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RET proto-oncogene testing in infants presenting with Hirschsprung disease identifies 2 new multiple endocrine
Elizabeth A Fialkowski1, Mary K DeBenedetti, Jeffrey F Moley
1Washington University School of Medicine, Saint Louis, MO 63110, USA. fialkowskie@wudosis.wustl.edu
Background:
Multiple endocrine neoplasia 2A (MEN 2A) is a genetic syndrome manifesting as medullary thyroid carcinoma (MTC), hyperparathyroidism, and pheochromocytoma. Multiple endocrine neoplasia 2A results from mutations in the RET proto-oncogene. Hirschsprung disease (HSCR) is a rare manifestation of MEN 2A and has been described in known MEN 2A families.
Methods:
Here we describe 2 MEN 2A families that were only identified after the diagnosis of HSCR.
Results:
Kindred 1: A boy presented in infancy with HSCR. Genetic screening revealed a C609Y mutation, which is consistent with MEN 2A. Evaluation of his sister, father, and grandmother revealed the same mutation. All 3 had thyroidectomies demonstrating C-cell hyperplasia. The grandmother had a microscopic focus of MTC. Kindred 2: An infant boy and his sister were diagnosed with HSCR as neonates. Genetic testing demonstrated a C620R gene mutation consistent with MEN 2A. Total thyroidectomies revealed metastatic MTC in the father and C-cell hyperplasia in both children.
Conclusions:
Hirschsprung disease can be the initial presentation of MEN 2A. We strongly recommend that genetic screening be performed in patients presenting with HSCR, looking for the known RET mutations associated with MEN 2A. If a mutation consistent with MEN 2A is detected, genetic screening of all first-degree relatives in the kindred is recommended.
Insights
Hirschsprung disease (HSCR) can be the first sign of Multiple Endocrine Neoplasia 2A (MEN 2A), a genetic disorder. Genetic screening for RET mutations in HSCR patients and their families is recommended for early diagnosis and management.
Area of Science:
- Genetics
- Endocrinology
- Pediatrics
Background:
- Multiple Endocrine Neoplasia 2A (MEN 2A) is an inherited disorder characterized by medullary thyroid carcinoma, hyperparathyroidism, and pheochromocytoma, caused by RET proto-oncogene mutations.
- Hirschsprung disease (HSCR), a rare congenital condition affecting the large intestine, is an uncommon but recognized manifestation of MEN 2A.
Observation:
- This study details two families where MEN 2A was diagnosed only after patients presented with HSCR.
- In one family, a boy with HSCR carried a C609Y RET mutation; his relatives showed C-cell hyperplasia or medullary thyroid carcinoma (MTC).
- In the second family, infants with HSCR had a C620R RET mutation; their father had metastatic MTC, and the children had C-cell hyperplasia.
Findings:
- HSCR can be the initial clinical presentation of MEN 2A.
- RET proto-oncogene mutations associated with MEN 2A were identified in patients with HSCR.
- Affected family members exhibited varying degrees of thyroid pathology, from C-cell hyperplasia to MTC.
Implications:
- Genetic screening for RET mutations in patients with HSCR is crucial for identifying potential MEN 2A cases.
- Early diagnosis of MEN 2A through HSCR screening allows for timely intervention and management of associated endocrine tumors.
- Screening first-degree relatives of individuals with identified MEN 2A-associated RET mutations is recommended to detect the syndrome early.
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