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278 Cards in this Set
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Type I Glycogenosis
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Glucose-6 phosphatase deficiency
Type I Glycogenosis, Von Gierke Dz Hepatic/renal enlargement PAS+ glucogen storage vacuoles in many cells Severe Hypoglycemia: failure to thrive, stunted growth, convulsions Hyperuricemia (gout) Xanthomas Bleeding (platelet dysfnx) |
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Pompe's Dz
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lysosomal α-1,4--glucosidase deficiency
(aka acid maltase); Type II Glycogen Storage Dz, technically also a lysosomal storage dz Glycogen in lever, heart, SkM w/ Muscle Hypotonia Micro: clear glycogen deposits in muscle Pediatric form: Massive cardiomegaly → early death Mn: -P-ompe's trashes the -P-ump Adult form: only SkM involved |
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trinucleotide repeat expansions in coding regions
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Huntington's Dz
expansion of CAG w/in coding region during spermatogenesis aggregated misfolded proteins → apoptosis polyglutamine gain of fnx → neuotoxicity → chorea & dementia |
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McArdle’s Syndrome
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aka Type V Glycogenosis
deficiency of muscle phosphorylase produces myopathic glycogenolysis adult onset: muscle cramps & weakness w/ exercise: myocytolysis & rhabdomyolysis → ↑ [ammonia]serum, myoglobinuria, abnormal lack of ↑ [lactate]serum Px: normal longevity p155; Mn: McArdle-McVardle, the M stands for Muscle |
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Fragile X Syndrome
Gene, Protein, Normal Fnx, Phenotype, Inheritance |
FMR1 "Familial MR" gene normal fnx: FMRP binds mRNA and regulate synaptic protein synth (esp proteins which ↨ synapse fnx); most expressed in CNS and gonads
Fragile X is CGG expans'n w/in UTR; Normal <50 → >200 → methylatn & LOF IQ <60, Long face,macro-orchidism, [macrognathism, large everted ears, hyperextensible joints, high arched palate, mitral valve prolapse] Premutatns: 50-200; most expansn during oogenesis: grandsons via daughter most affected aSx Carrier Males: Anticipation: Brothers have 9% risk, grandsons have 40% risk ---FXTAS: Fragile X associated tremor/ataxis syndrome occurs in ~1/3 starting 50's Affected Females (~half = MR & Premature Ovarian Failure) --Odd for X-linked |
"fragile" chrom appears broken
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Epigenetic
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heritable changes in gene expression not caused by alteration in DNA sequence, including tissue specific gene expression and genome imprinting. Phenotypic variations between monozygotic twins are due to epigenetics.
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Congenital
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condition that is present at birth; Huntingtons is genetic but not congenital.
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Missence mutation
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Factor V Leiden mutation, Alpha 1 antitrypsin deficiency, Sicle Cell Anemia #6 glutamic acid --> valine turns Ba globin chain into a Bs globin chain
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Nonsense mutation
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B-globin of beta thalassemia
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Defective splicing
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Prothrombin mutation: point mutation in non-coding sequence produces hypercoagulability
Hereditary spherocytosis: point mutations in non-coding sequences result in decreased ankyrin & failure to assemble spectrin |
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Blood Type O
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Frameshift mutation inactivates enzyme
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CFTR
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3bp frameshift deletion: chloride/sodium channel abnormalities
(Review Cystic Fibrosis) |
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Functional pleiotropy
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single mutation has multiple effects: sickle cell anemia, marfan's syndrome (fibrillin)
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Genetic heterogeneity:
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same defect produced by different mutation: deafness >20 genetic causess, 16 recessive
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Autosomal dominant disorders:
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New mutations are frequently expressed
Often AD diseases not familial (30%) New mutations likely from father diseases reducing reproductive capability disproportionately new mutations (obviously) AD>AR to be delayed onset eg huntingtons to have incomplete penetrance to have variable expressivity (different severity w/in family) 50% reduction of gene product causes disease Gene product is usually structural, not enzymatic eg LDL receptor |
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Blue sclera
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osteogenesis imperfecta
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Dominant negative
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mutant allele impairs fnx of normal allele eg osteogeneis imperfected, defective collagen chain interferes with assembly of normal proteins --> severe collagen defficiency
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Gain of Fnx
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Huntingtons trinucleotide amplification produces Huntingtin polyglutamine: toxic to neurons w/ GABA receptors
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Know table 5-1 listing autosomal dominant diseases
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Nervous System: Huntingtons 4p, Neurofibromatosis 17q, Myotonic dystrophy
Tuberous Sclerosis Urinary: Polycystic Kidney Disease (Adult) 4q, Wilm's Tumor 11p, GI familial polyposis coli 5q Musculoskeletal: Marfan's, Ehler-Danlos (some), Osteogenesis Imperfecta 1-4, Achondroplasia Metabolic: Familial hypercholesterolemia, Acute intermittent porphyria Hematopoietic: Hereditary Spherocytosis, Von Willebrand's Disease |
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Know table 5-1, autosomal recessive disorders
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---Metabolic: CF, Phenylketonuria, Galactosemia, Homocystinuria, Lysosomal Storage Dz's, alpha1 anti-trypsin deficiency, Wilson's disease, Hemochromatosis, Glycogen storage disease
--Hematopoietic: Sickle Cell Anemia, Thalassemias --Endocrine: Congenital adrenal hyperplasia --Skeletal: Ehelrs Danlos (some), Alkaptonuria --Nervous: Neurogenic muscular atrophies, Friedreich ataxia, spinal muscular atrophy |
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Autosomal Recessive Disorder Characteristics
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low frequency likely consanguinous marriages
high frequency likely confers disease resistance expression within kindred is uniform (no variable expressivity) complete penetrance is common onset usually early in life sporadic new mutations not readily manifested usually enzymatic defects |
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characteristics of X-linked recessive disorders
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All sex linked are X linked
SRY = sex determining region of Y chromosome; mutations = infertility Affected females are rare All males are affected: do not transmit to sons, all daughters are carriers |
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Know table 5-3, list of X-linked recessive disorders.
