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138Chromosomal/trisomyNewborn w/ flat face, epicanthal folds, Brushfield spots on iris, single palmar crease: Down syndromeEt: Trisomy 21Pathophys: Maternal nondisjunction (MCC)Robertsonian translocation = 1 part of one chromosome goes to another --> teeny-tiny chromosome + big boy chromosomeDx: elevated bHCG + inhibin, low AFP + estriol, karyotypingSx (mostly from neural crest issues): Endocardial cushion defects w septa + valves --> atria and ventricles not separated properlyDuodenal atresia --| recanalizationVs. jejunal atresia d/t vascular insult in utero Hirschsprung disease --| Auerbach/Meissner plexi Sx: meconium ileusC/b ALL, Alzheimers (amyloid-precursor protein on chr21)RF: advanced maternal age = less eggs to fertilize, higher likelihood of fertilizing nondisjunction eggSecond most common trisomy: Edwards SyndromeEt: Trisomy eighteenRF: advanced maternal ageSx: prominent occiput, micrognathia, overlapping digits, rocker-bottom feet, death by age1-2Least common trisomy: Patau syndromeEt: Trisomy 13RF: advanced maternal age Sx: microcephaly, micropthalmia, holoprosencephaly, multiple digits, cleft lip/palate, rocker-bottom feet, death <1YCat-like cry: cri-du-chat syndromeEt: chr5 defectSx: microcephaly, high-pitched cat-like cry6mo losing motor milestones, fasciculations: spinomuscular atrophyEt: chr5 @ SMR1 genePathophys: destruction of anterior horn cells in spinal cordWhite reflex/leukocoria: retinoblastomaEt: chr15 Rb tumor suppressor deletionC/b osteosarcomaVisual problems (no iris), flank mass, posterior urethral valves, ID: WAGRSx: Wilms tumor + aniridia + genitourinary + mental retardation Et: chr11 gene deletion Beckwith-Wiedemann SyndromeSx: Wilms tumor, macroglossia, hemihypertrophy, hepatoblastomaSeizures at birth d/t hypoglycemia <-- overgrowth of pancreatic islet beta cells (insulin)25M infertility, 6', breast tissue, micropenis: Klinefelter syndromeEt: 47XXYPathophys: gonads do not work --> no inhibition @ pituitary --> elevated FSH/LH (hypergonadotropic hypogonadism)Sx: no sperm, female distribution of hair Female w short stature, short posterior hairline: Turner SyndromeEt: 45XOPathophys: second X chromosome is necessary for forming ovaries! Therefore they have streak ovaries --> no estrogen --> defect in secondary sexual characteristics Sx: cubitus valgus (elbow turned inward)short stature, low posterior hairlinecongenital lymphedema (cystic hygromas, webbed neck)primary amenorrheacoarctation of the aortaDelayed radial-femoral pulsed/t stenosis past the subclavian Bicuspid aortic valve --> early onset aortic stenosis*MCC of aortic stenosis <70Y! (afterwards: senile calcification)Horseshoe kidney Later in life, abdominal mass: streak ovary --> gonadoblastoma hypergonadotropic hypogonadism Vs: athlete that works out a ton --> shut down HPG axis --> hypogonadotropic hypogonadismVs. Hypothyroidism --> elevated TSH --> prolactin --| GnRH, FSH, LHVs. Kallmann syndrome --| GnRH cellsGenomic imprinting disorders or uniparental disomyObesity, hypotonia, deletion of paternal chr15: Prader-WilliInappropriate laughter, deletion of maternal chr15: Angelman?Autosomal recessive: enzyme defects, earlier sx, need 2 bad copies of allele5th percentile weight, 10th percentile weight, recurrent infections: cystic fibrosisEt: chr7 deltaF508 @ CFTR channelPathophys: Cl does not leave the cell --> attracts extracellular sodium --> water follows --> thick secretions of exocrine, sweat glandsSx: Pancreas: fat malabsorption ADEK (night blindness, secondary hyperpara, cerebellar ataxia, acanthocytosis, bleeding), Recurrent sinus infections d/t impaired mucus clearanceInflammatory response --> "cystic" dilation of airways = bronchiectasis + fibrotic damage Pneumonia 1) Staph aureus 2) Pseudomonas Burkholderia cepacia --> TERRIBLE pulm infection --> sudden death 2/2 pneumoniaPlugging of seminiferous tubules, agenesis of vas deferens --> infertility Meconium ileus Secondary primary biliary cholangitis d/t thick secretions of bile canaliculi Tx: Ivacaftor Dx: sweat chloride test, conductance of nasal epithelium, low serum trypsinogen (pancreas), DNA