The familial MEN syndromes are characterized by clustering of benign and malignant endocrine tumors and other systemic manifestations. MEN type 1 includes combinations of more than 20 different types of tumors, but the most characteristic are tumors of the parathyroid, pituitary, and pancreatic glands. The term multiple refers both to the occurrence of multiple tumors in the same gland and to multiple different kinds of tumors in the same individual and/or family. MEN1 is inherited as an autosomal dominant disease with variable penetrance and a prevalence of 1 in 30,000 to 1 in 50,000.98 The MEN1 gene has been localized to chromosome 11q13 and encodes a protein called menin. Menin is thought to interact with one or more transcription factors in the nucleus, and loss of its function is thought to be the mechanism of tumor formation in the syndrome.99 Much of the morbidity associated with this syndrome is attributable to the excess production of hormones. Hyperparathyroidism from parathyroid tumors is the most common (more than 90%) and earliest manifestation of the syndrome, occurring in the third decade of life and involving three or all four parathyroid glands. Enteropan-creatic islet cell tumors occur in 30% to 75% of MEN1-affected individuals and usually present with symptoms of hormone excess after age 40 years. Tumors occur both in the pancreas and in the duodenum and are commonly multi-centric. Hormones secreted by pancreatic islet cell tumors can include chromogranin A and B, pancreatic polypeptide, glucagons, insulin, proinsulin, somatostatin, gastrin vaso-active intestinal polypeptide (VIP), serotonin, calcitonin, growth hormone (GH)-releasing factor, and neurotensin.99 The prevalence of pituitary adenomas in MEN1 ranges from 10% to 60%, and most are less than 1 cm in diameter. Other rare manifestations of MEN1 include carcinoid tumors, adrenal cortical hyperplasias, lipomas, and angiofibromas.
MEN1 germ-line mutation testing is recommended for index cases with clinical MEN1 manifestations and their at-risk relatives. Periodic biochemical testing for hormone excess is a less efficient alternative. Management of MEN1 tumors includes surgery as well as medical management of hormone-secreting tumors. The treatment of choice for primary hyperparathyroidism is total parathyroidectomy, with immediate autotransplantation of parathyroid tissue to an accessible site, usually the forearm.100 Subtotal parathy-roidectomy is associated with a high rate of subsequent recurrence. Insulinomas are often treated with surgical resection because of the difficulty in achieving medical management. Surgery for other islet cell tumors is controversial, as most are multicentric and can often be managed medically. Treatment of pituitary tumors depends on the type of adenoma but does not differ from that for sporadic pituitary tumors. Regular screening for hormone excess in known or suspected mutation carriers is controversial. If elected, annual biochemical screening should begin in early childhood and continue for life. Tumor imaging [e.g., magnetic resonance imaging (MRI) of the pancreas and pituitary] are recommended every 3 to 5 years.99
As in MEN1, the MEN2 syndromes represent several variants of benign and malignant tumors, all of which, however, show a high penetrance for medullary thyroid cancer (MTC), a rare calcitonin-producing tumor of the parafollicular cells of the thyroid gland.99 All MEN2 syndromes are caused by germ-line mutations that activate the RET proto-oncogene, located on chromosome 10q11.2, which encodes the RET (rearranged during transfection) protein, a tyrosine kinase receptor expressed in tumors of neural crest origin.101 RET activates several downstream pathways involved in cell growth, survival, and differentiation.102 MEN2A, which accounts for 90% of all MEN2 cases, is characterized by MTC in 90% of mutation carriers, unilateral or bilateral pheochro-mocytomas, tumors of the adrenal chromaffin cells, in 50% of carriers, and multicentric parathyroid tumors in 20% to 30%. MEN2B accounts for 5% of MEN2 cases and is characterized by MTC, pheochromocytoma, and developmental abnormalities including mucosal and intestinal ganglioneu-romatosis, marfanoid habitus, neurofibromas, and medullated corneal nerve fibers. MTC in MEN2b occurs at an earlier age and is thought to have a more aggressive course. MTC in multiple family members (four cases or more) is the only manifestation of familial MTC (FMTC) and is thought to have a more benign course. Other rare variants include MEN2A with cutaneous lichen amyloidosis and MEN2A or FMTC with Hirschsprung's disease.
DNA sequencing for RET mutations is clinically available and is indicated for all index cases and their at-risk relatives. Approximately 2.5% to 7% of mutations in RET are spontaneous new mutations, and therefore, genetic screening is recommended for all individuals with MTC, regardless of family history. RET mutations exhibit a characteristic geno-type-phenotype correlation, with specific mutations associated with each variant of the syndrome. Because C cell hyperplasia is a precursor lesion to MTC, serum calcitonin levels provide an excellent tumor marker, particularly to monitor the tumor status of those diagnosed with MTC. Primary prevention is recommended in mutation carriers, however, with total thyroidectomy in childhood (before age 5 years in MEN2a and before 1 year in MEN2B). Pheochromo-cytomas usually present at a later age than MTC (between 30 and 40 years) with intractable hypertension and/or hypertensive crisis. Screening for pheochromocytoma is done by measurement of plasma metanephrines or 24-hour urinary catecholamines or metanephrines.99 Abdominal MRI is performed to confirm the diagnosis in suspected cases. Prophylactic adrenalectomy is not recommended because of the dangers of adrenal insufficiency. Hyperparathyroidism may present with hypercalciuria or renal calculi but is often asymptomatic. MEN2-associated hyperparathyroidism is managed in a manner similar to sporadic forms.
There are several other rare genetic syndromes associated with cancer susceptibility, including basal cell nevus syndrome, von Hippel-Lindau syndrome, retinoblastoma, and neurofibromatosis (see Table 25.1), which are described in depth by Offit.1
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