Abstract
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1)
There are three types of Multiple Endocrine Neoplasia (MEN): Type 1 is due to a Menin mutation, and Type 2A and Type 2B are due to Ret mutations.
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2)
MEN Type 1 has a high penetrance for parathyroid hyperplasia.
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3)
One-third of patients with gastrinomas have MEN Type 1.
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4)
MEN Type 2A and 2B are characterized by medullary thyroid carcinoma and pheochromocytomas.
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-
1)
There are three types of Multiple Endocrine Neoplasia (MEN): Type 1 is due to a Menin mutation, and Type 2A and Type 2B are due to Ret mutations.
-
2)
MEN Type 1 has a high penetrance for parathyroid hyperplasia.
-
3)
One-third of patients with gastrinomas have MEN Type 1.
-
4)
MEN Type 2A and 2B are characterized by medullary thyroid carcinoma and pheochromocytomas.
Introduction
Multiple Endocrine Neoplasia (MEN) Type 1 was discovered in 1954 when a previously reported syndrome of pituitary, parathyroid, and pancreatic tumors was discovered to be inherited by a dominant trait. The earliest report was in 1903 of a patient with a pituitary adenoma causing acromegaly and three enlarged parathyroid glands. In the 1960s, MEN Type 2A and Type 2B were described, and the phrase “multiple endocrine neoplasia” was formed.
Outline
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I.
Multiple Endocrine Neoplasia (MEN) Type 1
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A.
Epidemiology:
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1.
Autosomal dominant mutation in the gene, Menin.
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2.
Menin acts as a tumor suppressor.
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3.
Affects 1 in 30,000 people in the USA.
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4.
Defined by possessing two of three major syndromes listed below.
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5.
One-third of MEN related deaths are caused by MEN Type 1-associated malignancies.
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1.
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B.
Syndrome
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1.
Pituitary Tumors
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a.
10–60% of patients with MEN type 1
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b.
Most commonly a prolactinoma (20%)
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c.
Can also be Adrenocorticotropic Hormone (ACTH)-secreting or Growth Hormone secreting
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d.
Diagnose with brain Magnetic Resonance Imaging (MRI) and serum prolactin levels
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e.
Treat with dopamine agonists
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f.
Monitor with prolactin levels yearly and MRI brain every 3–5 years
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a.
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2.
Primary Hyperparathyroidism
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a.
Leads to multigland parathyroid hyperplasia. Compare this to the general population, where 80% of primary hyperparathyroidism is due to adenomas
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b.
High penetrance rate, and therefore 90% of MEN Type 1 patients get parathyroid hyperplasia by age 40, and nearly 100% by age 50
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c.
Diagnosis: elevated serum calcium and parathyroid hormone levels
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d.
Surgical Treatment:
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i.
Subtotal parathyroidectomy (typically 3 1/2 gland excision) with cervical thymectomy
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ii.
Total parathyroidectomy with autotransplantation of 1/2 gland with cervical thymectomy (most commonly used site is the sternocleidomastoid muscle)
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i.
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e.
Monitor with calcium and parathyroid hormone levels
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f.
Recurrence is common and may require further resections
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a.
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3.
Pancreatic Neuroendocrine Tumors (PNET)
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a.
Most common overall: non-functioning PNET
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b.
Most common functioning PNET: Gastrinoma (~40%)
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i.
If found to have gastrinoma, evaluate for MEN Type 1. The Menin mutation is present in approximately 1/3 of patients with gastrinoma
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ii.
Symptoms
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a.)
Intractable peptic ulcers due to increased gastrin secretion (Zollinger–Ellison Syndrome)
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b.)
Reflux esophagitis
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c.)
Chronic diarrhea
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a.)
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iii.
Diagnosis:
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a.)
Upper endoscopy: confirm peptic ulcer disease
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b.)
Fasting serum gastrin > 10× upper limit of normal AND gastric pH < 2
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c.)
If fasting serum gastrin < 10× upper limit of normal, need confirmatory tests with secretin stimulation and/or basal acid output
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d.)
Imaging:
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i.)
Dotatate positron emission tomography (PET) or somatostatin scintigraphy
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ii.)
Look for multiple small tumors in the gastrinoma triangle: Junction of cystic duct and common bile duct, junction of head and neck of pancreas, junction of second and third parts of duodenum
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i.)
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a.)
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iv.
Treatment
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a.)
Parathyroidectomy—correction of hypercalcemia can improve symptoms
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b.)
If symptoms are well controlled—medical management with proton pump inhibitors
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c.)
