Extra-Endocrine Features in Infancy as Early Clues to MEN2B

Multiple endocrine neoplasia type 2B (MEN2B) is a rare autosomal-dominant cancer predisposition syndrome in which prognosis is strongly influenced by the stage of medullary thyroid carcinoma at diagnosis. Virtually all affected children exhibit 1 or more extra-endocrine features during childhood, offering an opportunity for timely recognition. We retrospectively reviewed 5 pediatric patients with MEN2B managed at Bambino Gesù Children’s Hospital, all carrying the highest-risk RET proto-oncogene mutation (M918T); 4 cases were de novo and 1 was maternally inherited. In each case, genetic testing was prompted by extra-endocrine manifestations observed during infancy or early childhood, including chronic constipation, congenital clubfoot, and alacrimia. Recognition of these early clinical features led to genetic diagnosis before or at the onset of endocrine disease and enabled timely surgical management. This case series highlights the spectrum of extra-endocrine manifestations that may precede endocrine disease in MEN2B and emphasizes their value as early diagnostic clues. Early recognition of these features may facilitate prompt genetic testing and timely thyroidectomy before metastatic medullary thyroid carcinoma develops.