Lecture 28: MEN Disorders Flashcards
How are MEN disorders inherited?
Autosomal Dominant
What defines a MEN disorder?
Tumors in 2+ endocrine organs
What is MEN1 also known as?
Wermer syndrome
What do 90% of MEN1 disorders have in common in terms of gene mutation?
Germline mutation in the menin gene.
What is the function of menin?
Tumor suppression
What age do most people show manifestations of MEN1 by?
40
What are the MC organs affected in MEN1?
- Parathyroid
- Pancreas
- Pituitary (anterior)
3 P’s
MEN have 1 Penis that Pees and Pisses
What imaging modality should be used to search for MEN1 tumors?
CT/MRI
What is the MC initial presentation for a majority of MEN1 patients?
Primary hyperparathyroidism (PHPT)
What is the key difference between regular PHPT and PHPT due to MEN1?
MEN1 PHPT is usually much earlier in onset, 20-25.
What two scans can help locate the tumor in the parathyroid for MEN1?
US and nuclear scan for thyroid/parathyroid.
What are the 2 surgical options for PHPT? Risks?
- Partial: 3.5 glands removed w/ risk of surgical failure.
- Full w/ autotransplantation: risk of permanent hypoparathyroidism
- Overall: surgical failure, recurrence, and ectopic parathyroid tissue are common.
What are the nonsurgical options for PHPT due to MEN1?
- Oral cinacalcet
- Avoid oral calcium and thiazides.
What are the 5 GEP-NETs?
Gastro-entero-pancreatic neuro-endocrine tumors
- Gastrinoma (MC)
- Insulinoma (2nd MC)
- Glucagonoma
- VIPoma (Vasoactive intestinal peptide)
- Ppomas and non-functioning pancreatic NETs
What do gastrinomas secrete and where are they usually found?
- Secretes gastrin, which stimulates secretion of gastric acid and motility.
- Found in the duodenum
What is zollinger-ellison syndrome?
Gastrinomas with hypersecretion of gastric acid and recurrent peptic ulcers.
What is the clinical presentaiton of someone with a gastrinoma?
- Hyperacidic stomach
- PUD
- GERD
- Diarrhea
What inhibits gastrin release?
Secretin
What fasting serum gastrin is diagnostic for a gastrinoma?
> 1000 pg/mL
What test can be performed to check for a gastrinoma?
Secretin stimulation test, which is positive if serum gastrin levels stay > 120 pg/mL over baseline levels.
What meds can affect a secretin stimulation test?
PPI/H2 blockers.
How do we manage a gastrinoma?
- Long-term PPI w or w/o H2 blocker
- Control hypercalcemia
- Surgery usually only recommend to prevent liver mets.
PPIs: Omeprazole, Esomeprazole
H2 Blockers: Cimetidine, Famotidine
What is the origin cell of an insulinoma?
Beta cell in the islets of Langerhans
What is the main clinical finding of an insulinoma?
Hypoglycemia
How do we evaluate for an insulinoma?
- 72-hour fast in the hospital.
- Plasma insulin should rise
- C-peptide should rise
How do we manage an insulinoma?
- Surgical removal RECOMMENDED
- Med tx while awaiting surgery
- Frequent carb intake
- Oral Diazoxide (K-channel inhibitor that inhibits insulin secretion)
- Octreotide: at high doses, inhibits insulin and other hormones. Often used as a diazoxide alternative.
What is the clinical presentation of a glucagonoma?
- Weight loss (MC)
- Hyperglycemia
- Necrolytic migratory erythema
- Stomatitis
How do we evaluate for a glucagonoma?
- Elevated BG
- Elevated fasting blood glucagon levels > 150 pg/mL
How do we manage a glucagonoma?
- Control BG
- Octreotide (also inhibits glucagon)
- Surgical excision if a single lesion can be localized.
What are the clinical findings associated with a VIPoma?
- Hypokalemia
- Hypomagnesemia
- Tea colored and odorless diarrhea
- Vasodilation (Flushing)
- Iron/B12 deficiencies
- Hypercalcemia
- Osteoporosis
- Hyperglycemia
What diagnoses VIPoma?
Serum VIP conc > 75 pg/mL with repeat testing to confirm.
How do we manage a VIPoma?
- Correct imbalances
- Octreotide
- Surgical excision of primary tumor if NO mets.
What is the main concern with a Ppoma?
Mets to the liver.
No hormone syndrome generally present.
How do we manage a Ppoma?
- If low mets likelihood: excise tumor
- If surgery risky, avoid bc loss of pancreatic tissue can be devastating
How do most pituitary adenomas present in terms of size in MEN1?
Macroadenoma > 1cm in diameter
What is the MC pituitary adenoma in MEN1?
Prolactinoma (60%)
How does a prolactinoma present in females?
- Galactorrhea
- Amenorrhea
- Infertility
How does a prolactinoma present in males?
- Loss of libido
- Impotence
- Gynecomastia
- Infertility
- Galactorrhea??
What is the 2nd MC pituitary adenoma in MEN1?
GH
How do we manage a pituitary adenoma?
- Selective transsphenoidal adenomectomy
- Prolactinoma: cabergoline
- GH/acromegaly: octreotide
- Excessive ACTH: Pasireotide
When is surgery for an adrenal adenoma indicated?
Malignancy, aka > 4cm in diameter
What is recommend to treat a carcinoid tumor?
Surgical excision
What is the recommended treatment for a meningoma?
Refer to neurosurgery so they can decide.
What is a facial angiofibroma or collagenoma?
