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Endocrine > 193. Endocrine Genetic Syndromes > Flashcards

193. Endocrine Genetic Syndromes Flashcards

1
Q

Monogenetic DM (MODY)

  • type of disease
  • type 2 vs type 3 (tx)

T2 DM

  • genetic basis
  • enviro factors

What is pharmacogenetics?

A

MODY: single gene defect (AD) leading to development of DM

  • misdx as T2DM, and lacking of DM auto-antibodies
  • type 2: defect in glucokinase gene (glu sensor, needs higher BG to trigger insulin, mild CP, no risk CVD, tx with diet
  • type 3: defect in HNF1-a, abnormal ins secretion, low renal threshold for glu (glycosuria), risk of CVD, tx with SUs

T2DM

  • genetics: complex interaction of multiple genes + enviro (39% pts with T2DM have 1 parent with T2DM; 1st degree relative has 5-10x higher risk than relative w/o T2DM, SNPs involved in development of pancreas, ins synthesis, ins secretion, ins action)
  • enviro: diet + obesity: leads to peripheral resistance to ins-mediated glu uptake, decreased sensitivity of b-cells to glu, lifestyle modifications improve ins sensitivity

Pharmacogenetics: help understand link b/w genetic variation and response to medications - may optimize and individualize tx plans based on genetics

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2
Q

Klinefelter’s Syndrome

  • what is it
  • CP

Turner Syndrome

  • what is it
  • CP
A

KS: most common cause of male hypogonadism (1/1000 males)
most common genotype: 47XXY (nondisjunction of sex chromosomes, may be mosaic)
CP: long length arms/legs, gynecomastia, psychosocial abnormality, inattention, impairment of linguistic fx, small firm testes with low sperm count + infertility

TS: most monosomies are lethal during early fetal development
Most common genotype: 45 XO - partial monosomy or mosaicism
CP: lack 2nd X chromosome = small ovaries with few/no follicles, streak gonads leading to infertility, short stature, shield chest, swelling of hands/feet, low set hairline, heart disease, horseshoe kidney, ear infections/hearing loss, nonverbal learning disability

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3
Q

Congenital Adrenal Hyperplasia

  • what are they, prevalence
  • 21 Hydroxylase Deficiency: genetics, effect
  • Classic Virilizing CAH: cp in boys and girls
A

CAH: AR disorders causing enzyme deficiency in synthesis of cortisol, aldo, or both
Prevalence: 67% salt losing, 33% simple virilizing
Affects all races/sexes equally

21-H Deficiency: most common form CAH

genetics: unequal crossover of CYP21A1 (active gene) + CYP21A1P (non-fx pseudogene) on CH.6p21 causing deletions
- blocks MC and GC synthesis = salt-wasting HyperK, adrenal crisis in first week of life, high amounts of androgens

Classic Virilizing CAH:
Females: ambiguous genitalia at birth due to excess androgens
Males: present at 1-4 weeks with FTT, vomiting, dehydration, hypotension, hypoNa, hyperK, shock

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4
Q 
Multiple Endocrine Neoplasia:
MEN I: CM, genetics
MEN IIA: CM
MEN IIB: CM
MEN II Genetics
A

MEN I: Parathyroid (1’ HPTH - most common manifestation in pts 20s-40s, tx with 3.5 gland resection), Pituitary (Prolactinoma most common), Pancreatic/Duodenal Tumor (gastrinoma most common, then insulinoma, non-fx)
Genetics: mutation in MEN1 gene (menin protein) in TWO-HIT - inherit 1 mutation from parent (AD), receive 2nd hit during life leading to tumor formation

MEN IIA: MTC (90-95%), 1’ HPTH, PCC, Hirschsprung’s Disease, Cutaneous Lichen Amyloidosis
Familial MTC - only MTC seen

MEN IIB: MTC (100% - earlier, more aggressive), PCC, Intestinal ganglioneuromatosis, specific phenotype of scoliosis, high arch palate, tongue neuroma, lip bumps, ptosis

MEN II Genetics
AD gain of Fx mutation of RET proto-oncogene (RTK - causes growth and differentiation in multiple tissues)
MEN IIA/FMTC: mutation of EC domain
FMTC: germline mutation
MEN IIB: germline mutation in TK2 domain
Strong genotype-phenotype correlation
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5
Q

Hereditary PCC/PGL

  • sx triad
  • what diseases have this?
A
  1. episodic headache
  2. sweating
  3. tachycardia

10% malignant and invade locally or with distant mets

seen in MEN IIA, MEN IIB, VHL, NF1

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6
Q

Von Hippel-Lindau (VHL)

  • genetics
  • CM
A

AD syndrome, two hit model with germline mutation in VHL tumor suppressor gene
CM: hemangioblastoma (brain and eye), renal cell carcinoma, PCC, tumor of middle ear, neuroendocrine tumor of pancreas

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7
Q

Neurofibromatosis 1 (NF1)

  • genetics
  • CM
A

Genetics: AD mutation in NF1 - tumor suppressor gene
Complete penetrance: 100% of people with gene have disease
Variable expressivity: people with disease have slightly different CMs

CM: Lisch nodules, inguinal/axillary freckling, cafe-au-lait spots, neurofibroma, optic pathway gliomas (may cause gigantism due to GH secretion), endocrine tumors (PCCs, PGLs, GI tract/pancreatic tumors)

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8
Q

Li-Fraumeni Syndrome

  • genetics
  • CM
A

AD mutation in p53 - delays cell cycle progression to allow for DNA repair or apoptosis (mutation: Damaged DNA survives and proliferates)

CP: sarcomas, premenopausal breast cancer, brain tumor (glioma, medulloblastoma), adrenocortical tumors

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9
Q

Carney complex

  • genetics
  • CM
A

AD inactivation of PKAR1A
CM:
Endocrine: adrenocortical tumors (Cushing’s Syndrome - primary pigmented nodular adrenocortical disease; adrenocortical cancer - secretes androgens, cortisol)
thyroid nodules, pit adenomas, large cell tumor of testicles, ovarian cysts
Non-endo: Skin lentigines (lips, ear, cheek), blue nevi, myxomas, cafe-au-lait spots
Eyes: pigmented lesions of conjunctiva and palpebrae
myxomas - cardiac, breast, osteochondrocytes

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10
Q

McCune Albright Syndrome

  • genetics
  • CM
A

Genes: post-zygotic (somatic mosaicism) activating mutation in G-alpha subunit of G-protein (sx vary based on mosaicism)

Triad: fibrous dysplasia of BONE, Precocious Puberty (peripheral PPP), cafe-au-lait skin hyperpigmentation
other CM: hyperfx endocrinopathies (PPP, hyperthyroid, GH excess, hyperPRL, hyperCortisol), heart disease, renal phosphate wasting, hepatobiliary dysfx

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11
Q

Autoimmune Polyglandular Syndromes

  • genetics
  • types
A

mutations in AIRE gene - modulates transcription of peripheral self-antigens in thymus presented by HLA mLc’s to maturing T cells

APS1: chronic candidiasis, chronic hypoparathyroid, autoimmune adrenal insufficiency

APS2: autoimmune adrenal insufficiency + autoimmune thyroid disease OR T1DM

APS3: autoimmune thyroid disease + other autoimmune disease

APS4: 2+ organ-specific auto-immune disease

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12
Q

Pitfalls to Genetic Testing

- what is allelic and locus heterogeneity

A

AH: multiple different mutations of same gene, must sequence WHOLE gene to find defect

LH: similar disease phenotype occurs from mutations in different genes, must think of multiple different genes to test!

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Endocrine (23 decks)

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