Endocrine Syndromes Flashcards by Kyra Porter

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

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MEN1 - associated gene

*menin 1 (MEN1) gene
*inheritance = autosomal dominant

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MEN1 - associated tumors

*3 P’s:
1. Pituitary adenoma
2. Parathyroid adenoma (hyperparathyroidism)
3. Pancreatic neuroendocrine tumors

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MEN1 - additional manifestations

*skin findings: lipomas, angiofibromas, collagenomas
*adrenal tumors
*thyroid tumors
*uterine leiomyomas
*breast cancer

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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

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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

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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)

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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

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MEN1 - pituitary adenoma

*40% of pts with MEN1
*prolactinoma > acromegaly > other

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MEN1 - pancreatic neuroendocrine tumors

*30-70% of pts with MEN1
*gastrinoma > non-functioning > insulinoma > other
*most common cause of death from this disease

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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

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MEN2A - associated gene

*RET proto-oncogene
*inheritance = autosomal dominant

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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)

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MEN2A - additional manifestations

*2 possible variants:
1. cutaneous lichen amyloidosis
2. Hirschsprung’s

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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

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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**