AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Multiple endocrine neoplasia (MEN) syndromes consist of 2 categories, MEN 1 and MEN 2. Since 1975, MEN 2 (Sipple syndrome) has been subcategorized into MEN 2a and MEN 2b.

The combination of parathyroid tumors, pancreatic islet cell tumors, and pituitary hyperplasia or tumor formation is called MEN 1. It is an autosomal dominant disorder, but it may also occur sporadically as a result of new mutations.

In 1954, Wermer was the first to describe the syndrome as a distinct clinical entity.

Pathophysiology

Parathyroid tumors

Hyperparathyroidism is the most common manifestation of MEN 1, caused by hyperplasia of multiple parathyroid glands. Penetrance is almost 100% by age 50 years.

Clinical manifestations include urolithiasis, bone abnormalities, and, in severe cases, generalized weakness and mental or cognitive dysfunction.

Hyperparathyroidism in MEN 1 differs from sporadic cases by earlier age at presentation, involvement of multiple glands, and high recurrence rate postoperatively (50% by 8-12 y after surgery).

Enteropancreatic tumors

Pancreatic islet cell tumors represent the second most common manifestation of MEN 1 and occur in 80% of patients. Tumors are often multicentric and may undergo malignant transformation. Often, they produce multiple peptides and biogenic amines.

Nonfunctioning pacreatic endocrine tumors are the most common pancreatic tumors, occurring in 80-100% of cases. However, the name is a misnomer because most of them produce pancreatic polypeptide. The tumor mass, even at an advanced stage, may not cause a clinical syndrome outside of its mass effect. They may be malignant, however tumors less than 2 cm in size have low risk of metastasis or death. Average life expectancy of patients with nonfunctioning pacreatic endocrine tumors is decreased when compared to MEN 1 patients who do not have them.

Gastrinomas are the most common cause of symptomatic disease and are found in approximately 60% of patients with MEN 1. Compared to the sporadic form of gastrinomas in Zollinger-Ellison syndrome (ZES), tumors in MEN 1 are more often duodenal, small, and multicentric, thus diminishing the probability of surgical cure. The features predictive of poor prognosis include pancreatic location of lesions, metastases, ectopic Cushing syndrome, and height of gastrin levels. Development of gastrinomas is preceded by multifocal hyperplasia of the gastrin-producing cells. Long-standing MEN 1/ZES may lead to development of gastric carcinoid tumors that might be aggressive.

Insulinomas account for approximately 20-35% of functional pancreatic islet cell tumors. Similar to gastrinomas, they can be multicentric (10-20%), where 25% metastasize either to regional lymph nodes or to the liver.

Glucagonomas occur in 3% of patients with MEN 1 and are silent or present with hyperglycemia. Only a few patients show the typical skin lesions known as necrolytic migratory erythema.

The occurrence of the watery diarrhea, hypokalemia, hypochlorhydria, and acidosis (WDHA) syndrome (incidence approximately 1%) may be due either to either a pancreatic islet cell or to a carcinoid tumor.

Pituitary tumors

These often-multicentric tumors occur in more than 50% of patients and are clinically apparent in up to 20% of patients. These tumors tend to be larger and more aggressive than those not associated with MEN 1.

Prolactinomas are the most common pituitary tumor in patients with MEN 1.

Growth hormone–producing tumors account for 25% of these adenomas. Growth hormone levels rise due to autonomous secretion from the pituitary tumor or, less commonly, by production of growth hormone–releasing factor by a pancreatic or other endocrine tumor.

A pituitary tumor or carcinoid tumor that produces corticotropin can cause Cushing syndrome in patients with MEN 1. Ectopic production of corticotropin-releasing factor from a pancreatic islet cell tumor also has been described.

Other tumors associated with MEN 1

Carcinoid tumors occur occasionally in patients with MEN 1, usually in the foregut (eg, thymus, lungs, stomach, duodenum). In men, especially smokers, the thymus is most often affected. Thymic carcinoids associated with MEN 1 are often nonfunctional and aggressive. In women, the lung is affected most often. Carcinoids may release ectopic adrenocorticotropic hormone.

