AUTHOR INFORMATION

Section 1 of 11

Authored by Robert J Ferry, Jr, MD, Associate Professor of Pediatrics, Training and Research Director, Division of Pediatric Endocrinology, Departments of Pediatrics, Cellular & Structural Biology, University of Texas Health Science Center, San Antonio; Field Surgeon, Army Medical Dept, Texas National Guard

Coauthored by Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine; Christian A Koch, MD, FACE, CNS, Director, Professor, Division of Endocrinology, University of Mississippi at Jackson; George P Chrousos, MD, FAAP, MACP, MACE, Professor and Chair, Department of Pediatrics, Athens University Medical School

Robert J Ferry, Jr, MD, is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Edited by Arlan L Rosenbloom, MD, Adjunct Distinguished Service Professor Emeritus, Department of Pediatrics, University of Florida College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Lynne Lipton Levitsky, MD, Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor, Department of Pediatrics, Harvard University Medical School; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; and Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital

Author's Email:	Robert J Ferry, Jr, MD
Editor's Email:	Arlan L Rosenbloom, MD

eMedicine Journal, July 27 2006, VOLUME 7, Number 7

INTRODUCTION

Section 2 of 11

Background: First reported in 1963 by Wermer, multiple endocrine neoplasia (MEN) syndromes consist of rare, autosomal dominant mutations in genes regulating cell growth. Current classification recognizes MEN type 1 and MEN type 2, with subcategories MEN 2A (Sipple syndrome) and MEN 2B. The menin protein produced from the MENIN gene is a tumor suppressor. Loss of this protein allows tumors to arise. Ret protein produced from the RET gene can be constitutively activated, causing abnormal cell proliferation.

Type 1 MEN is defined by hyperfunctioning tumors of all four parathyroid glands, pancreatic islets (including gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide (VIP) tumor (VIPoma), or pancreatic polypeptide–producing tumor [PPoma]), and the anterior pituitary (including prolactinoma, somatotropinoma, corticotropinoma, or nonfunctioning tumors). Other associated tumors include lipomas, angiofibromas, or those located in the adrenal gland cortex.

Type 2A MEN is defined by medullary thyroid carcinoma (MTC), pheochromocytoma (about 50% of cases), and hyperparathyroidism caused by parathyroid gland hyperplasia (about 20% of cases).

Familial MTC also exists. Familial MTC is hereditary MTC without other associated endocrinopathies, although adrenomedullary hyperplasia secondary to a germline RET mutation may still be present but undiagnosed.

Type 2B MEN is defined by medullary thyroid tumor and pheochromocytoma. Associated abnormalities include mucosal neuromas, medullated corneal nerve fibers, and marfanoid habitus.

Pathophysiology: The MENIN gene responsible for type 1 MEN is located on chromosome 11 and produces a tumor suppressor protein called menin. The MENIN gene is ubiquitously expressed and localized to the nucleus of cells. (The former term APUD [amine precursor uptake and decarboxylation] system is obsolete.) Neuroendocrine tumors derive from the so-called APUD cells but also arise from pluripotent stem cells of the respective tissue (eg, pituitary tissue). Patients with type 1 MEN possess a germline mutation in the MENIN gene but develop tumors only with inactivation of the wild-type allele.

Most tumors arise in the pituitary gland and pancreatic islet cells and most cases of hyperparathyroidism are sporadic. Only a few cases are related to type 1 MEN.

The gene responsible for type 2 MEN is a proto-oncogene called RET. In contrast to MENIN of type 1 MEN, RET is specifically expressed in neural crest–derived cells, such as the C cells in the thyroid gland and the chromaffin cells in the adrenal gland. Whether RET is also expressed in the parathyroid glands remains unknown, especially considering the low rate of hyperparathyroidism in patients with type 2A MEN and the lack of hyperparathyroidism in type 2B MEN. RET encodes the tyrosine kinase RET protein subunit of a cell surface receptor. Activation of RET leads to hyperplasia of target cells in vivo. Subsequent secondary events then lead to tumor formation.

Most cases of MTC and/or pheochromocytoma are sporadic. Only about 10% of cases are hereditary and related to type 2 MEN.