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Musculoskeletal: Duchenne Muscular Dystrophy, Becker Musculodistrophy
Blood: Hemophilia's A & B, Chronic granulomatous disease, G-6-P dehydrogenase deficiency Immune: Bruton's Agammaglobulinemia, Wiskott-Aldrich Syndrome, SCID Metabolic: Diabetes insipidus, Lesch-Nyhan Syndrome Nervous: fragile X syndrome Reproductive: Testicular Feminization Misc: Hunter's Syndrome, Fabry's Disease |
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What are the features of X-linked dominant Inheritance. Describe the features of the X-linked dominant example disease.
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Infrequent
Males cannot transmit to sons Vitamin D resistant Rickets aka X-linked hypophasphatemia: point mutation of vitamin D receptor PHEX → ↑ renal tubular excretn of phosphate → hypophosphatemia → childhood osteomalacia w/ genu varum [also Rett Syndrome] |
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Cori's Dz
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Type III Glycogen Storage Dz
debranching enzyme [ α-1,6-glucosidase ] deficiency accumulation of glycogen in liver, heart, muscle A milder version of Von Gierke Type I GSDz, as GNG remains intact Similar Sx: hepatomegaly hypoglycemia: stunted growth, failure to thrive, convulsions |
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What are the genetic and biochemical defect, accumulation and clinical features of alkaptonuria?
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Deficiency of homogentisic oxidase
no conversion of homogentisic acid --> methylacetylacetate homogentisic acid deposits in collagen and cartilage Clinical: Ochronosis: blue-black pigmentation in cartilage of ears, nose Severe cripplign arthritis at early age starting in intervertebral discs --> knees, shoulders, hips; oddlyspares hands and feet urine turns black on exposure to light |
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What are the inheritance and clinical features of neurofibromatosis, type I? Know the gene, gene product, and risks of this disease.
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von Recklinghausen's disease
NF-1 chrom17 for neurofibromin normally downregulates p21 ras oncogene AD, 100% penetrance w/ variable expressivity Multiple neurobiromas (neurla tumors) Cafe-au-lait spots w/ smooth borders over nerve trunks pigmented iris hamartomas aka lisch nodules (present |
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p & q
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p is short arm "petite"
q is long arm |
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Xp21.1
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X chromosome, short arm, region 2 band 1, sub-band 2
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Robertsonian translocation
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reciprocal translocation at centromere of 2 acrocentric chromosome --> one very large chromosome, one very small chromosome
pt is phenotypically normal with abnormal offspring eg familial Down's Syndrome |
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What are the clinical features of Down Syndrome? List types of chromosome defects; contrast types as to phenotype. What type may be inherited (describe the chromosome defect)? What prenatal screening tests are used for the diagnosis?
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woah
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What are MiRNA and SiRNA and what are functions/potential uses ?
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miRNA pairs with post-transcirptional mRNA: regulatory gene products
siRNA: small interfering RNA's introduced by researchers may some day be used for lab tests: early dx of acquired dz's potential theraputic uses vs. CA, infx disease, etc |
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What are the genetic defect and clinical features of Prader-Willi syndrome? Of Angelman syndrome?
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Epigeneitc process: selective inactivation of either maternal or paternal allele
Prader-Willi: MR, short stature, hypogonadism, obesity due to decreased satiety peptide YY, paternal interstitial delection chrom 15: 46XY del (15)(q11q13) + Universially Maternally imprinted (inactivated) Prader-Willi (Syndrome preventing) genes Angelman Syndrome "Happy Puppet Syndrome" MR, seizures, ataxia, inappropriate laughing maternal interstitial deletion chrom15 + + univerally paternally imprinted (inactivated) (Angelman Syndrome preventing) UBE3A gene |
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Recognize the pedigree of mitochondrial inheritance. Know the features of two mitochondrial diseases.