Surgical Treatment:
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i.)
May include mucosal resection of duodenum along with distal pancreatectomy.
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ii.)
Incredibly difficult to remove all tumors surgically, and this should be used primarily as a debulking procedure.
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i.)
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a.)
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v.
Monitor with gastrin levels and dotatate-PET or somatostatin scintigraphy
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i.
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c.
Other functioning PNETs: insulinoma (~10%), glucagonoma, vasoactive intestinal peptide tumor (also known as VIPoma)
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a.
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4.
Additional Manifestations
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a.
Lipomas
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b.
Non-functioning adrenal cortical tumors
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c.
Facial angiofibromas
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d.
Rare manifestations: pheochromocytoma, carcinoid tumors
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a.
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1.
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C.
Diagnosis
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1.
Most common de novo presentation is recurrent hyperparathyroidism in middle age
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a.
Patient has history of removal of one parathyroid adenoma in their 20s.
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b.
In reality, the patient has parathyroid hyperplasia, not parathyroid adenoma.
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a.
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2.
The second most common de novo presentation (25%) is anterior pituitary adenoma.
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3.
Screening recommendations for patients who have family history of MEN Type 1:
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a.
Genetic testing for Menin mutation.
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b.
At age 5: fasting glucose, insulin, prolactin, Insulin-like growth factor (IGLF)-I, brain MRI.
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c.
At age 8: calcium and PTH levels.
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d.
At age 20: gastrin, secretin-stimulated gastrin, chromogranin-A, glucagon, proinsulin, and computed tomography (CT), dotatate-PET, or somatostatin scintigraphy.
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a.
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1.
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A.
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II.
MEN Type 2A and 2B
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A.
Epidemiology:
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1.
Autosomal dominant mutation in the gene, Ret
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2.
Ret is a proto-oncogene
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3.
Affects 1 in 35,000 people in the USA
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1.
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B.
Syndrome
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1.
Medullary Thyroid Carcinoma
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a.
Most common cause of death in MEN 2A
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b.
Manifests in 90% of patients
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c.
Surgical Treatment: prophylactic total thyroidectomy and central neck dissection (all lymphatic tissue between sternal notch and hyoid bone, and between the jugular veins)
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i.
Known MEN 2A patients—perform by age 1–5 years old.
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ii.
If discovered de novo, after age 10–15, include ipsilateral modified radical neck dissection on affected side due to high incidence of lymph node metastasis.
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iii.
If discovered de novo, check calcitonin level, and look for distant metastasis. If distant metastases are present, then do not perform thyroidectomy or lymph node dissections.
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i.
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d.
Monitor with calcitonin and carcinoembryonic antigen (CEA) levels, and with neck ultrasounds yearly
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a.
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2.
Pheochromocytoma
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a.
This must be treated first before any neck surgery for medullary thyroid cancer
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b.
Manifests in 50% of these patients
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c.
Diagnosis:
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i.
Biochemical tests: plasma or 24-h urine metanephrines
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ii.
Imaging tests: CT or MRI abdomen, Meta-iodobenzylguanidine (MIBG) scan
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i.
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d.
Treatment: alpha blockade and then adrenalectomy
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e.
Monitor for recurrence with urine or plasma metanephrines, and CT or MRI abdomen
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a.
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3.
Additional Manifestations
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a.
MEN Type 2A
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i.
Primary Hyperparathyroidism
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a.)
Manifests in 20–30% of these patients
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b.)
May be due to single adenoma vs. multigland hyperplasia
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c.)
Diagnosis: elevated serum calcium and parathyroid hormone levels
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d.)
Surgical Treatment: parathyroidectomy (extent may vary)
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e.)
Monitor with calcium and parathyroid hormone levels
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a.)
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ii.
Cutaneous lichen amyloidosis
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iii.
Hirschsprung’s disease
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i.
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b.
MEN Type 2B
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1.
Mucosal neuromas
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2.
Marfanoid habitus
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1.
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a.
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1.
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C.
Diagnosis
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1.
De novo presentation may be medullary thyroid cancer or pheochromocytoma
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2.
If genetic history is known
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a.
Genetic testing for Ret mutation of various codons—some are considered more aggressive than others
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b.
Prophylactic total thyroidectomy with central neck dissection by age 1–5
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i.
By age 1 for level 3 codon mutations-most aggressive, often will have microscopic tumor already by age 1
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ii.
By age 5 for level 2 or level 1 codon mutations
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i.
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c.