MEN type 1

Hyperparathyroidism is the most common manifestation of type 1 MEN (80% of presentations) and results from hyperplasia of all 4 parathyroid glands. Abnormalities of parathyroid hormone (PTH) secretion may affect children before the age of 10 years. Islet-cell tumors secreting predominantly gastrin are called gastrinomas, and gastrinomas frequently metastasize. Children rarely have gastrinomas. Pituitary tumors (eg, as prolactinoma) affect children as young as 5 years. Adrenal involvement includes silent adenomas, adrenocortical hyperplasia, cortisol-secreting adenomas, and, rarely, carcinomas. Thymic and bronchial carcinoid tumors can be associated with type 1 MEN. Lipomas and angiofibromas may often lead to the diagnosis of type 1 MEN before the endocrine manifestations.

MEN type 2A (Sipple syndrome)

MEN 2A accounts for most cases of MEN 2. In general, type 2 MEN affects about 1 in 40,000 individuals, and fewer than 1000 kindreds are known worldwide. C-cell hyperplasia develops early in life and can be viewed as the precursor lesion for MTC, which often arises multifocally and bilaterally. RET germline mutation testing has replaced the pentagastrin and calcium stimulation tests for the diagnosis of C-cell hyperplasia and/or MTC. This advance is especially important for children, because the stimulation tests were unpleasant, and reference values for calcitonin were not established in children.

In addition, stimulation tests are inaccurate for diagnosis of MTC, as demonstrated with prophylactic thyroidectomy based on positive results on RET germline mutation tests. In studies, about 50% of patients with a negative pentagastrin result but a positive RET mutation had already developed MTC. These data supported the recommendation to perform prophylactic thyroidectomy with lymph node dissection in children older age 5 years with positive RET mutations. Most commercial RET mutation tests search for only part of the RET proto-oncogene (exons 10, 11, 13, 14, 15, 16) and typically help in identifying 97% of patients with type 2 MEN.

Pheochromocytoma are bilateral in 70% of cases and develop on the background of adrenomedullary hyperplasia secondary to an RET germline mutation. Biochemical and/or imaging manifestations occurs in about 50% of patients. The peak age at onset is approximately 40 years, but children as young as 10 years are reported. Therefore, annual surveillance for plasma and/or urine catecholamines, including metanephrines, is recommended in children older than 6 years.

Less than 25% of patients develop frank hyperparathyroidism, and this condition is rare in childhood. Reasons for this low prevalence and discrepancy in type 2B MEN are unknown. Although various RET mutations can cause type 2B MEN, those mutations within exon 16 are most often reported in association with hyperparathyroidism.

MEN type 2B

Type 2B MEN represents about 5% of all cases of MEN type 2. Patients have some aspects of a distinctive marfanoid phenotype and mucosal neuromas. MTC is relatively aggressive and frequently occurs in childhood. Some children may develop MTC at as young as 12 months of age. Therefore, prophylactic thyroidectomy with lymph node dissection is recommended in those younger than 5 years who have a RET germline mutation in exon 16. Pheochromocytomas also occur earlier than in patients with type 2A MEN, and patients have the same features arising in the context of adrenomedullary hyperplasia, multifocality, and often bilateral involvement. In contrast to MTC, which frequently metastasizes, metastatic pheochromocytoma rarely occurs in patients with type 2 MEN (0-25%). An important parameter in this setting is the follow-up period and the time of first occurrence or diagnosis.

Carney complex

Carney complex is a distinct rare type of MEN characterized by primary pigmented adrenocortical disease, pituitary adenoma, Sertoli-cell tumors, thyroid nodules, and additional nonendocrine features. The most commonly associated features are cardiac and skin myxomas, melanotic schwannomas, and lentigines.

Frequency:

• In the US: The prevalence in adults is about 0.02-0.2 cases per1000 persons. Data for children are not available.

Mortality/Morbidity: Death related to MEN can be caused by complicated peptic ulcer disease, metastases of endocrine pancreatic tumors, severe hypercalcemia with arrhythmias, metastatic MTC, catecholamine release–related arrhythmias, coronary heart disease, stroke, heart failure, and/or arrhythmias from cardiac myxomas.