testingChild w/ musty odor, ID: phenylketonuria Et: deficiency of phenylalanine hydroxylase BH4 cofactor; mutation in tetrahydropterine reductase could cause similar sxPathophys: buildup of phenylalanine SxToxicity @ neuronsMusty odor (phenyl = benzene ring = aromatic compound)Albinism d/t deficiency of tyrosine (--> melanin)Tx: no phenylalanine in diet, avoid aspartame (artificial sweeteners) Dx: newborn screen Ppx: mom has PKU --> needs to be placed on careful diet during pregnancy; phenylalanine can cross placenta --> sx in baby25Y, osteoarthritis, black joints on synovial analysis, discoloration of ears/nose: alkaptonuria/ochronosisEt: deficiency of homogentisic acid oxidase Sx: "cartilage fetish"AlbinismEt: deficiency in tyrosinasetyrosine --tyrosinase--> melaninSx: oculocutaneous albinismC/b basal cell/squamous cell carcinoma (melanin helps absorb some of the bad UV)Cherry-red spot on macula, loss of motor milestones, no HSM: Tay-Sachs diseaseLysosome = "waste basket of the cell" Et: deficiency of hexosaminidase A --> buildup of GM2 ganglioside (@CNS)Sx: hyperreflexia, ID, cherry-red (ganglion cells in retina enlarge, engorge/compress blood vessels), death <2YRF: Ashkenazi-Jewish heritageNiemann-Pick DiseaseEt: deficiency of sphingomyelinase --> buildup of sphingomyelin in macrophages (@ reticuloendothelial system = liver, spleen, bone marrow + @CNS)Sx: cherry-red spot on macula, hyperreflexia, ID, hepatosplenomegaly (c/b thrombocytopenia)Pancytopenia, macrophages on bone marrow biopsy w/ crumpled paper appearance: Gaucher diseaseEt: deficiency of glucocerebrosidase @ macrophages in reticuloendothelial system Sx: ineffective erythropoiesis, joint problems ^^^Corneal clouding, coarse facial features: Hurler syndromeEt: mutation in alpha-L-iduronidase --> buildup of heparin + dermatan sulfateSx: Vs. Hunter syndrome (X-linked recessive): mutation in alpha-iduronate sulfatasePathophys: buildup of heparin + dermatan sulfateSx: no corneal clouding or coarse facial featuresVon Gierke disease (Type 1 GSD)Et: deficiency of glucose-6-phosphatase (glycogen-->glucose) --> buildup of G6P in liver --> hepatic cells expand, explode! Sx: hypoglycemia between meals d/t lack of gluconeogenesis Pompe disease (Type 2 GSD)Et: deficiency of alpha-1,4-glucosidase/acid maltaseSx: heart failureCori disease (Type 3 GSD)Et: deficiency of debranching enzyme/alpha-1,6-glucosidase (@muscle, liver)Sx: hepatosplenomegaly, muscle sxMcArdle's disease (Type 5 GSD)Et: deficiency of glycogen (myo)phosphorylase @muscleSx: muscle cramping w/ exerciseI-cell disease: --| phosphotransferase --> cannot put mannose-phosphate on things, so things are improperly transportedFA oxidation disordersMedium chain, long chain FA: metabolized @ mitochondriaMCAD/LCAD --| beta-oxidation --> impaired FA oxidation --> elevated acylcarnitineVs. carnitine deficiency: low acylcarnitineVery long chains: metabolized @ peroxisomeAdrenoleukodystrophy: demyelination, cerebellar ataxia, death <2YHemophilia C --| Factor 11African missionary with oxidizing drug --> hemolytic anemia: G6PD Sx: heinz bodies, bite cellsDx: G6PD assay weeks after episode?X-linked recessive (sx @ boys)Immunodeficiencies! Recurrent infections, hypopigmented skin (eczema), low platelets: Wiskott Aldrich syndromeChronic Granulomatous DiseaseEt: deficiency in NADPH oxidaseSx: recurrent infections w Staph aureus (abscesses)Dx: tetrazolium, dihydrorhodamine testTx: interferon-gammaVs. Interferon alpha --| HepCInterferon beta --| MSKiddo w/ gout, chews off fingers/toes: Lesch-Nyhan syndromeEt: deficiency of HGPRT (purine salvage pathway)Sx: hyperuricemia --> toxicity @ neurons, self-mutilationBruton's agammaglobulinemiaEt: mutation in Bruton's tyrosine kinase (B-cells)Sx: small tonsils, bacterial infectionsTx: IVIGHemophilia A --| Factor 8Sx: elevated PTTDx: correct w mixing studies (but sometime create Ab-factor8)Hemophilia B --| Factor 9Sx: elevated PTTDx: correct w mixing studies (but sometime create Ab-factor9)Meinke's disease/kinky hair diseaseEt: ATP7A mutation (copper metabolism)Vs. ATP7B Wilson's disease (copper @ basal ganglia, liver dz, psych, Kayser, c/I copper IUD, tx