Cutaneous tumors include angiofibromas (occurring in 40-80% of patients) and collagenomas. They are often multifocal. Finding of more than 3 angiofibromas and any collagenomas has a sensitivity of 75% and specificity of 95% for diagnosis of MEN 1. This criterion has greater sensitivity than pituitary or adrenal disease and comparable to hyperparathyroidism in some studies.

Lipomas, subcutaneous and visceral, are found in one third of patients. They have loss of heterozygosity for chromosome band 11q12-12 and are associated with defective globular (G) protein function.

Adrenal tumors are most often benign and consist of nonfunctional cortical adenomas or diffuse or nodular hyperplasia. They occur in 20-40% of patients. Adrenal cortical carcinomas are rare.

Thyroid adenomas (5-30% of patients) have little clinical significance.

Frequency

United States

The estimated prevalence is 0.02-0.2 cases per 1000 population.

Mortality/Morbidity

Patients with MEN 1 have a decreased life expectancy, with a 50% probability of death by age 50 years.

• Half of the deaths result directly from a malignant process or a sequela of the endocrine disease



• ZES is the major cause of morbidity and mortality in patients with MEN 1



• In a series of 103 patients with MEN 1, 46% died from causes related to their endocrine tumors at a median age of 47 years.

Race

No racial differences exist.

Sex

There is about equal female-to-male ratio.

Age

The peak incidence of symptoms is during the third decade of life in women and during the fourth decade of life in men.

• Hyperparathyroidism, the most common abnormality in MEN 1, develops in patients aged 20-40 years, but it may appear in individuals as young as 17 years



• In related individuals, occult MEN 1 can be detected with screening (more effectively in persons >18 y).



• The degree of penetrance at age 20 years is approximately 43%, at age 35 years is approximately 85%, and at age 50 years is 94%.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

• Hyperparathyroidism: Although the initial clinical manifestation of MEN 1 usually is hyperparathyroidism, some patients may have ZES prior to primary hyperparathyroidism.



• Gastrinoma: The symptoms due to a gastrin-secreting tumor consist of abdominal pain and diarrhea or complications of peptic ulcer disease, such as ulcer perforation or bleeding.



• Insulinomas also may be identified prior to hypercalcemia.

Physical

The clinical picture depends on the endocrine organs involved and the hormones secreted. It varies from patient to patient.

• Hyperparathyroidism
  
  
  • This usually presents with mild hypercalcemia, and patients rarely develop nephrolithiasis.
  
  
  
  • Other manifestations include bone abnormalities and musculoskeletal complaints.
  
  
  
  • In severe hypercalcemia, generalized weakness and alterations of mental status may develop.
  
  
  
  • These features are not different from those for other forms of hypercalcemia.
     
• Gastrinoma: Symptoms caused by ZES include diarrhea and upper abdominal pain due to peptic ulcers and esophagitis.



• Insulinoma: Fasting hypoglycemia is a frequent presenting symptom of this disorder.



• Glucagonoma
  
  
  • The glucagonoma syndrome consists of a rash (necrolytic migratory erythema), anorexia, anemia, diarrhea, venous thrombosis, and glossitis.
  
  
  
  • The full syndrome is rarely expressed. However, most patients have some hyperglycemia.
     
• Pituitary tumors
  
  
  • Symptoms including headache and visual-field defects may be due to local tumor growth.
  
  
  
  • Prolactinomas may cause erectile dysfunction or decreased libido in men, while women may develop amenorrhea and galactorrhea.
  
  
  
  • Growth hormone–secreting tumors may result in acromegaly. This is a slow process and is rarely clinically identifiable.
  
  
  
  • Cushing syndrome may also occur.
     