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Mitos entirely inherited from mother, never from father
Heteroplasmy: coexistant wild & mutatnt mtDNA Genes for respiratory chain enzymes: most effected organs: CNS, SkM, CarM, Liver, Kidneys Variable expression Leber heretidary optic neuropathy: progressive bilateral loss of cenral vision early adulthood onset 25+-10, cardiac conduction defects MELAS: Mitochondrial encephalopathy, lactic acidosis, and stroke like episodes motor and cognitive dvlpt delays Stroke like episodes --> progressive dementia assoc. w/ exercise intolerance, visual abnormaliteis, cardiomyopathies etc. |
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male pseudohermaphroditism. What is the most common cause and what are the features of this cause? List additional causes and features where given.
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Phen: female w/ normal breasts, bind pouch vagina, no uterus, amenorrhea
Y chrom & testes present but w/ ambiguous-to-female external genitalia or genital ducts Multiple causes, usually X-linked defective androgen receptor → Testicular feminization aka complete androgen insensitivity sro Else: WT gene (chrom 11): Transcriptl Activator for Gonadal & Renal Differentiation → defective testicular differentiation → Denys Drash: nephropathy, genital ambiguity, Wilm's Pediatric Kidney Tumor → WAGR: Wilm's Tumor, genital ambituity risk for gonadoblastoma, aniridia, MR Defective testicular hormone synth: 17-ketosteroid reductase, 5 alpha reductase |
p167
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Define female pseudohermaphroditism. What is the most common cause and what are the features of this cause?
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XX female w/ AR 21 hydroxylase deficiency → congential adrenal hyperplasia → excess androgen during embryogenesis
→ normal ovaries & internal genitalia, male external genitalia |
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What defines a true hermaphrodite? What are some causes?
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Both ovaries and testes present: either one testis + contralateral ovary or "ovotestis"
Chimera: individuals of 2+ zygotes (us. in vitro fertilization) Cryptic Chimera: 46XX w/ translocation of Y to autosome Mosaic: 46XX + 46XY |
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What are the clinical features of Turner Syndrome? List types of chromosome defects
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hypogonadism in phenotypically normal females 2* to complete or partial monosomy of X chrom
almost all 45X nonviable and abort ~20 wks gestation of the living: most pts 45X but actually moasics if tested some pts structural abnormalities which produce partial X monosomy deletions w/ isochrome, deletions w/ ring (14%) often mosaics: (29%), karyotype heterogeny correlates w/ phenotype variations --45,X/46XX, 45X/46XY, 45X/47XXX, 45X/46X,q(X)(q10) Evident at birth: Peripheral Lymphedema, Lymphedema of neck: "webbed neck," severe cystic hygroma, Short Stature: SHOX gene haploinsufficiency --Shield Chest (broad w/ widely spaced nipples), Multiple Pigmented Nevi (moles), Cubitus Valgus: wide carrying angle, Short 4th metacarpal (Knuckle-Knuckle-Dimple-Knuckle), Primary amenorrhea: streak ovaries, Metabolic Syndrome, Risks for autoimmunities esp Hashimoto, Often coarctation of aorta w/ childhood mortality Do not give Growth Hormone, worsens Hyperglycemia |
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XYY sro
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Excessively Tall Male w/ Severe Acne
[Normal Intelligence, Normal Fertility] |
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What are the clinical features of Klinefelter syndrome? What is the most common karyotype?
What complications are associated with this Syndrome? |
Y + ≥2X, mostly 47XXY's
2° to parental non-disjunction; maternal Ndj 2° to age Androgen Receptor (located X) contains CAG trinucleotide repeat polymorphism; shorter CAG both more active & preferentially silenced (physiologic in normal XX to use least active androgen receptor) → Sx hypogonadism w/ severe oligospermia to aspermia, common cause of male infertility Phen: Long Legs, ↓ IQ (≠MR) & Eunuch-like (gynecomastia, small penis, no virilization) ↑ # X's = ↓ IQ ↑ FSH, ↑ E ± ↓ T Risks: ↑ 20x extragonadal germ cell tumors & breast CA |
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Genetics of Sexual Differentiation
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Y chromosome determines male sex regardless of number of X chroms
SRY: Sex Determining Region in Y is in the short arm of the chrom and includes translational activator SIP-1 for dvlpt of male phenotype SRY mutations/translocations → XY females, XX males Lyon Hypothesis: Inactivation of either paternal or maternal X chromosome happens randomly in each cell at gestation day 16; all females are mosaics. XIST gene inactivates one X chrom by coating it with non-coding RNA; Pseudoautosomal region: 25% of X genes remain active on both chroms: these have normal, non-sex determining functions & a homologous region on Y. |
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22q11- sro
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Deletion of TBX1 (T-box) gene: no PAX9 transcription factor, normally expressed in pharyngeal mesenchyme for 3rd & 4th pharyngeal pouches: dvlpt of palate, parathyroids, thymus
Conotroncal (outflow) defects, facial dysmorphism, developmental delay, ± T cell immmunodeficiency psychiatric comorbidities: ADD, Bipolar & Schizophrenia Velocardiofacial Sro: Cleft Palate, Prominent nose w/ Retrognathism, Outflow abnormalities, Learning Disabled DiGeorge Sro: T cell immunodef, HypoCa2+, Outflow abnormalities, mild facial abnormalities |