• Zollinger-Ellison syndrome (ZES) is the major cause of morbidity and mortality in type 1 MEN.

• In 1998, Doherty et al reported 103 patients with type 1 MEN. In this series, 46% of patients died from causes related to their endocrine tumors after a median of 47 years.

• Mortality in type 2B MEN is due mainly to the aggressive nature of MTCs.

Race: No racial predilection is known.

Sex: The male-to-female ratio is 2:1.

Age: Patients with hyperparathyroidism in type 1 MEN most often present at 20-40 years of age, but the disease may appear in children younger than 10 years.

• Type 1 MEN can be detected in individuals from kindreds with testing before age 18 years (even younger, if desired). MENIN mutations occur throughout the gene, and new mutations continue to emerge. Mutation screening helps in identifying as many as 85% of patients with type 1 MEN.

• The degree of penetrance of type 1 MEN at age 20 years is about 43%.
  
  
• MEN type 2 is highly penetrant and should be diagnosed by RET mutation testing before age 5 years. If mutation tests are positive, subsequent prophylactic thyroidectomy with lymph node dissection is recommended. If a parent has type 2B MEN, earlier diagnosis is recommended for the affected adult's child, because the disease is relatively aggressive.

• All MEN syndromes are rare in children.

CLINICAL

Section 3 of 11

History:

• MEN type 1


• • Hyperparathyroidism is most common initial clinical manifestation of MEN type 1. Some patients may manifest findings of ZES before they have hyperparathyroidism.
  
  
  
  • Symptoms of gastrinoma may become clinically apparent, with either abdominal pain and diarrhea or with complications, such as ulcer perforation or bleeding.
  
  
  
• MEN type 2A


• • All patients develop MTC on the basis of C-cell hyperplasia.
  
  
  
  • About 50% of patients with MTC manifest pheochromocytoma (usually late in life), and 20% of patients are hyperparathyroid.
  
  
  

Physical: The clinical picture depends on the glands involved and the hormones secreted.

• MEN type 1


• • Hyperparathyroidism occurs with mild hypercalcemia and bone abnormalities. Musculoskeletal symptoms have also been observed in adults but rarely in adolescents.
  
  
  
  • Gastrinoma causes diarrhea, abdominal pain due to peptic ulcer disease, and esophagitis.
  
  
  
  • Insulinoma causes hypoglycemia.
  
  
  
  • Glucagonoma can cause hyperglycemia. Rare cases of type 1 MEN are associated with erythema, anemia, diarrhea, or venous thrombosis.
  
  
  
  • Pituitary tumors may cause headaches, visual field defects, and other effects depending on hormone production.
  
  
  
• MEN type 2A


• • MTC causes 1 or more firm nodules, which are often associated with enlarged cervical lymph nodes.
  
  
  
  • Pheochromocytoma causes hypertension, sweating, palpitations and tachycardia, headache, emotional lability, nausea, vomiting, polyuria, and polydipsia.
  
  
  
• MEN type 2B


• • Marfanoid phenotype develops in all patients. Phenotypic characteristics include a slender body build, long and thin extremities, abnormal laxity of joints, and, in many cases, a high-arched palate, pectus excavatum, or pes cavus.
  
  
  
  • The facies is characterized by enlarged thick lips as a result of embedded mucosal neuromas.
  
  
  
  • Neuromas may be found on the surface of the lips, tongue, eyelids, and cornea.
  
  
  
  • Ganglioneuromas may occur at any level of the GI tract, causing constipation or diarrhea due to abnormal control of intestinal motility.
  
  
  
  • MTC may appear within the first year of life.
  
  
  

Causes:

• The gene for MEN type 1 has been localized to chromosome band 11q13. It is a tumor suppressor gene that encodes menin, a nuclear protein.



• The gene for MEN type 2 is RET, located on chromosome band 10q11.2. In MEN type 2A, 95% of RET mutations occur in exons 10, 11, and 14. Mechanisms of tumorigenesis in vivo recently elucidated show allelic imbalance between mutant and wild type RET alleles. In MEN type 2B, RET mutations in exon 16 are found in 95% of cases.



