Endocrine Syndromes Flashcards
multiple endocrine neoplasia syndromes (MEN) - overview
*all 3 are autosomal DOMINANT (50% chance of inheritance)
*MEN1 = menin 1 gene; 3 Ps - Pituitary adenoma, Parathyroid adenoma, Pancreatic neuroendocrine tumors
*MEN2a = RET proto-oncogene; 2 Ps - medullary thyroid carcinoma, Parathyroid adenoma, Pheochromocytoma
*MEN2b = RET proto-oncogene; 1 P - medullary thyroid carcinoma, Pheocromocytoma
MEN1 - associated gene
*menin 1 (MEN1) gene
*inheritance = autosomal dominant
MEN1 - associated tumors
*3 P’s:
1. Pituitary adenoma
2. Parathyroid adenoma (hyperparathyroidism)
3. Pancreatic neuroendocrine tumors
MEN1 - additional manifestations
*skin findings: lipomas, angiofibromas, collagenomas
*adrenal tumors
*thyroid tumors
*uterine leiomyomas
*breast cancer
MEN1 - clinical diagnosis
*a patient presenting with 2 or more MEN1-associated tumors
*recall: MEN1 associated tumors = pituitary adenoma, parathyroid adenoma, and/or pancreatic neuroendocrine tumors
MEN1 - familial diagnosis
*a patient with 1 MEN1-assocaited tumor and first-degree relative with MEN1
*recall: MEN1 associated tumors = pituitary adenoma, parathyroid adenoma, and/or pancreatic neuroendocrine tumors
MEN1 - genetic diagnosis
*an individual who has a MEN1 mutation but does not have clinical or biochemical manifestations of MEN1 (i.e. a mutant gene carrier)
MEN1 - hyperparathyroidism / parathyroid adenoma
*95% of pts with MEN1
*younger age at diagnosis (in 20’s, compared to 50’s in sporadic hyperpara)
*multiple adenoma / 4 gland hyperplasia most commonly
MEN1 - pituitary adenoma
*40% of pts with MEN1
*prolactinoma > acromegaly > other
MEN1 - pancreatic neuroendocrine tumors
*30-70% of pts with MEN1
*gastrinoma > non-functioning > insulinoma > other
*most common cause of death from this disease
MEN2A - overview
*hallmark = medullary thyroid cancer
*100% of pts will get medullary thyroid cancer at some point
*monitor calcitonin levels, and treat with prophylactic thyroidectomy
*about 50% get pheochromocytoma
*about 30% get hyperparathyroidism (parathyroid adenoma)
*associated with RET mutation
MEN2A - associated gene
*RET proto-oncogene
*inheritance = autosomal dominant
MEN2A - associated tumors
*medullary thyroid carcinoma (secrete calcitonin; amyloid deposits on histology)
*plus, 2 P’s:
1. Parathyroid adenoma (hyperparathyroidism)
2. Pheochromocytoma (adrenal medulla tumor secreting catecholamines)
MEN2A - additional manifestations
*2 possible variants:
1. cutaneous lichen amyloidosis
2. Hirschsprung’s
MEN2B - overview
*hallmark = medullary thyroid cancer
*early onset, aggressive MTC (often before age 10)
*mucosal neuromas & alacrima (inability to make tears) may be a tip-off
*also associated with Marfinoid habitus
*associated with RET mutation
MEN2B - associated gene
*RET proto-oncogene
*inheritance = autosomal dominant
MEN2B - associated tumors
1. medullary thyroid carcinoma (secrete calcitonin; amyloid on histology)
2. mucosal neuromas (benign tumors on lips, mouth, etc)
*plus 1 P:
1. Pheochromocytoma (adrenal medulla tumor secreting catecholamines)
MEN2B - additional manifestations
1. Marfinoid habitus
2. alacrima (inability to make tears)
3. poor muscle tone, failure to thrive
neuroendocrine tumors (NETs) - overview
*neuroendocrine tumors (NETs) is an umbrella term that encompasses all tumors that are derived from neuroendocrine cells
*can be categorized in a few ways:
1. functional vs. non-functional
2. well-differentiated (low-grade) vs. poorly differentiated (high grade)
3. pancreatic (pNET) vs. outside the pancreas (carcinoid tumor)
*other distinct tumors also fall under this umbrella, including pheochromocytoma and medullary thyroid carcinoma
functional neuroendocrine tumors (NETs) - examples
note - “functional” = makes hormones
*carcinoid tumor/syndrome
*insulinoma
*gastrinoma (Zollinger-Ellison syndrome)
*VIPoma
*glucagonoma
*somatostatinoma
carcinoid tumors - overview
*most commonly arise in digestive tract, with small intestine (midgut) being most common site; can also be bronchopulmonary
*arise from enterochromaffin-like (ECL) cells
*may secrete SEROTONIN and other vasoactive substances
carcinoid syndrome - overview
*when serotonin (5-HT) reaches systemic circulation (LIVER METASTASIS) and leads to systemic features from vasoactive substances
*most commonly occurs from carcinoid tumors in the midgut/small bowel
*does not occur with all carcinoid tumors