• Carcinoid syndrome: Features include flushing, diarrhea, and bronchospasm. They are not common in MEN 1.

Causes

The putative gene for MEN 1 has been localized to chromosome band 11q13 and codes for the menin protein.  Loss of heterozygosity for this region is associated with MEN 1, suggesting that the gene has tumor suppression function. Patients inherit one mutated copy of the gene and require a somatic mutation of the second copy for tumor development.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Pancreatic islet cell tumor should also be considered.

Hyperparathyroidism in MEN 1 must be separated from other familial forms of hypercalcemia, including familial parathyroid hyperplasia and familial adenomatous hyperparathyroidism. Familial hypocalciuric hypercalcemia may also have a similar presentation. These latter 2 have no pancreatic or pituitary manifestations.

Conditions other than ZES that are associated with elevated serum gastrin levels include retained gastric antrum, gastric outlet obstruction, hypercalcemia,  massive small bowel resection, atrophic gastritis, and treatment with proton pump inhibitors.

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• Lab studies in known MEN 1 carriers screen for the different syndromes expressed by tumors expressed in multiple endocrine adenopathy (MEA) type 1.



• Gastrinomas
  
  
  • Combination of elevated gastrin levels and increased gastric acid output. Gastric acid output is measured if gastrin is high (measured by pH probe).
  
  
  
  • If serum gastrin is high (normal is <115 ng/mL) or if gastric acid output is high, then gastrin levels could be evaluated after secretin stimulation. An increase of gastrin level by more than 200 ng/mL after an intravenous injection of secretin at 2 IU/kg of body weight is abnormal.
  
  
  
  • The secretin test is necessary to exclude other diseases associated with pathologically increased serum gastrin levels.
     
• Insulinomas
  
  
  • Perform a fasting hypoglycemia test when inappropriately elevated serum insulin, C peptide, or proinsulin concentrations are present.
  
  
  
  • A supervised 72-hour fast often is required if elevated fasted insulin (>72 pmol/L) and low fasted blood sugar (45 mg/dL) cannot be documented in the setting of suspected hypoglycemia.
     
• Glucagonoma: Elevated serum glucagon levels and hyperglycemia are present.



• Watery diarrhea syndrome: Elevated serum levels of vasoactive intestinal polypeptide are present.



• Carcinoids: Elevated levels of serotonin, chromogranin A, calcitonin, and corticotropin are present. Elevated urinary levels of 5-hydroxyindoleacetic acid also are present.



• Pituitary tumors: Assess growth hormone levels (IGF-1) and prolactin.



• Hyperparathyroidism
  
  
  • Calcium and intact parathyroid hormone (PTH) levels are outside of the normogram range for the specific laboratory concurrent calcium/PTH determinations.
  
  
  
  • Dual-energy x-ray absorptiometry may be useful in assessing chronic bone mineral loss. Significant bone loss, both absolute (T score) and for age (Z score), may be an indicator for parathyroid surgery even in the absence of other clinical symptoms or marked hypercalcemia.

Imaging Studies

• Pituitary tumors: An MRI, with attention to the sella turcica region, is the test of choice when biochemical evidence of pituitary disease is found.



• Some tumors may not be functioning; however, asymptomatic patients should also be screened regularly (every 3-5 y).



• Gastrinomas
  
  
  • Somatostatin receptor scintigraphy is the imaging procedure of choice for gastrinomas. Its sensitivity range is 70-90%.
  
  
  
  • Somatostatin receptor scintigraphy can be enhanced by selective arterial secretagogue test with secretin or calcium infusion (in 10% of cases of gastrinomas secretin is not diagnostically useful).
  
  
  
  • Operative intervention should be preceded by CT scan or MRI.
  
  
  • Endoscopic ultrasonography detects tumors in the pancreatic head but rarely in the duodenal wall. It is more sensitive than CT or transabdominal ultrasound.
     
• Insulinomas
  
  
  • CT scan and MRI are recommended first.
  