• So-called inactivating mutations due to deletions of RET are associated with congenital neurologic defects, such as aganglionic colon (ie, Hirschsprung disease). Of interest, these mutations also occur on exons 10 and 11 (associated with MEN type 2A).

DIFFERENTIALS

Section 4 of 11

Carcinoid Tumor
Gastroesophageal Reflux
Hypercalcemia
Pheochromocytoma
VIPoma
Zollinger-Ellison Syndrome

Other Problems to be Considered:

Mastocytosis
MEN type 1: gastrinoma, adrenal adenoma, and glucagonomas
MEN type 2B: medullary carcinoma of the thyroid, mucosal neuromas, and ganglioneuromas

Other conditions associated with elevated gastrin levels

Massive small-bowel resection
Hypercalcemia
Treatment with histamine 2 (H₂) blockers or proton-pump inhibitors (PPIs, eg, omeprazole)
Gastric-outlet obstruction

WORKUP

Section 5 of 11

Lab Studies:

• Laboratory studies include investigations of the different tumor-expression patterns.


• • Gastrinomas (ZES): Serum gastrin levels exceed 115 ng/mL and increase >200 ng/mL after secretin challenge (intravenous injection of secretin, 2 U/kg)
  
  
  
  • Insulinoma: Results may show fasting hypoglycemia with inappropriately elevated serum insulin, C-peptide, or proinsulin concentrations. When the serum glucose level is <60 mg/dL, the serum insulin level should be <2 mU/mL. A serum insulin level > 2 mU/mL during hypoglycemia is consistent with hyperinsulinism.

    Additional diagnostic criteria include the following:

    • Decreased fasting tolerance (defined during a controlled inpatient fast)

    • Inappropriate glycemic response to glucagon challenge when the patient is hypoglycemic, ie, increase in serum glucose level by >30 mg/dL from a baseline of <60 mg/dL within 20 minute after glucagon 1 mg is given intravenously or subcutaneously

    • Suppressed lipolysis (free fatty acid concentration < 20 mM)

    • Suppressed ketogenesis (undetectable plasma acetoacetate or beta-hydroxybutyrate) when the patient is hypoglycemic

    • Acute insulin response to peripheral venous or intra-arterial calcium challenge (performed at centers including the University of Texas Health Science Center at San Antonio and the Children's Hospital of Philadelphia)
  
  
  
  • Glucagonoma: Findings are hyperglycemia with elevated serum glucagon levels.
  
  
  
  • Watery diarrhea syndrome: Serum levels of VIP are elevated.
  
  
  
  • Carcinoids: Levels of serotonin, urinary 5-hydroxyindoleacetic acid (5-HIAA), calcitonin, and 24-hour urinary free cortisol and corticotropin are elevated.
  
  
  
  • Pituitary tumors: Tests show persistent elevation of serum somatotropin (growth hormone [GH]) during oral glucose challenge; serum free or total insulinlike growth factor (IGF)-I level > 2 standard deviations (for age, sex, and Tanner stage), or elevated serum prolactin levels.
  
  
  
• MEN type 2


• • MTC: Patients frequently have elevated calcitonin levels.
  
  
  
  • Pheochromocytoma: Total urine catecholamine secretion exceeds 100-300 mcg/d (over 24 h). Serum levels >2000 mcg/mL are pathognomonic. Measuring plasma and urine metanephrines with a 24-hour collection is best.
  
  
  

Imaging Studies:

• MEN type 1


• • Gastrinomas: Somatostatin-receptor scintigraphy (SRS) has a sensitivity of 70-90%, which is more than that of any other imaging procedure. Endoscopic ultrasonography depicts tumors in the pancreatic head but rarely in the duodenal wall.
  
  
  
  • Insulinomas: Perform CT scanning and MRI first. SRS findings are positive in about 50% of patients. Intraoperative ultrasonography of the pancreas is highly recommended to detect additional tumors.
  
  
  
  • Pituitary tumors: Perform MRI and/or CT scanning after biochemical evaluation.
  
  
  
• Pheochromocytoma: Radiologic imaging for pheochromocytoma includes CT scanning, MRI, metaiodobenzylguanidine (MIBG) scanning, OctreoScan imaging, and positive emission tomography (PET).



