# RET (C620R) Mutation in a Hirschsprung Disease Family: A Case Report Unveiling Asymptomatic Pheochromocytoma and Unmanifested Medullary Thyroid Carcinoma

## TL;DR

A family with Hirschsprung disease and a RET gene mutation had asymptomatic pheochromocytoma but no thyroid cancer, highlighting the need for tailored monitoring.

## Contribution

This case report identifies a RET (C620R) mutation in a Hirschsprung family and reveals an asymptomatic pheochromocytoma without thyroid cancer manifestation.

## Key findings

- The RET c.1858T>C (p.C620R) variant was found in a family with Hirschsprung disease.
- A pheochromocytoma was detected via plasma-free metanephrines screening in one family member.
- No medullary thyroid carcinoma was observed despite the moderate-risk RET variant.

## Abstract

RET gene variants have been reported in a proportion of patients with familial Hirschsprung disease (F-HSCR), and certain variants are also associated with hereditary medullary thyroid carcinoma (MTC). Clinical guidelines have been developed to support decision-making regarding the timing of prophylactic surgery based on individual risk stratification. These recommendations emphasize the importance of tailoring the timing of thyroidectomy to the specific risk category assigned to each genetic variant, with the goal of preventing disease progression while minimizing unnecessary intervention. We encountered a case of F-HSCR associated with the germline c.1858T>C (p.C620R) RET activating variant in exon 10, which is known to confer moderate risk for MTC. Although only a limited number of MTC cases have been reported in the context of Hirschsprung disease (HD), and it remains unclear whether the management should align with that of MEN2A, we initiated surveillance for MTC in this family. No elevation of key markers, including carcinoembryonic antigen (CEA) or calcitonin, was observed, and no cases of MTC were detected across generations. However, a pheochromocytoma (PHEO) was diagnosed in one family member through screening for plasma-free metanephrines (fMNs). We present our findings in this family and provide a review of relevant literature.