Introduction:

Multiple endocrine neoplasia type 2A (MEN2A) syndrome caused by a pathogenic germline mutation in the RET protooncogene, is  amongst other things associated with increased risk of medullary thyroid carcinoma (MTC). Mostly, MEN2A is diagnosed at genetic screening after clinically apparent disease is found in an index patient. In patients harboring the mutation, prophylactic thyroidectomy is considered. We describe a family with a mutation in the RET as incidental finding at whole genome sequencing (WGS) and critically discuss the consequences.

Case description:

A 57 year old woman was referred because of a Val804Met mutation in the RET protooncogene found at WGS performed because of a coagulation disorder. Subsequent screening showed the same mutation in 5 family members (2 male,3 female, median age 50yr). Affected individuals underwent neck ultrasound and biochemical screening for MTC , pheochromocytoma and hyperparathyroidism. No evidence for MEN2A related diseases was found, except for slightly elevated calcitonin in 2 patients (4.6 and 3.4 pmol/l respectively , normal <2.8 pmol/l).  There were no symptoms of MEN2A related diseases in deceased family members. Watchful waiting was chosen, including regular neck ultrasounds and biochemical screening. So far, median follow-up is 11 months (range 6-15).

Discussion:

The absence of MEN2A related diseases suggests low penetrance of the Val804Met mutation. All but one of our patients were > 49 years, none had evidence of MTC. Our observation is in line with recent literature challenging the routine thyroidectomy in cases with Val804Met mutation, based on an estimated penetrance of this specific mutation of only 4%. Especially when this mutation is incidentally found, thyroidectomy should not be performed routinely.