• Nonfunctioning pancreatic endocrine tumors: After MEN type 1 is confirmed, perform pancreatic endoscopic ultrasonography to monitor progression of nonfunctioning pancreatic endocrine tumors. Their incidence is high (54.9%), though their clinical significance remains uncertain. Follow-up of lesions discovered should be coordinated with experienced subspecialists.

• Parathyroid glands: The glands show hyperplasia and diffuse or nodular proliferations of chief cells, mixed with some oncocytic cells. All glands are involved.

• Pancreas: Numerous microadenomas (mostly in the pancreatic tail) are present. The tumors display a trabecular pattern. Immunohistochemically, tumor cells stain with antibodies directed to pancreatic polypeptide, glucagon, insulin, and gastrin.

• Duodenum: Duodenal tumors most often are gastrinomas in the first part of the duodenum. They stain positive for gastrin and may metastasize to regional lymph nodes.

• Stomach: In the stomach, diffuse hyperplasia of enterochromaffin-like (ECL) cells is found, associated with tumors of considerable size but rarely of metastatic potential.

• Pituitary: Most tumors are single, are found in the anterior part of the gland, and they produce prolactin and/or GH and occasionally corticotropin.

TREATMENT

Section 6 of 11

Medical Care:

• Hypercalcemia: For patients with MEN type 1 who have hypercalcemia, surgery is the treatment of choice, including removal of 3.5 parathyroid glands.



• Gastrinoma: The current treatment consists of PPIs to reduce acid hypersecretion.



• Insulinoma: Surgery is the therapy of choice. Unresectable tumors are treated with diazoxide.



• Glucagonoma: Glucagonomas are removed surgically.



• VIPoma: Octreotide controls symptoms (diarrhea) in 80% of patients; however, surgical tumor removal should be attempted.



• Prolactinoma: Prolactinomas are treated with dopamine agonists, such as bromocriptine or cabergoline.

• GH-producing pituitary tumor: These tumors are treated by transsphenoidal surgery; in rare instances, medical therapy with a GH receptor antagonist is recommended.

Surgical Care:

• MEN type 1 with hyperparathyroidism: In patients with MEN type 1 who have hyperparathyroidism, surgery is the treatment of choice if any of the following conditions are present


• • Serum albumin–adjusted serum calcium level is > 3 mmol/L (>12 mg/dL)
  
  
  
  • Kidney stones
  
  
  
  • PTH-induced bone disease
  
  
  
• ZES–MEN type 1: In patients with ZES–MEN type 1, parathyroid surgery is indicated even in mild forms of hypercalcemia because serum calcium levels in the reference range are often associated with low serum gastrin levels and consecutively low gastric acid secretion.


• • Removal of 3.5 or 4 parathyroid glands controls hypercalcemia. If 4 glands are removed, immediate autograft of parathyroid tissue into the musculature of the nondominant arm is indicated.
  
  
  
  • Some authors recommend taking careful operative notes and marking the residual parathyroid tissue with clips because reoperation in patients with MEN type 1 is likely.
  
  
  
• Gastrinoma


• • The role of surgery in ZES and MEN type 1 remains controversial because cure is achieved only occasionally. Most tumors are multicentric, raising the possibility of recurrence. Surgery may be indicated in patients with positive findings on imaging studies and no distant metastases.

  • Gastrinomas are found in the duodenal wall, the pancreas, or in lymph nodes.

  • Local tumor excision is preferred, with larger tumors of the pancreatic body or tail removed by distal pancreatectomy. This approach may reduce the risk of subsequent metastatic disease to the liver.

  • Resection of liver metastases may be beneficial.

  • Total pancreatectomy is not indicated because of the deleterious effects of this procedure (eg, pancreatic exocrine insufficiency, diabetes mellitus).
  
  
  
• Insulinoma: Insulinomas are single large tumors that can be enucleated.
  • Resection may result in cure, although insulinomas in MEN type 1 may be multicentric.

  • Some authors recommend subtotal pancreatectomy (>80% of the pancreas) in patients with multiple tumors or when the tumor is not localized.