Monitor calcitonin, CEA, and neck ultrasounds yearly
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d.
Start screening for pheochromocytoma by age 5 with yearly metanephrines and abdominal imaging
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a.
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1.
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A.
Additional Notes
The hereditary nature of Multiple Endocrine Neoplasia syndromes makes it important to consider other family members when treating a child with MEN syndrome. Often parents will be aware that the condition runs in their family. After a child has been diagnosed with MEN, it is important to screen siblings. Consultation with a geneticist will help with preparing for the implications of a positive finding on genetic screening. For example, diagnosis of MEN2A indicates that prophylactic total thyroidectomy is necessary by age 5-years-old. Operation can carry complications such as recurrent laryngeal nerve dissection, or hypocalcemia [1]. A longitudinal study of a large proband with MEN2A syndrome has demonstrated that prophylactic total thyroidectomy leads to long-term protection against thyroid cancer [2].
Treating children with MEN syndrome may reveal some features that are different from the disease in adults. A recent report stated that the marfanoid stature present in adults with MEN2B was not present in a series of children with MEN2B, who actually had short stature [3].
Study Questions
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1)
The most common pancreatic neuroendocrine tumor in MEN Type 1 patients is:
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a.
Insulinoma
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b.
Gastrinoma
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c.
Non-functioning tumor
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d.
Glucagonoma
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a.
Answer to Question 1: (c.) Non-functioning tumor. The most common pancreatic neuroendocrine tumor in MEN Type 1 syndrome is a non-functioning tumor. The most common functioning pancreatic neuroendocrine tumor in MEN Type 1 is a gastrinoma.
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2)
For patients with aggressive mutations of RET in MEN Type 2 syndromes, total thyroidectomy should be performed by age:
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a.
5
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b.
1
-
c.
10
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d.
2
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a.
Answer to Question 2: (b.) 1. For patients with level 1 or level 2 mutations, which are lower risk than level 3, they should undergo thyroidectomy by age 5. For patients with level 3 codon mutation, which are the most aggressive, they should undergo thyroidectomy by age 1.
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3)
Which of the following are correct in terms of most common pathology within each MEN syndrome?
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a.
Medullary thyroid carcinoma/MEN Type 2A
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b.
Gastrinoma/MEN Type 1
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c.
Pheochromocytoma/MEN Type 2B
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d.
Prolactinoma/MEN Type 1
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a.
Answer to Question 3: (a.) Medullary thyroid carcinoma/MEN Type 2A. Primary hyperparathyroidism is the most common manifestation of MEN Type 1, with nearly 90% of patients developing primary hyperparathyroidism by age 40 and nearly 100% by age 50. Medullary thyroid carcinoma is the most common manifestation of MEN Type 2A and 2B, with nearly 90% of patients developing medullary thyroid carcinoma. Pheochromocytoma is also present in MEN Type 2A and 2B, although only 50% of patients will develop it.
References
Tartik A, Arkan G, Kaya C, Karabulut R, Turkyilmaz Z, Sonmez K. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2 syndrome. Gazi Med J. 2021;32(4):589–90.
Grubbs EG, Lechan RM, Edeiken-Monroe B, Cote GJ, Trotter C, Tischler AS, Gagel RF. Hereditary endocrine tumours: current state-of-the-art and research opportunities: early thyroidectomy in multiple endocrine neoplasia: a four decade experience. Endocr Relat Cancer. 2020;27(8):T1–8.
van den Broek MFM, van Santen HM, Valk GD, Verrijn Stuart AA. Children with multiple endocrine neoplasia type 2B: not tall and marfanoid, but short with normal body proportions. Clin Endocrinol. 2021;95(3):453–9.
Further Reading
Brandi ML, Gagel RF, Bilezikian JP, et al. CONSENSUS: guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metabol. 2001;86(12):5658–71.
Carney JA. Familial multiple endocrine neoplasia: the first 100 years. Am J Surg Pathol. 2005;29(2):254–74.
Jensen RT, Ito T. Gastrinoma. [Updated 2020 Nov 21]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext. South Dartmouth, MA: MDText.com. 2000. https://www.ncbi.nlm.nih.gov/books/NBK279075/. Accessed 22 Nov 2021.
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Campbell, R., Mao, M. (2022). Multiple Endocrine Neoplasia Syndromes. In: Coppola, C.P., Kennedy, Jr, A.P., Lessin, M.S., Scorpio, R.J. (eds) Pediatric Surgery. Springer, Cham. https://doi.org/10.1007/978-3-030-96542-6_64
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