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Cri du Chat Syndrome
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5p deletion
High pitch "Cry of Cat" for First Year Low Birth Weight, Microcephaly w/ severe MR Hypotonia, Round facies failure to thrive, ± reach adulthood |
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DiGeorge Syndrome:
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vast majority of DiGeorge are del22q11
thymic hypoplasia w/ T cell immunodeficiency Hypoplasia of parathyroids w/ hypocalcemia congenital heart defects |
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The 5 Distinct Deletion Syndromes
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del (5p-): Cri du Chat
del (22q11): DiGeorge & Velocardiofacial Syndromes del (11p-): Wilm's Tumor; WAGR del (13q-): retinoblastoma del (15)(q11p13): Prader-Willi; Angelman other deletions assoc w/ MR include deletions of arms of 18, 8, 21, 22, often forming ring chroms |
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Trisomy 13
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Patau syndrome
uniformly fatal w/in first year, vast majority <1mo ultimate cause: maternal age Phen: Cleft Palate, Cleft Lip, Polydacyly, Microcephalus w/ Narrow forehead, closely spaced eyes ± cyclopia, MR, umbilical hernia, rocker bottom feet, IUGR, Inside: Congenitla heart disease, renal defects Mn: Think P's: cleft Palate, cleft liP, Polydactyly, holoProsencephaly (forebrain dvlpt failure) Prenatal Screen: low PAPPA, low hCG [Pregnancy Assoc. Plasma Protein A] |
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Trisomy 18
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Edwards Syndrome usually nondisjunction or mosaic
IUGR small face to head ratio w/ micrognathia prominent occiput, low set ears, flat helices enlarged first finger: overlapping fingers congenital heart disease horseshoe kidney rocker bottom feet mental retardation mean survival 2 mo, overwelming majority die in infancy |
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Prenatal screen of Down Syndrome
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quadruple scren
↑ beta-HCG ↑ inhibin A ↓ AFP ↓ PAPPA (Pregnancy Associated Plasma Protein A) Fetal US: nuchal lucency, cardiac and intestinal anomalies → amniocentesis for chromosomes |
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Define proptosis. Review causes. Know orbital neoplasms, pseudotumor and its differential diagnosis.
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Forward displacement of eye: produces painful corneal exposure & risk of drying
DDx: Lacrimal gland lesions: sarcoid & neoplastic Optic nerve tumors: glioma, meningioma Graves' Ophthalmopathy Inflammatory conditions --extension of ethmoid sinuisits/cellulitis --Mucormycosis (DKA) --Wegener's Granulomatosis: cANCA positive primary to orgibt or 2* to sinusitis --Ideoapthic inflam/pseudotumor --Chromic inflam/fibrosis of lacrimal gland, orbital muscle or fascia-sclera Orbital Neoplasms --Hemangiomas: most freq 1* tumors: Capillary Hemagioma of Infancy produces vision loss by mechanical block --Lacrimal gland pleomorphic adenoma --Malignant lymphoma --Mets to orbit, esp neuroblastoma: periochylar ecchymoses |
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blepharitis, blepharoconjunctivitis, hordeolum, chalazion, wen
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blepharitis: inflammation of eyelid skin
caused by: any cause of dermatitis blepharoconjunctivitis: eyelids and conjunctiva both inflamed [caused by: any cause of dermatitis] hordeolum: "stye" acute purulent inflammatn of superficial gland or hair follicle of eyelid. involves meibomian or glands of Zeis, usu. Staph aureus chalazion: painless nodule/papule of eyelid; Chronic granulomatous inflam of meibomian glands probably 2° to obstrx & FA extravasatn; DDx: sebaceous adenocarcinoma → excise wen: epidermal inclusion and dermoid cysts |
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Neoplasms of the Eyelids
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1. Basal cell carcinoma: most common malignancy of eyelid
esp medial canthus & lower eyelid Invades orbit Excellent Px for Life, Vision in Danger 2. Sebaceous carcinoma: malignant; 2 patterns: -tumor/nodule formatuion -Paget-like growth which thickens eyelid & resembles blepharitis mets to parotid & submandibular glands, fairly good Px (75%) 3. squamous cell carcinoma- malignant 4. Syringoma- benign eccrine tumor of lower eyelids |
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5 causes of conjunctival scarring
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Chlamydia trachomatis → "trachomatous pannus" vascularized CT layer opacifies cornea & distorts eyelids
Caustic alkali → scarring Ocular cicatricial pemphigoid (autoimmune); Cicatricial ≈ pannus Iatrogenic (Rx rxn) Surgical removal |
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Define and recognize morphology of pterygium
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Winglike proliferation of fibrovascular tissue extending from inner canthus onto cornea caused by sun exposure, manifests in adults +- bilateral, dose not cross midline
Histologically identical to pinguecula, may calcify. Dissects into Bowman's layer (acellular layer beneith BM on anterior surface of corna) may impair vision, may cause astigmatism |
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List conjunctival neoplasms.