penicillamine/trientine)*penicillamine/trientine = chelators; ae: zinc deficiency (also chelated)Sx: death <2Y?Autosomal dominant: structural protein or receptor defect, later sxIf two copies of bad dominant allele: death in utero i.e. lethal form of osteogenesis imperfecta19Y, father died from MI @30Y, severe chest pain, STEMI, xanthelasma/xanthomas: familial hypercholesterolemiaEt: mutation in LDL receptor --> will not clear cholesterolType 1: No LDL receptorType 2: LDL receptors do not reach surface of the cell (--| exocytosis pathway)Type 3: LDL has trouble binding to LDL receptor; MCCType 4: LDL binds to LDL receptor but not endocytosedType 5: --| recycling LDL receptorSx: accelerated atherosclerotic dzTx: statin, PCSK9 inhibitors (-cumab)6'5", hyperextensible joints, displacement of lens, tearing chest pain radiating to back: Marfan's syndromeEt: mutation on chr15 fibrillin gene/FBN1 (maintains integrity of elastic fibers)Sx:Mitral valve prolapse/myxomatous degenerationImpaired elasticity of arteries (@intima) --> dilation without collapse --> aneurysm --> ascending aortic dissection (highest pressure vs. abdominal aorta) --> pull leaflets apart --> aortic regurgitation Circle of willis aneurysm --> subarachnoid hemorrhageLens subluxation/ectopia lentis: up and out Marfan's syndromeHomocystinuria Aut domAut recFibrillin mutationCystathionine beta-synthase deficiencyLens up and outLens down and outNormal intelligenceID?*B6/B9/B12 elevate homocysteine*Problems w/ wound healing, hyperextensible joints: Ehlers-Danlos syndromeEt: mutation in Type 3 collagen Sx: aortic dissection, thoracic aortic aneurysm, wound dehiscence, rupture of colon (thicker fecal material d/t water absorption --> wall of colon w type3 collagen struggles)Kiddo w blue sclera, fractures, short: osteogenesis imperfecta Et: defect in Type 1 collagen (COL1)Kiddo w hematuria, hearing problems, cataracts: Alport syndromeEt: defect in Type 4 collagen COL4A5 (@eye, ear, kidney)*X-linked dominantVs. Goodpasture syndrome: Ab-Type4collagenKiddo w short stature, dwarf, problems w long bone growth: achondroplasiaEt: mutation in fibroblast-growth-factor3Café au lait spots, growths on body: NF1Et: chr17 @ neurofibromin = tumor suppressor of p21 (RAS cascade)Sx: neurofibromas, meningiomas, pheochromo, Lisch nodules (hamartomas @ iris)NF2Et: chr22 @ merlin = tumor suppressor that tells cells when they're too close (contact inhibition)Sx: bilateral acoustic neuromasPosterior fossa mass, hematocrit 60%: VHLEt: chr3 @ VHL gene = ubiquitination of proteins that cause growth/proliferationSx: hemangioblastoma (esp @cerebellum, inhibited downregulation of HIF1 vascularization), EPO production, cysts @ liver/pancreas, bilateral renal cell carcinomaMultiple polyps in colon: FAPPpx: colonoscopies <20Y+ medulloblastoma = Turcot syndrome+ soft tissue osteoma = Gardner syndromeHgb 8, paternal relatives have blood disorders: hereditary spherocytosisEt: mutation in ankyrin, spectrin, band3.2Tx: splenectomyF with heavy menstrual bleeding: Von Willebrand DiseaseEt: deficiency of VWFDx: normal plt, elevated PTT?Trinucleotide repeatAutosomal dominantMyotonic dystrophyEt: CTG @ DMPK1Sx: trouble releasing grip, early baldingHuntington's Et: CAG @ chr4w/ anticipation!Sx: choreiform movements, dementia, inappropriate behaviorDDx choreiform movements:Huntington'sSydenham chorea 2/2 rheumatic feverLesion @ subthalamic nucleus = contralateral hemiballismusPANDAS = pediatric autoimmune neuropsych disorder 2/2 GASVs. myoclonusNeuroblastoma (flank mass, posterior mediastinum, calcified, crosses midline): "opsoclonus-myoclonus syndrome"Crutzfeld-Jakob disease: elevated 14-3-3, prionSerotonin syndromeTx: haloperidol, tetrabenazineX-linked dominant (only 2 = Fragile X + Alport!)Big ears, testicles, long face, ADHD/autism: Fragile X syndromeEt: CGG repeatAutosomal recessiveFriedrich ataxiaEt: GAA repeat?Mitochondrial disorders: from mom!Leber optic neuropathyMELAS = mitochondrial dz "ragged red fibers" --> encephalopathy, lactic acidosis, stroke?Multifactorial inheritanceNeural tube defectsCongenital heart diseaseT2DM ................
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