  
  
  • Somatostatin receptor scintigraphy findings may be positive in up to 50% of patients with insulinomas. It is best used in conjunction with SPECT (single-photon emission CT).
  
  
  
  • Endoscopic ultrasonography, reported sensitivity of detection up to 94%.
  
  
  
  • Selective arterial calcium stimulation with hepatic venous sampling is often required as in patients with MEN 1 multiple lesions are likely to be present. The imaged lesion may not be the one causing the symptoms.
  
  
  
  • Intraoperative ultrasonography can be helpful.
     
• Parathyroid tumors
  
  
  • Sestamibi scans of the parathyroids may be useful for localization if surgery is anticipated.
  
  
  
  • This is particularly true for identifying adenomas, although most patients with MEN 1 have hyperplasia.
     
• Nonfunctioning pancreatic tumors: Endoscopic ultrasonography can identify tumors in 55% of asymptomatic patients.

Other Tests

Genetic testing

• Sequence analysis of the MEN gene for menin by polymerase chain reaction techniques provides best evidence of gene carrier status. This test is performed in several commercial laboratories and is recommended in asymptomatic first-degree relatives of affected individuals who are younger than 35 years.



• If test findings are normal on 3 occasions and patients are older than 35 years, patients are declared noncarriers. Offspring testing is not necessary.



• Nongenetic screening for investigation of MEN 1 gene carrier status can be conducted by measuring serum calcium, PTH, and serum prolactin every 3 years starting after age 5 years. Other tests include glucose, gastrin, insulin, proinsulin, and glucagon. Chromogranin A may be added where resources allow. Although these individual tests are less expensive than genetic testing, they are more expensive in the aggregate.

Screening for tumor expression

• Screening for tumor expression after MEN 1 gene carrier status is established includes biochemical studies on a yearly basis and imaging every 3-5 years.



• Biochemical screening involves performing fasting glucose, insulin, prolactin, and IGF-1 levels starting after age 5 years; calcium (preferably ionized) and intact PTH starting after age 8 years; and gastrin (with gastric acid output and secretin stimulation test if gastrin is high), chromogranin A, glucagon, and proinsulin starting after age 20 years, on an annual basis.



• Imaging studies include brain MRI starting after age 5 years and chest/abdominal CT or MRI for foregut carcinoids and enteropancreatic tumors starting after age 20 years, every 3-5 years.

Histologic Findings

In the parathyroids, the glands show diffuse or nodular proliferations of chief cells, admixed with some oncocytic cells. Usually, all 4 glands are involved and show signs of hyperplasia.

In the pancreas, numerous microadenomas, usually in the pancreatic tail, are present. The tumors display a trabecular pattern and may show conspicuous connective tissue stroma. Immunohistochemically, expression of multiple hormones is found. Pancreatic polypeptide and glucagon are expressed most often, followed by insulin and, rarely, gastrin. Nesidioblastosis and islet cell hyperplasia are not features of MEN 1, as previously thought.

In the duodenum, most tumors are found in the first part of the duodenum. They all stain positive for gastrin and metastasize to regional lymph nodes.

In the stomach, diffuse hyperplasia of enterochromaffinlike (ECL) cells are found, often associated with carcinoid tumors of considerable size (rarely metastases).

In the pituitary, most tumors that produce growth hormone are found in the anterior part of the gland and usually are single.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

• Hyperparathyroidism: Surgery is the treatment of choice. In patients who cannot undergo surgery, bisphosphonates may be useful. Calcium-sensing receptor agonists (calcimimetics), a novel class of drugs, have a potential role in the management of hyperparathyroidism associated with MEN 1 by directly reducing PTH release.



• Gastrinoma: Inhibition of acid hypersecretion is achieved with proton pump inhibitors. Metastatic gastrinoma may be treated with streptozocin and doxorubicin. Octreotide might decrease tumor progression; however, benefit is controversial.



