal <3.8, respectively). He underwent a total thyroidectomy and bilateral central node dissection, with pathology confirming bilateral MTC (2.7 cm and 1.0 cm), metastatic in 4 of 10 positive lymph nodes (largest focus 2 mm). Whole body PET/CT post-operatively did not show metastatic disease. The patient’s son also had multiple thyroid nodules on ultrasound without lateral nodal metastases and elevated calcitonin and CEA levels (3015 pg/ml, normal ≤10, and 433 ng/mL, normal <2.5, respectively). MRI of the abdomen and pelvis was negative for pheochromocytomas. He underwent total thyroidectomy and bilateral central neck dissection, with pathology showing bilateral MTC (2.7 cm and 1.0 cm) with 0 of 14 positive lymph nodes. For both the patient and his son, calcitonin and CEA levels normalized following thyroidectomy and surveillance over a year later reveals no evidence of disease. Conclusion: Early diagnosis of MEN type 2B is important as MTC develops early in life and is the leading cause of death in these patients. When diagnosed early, prophylactic thyroidectomy in childhood is indicated and can improve long-term survival. There are salient phenotypic features associated with this disease which were unfortunately not recognized early in this patient and his son. Fortunately, their MTC presentations appear to be relatively indolent despite their late diagnoses, and they will continue to be closely monitored for recurrent disease.
Identification of a secondary RET mutation in a pediatric patient with relapsed acute myeloid leukemia leads to the diagnosis and treatment of asymptomatic metastatic medullary thyroid cancer in a parent: a case for sequencing the germline