A tumor of fibrous or collagen tissue.
What are the screening recommendations for MEN1?
- 2+ MEN1 endocrine-related syndromes present
- First-degree relative of a MEN1 mutation carrier even if asymptomatic.
How is MEN1 screened?
Direct DNA testing for MEN1 gene mutations.
What is MEN2 also known as?
Sipple syndrome
What characterizes a MEN2 disorder?
- Medullary thyroid carcinoma (MTC)
- Pheo
- Parathyroid tumors
MTC-Pheo-Para
Men have 2 Pee!
What mutation characterizes MEN2?
RET proto-oncogene mutations
Where are RET genes found? Function?
- Thyroid, parathyroid, and adrenal glands
- Produces a signaling protein within nerve cells
- Excessive activation of the protein causes tumor formation.
What are the 3 types of MEN2 disorders?
- MEN2A: MTC, pheo, para
- MEN2B (MEN3): MTC, pheo, skeletal/soft tissue
- Familial MTC only
What feature is shared in all MEN2 subtypes?
MTC
What is the primary feature of MTC?
Increased secretion of calcitonin
A functional parathyroid is still able to counteract the effects.
What are the clinical findings associated with MTC?
- Solitary thyroid nodule
- Cervical LAN
- Hoarseness/dysphagia
- Distant Mets
What diagnostic studies should we order for suspected MTC? Expected results?
- Serum calcitonin: elevated if nodule palpable
- FNA Biopsy
- Genetic testing for RET gene
- PET scan for mets suspicion
Where does mets tend to begin if it originates from MTC?
Cervical lymph nodes
Most local regional nodes.
What is the treatment for MTC?
- Total thyroidectomy with lifetime LT4
- Prophylactic total thyroidectomy offered to people with + RET but are asymptomatic
- AVOID GLP-1 DRUGS!!!!!!!!!!!!!!!!!
How does pheo tend to present in MEN2?
BILATERAL in 60-80% of cases
What is the classic triad that suggests pheo?
- Episodic sweating
- HA
- Tachycardia
How do we treat Pheo?
- Alpha blockade prior to sx (10-14d)
- Surgical removal FIRST (prior to any other tumor in MEN2)
What clinical presentations might be found in MEN2B specifically?
- Marfanoid habitus
- Neuromas (eye, conjunctiva, nasal/laryngeal/bucca mucosa, tongue, lips)
- Hypertrophied lips
- Intestinal autonomic ganglion dysfunction (chronic constipation)
What are some possible complications for MEN2B pts with chronic constipation?
- Multiple diverticula
- Megacolon
What are the screening recommendations for MEN2/3?
- All patients with MTC (possible de novo mutation)
- All patients with MTC + family Hx of associated tumors
- All patients with MTC + Pheo even without FMHx.
- All patients with bilateral Pheo
- All patients with unilateral pheo, esp if associated increased calcitonin levels.
What causes MEN4?
Germline mutation in CDKN1B
How is MEN4 similar to MEN1? Different?
- Similar: prone to the same tumors.
- Different: additional tumor propensity, such as adrenal, renal, testicular, and neuroendocrine cervical carcinoma
- Primary ovarian failure
What is autoimmune polyendocrine syndrome or polyglandular autoimmune syndrome (PGA syndromes)?
Rare immune endocrinopathies characterized by coexistence of 2+ insufficiencies due to autoimmune mechanisms.
What is PGA syndrome type 1 also known as?
Juvenile PGA
What causes PGA type 1?
AIRE (autoimmune regulator gene) gene mutation on chromosome 21.
What is the function of the AIRE gene?
- Makes a protein in the thymus called autoimmune regulator that helps T-cells with self-recognition.
What are the 3 possible endocrinopathies associated with PGA type 1?
- Chronic mucocutaneous candidiasis (MC in infancy, as thrush that does not respond to standard tx.)
- Acquired hypoparathyroidism (2nd MC after years of chronic fungal infections)
- Adrenal failure (addison’s)
What is the MC additional organ presentation in PGA type 1 for females?
Gonadal failure
What additional findings are associated with PGA type 1?
- Poor dentition
- DM1
- Thyroid disease
- Alopecia and Vitiligo
- Intestinal malabsorption/pernicious anemia
- Chronic hepatitis
- Nail dystrophy
- Debilitating diarrhea or obstipation
How is PGA type 1 diagnosed? Confirmed?
- 2 out of 3 endocrinopathies confirmed via lab testing
- Antibodies to anti-interferon alpha and omega
- Genetic analysis is confirmatory.
How is PGA type 1 treated/managed?
- Ketoconazole
- Hormone replacement
- Increased risk of addisonian crisis when initiating treatment!!!
Adrenal insufficiency must be treated first if present.
What causes PGA type 2?
HLA gene mutations on chromosome 6
Who is PGA type 2 MC in?
3x more likely in females.
What is MC etiology of PGA type 2?
Idiopathic, thought to be due to genetic and environmental factors.
What characterizes PGA type 2?
- Primary adrenal failure (initial)
- Autoimmune thyroid disease
- Type 1 DM
- Primary hypogonadism
2 or more!!!
Add IT:
Addison’s
Insulin dependent DM
Thyroid disease
How do we diagnose PGA type 2?
Testing for the individual conditions.
How do we manage PGA type 2?
Screening every 1-3 yr for most common abnormalities.
How do we treat PGA type 2?
- Graves: radioactive iodine
- Hormone replacement: thyroid, gonadal, adrenal, pancreas
- Treat for addison’s before treating anything else