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Squamous neoplasias: generally indolent
--papilloma is benign, 2* to HPV --intraepithelial neoplasia 2° to UV or HPV --invasive carcinoma: still indolent Melanocytic neoplasms --nevi (pigmented moles) common --malignant melanomas: arises unilaterally within 1* acquired melanosis w/ atypia esp caucs, spreads to parotid, decent Px (75%) Mucoepidermoid carcinoma: rare, aggressive |
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Define keratitis. List causes. What is the most common cause of corneal ulcer? Describe morphology. What are the consequences of keratitis, corneal ulcers?
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inflammation of the cornea
Caused by various organisms Most common cause of corneal ulcer: herpes simplex unilateral, recurrent, produces dendritic ulcer sequelae: corneal scar & vision loss Else Fungi, bacteria, HZV, protozoa Acanthamoeba: Protozoa 2° to contacts; hard to tx, ± → meningitis |
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Describe band keratopathy and list causes of both types.
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opaque horizontal band across superficial central cornea, two types:
-Calcific band keratopathy: deposition of Ca2+ in bowman's layer caused by hypercalcemia or Juvenile RA -Chronic actinic keratopathy: UV light damage forms yellow band |
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What are causes of keratoconus?
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bilateral progressive thickening of cornea into cone shape
Down syndrome, Marfan Syndrome, Ideopathic [causes irregular stigmatism Tx: rigid contact lenses or corneal transplant] |
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Define cataract. List causes, symptoms. What is the significance?
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lenticular opacity, a major cause of blindness worldwide
causes: mostly aging, congenital, UV light, DM, Wilson's disease, Galactosemia, Radiation, Trauma, Corticosteroids, Rubella, Skin diseases: atopic dermatitis, scleroderma; Ocular diseases: uveitis, glaucoma, retinitis pigmentosa Sx: Early: impaired night vision, halos arounds treet lights progressively blurred vision Late: grossly visible opacity, complete vision loss Complications: Glaucoma, Autoimmune endophthalmitis to lens proteins Tx: surgical removal +- prosthetic lens implantation. extracapsular not likely to opacify like capsular |
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What is glaucoma? Contrast the two categories.
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collection of diseases characterized by combination of loss of visual field and optic cup changes; mostly assoc. w/ increased intraocular pressure, but not always
open angle glaucoma: aquous humor has unhindered access to trabecular network; resistance to outflow is present Closed angled glaucoma: pierpheal zone of iris adheres to trabecular meshwork & blocks egress; Presents as extremely painful, taut, firm eye = medical emergency progressive vision loss, decreased visual fields |
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Pathogenesis of Open Angle Glaucoma
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open angle glaucoma: unhindered access to trabecular network; resistance to outflow is present
1°: majority of all glaucomas; pathogenesis poorly understood 2° causes: --clogged trabecular meshwork: trauma damaged RBC's, epithelial pigment granules, necrotic tumors, phacolytic (leaking cataract) --Sturge-Weber "Port Wine" Encephalotrigeminal Angiomatosis |
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2 Types of Ophthalmitis
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Endophthalmitis: involves the vitrious
Panophthalmitis: involves retina, choroid sclera, extends into orbit and causes cellulitis & proptosis |
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Define uveitis. List causes. What are symptoms of uveitis?
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Inflammation of 1+ components of uveal tract:
Iris, Ciliary body, choroid Causes: Infectious agents: Bacteira: TB, leprosy, syphilis, tularemia Viral: herpes zoster Fungi: incl. coccy Parasites: onchoocerciasis Extension of Retinal Infx: CMV, toxoplasmosis autoimmune ideopathic juvenile RA Granulomatous: sarcoidosis, sympathetic ophthalmitis (opthalmoplegaia), infectious agents eg TB, fungus Sx: painful, red eye photophobia, blurred vision, mild miosis pericornea halo & ciliary flush, assymmetric iris Complications: adhesions → glaucoma |
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List the eye lesions of sarcoidosis.
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Granulomatous uveitis: noncaseating; asteroid bodies
Calcific band keratopathy Mutton fat keratitic precipitates retinal candle wax drippings (perivascular inflmmation) Mikulicz dry eyes w/ lacrimal involvement [Sarcoidosis characterized by widespread non-caseating granulomas & elevated [ACE], esp in black females, manifests as restrictive lung disease w/ interstitial fibrosis] |
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Sympathetic Ophthalmitis
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rare complication of ocular truma
penetrating injury to 1 eye--> exposed pigment antigen of uveal melanocytes, retinal epithelial & neural cells --> granulomatous inflamation of both eyes 2 weeks after injury in the sympathetic eye: --Loss of accomodation --Blurred Vision --Photophobia Tx: removal of blind eye & long term immunosuppression |
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Melanocytic Neoplasms of the Eye
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benign choroidal nevi normal in caucs (10%), non-precursor to melanoma
1° malignant melanoma: rare, ↑ with age most common intraocular malignancy in adults = mets to choroid -Iris melanoma: visible pigmented mass ± light colored: distorts pupil ± glaucoma -Ciliary body melanoma: loss of accomodatn, localized cataract, ± glaucoma Sx of visual impairment: retinal detachment, hemorrhage, edema PE: pigmented lesion on fundoscopic exam, often pale Labs: S-100+ (Neural Crest) Px: Mets to Liver Late mets ≈ good 5 year Px, bad 10yr Px (80%), (40%) |
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What are the clinical features, prognosis, metastatic sites of malignant melanoma?
