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RESUMEN

La neoplasia endocrina mltiple de tipo 1 (MEN1) es un sndrome tumoral hereditario poco


frecuente. Se caracteriza por la presencia de tumores de la paratiroides, del pncreas endocrino y
de la hipfisis anterior. La penetrancia es extremadamente alta y la frecuencia es igual para ambos
sexos. La prevalencia es de aproximadamente 1 de cada 30.000 personas. Se han descrito tanto
casos familiares como espordicos. La forma espordica se caracteriza por la presencia, en un solo
paciente, de dos de los tres tumores principales que se relacionan con el MEN1 (adenoma de la
paratiroides, tumores enteropancreticos y tumores hipofisarios), mientras que en los casos
familiares haba al menos un familiar de primer grado afectado por uno de los tumores endocrinos
caractersticos. Se han descrito tambin otras lesiones endocrinas y no endocrinas como tumores
adrenales corticoides, y carcinoides en bronquios, tracto gastrointestinal y timo, lipomas,
angiofibromas y colagenomas. El sndrome se transmite de forma autosmica dominante. El
sndrome MEN1 est provocado por la presencia de mutaciones que inactivan el gen supresor de
tumores MEN1. El gen MEN1 se sita en el cromosoma 11q13 y codifica para la menina, una
protena nuclear de 610 aminocidos. Esta protena no tiene homologa de secuencia con otras
protenas humanas conocidas. Este gen est probablemente implicado en la regulacin de diversas
funciones celulares tales como la replicacin y la reparacin del ADN. La combinacin de las
investigaciones clnicas y genticas, junto con la mejora del conocimiento de la gentica molecular
de este sndrome, ha permitido mejorar el manejo clnico de los pacientes. El tratamiento consiste
en ciruga y/o terapia farmacolgica, asociada frecuentemente con radioterapia y quimioterapia.
El anlisis de ADN permite la identificacin temprana de las mutaciones en la lnea germinal que se
producen en los portadores asintomticos de este gen. Para stos se recomienda un seguimiento
regular (con anlisis bioqumicos y/o radiolgicos peridicos) para ver el desarrollo de los tumores
y lesiones asociadas a MEN1.










Disease characteristics. Multiple endocrine neoplasia type 1 (MEN1) syndrome includes varying
combinations of more than 20 endocrine and non-endocrine tumors.
Endocrine tumors become evident by overproduction of hormones by the tumor or by growth of the tumor
itself.
Parathyroid tumors are the main MEN1-associated endocrinopathy; onset in 90% of individuals
is between ages 20 and 25 years with hypercalcemia evident by age 50 years; hypercalcemia
causes lethargy, depression, confusion, anorexia, constipation, nausea, vomiting, diuresis,
dehydration, hypercalciuria, kidney stones, increased bone resorption/fracture risk,
hypertension, and shortened QT interval.
Pituitary tumors include prolactinoma (the most common) which manifests as
oligomenorrhea/amenorrhea and galactorrhea in females and sexual dysfunction in males.
Well-differentiated endocrine tumors of the gastro-entero-pancreatic (GEP) tract can manifest as
Zollinger-Ellison syndrome (gastrinoma); hypoglycemia (insulinoma); hyperglycemia, anorexia,
glossitis, anemia, diarrhea, venous thrombosis, and skin rash (glucagonoma); and watery
diarrhea, hypokalemia, and achlorhydria syndrome (vasoactive intestinal peptide [VIP]-secreting
tumor).
Carcinoid tumors are non-hormone-secreting and can manifest as a large mass after age 50
years.
Adrenocortical tumors can be associated with primary hypercortisolism or hyperaldosteronism.
Non-endocrine tumors include facial angiofibromas, collagenomas, lipomas, meningiomas,
ependymomas, and leiomyomas.
Diagnosis/testing. Clinical diagnostic criteria for MEN1 syndrome include the presence of two endocrine
tumors that are parathyroid, pituitary, or GEP tract tumors. Biochemical testing detects an increased
serum concentration of parathyroid hormone and calcium in primary hyperparathyroidism, increased
serum concentrations of prolactin from a prolactinoma, and increased serum concentrations of gastrin,
insulin, and VIP from tumors of the GEP tract. Prolactinomas are imaged by MRI, neuroendocrine tumors
(NETs) are detected by somatostatin receptor scintigraphy, and pancreatic endocrine tumors are
detected by endoscopic ultrasound. Molecular genetic testing ofMEN1, the only gene in which mutations
are known to cause MEN1 syndrome, detects MEN1 mutations in about 80%-90% of probands
with familial MEN1 syndrome and in approximately 65% of simplex cases (i.e., a single occurrence of
MEN1 syndrome in the family).
Management. Treatment of manifestations: Hyperparathyroidism is treated with subtotal
parathyroidectomy and cryopreservation of parathyroid tissue or total parathyroidectomy and
autotransplantation of parathyroid tissue; recent studies suggest that long-acting release octreotide or
calcimimetic could be also effective; prior to surgery, bone anti-resorptive agents are used to reduce
hypercalcemia and limit bone resorption. Prolactinomas are treated with dopamine agonists (cabergoline
is the drug of choice). Growth hormone-secreting tumors causing acromegaly are treated by
transsphenoidal surgery; medical therapy for growth hormone-secreting tumors includes somatostatin
analogs, octreotide, and lanreotide. ACTH-secreting pituitary tumors associated with Cushing syndrome
are surgically removed; non-secreting pituitary adenomas are treated by transsphenoidal surgery. Proton
pump inhibitors or H2-receptor blockers reduce gastric acid output caused by gastrinomas. Surgery is
indicated for insulinoma and most other pancreatic tumors. Long-acting somatostatin analogs can control
the secretory hyperfunction associated with carcinoid syndrome. Surgical removal of adrenocortical
tumors that exceed 3.0 cm in diameter can prevent malignancy.
Prevention of primary manifestations: Thymectomy may prevent thymic carcinoid in males, particularly in
smokers.
Prevention of secondary complications: Measure PTH and/or serum calcium to assess for
hypoparathyroidism following subtotal or total parathyroidectomy. Measure urinary catecholamines prior
to surgery to diagnose and treat a pheochromocytoma to avoid blood pressure peaks during surgery.
Surveillance: Serum concentrations of calcium from age eight years, gastrin from age 20 years, and
prolactin from age five years; abdominal CT or MRI from age 20 years and head MRI from age five
years. Consider fasting serum PTH concentration and yearly chest CT.
Evaluation of relatives at risk: Because early detection affects management, molecular genetic testing is
offered to at-risk members of a family in which a germline MEN1 mutation has been identified.
Genetic counseling. MEN1 syndrome is inherited in an autosomal dominant manner. Approximately
10% of cases are caused by de novo mutations. Each child of an individual with MEN1 syndrome has a
50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if
the disease-causing mutation in a family is known.