*classically presents with episodic flushing, diarrhea, and wheezing
carcinoid syndrome - clinical features
*EPISODIC FLUSHING, diarrhea, wheezing
*due to SEROTONIN, bradykinin, histamine, others
carcinoid heart disease
*serotonin in systemic circulation reaches the right heart, and causes right-sided valve disease (fibrosis/stenosis, regurgitation, right heart failure)
*as serotonin passes through the lungs, it is metabolized to its inactive breakdown products (lungs contain monoamine oxidase); therefore, left side of heart is spared
carcinoid syndrome - diagnosis
*24h urine 5-hydroxyindole acetic acid (5-HIAA) (looking for breakdown product of serotonin in the urine)
*imaging (octreoscan, Ga 68 PET-Dotatate)
carcinoid syndrome - treatment
*surgery, if possible
*otherwise, somatostatin analogues (ex. octreotide), other chemotherapy
neuroendocrine tumors (NETs) - somatostatin receptors
*NETs possess somatostatin receptors on the surface of their cells
*somatostatin (aka the “anti-hormone”) inhibits release of hormones: inhibits release of pituitary hormones, pancreatic hormones, and gastrin
*therefore, we can use somatostatin analogues (octreotide, lanreotide) to inhibit hormone release from these tumors
insulinoma - overview
*tumor that arises from beta cells in the pancreas
*autonomously secrete insulin → hypoglycemia
insulinoma - diagnosis
*to establish a diagnosis, patient should meet Whipple’s Triad:
1. documented hypoglycemia < 55
2. symptoms of hypoglycemia (diaphoresis, tremors, weakness, confusion, seizures)
3. symptoms resolve with consuming food to raise sugar
*we then try to measure labs during an episode of hypoglycemia
insulinoma - hypoglycemia labs for dx
*in a patient with an insulinoma, during a hypoglycemic event, expect:
-insulin level: high (even normal is inappropriate because it should be low in a normal person)
-C peptide: high (even normal is inappropriate because it should be low in a normal person)
gastrinoma - overview
*aka Zollinger-Ellison Syndrome (Z-E syndrome)
*tumor arises from G-cell (gastrin-producing cells) in the duodenum, gastric antrum, or pancreas
*autonomous gastrin secretion → increased acidity in the stomach → ULCERS
VIPoma - overview
*VIP = vasoactive intestinal peptide
*VIPoma aka Pancreatic Cholera
*classic triad: watery diarrhea, hypokalemia (mostly from diarrhea), achlorhydria (lack of hydrochloric acid; VIP inhibits acid secretion) / increased gastric pH
*these patients can also have flushing (vasoactive)
glucagonoma - overview
*arises from alpha cells in pancreas
*glucagon functions as the opposite of insulin: inhibits glucose uptake into cells
*results in diabetes, weight loss, and a characteristic rash
*characteristic rash = Necrolytic Migratory Erythema: red blistering rash, usually on lower extremities
somatostatinoma - overview
*arises from the D-cells (delta cells)
*somatostatin = anti-hormone
*main signs/symptoms:
-decreased insulin production → diabetes
-decreased pancreatic exocrine function → steatorrhea / diarrhea
-decreased gallbladder contractility → cholelithiasis
autoimmune polyglandular syndromes - overview
*most autoimmune endocrine disorders occur in isolation; however, there are situations when patients will develop multiple autoimmune endocrine disorders +/- other autoimmune disorders
*2 distinct syndromes exist: APS-I and APS-II
autoimmune polyglandular syndromes: APS-I
*associated with mutations in the AIRE gene (autoimmune regulator gene: responsible for presenting various antigens in the thymus to help week out the T cells that target self)
*autosomal recessive
*presents in INFANCY
*associations:
-mucocutaneous candidiasis
-autoimmune hypoparathyroidism
-Addison’s disease (primary adrenal insufficiency)
-ectodermal dysplasia (pitted nails, poor enamel)
-primary ovarian failure
-pernicious anemia
-T1DM
-hypothyroidism
autoimmune polyglandular syndromes: APS-II
*polygenic
*presents age 20-60 years
*2 or more of the following:
-Addison’s disease
-autoimmune thyroid disease (Grave’s or Hashimoto’s)
-T1DM
-celiac disease
-primary hypogonadism
-myasthenia gravis
McCune-Albright Syndrome
*activating mutation in GNAS gene → constitutively active G-protein coupled receptor → cAMP signaling → hormone hypersecretion
*classic triad: fibrous dysplasia of bone (results in fractures), Cafe-au-lait spots, precocious (early) puberty
*also, hyperthyroidism, growth hormone excess, hypercortisolism
note - the Cafe-au-lait spots are “Coast of Maine” presentation