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most common non-skin melanoma
most common 1* intraocular malignancy in caucasians occurs in conjunctiva or uveal tract melanocyte: neural crest derived S-100 positive Iris melanoma isible pigmented mass +- light colored: distorts pupil +- causes glaucoma Ciliary body melanoma: loss of accomodation, localized gataract, +- causes glaucoma Pigmented lesion on fundoscopic exam often pale, Sx of visual impairment: retinal detachment, hemorrhage, edema Liver mets most common Late mets means: 5 year Px: Good (80%), 10 yr Px: Bad (40%) |
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Adenohypophysis:
Embryonic Origin, Regulation, Cell Types |
Anterior Pituitary Derived from Rathke pouch of Oral Cavity. Hypothalamic control via portal vascular system, all positive acting hormones except DA which constitutively suppresses prolactin.
3 cell types by H&E, 5 cell types by immunostaining Acidophiles: Somatotrophs: half of anterior pituitary, secrete GH Mammotraophs/Lactotrophs: Prolactin Basophiles: Gonadotrophs: secrete FSH & LH Thyrotrophs: TSH Corticotrophs: pro-opiomelanotropin derivatives: ACTH, beta lipotropin (MSH, endorphins etc) "Chemophobes" are degranulated Chemophiles |
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Neurohypophysis
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outpouching from floor of 3rd ventricle, tied to hypothalamus by pituitary stalk, independent circulation (vs. anterior pituitary)
pituicytes are modified glial cells from hypothalamus Secretes: Oxytocin & ADH aka Vasopressin ADH: released in response to ↑ plasma oncotic pressure or ↓ BP (atrial receptors, not ANP); inhibited by hypervolemia/atrial distention Oxytocin: uterine & breast lobule contraction |
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What is the most common cause of pituitary hormone excess?
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Anterior Pituitary Adenomas
1/7 of all primary intracranial neoplasms incidental finding in 1/7 of all autopsies Most common (1/3) are fnxl prolactinomas |
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What is a fairly cause of deficiency of pituitary hormones?
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pituitary adenomas?
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most common type of familial pituitary adenomas
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Overwhelming Majority of Adenomas are Sporatic
5% familial & the majority of familial are MEN1 KO's ("Multiple Endocrine Neoplasia") Menin is a tumor suppressor transcription regulator Wermer's MEN1 Sro: 1° Hyperparathyroidism Pancreatic Zol-Ell Gastrinomas, Insulinomas Pituitary: Fnx GH, Prolactin & ACTH adenomas |
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Define pituitary macroadenoma by size; what are the clinical features and local effects of macroadenoma? Recognize MRI of macroadenoma.
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Macroadenoma is >1cm, more likely to be hormonally silent but cause local effects
Enlarged sella turica on imaging Bitemoral hemianopsia +- Increased intracranial pressure: HA, Nausea, Vomitting |
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Most Common Pituitary Neoplasm:
SSx, Tx |
1/3 of all Pituitary Neoplasms are Fnxl Prolactinomas w/ Hyperprolactinemia:
Amenorrhea, Galactorrhea, Loss of Libido, Infertility "pituitary stone" dystrophic calcification Tx: Dopamine Agonists: Bromocriptine or Cabergoline |
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What are the clinical features, pituitary morphology, and complications of growth hormone producing pituitary tumor?
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Many (40%) caused by expansion of gsp oncogene: GNAS1: GTPase deficient alpha subunit of Gs
Histology: classic Acidophilic Adenoma ± prolactin secretion; Hypoglycemia → ↑ GHRH → GH → IGF-1 Hyperglycemia, somatostatin → ↓ GH Most sensitive test is failure to suppress GH with oral glucose load Tumor before Epiphyseal Closure: Gigantism Tumor after Epiphyseal Closure: Acromegaly Enlargement of all organs incl. Thyroid Complications: DM, Osteoporosis, HTN, CHF, GI tumors; Local Effects w/ Gonadal Dysnfx |
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What are the clinical features and pituitary morphology of the corticotroph adenoma?