  • Surgical debulking in metastatic disease may reduce hypoglycemia to a certain extent.

  • Intraoperative ultrasonography facilitates tumor identification. Other methods include intraoperative monitoring of plasma glucose and insulin levels.

• VIPoma: In VIPoma, resection of single and multiple tumors is indicated, which may include a pancreatic tail resection.

• Carcinoid tumors: Carcinoid tumors are removed surgically; half of tumors are locally invasive or metastatic, particularly thymic carcinoids.

• Pituitary tumors
  • Transsphenoidal pituitary surgery is aimed at resection of any pituitary mass, particularly in acromegaly.

  • Patients with incomplete resection remain on treatment with dopamine agonists.

• Prolactinoma: Prolactinomas may be large and multicentric. The recurrence rate after surgical removal is high. Medical treatment is now the therapy of choice. Transsphenoidal surgery with external radiation therapy (external beam or gamma knife) is indicated in patients in whom long-term bromocriptine therapy is ineffective.

• MEN 2
  • Total thyroidectomy with radical lymph-node dissection is recommended in patients aged 5 years if an RET germline mutation is identified. All regional lymph nodes must be removed, even if they are not suspected macroscopically. Before any surgery, screening for pheochromocytoma must be performed.

  • Pheochromocytoma requires surgical excision under alpha-adrenergic blockade, starting 7-10 days before surgery.

MEDICATION

Section 7 of 11

Medical therapy is directed toward the specific endocrine syndromes.

Drug Category: Somatostatin analogs -- Sandostatin acts similarly to the natural hormone somatostatin by suppressing peptide secretion from gastroenteropancreatic tumors.

Drug Name	Octreotide acetate (Sandostatin) -- Acts primarily on somatostatin receptor subtypes II and V. Inhibits GH secretion, and other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides. Controls diarrhea in 80% of patients. Progressive increases in dosage may be necessary.
Adult Dose	50 mcg/d SC q12h initially; may increase dose to 200-300 mcg/d, based on tolerability and response
Pediatric Dose	200-300 mcg/d SC divided bid/qid during initial 2 wk; individual dosage adjustment prn to control symptoms
Contraindications	Documented hypersensitivity
Interactions	Associated with altered nutrient absorption; consider effect on PO drug absorption; may reduce effects of cyclosporine; patients taking insulin, PO hypoglycemics, beta-blockers, and calcium channel blockers may require dosage adjustments
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adverse effects are primarily related to altered GI motility, including nausea, abdominal pain, diarrhea, and increased incidence of gallstones and biliary sludge; because of alteration in counterregulatory hormones (eg, insulin, glucagon, GH), hypoglycemia or hyperglycemia may be observed; bradycardia, cardiac conduction abnormalities, and arrhythmias have been reported; because of inhibition of thyroid-stimulating hormone (TSH) secretion, hypothyroidism may also occur; exercise caution in patients with renal impairment; cholelithiasis may occur; possibility of GH suppression requires monitoring of children's growth

Drug Category: Gastric acid inhibitors -- Gastric acid secretion with PPIs is mandatory to prevent complications of gastric acid hypersecretion. PPIs are safe and cause no adverse effects even after long-term use. The goal is to reduce the basal acid output to levels <10 mEq/h 1 hour before the next dose in patients without previous acid-reducing gastric surgery and to < 5 mEq/h in patients with previous acid-reducing gastric surgery.

Drug Name	Omeprazole (Prilosec) -- Substituted benzimidazole that suppresses acid secretion by specifically inhibiting the H+/K+ adenosine triphosphatase (ATPase) at the secretory surface of parietal cell.
Adult Dose	20-60 mg/d PO initially; if >80 mg/d, administer in divided doses
Pediatric Dose	Not established Suggested dosing: Administer as in adults; dose must be adjusted to the individual BAO
Contraindications	Documented hypersensitivity
Interactions	Prolongs elimination of diazepam, warfarin, and phenytoin; theoretically interferes with absorption of drugs for which gastric pH important determinant of bioavailability (eg, ampicillin esters); may decrease effects of itraconazole or ketoconazole
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	ECL cell tumors in stomach observed in rats; long-term data not available; headache, diarrhea, and abdominal pain may occur

Drug Category: Hyperglycemic agents -- These agents inhibit insulin release from the tumor.