• Insulinoma: No curative long-term medical treatment exists for insulinomas. Surgical tumor removal is the treatment of choice. Treat unresectable tumors with diazoxide. Long-acting somatostatin analogs can be useful in controlling hyperinsulinemia.



• Glucagonomas: Surgical extirpation is indicated.



• Vasoactive intestinal polypeptide tumor (VIPoma): Octreotide controls symptoms in 80% of cases, although surgical tumor removal should be attempted.



• Prolactinomas: These are best treated with bromocriptine or other dopamine agonists.



• Patients with symptomatic carcinoid tumors require somatostatin.

Surgical Care

• In general, surgery is indicated to control symptoms that are medically intractable and to prevent metastases of enteropancreatic neoplasms.



• Surgery is the treatment of choice for hyperparathyroidism in patients with MEN 1, if the following occur:
  
  
  • Serum albumin-adjusted calcium level is higher than 3 mmol/L (12 mg/dL).
  
  
  
  • Kidney stones are found.
  
  
  
  • PTH-induced bone disease, including osteoporosis, is present.
     
• In patients with ZES/MEN 1, parathyroid surgery is favored by some even in milder forms of hypercalcemia because normal serum calcium levels are often associated with lower serum gastrin levels and, consequently, lower gastric acid secretion. However, recently, due to effective pharmacotherapy for ZES, it is not considered to be a significant indication for surgery.



• For parathyroid hyperplasia, the two recommended surgical approaches are subtotal parathyroidectomy (with removal of 3.5 parathyroid glands) and total parathyroidectomy (with removal of all 4 glands) and immediate autograft of parathyroid tissue into the musculature of the nondominant arm. The current approach seems to be shifting back to removal of 3.5 glands. Hypocalcemia is more frequent with total parathyroidectomy.  



• Surgeons should make careful operative notes and mark the residual parathyroid tissue with clips because reoperation is likely in patients with MEN 1. Recurrence is reported in 43% of patients at 10 years of follow-up.



• At the time of parathyroidectomy, thymus might be removed to prevent  carcinoid tumor.



• With gastrinoma, the role of surgery in ZES and MEN 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. Removal of tumors larger than 2 cm in diameter reduces frequency of liver metastasis, which is an important prognostic factor.
  
  
  
  • Gastrinomas are found in the duodenal wall, the pancreas, or the 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. Surgery may also provide symptomatic relief in patients with large, locally metastatic tumors.
  
  
  
  • Resection of liver metastases may be beneficial.
  
  
  
  • Total pancreatectomy is not indicated because of the deleterious effects of this procedure (ie, pancreatic exocrine insufficiency and diabetes mellitus).
     
• Insulinomas are most often single large tumors that can be enucleated. Resection may result in cure, although insulinomas in patients with MEN 1 may be multicentric and small. A problem in these familial cases is that the lesion detected radiologically may not be the one causing hypoglycemia. Insulin measurements in the portal or hepatic veins may be required to localize the insulin secretion.
  
  
  • Some authors recommend subtotal pancreatectomy (80% or more 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.
     
• Glucagonomas are similar to insulinomas, and resection of single glucagonomas most often results in cure.



• For VIPomas, resection of single and multiple tumors is indicated, which may include a pancreatic tail resection.



• In pituitary tumors, transsphenoidal pituitary surgery is aimed at resection of any pituitary mass, especially in acromegaly, Cushing, or nonfunctional tumors.



• Prolactinomas may be large and multicentric. Patients with prolactinomas should continue treatment with dopamine agonists.
  
  
  • The recurrence rate after surgical removal is high.
  
  
  
  • Transsphenoidal surgery with external radiation therapy (eg, external beam or gamma knife) is indicated in patients in whom long-term dopamine agonist therapy becomes ineffective.
     
• Carcinoid tumors are removed surgically; half of them are locally invasive or metastatic, particularly thymic carcinoids.



• For lipomas, local excision is the therapy of choice if troublesome symptoms are present.