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Hypersecretion of POMC --> ACTH (corticotrophin), MSH (lipotrophin), endorphins & enkephalins
Small basophilic PAS positive adenomas which stain positive for POMC, ACTH derivatives and beta endorphin Cushing's Syndrome |
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DDx Cushing's Syndrome
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Cushing's Disease: Pituitary Adenoma (Hyperpigmentation)
Adenocortical adenoma/hyperplasia Paraneoplastic manifestation of Small cell carcinoma of the lung Exogenous steroids |
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Nelson's Syndrome
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Pituitary adenoma enlarges from pre-existing microadenoma after removal of adrneal glands for bilateral hyperplasia: macroadenoma local effects, Pituitary Insufficiency with hyperpigmentation, markedly on flexor surfaces (from MSH)
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What are the clinical features of gonadotroph adenomas?
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tend to be large with local sx, hyperfunction are rare
paradoxical 2* gonadal hypofunction middle aged patient, probably presents with pituitary apoplexy immunostains for beta subunit of FSH |
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What are the features of thyrotroph adenoma?
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Rare: 2* hyperthyroidism
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What are the frequency and consequences of nonfunctioning adenomas and of carcinoma?
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~25% of all pituitary tumors, produce local effects, esp hypopituitarism
carcinomas are rare and nonfunctional |
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Define panhypopituitarism? What lab tests are performed to make this diagnosis? List causes.
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difciency of anterior pituitary, manifests only after most (75%) of pituitary has been destroyed.
Usually caused by trumatic injury, else mass lesions, surgery, radiation, apoplexy, ischemic necrosis (sheehan syndrome), rathke cleft cyst, empty sella turcica syndrome (1*: obese multiparous women, 2* ischemic necrosis etc) genetic defects, hypothalamic lesions |
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pituitary apoplexy
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hemorrhage into pituitary gland
often 2° to adenoma Acute onset: excruciating HA, diplopia, Hypopituitarism Neurosurgical emergency: will cause Cardiovascular collapse |
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Sheehan syndrome
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necrosis of anterior pituitary 2* to shock 2* hemorrhage from labor
hypogonadism is first sx, onset may be years delayed from event |
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What are other causes of ischemic pituitary injury?
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DIC, Shock, CNS truma
Sickle Cell |
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What are the hypothalmic causes of panhypopituitarism?
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Benign Tumors: gliomas & craniopharyngiomas;
Metastatic Tumors: breast & lung Radiation for nasopharyngeal tumors Inflammatory/Infiltrative Diseases: Sarcoidosis, TB |
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What are the origin, morphology and clinical Features of the craniopharyngioma?
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benign tumor from vestigial remnants of Rathke's pouch
Bimodal age grouping: 10yo ± 5, or >50 Hypo or hyperfunction of pituitary solid or cystic squamous, frequently calcified excellent Px Histologically: Adamantinomatous in young Paipplary in Adults |
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Know the manifestations of panhypopituitarism
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Initially with loss of gonadogrophs followed by loss of thyrotrophs follwed by ACTH deficiency and death
Gonadotropin deficiency Children: retarded sexual maturation Adults: loss of libido, pubic & axillary hair --Males: impotence, loss of muscle mass, decreased facial har --Females: amenorrhea, infertility TSH deficiency: 2ndry hypothyroidism ACTH deficiency: adrenal failure w/o skin hyperpigmentation |
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What are the clincial features of central diabetes insipidus?
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ADH deficiency: polyuria, polydipsia, excessive thirst; large volume, low specific gravity
genetic is extremely rare Dx: urine/serum osmolality measured after withholding water repeate with Desmopressin test plasma vasopressin level after infusion of hypertonic saline Tx: Desmopressin DDAVP |
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Hand Schuller Christian Dz
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eosinophilic granulomas (langerhans cells)
traid of calvarial defects exophthalmos diabetes inspidius ± hepatosplenomegaly, lymphadenopathy, fever, skin rash |
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What are the causes and labs of SIADH? Which cause is the most common?
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Hyponatremia, Hemodilution --> cerebral edema with neurologic dysfnx
Vast Majority of cases are paraneoplastic manifestation of Small cell carcinoma of lung: CNS causes: local injury (hemorrhages, thromboses, infections) pulmonary disorders: TB, pneumonia drugs |
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Differentiate Between Dwarfs
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Pituitary Dwarfism: Proportional Dwarfism w/ delayed sexual dvlpt ± thyroid, adrenocrtical insufficency
majority are idiopathic w/ normal anatomy Tx: GH before epiphyseal plate closure Pyknodysostosis: AR sro of generalized developmental disorder w/ proportionate dwarfism; ↑ bone density and fragrility, short digits, small face, absent distal end of clavical Diastrophic Dwarfism: AR sro of short limbs, cauliflower ears, short 1st metacarpal (hitch-hikers thumb) ± deafness; Achondroplasia [Non obj]: AD LOF in Fibroblastic Growth Receptor 3: normal trunk, enlarged head, short limbs 80% new mutations |
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Hyperkeratosis, Parakeratosis, Acanthosis, Acantholysis, Spongiosis, Paillomatosis, Exocytosis, Erosion, Ulceration, Vacuolization, Lentigenous
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Hyperkeratosis: increased thickness of stratum corneum
Parakeratosis: retention of cell nuclei w/in stratum corneum Acanthosis: epidermal hyperplasia Acantholysis: loss of intercellular connections w/ loss of cohesion btw keratinocytes Spongiosis: intracellular edma of epidermis Paillomatosis: surface levation caused by hyperplasia epidermis and enlargement of contiguous dermal papillae Exocytosis: infiltration of epidermis by inflammatory cells Erosion: discontinuity of skin exhibiting incomplete loss of epiderms Ulceration: discontinuity of skin exhibitin complete loss of epidermis & portsion of dermis & some subcu ts Vacuolization: fromationof vacuoles w/in or adjacent to cells, often involving the basal cell-basement membrane zone Lentigenous: linear pattern of melanocyte proliferation within the epidermal basal cell layer. Lentigious melanocytic hyperplasia may be ractive or neoplastic |
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Understand the bolded microscopic terms. Recognize skin pathologies that are characterized
by each. |
?