Drug Name	Diazoxide (Proglycem) -- Binds sulfonylurea receptor (SUR1) of the pancreatic beta cell, inhibiting insulin secretion. PO form opens K ATP channels and inhibits insulin secretion. Increases blood glucose level within 1 h by inhibiting insulin release from insulinoma. Unlike rapid IV administration, PO not antihypertensive.
Adult Dose	3-8 mg/kg/d PO divided tid q8h
Pediatric Dose	5-15 mg/kg/d PO divided tid q8h
Contraindications	Documented hypersensitivity; functional hypoglycemia
Interactions	May decrease serum hydantoin levels, possibly decreasing anticonvulsant effects; thiazide diuretics may potentiate hyperuricemic and hypoglycemic effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Start only under close clinical supervision; prolonged treatment requires regular monitoring of urine for sugar and ketones; blood sugar levels should be monitored for dose adjustments; plasma half-life prolonged in impaired renal function; lanugo-type thick hair growth occurs in children in frontotemporal areas, extremities, and back; may cause sodium retention with edema

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• After parathyroid surgery, monitor serum ionized calcium and magnesium levels. Transient hypoparathyroidism frequently develops and requires calcium and vitamin D supplementation. In rare cases, hungry-bone syndrome may ensue, with rapid declines in serum calcium and magnesium levels.



• Somatostatin therapy is indicated particularly in patients with acromegaly in whom surgery did not achieve complete tumor removal. Tumor shrinkage can be expected in one third of patients



• Pregnancy may ensue on treatment with cabergoline or bromocriptine in patients with prolactinoma.

Further Outpatient Care:

• In MTC, measure serum calcitonin levels every 6-12 months after surgery. Elevated serum levels in the neck region indicate recurrence that possibly requires further surgery. However, micrometastases often cannot be visualized by using current imaging techniques.



• The resection of 1 endocrine tumor does not exclude a second tumor, even after an interval of several years. Patients need lifelong surveillance, as do their offspring.



• Pheochromocytomas are monitored with blood pressure and plasma catecholamine and/or metanephrine measurements to exclude recurrence.

In/Out Patient Meds:

• Patients with ZES–MEN type 1 need lifelong acid inhibition with PPIs.



• Chemotherapy with streptozocin and dacarbazine may reduce the size of nonoperable neuroendocrine tumors.

Deterrence/Prevention:

• Because early therapy substantially improves the patient’s prognosis, screening is of paramount importance in all forms of MEN.



• Risk factors include known MEN, a positive family history of MEN, ZES, ganglioneuromas, cutaneous neuromas, a marfanoid somatic phenotype, parathyroid hyperplasia, multicentric medullary carcinoma of the thyroid, and multicentric or bilateral pheochromocytomas.



• Screening tests include the following measurements based on the type of MEN:


• • MEN type 1 - Serum calcium and intact PTH, gastrin, glucose, prolactin, and free IGF-I determinations
  
  
  
  • MEN type 2A: - RET germline mutation testing and determinations of serum calcitonin and ionized calcium, plasma and 24-hour urinary free catecholamine, metanephrine, and vanillylmandelic acid levels
  
  
  
  • MEN type 2B - RET germline mutation testing and determinations of serum calcitonin and ionized calcium, plasma and 24-hour urinary free catecholamine, metanephrine, and vanillylmandelic acid levels
  
  
  
• If test results are in the reference range on 3 occasions and if the patient is older than 35 years, he or she can be declared a noncarrier. Offspring of noncarriers do not require testing.


• • Mutation analysis of the MENIN gene enables the identification of people carrying the gene.
  
  
  

Prognosis:

• MEN type 1


• • The prognosis is generally good in the presence of discrete parathyroid and pancreatic islet disease or pituitary adenoma.
  
  
  
  • Pancreatic islet cell carcinoma and carcinoids are slowly progressive.
  
  
  
  • Patients with gastrinoma in MEN type 1 may have a prognosis better than that of patients with the sporadic form of the disease.
  
