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A 16-year-old boy presents to his primary care physician after noticing an asymmetric enlargement in his neck. On exam, several masses are noted on his tongue. He also has a Marfanoid body habitus. The tongue masses are later identified as neuromas. Thyroidectomy reveals medullary thyroid cancer. What is the most likely genetic cause of this child's disorder?

A. Multiple endocrine neoplasia 2B (MEN2B) due to a gain-of-function mutation in the RET proto-oncogene

B. Multiple endocrine neoplasia 1 (MEN1) due to an inactivating mutation in the RET proto-oncogene

C. MEN1 due to a germline mutation in the MEN1 gene

D. MEN2B due to a mutation in the PRKARIA gene

E. McCune-Albright syndrome due to activating mutations of the G-protein subunit of adenyl cyclase system

Answer: A

With the patient's history of medullary thyroid cancer combined with neuromas on his tongue and Marfanoid body habitus, the patient most likely has MEN2B (Table 530-2). MEN2 syndromes, which are inherited in an autosomal dominant pattern, are caused by a gain-of-function mutation in the RET proto-oncogene, not an inactivating mutation of the gene.

MEN1, which encodes the tumor suppressor gene MENIN, is mutated in MEN1. The parathyroid glands, pituitary gland, and pancreatic islet cells are most often affected in MEN1. The most common endocrine abnormality in MEN1 involves hypercalcemia due to hyperparathyroidism. Pancreatic tumors, including gastrinomas and insulinomas, are the second most common endocrine problem in MEN1. Pituitary tumors occur in > 40% of MEN1 patients; prolactinomas are the most common, followed by tumors secreting growth hormone and adrenocorticotropic hormone (ACTH). The PRKARIA gene is responsible for Carney complex, which involves pituitary-independent Cushing syndrome along with an association of heart myxomas and lentigines. Activating mutations of the G-protein alpha subunit are associated with McCune-Albright syndrome, which presents with autonomous endocrine function, fibrous dysplasia, and/or café-au-lait macules.

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TABLE 530-2 DISEASE ASSOCIATIONS IN THE MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES
Multiple Endocrine Neoplasia Type 1
Parathyroid hyperplasia or adenoma
Islet cell hyperplasia, adenoma, or carcinoma
Pituitary hyperplasia or adenoma
Less common: carcinoid, pheochromocytoma, subcutaneous or visceral lipomas, cutaneous lichen amyloidosis
Multiple Endocrine Neoplasia Type 2
MEN2A
Medullary thyroid carcinoma
Pheochromocytoma
Parathyroid hyperplasia or adenoma
MEN2B
Medullary thyroid carcinoma
Pheochromocytoma
Mucosal and gastrointestinal neuromas
Intestinal neuronal dysplasia (presents like Hirschsprung disease)
Marfanoid features
Mixed Syndromes
Carney complex
Myxomas of heart, skin, and breast
Spotty cutaneous ...

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