Pediatric Multiple Endocrine Neoplasia Workup

Updated: Oct 11, 2017
  • Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Robert P Hoffman, MD  more...
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Workup

Approach Considerations

With testing, type 1 multiple endocrine neoplasia (MEN) can be detected in individuals from kindreds before age 18 years (or 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.

Screening

Because early therapy substantially improves the patient's prognosis, screening is of paramount importance in all forms of MEN. Clinical practice guidelines for MEN1 were released in 2012 to address some of the concerns in screening and evaluation of this condition. [12]

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:

  • Type 1 MEN - Serum calcium and intact PTH, prolactin, plasma chromogranin A, fasting gastrin, fasting glucose and insulin, and free IGF-I determinations
  • Type 2A MEN - RET germline mutation testing and determinations of plasma calcitonin, plasma free and total metanephrines and 24-hour urinary catecholamines (including fractionated metanephrines), and serum calcium levels
  • Type 2B MEN - RET germline mutation testing and determinations of serum calcitonin, plasma free metanephrines, and 24-hour urinary catecholamines, including fractionated metanephrines

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 permits the identification of people carrying a germline mutation.

For patients with family kindreds of type 1 MEN with known mutations, a separate series of routine screening recommendations has been established. These are available in guidelines from Brandi et al. [13]

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Imaging Studies

Gastrinomas

Somatostatin-receptor scintigraphy (SRS) has a sensitivity of 70-90%, which is more than that of any other imaging procedure. SRS depends on the SSR receptor profile (types 2 and 5, rarely type 3) and tumor size (>5 mm). Endoscopic ultrasonography can depict tumors in the pancreatic head but rarely in the duodenal wall.

Insulinomas

Perform high-resolution computed tomography (CT) scanning and magnetic resonance imaging (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, CT scanning, or both after biochemical evaluation.

Nonfunctioning pancreatic endocrine tumors

After type 1 MEN is confirmed, perform pancreatic endoscopic ultrasonography to monitor the progression of nonfunctioning pancreatic endocrine tumors. Their incidence is high (54.9%), although their clinical significance remains uncertain. Follow-up of lesions discovered should be coordinated with experienced subspecialists. [14, 15]

Pheochromocytomas

Radiologic imaging for pheochromocytomas includes CT scanning, MRI, metaiodobenzylguanidine (MIBG) scanning, OctreoScan imaging, and positron emission tomography (PET) scanning.

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Histologic Findings

Histologic findings in MEN include the following:

  • 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. [16]
  • Duodenum - Duodenal tumors are most often 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 enterochromaffinlike (ECL) cells is found and is 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 produce prolactin and/or GH, and, occasionally, corticotropin
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Laboratory Studies

Laboratory studies for MEN include investigations of the different tumor-expression patterns. Such studies include the following:

  • Gastrinomas (ZES) - Serum gastrin levels exceed 115 ng/mL and increase more than 200 ng/mL from baseline after secretin challenge (ie, intravenous [IV] injection of 2 U/kg of secretin); approximately two thirds of patients have basal gastrin levels of 150-1000 ng/mL
  • Glucagonoma - Findings are hyperglycemia with elevated serum glucagon levels
  • Watery diarrhea syndrome - Serum levels of vasoactive intestinal peptide are elevated; serum K levels may be low
  • Carcinoids - levels of serotonin, urinary 5-hydroxyindoleacetic acid (5-HIAA), calcitonin, and 24-hour urinary free cortisol and corticotropin may be elevated
  • Pituitary tumors - Tests reveal persistent elevation of serum somatotropin (growth hormone [GH]) during oral glucose challenge; serum free or total insulinlike growth factor (IGF)-I level more than 2 standard deviations (for age, sex, and Tanner stage); or elevated serum prolactin levels.

Insulinoma

Results may reveal fasting hypoglycemia with inappropriately elevated serum insulin, C-peptide, or proinsulin concentrations.

When the serum glucose level is less than 60 mg/dL, the serum insulin level should be less than 2 µU/mL. A serum insulin level of less than 2 µU/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, an increase in the serum glucose level by more than 30 mg/dL from a baseline of less than 60 mg/dL within 20 minutes after 1mg of glucagon is intravenously or subcutaneously administered
  • Suppressed lipolysis - Free fatty acid concentration below 20 mm
  • Suppressed ketogenesis (when the patient has hypoglycemia) - Undetectable plasma acetoacetate or beta hydroxybutyrate
  • Acute insulin response to peripheral venous or intra-arterial calcium challenge - Performed at centers that include the University of Texas Health Science Center at San Antonio and the Children's Hospital of Philadelphia

Type 2 MEN

Patients with MTC frequently have elevated calcitonin levels. In patients with pheochromocytoma, the total urine catecholamine excretion exceeds 100-300 μg daily (over 24 h). Serum levels of more than 2000 μg/mL are pathognomonic for pheochromocytoma. Measuring plasma free and urinary fractionated metanephrines with a 24-hour collection is best.

Type 2A multiple endocrine neoplasia (Sipple syndrome)

RET germline mutation testing has replaced the pentagastrin and calcium stimulation tests for the diagnosis of C-cell hyperplasia and 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 the 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. Optimal timing of prophylactic thyroidectomy is risk stratified and depends highly on the genetic signature. 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.

Pheochromocytomas are bilateral in 70% of cases and develop on the background of adrenomedullary hyperplasia secondary to an RET germline mutation. Biochemical manifestations, imaging manifestations, or both occur 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 free metanephrines and urinary catecholamines, including fractionated metanephrines, is recommended in children older than 6 years (although collecting 24-h urine samples in children is difficult).

In adults with an adrenal incidentaloma and hypertension, measuring plasma chromogranin A in addition to plasma free metanephrines may be helpful.

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