  
  
• MEN type 2A: The prognosis depends on the stage of medullary thyroid cancer, and it is generally good after prophylactic thyroidectomy.



• MEN type 2B


• • The prognosis for patients with MEN type 2B is worse than for patients with MEN type 2A because tumors, such as MTCs, are relatively aggressive, resulting in a 50% 10-year survival rate.
  
  
  
  • Therefore, individuals with an RET germline mutation in exon 16 should undergo early prophylactic thyroidectomy and screening for pheochromocytoma.
  
  
  

Patient Education:

• For excellent patient education resources, visit eMedicine’s Endocrine System Center. Also, see eMedicine’s patient education article Anatomy of the Endocrine System.



• Families can locate an endocrinologist and access helpful information through the Hormone Foundation and the NIDDK Endocrine and Metabolic Diseases Information Service, is a service of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• In patients with ZES–MEN type 1 who have hypercalcemia, perform parathyroidectomy before abdominal tumoral resection. Lowering serum calcium levels to the reference range may also normalize elevated gastric acid secretion.



• Pheochromocytoma in patients with MEN type 2 may be bilateral. Explore both adrenal glands during surgery.



• Patients with a pheochromocytoma and MTC should receive appropriate preparation with alpha-blocker therapy. Then, the pheochromocytoma must be removed first in to avoid life-threatening complications (eg, hypertensive crisis, arrhythmias) caused by the adrenal tumor.



• In cases of a pheochromocytoma, some adrenal cortex tissue should be left behind because patients may develop a contralateral tumor during the course of the disease, which requires adrenalectomy. This may help to avoid lifelong hormonal substitution with glucocorticoids.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which statement regarding medullary thyroid carcinomas (MTCs) is false?

A: In multiple endocrine neoplasia (MEN) type 2, MTCs are bilateral and multifocal.
B: In sporadic disease, MTC is usually unilateral.
C: MTC develops in 80% of patients with MEN type 2A.
D: One diagnostic criterion for MTC is an elevated calcitonin level because the tumor is derived from calcitonin-secreting cells.
E: MTC is associated with pheochromocytoma in as many as 50% of patients.

The correct answer is C: All patients with MEN type 2A develop MTC.

CME Question 2: Which statement regarding pheochromocytoma in children is false?

A: Plasma catecholamine levels >2000 mcg/mL are pathognomonic for pheochromocytoma.
B: Symptoms may include hypertension, nausea, and vomiting.
C: Laboratory findings may include elevated epinephrine and metanephrine excretion.
D: The predominant catecholamine found in the urine of children is vanillylmandelic acid.
E: Alpha-adrenergic blockade is necessary before surgery to prevent a hypertensive crisis.

The correct answer is D: Vanillylmandelic acid is detected in the urine of children and adults. However, its sensitivity is only about 60% compared to more than 90% for norepinephrine, epinephrine, normetanephrine, and metanephrine.

Pearl Question 1 (T/F): Patients with multiple endocrine neoplasia (MEN) type 2A who have medullary thyroid carcinoma tend to have a prognosis better than that of patients with MEN type 2B and medullary thyroid carcinoma (MTC).

The correct answer is True: Patients with MEN type 2B and MTC have a 10-year survival rate of 50%.

Pearl Question 2 (T/F): Prolactinomas are typically found in multiple endocrine neoplasia (MEN) type 2B.

The correct answer is False: Pituitary tumors, including prolactinomas, are part of MEN type 1, not MEN type 2.

Pearl Question 3 (T/F): Proton-pump inhibitors (PPIs) in children with Zollinger-Ellison syndrome should be replaced with histamine-2 receptor antagonists at some stage to avoid the adverse effects of PPIs.

The correct answer is False: Important long-term adverse effects of PPIs are not reported. Histamine-2 receptor antagonists may not control acid secretion effectively and, therefore, are not recommended.

Pearl Question 4 (T/F): Multiple endocrine neoplasia (MEN) type 2B accounts for 15-20% of all cases of MEN type 2.

The correct answer is False: MEN type 2B contributes to only about 5% of all cases of MEN type 2.

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Section 11 of 11

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