• For nonfunctioning pancreatic tumors, surgery might be considered for tumors larger than 2 cm, as tumor size correlates with risk of metastasis and death.

Consultations

This is a process that involves many organ systems, and significant difficulties in diagnosis and management are associated with each system. Multiple consultations are generally necessary, including consultations with an endocrinologist, gastroenterologist, neurosurgeon, general surgeon, and dermatologist. 

• Endocrinologist - Evaluation and treatment of insulinoma, glucagonoma, hyperparathyroidism, Cushing syndrome, and acromegaly



• Dermatologist - Evaluation of rash for specific patterns



• Gastroenterologist - Evaluation and treatment of gastrinoma, VIPoma, PPoma, and carcinoid tumor



• Neurosurgeon - Possible resection of growth hormone–producing macroadenoma; prolactin-producing microadenoma most often can be treated pharmacologically

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Because various syndromes may be expressed in patients with MEN 1, several medications may be indicated.

Drug Category: Somatostatin analogues

These drugs suppress peptide secretion of gastroenteropancreatic tumors or treatment of acromegaly. They have also been reported to relieve pain from spinal metastasis.

Drug Category: Proton pump inhibitors

Proton pump inhibitors inhibit gastric acid secretion by inhibition of the H⁺/K⁺-ATP-ase enzyme system in the gastric parietal cells. Esomeprazole (Nexium), omeprazole (Prilosec), pantoprazole (Protonix), rabeprazole (Aciphex), and lansoprazole (Prevacid) are available.

Drug Category: Dopamine agonists

Dopamine agonists are the treatment of choice in prolactinoma. In acromegaly, they are usually added to somatostatin analogues if complete remission has not been achieved. They have modest effects if used as a single agent for acromegaly. Bromocriptine (Parlodel) and cabergoline (Dostinex) are available.

Drug Category: Antihypoglycemic agents

These agents increase blood glucose by inhibiting pancreatic insulin release and possibly through an extrapancreatic effect.

Drug Category: Ergot alkaloid and derivative

Dopaminergic activity of some of these agents may reduce prolactin secretion.  

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• Monitor calcium levels after parathyroid surgery. Hypoparathyroidism may develop in 10-25% of patients. Recurrent hyperparathyroidism is also possible.



• Patients with acromegaly and residual tumor after surgery may respond favorably to somatostatin, which causes tumor shrinkage in approximately one third of cases.

Further Outpatient Care

• Hyperparathyroidism in patients with MEN 1 recurs in approximately 50% of patients within 10 years. Possible factors include the following:
• • Parathyroid cell growth can be an ongoing process.

  • A serum factor (eg, fibroblast growth factor) may stimulate endothelial cell growth in the parathyroid glands.

  • Hyperplasia results from expansion of multiple cell clones and not from a single cell type as in parathyroid adenomas.

• In patients with moderately elevated calcium levels, surgery may be postponed while the patient is assessed periodically, including serum creatinine, urine calcium, and bone density measurements.
• Carcinoid tumors may be associated with MEN 1. Perform careful endoscopic monitoring of fundic argyrophil cells or appropriate imaging at yearly intervals for known primary lesions.
• Hepatic artery embolization can be used to manage pancreatic tumors that have metastasized to the liver.

In/Out Patient Meds

• In patients with MEN 1 and gastrinoma, acid inhibition with proton pump inhibitors must be continued for life.
• Chemotherapy with streptozocin and dacarbazine may reduce tumor size in unresectable disease.

Transfer

• Because MEN 1 is a rare neuroendocrine disease, diagnosis and treatment should be performed in centers specializing in endocrinology.

Prognosis

• The prognosis in patients with MEN 1 and gastrinoma is considered better than in those with ZES alone.
• Whether surgery with tumor resection improves survival remains controversial. In one French study, complete resection of the primary tumor did not reduce the incidence of subsequent liver metastases.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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Article Last Updated: Jan 8, 2007