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What are the effects of UV radiation on the skin, including UV-related skin cancers?
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Solar elastosis and premature aging
Skin cancers and precancers irregularities of pigmentation; "age spots" lentigo senilis, lentigo solaris, freckles Activates immune complexes (SLE) blunts immune response actinic keratosis squamous cell carcinoma basal cell carcinoma malignant melanoma lentigo maligna |
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Define vitiligo. What is the likely pathogenesis and what diseases are associated with it?
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Partial or complete loss of pigment producing melanocytes w/in epidermis
Common in whites and blacks of all ages usually in wrists, axilla, perioral/periorbital, anogenital skin, knees well demarkated areas of depigmentation Autoimmunity probable, esp assoc w/ thyroid disase |
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What are the pathogenesis, manifestations and conditions associated with oculocutaneous albinism?
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Hereditary absence/reduction of melanin prodxn by intact melanocytes
Ocular albinism is X linked & limted to eyes Oculocutanous: no melanin in eyes, skin hair. Predisposes to actinic keratosies, basal cell carcinoma, squamous carcinoma and malignant melanoma, plus a range of ophthalmic problems 1/10k in whites and blacks, higher in navajos (founder effect) Tyrosinase positve OCA is most common type. Tyrosine transport P gene mutation, small amt of pigment over time Tyrosinease negative OCA: total absence of pigment: whitehair, red pupils, severe eye problsm |
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Melasma
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"Mask of pregnancy"
blotchy facial hyperpigmentation generally resolves after delivery [all causes: pregnancy, OCP's, hydantoins, exacerbated by sunlight] |
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Ephelis
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freckle
pigmented lesion of caucasians induced by sun exposure. increased malanin pigment w/o ↑ # melanocytes. [identical to cafe au lait spots contrast to benign lentigo: ↑ # melanocytes, does not ↑↓ seasonally] |
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Benign Lentigo
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Pigmented macule of hyperplastic melanocytes.
All ages, all races, unknown cause, does not fade seasonally [contrast to Ephelis/Freckle w/o ↑ melanocytes & w/ seasonality] |
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Nevocellular Nevi
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Nevocellular/Nevomalanocytic nevus: "mole" neoplasm of melanocytes; NRAS or BRAF mutations constitutively activate RAS/BRAF signalling, cell cycle still arrested by p16/INK4a
Congenital nevus; deep dermal proliferations of melanocytes present at birth; melanoma risk ↑ w/ size Common, benign nevocellular nevus: mole of melanocytes acquired throughout lifetime. increase in size and number during pregnancy. solid, fairly flat w/ well defined round borders. Progresses through following phases: Jnxl Nevus: melanocytes confined to epidermal-dermal jnx Comound Nevus: melanocytes at EDjnx + in dermis Dermal/Intradermal Nevus: melanocytes in dermis Dermal Nevus w/ Neurotization: cells take spindle orientation, fasicular growth |
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What is a blue nevus? Spitz nevus? Halo nevus?
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Blue nevus: spindle shaped melanocytes w/in dermis. Blue-black color 2* to dermal locatn; may appear like melanoma
Spitz nevus: spindle and epithelioid nevus: reddish nodule occurs in children; may resemble hemangioma; melanoma Halo nevus: depigmentation of skin around nevus 2° to lymphocytic infiltration. DDx: malignant melanoma may halo |
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dysplastic nevi.
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darker & thicker in center, irregular peripehry
lentiginous hyperplasia w/ atpical nuclei Often >5mm & numerous Precursor lesion of malignant melanoma |
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What are the gene and clinical features of familial dysplastic nevi?
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AD inherited CDKN2A gene complex (usually p16INK4a) or CDK4 germline mutation
50% malignant melanoma by age 60 often arises outside of moles |
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What is lentigo maligna?
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Hutchinson's Freckle
Non familial melanoma in situ in sun exposed areas precursor to lentigo maligna melanoma but remains in situ for years micro: atpyical melanocytes at epidermal-dermal jnx |
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What are the risk factors for malignant melanoma?
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>>Dysplastic nevus<<
Sun expsoure, 80% of which occurs before age 18 Blonde/Red Hair, Blue Eyes Severe sunburns in childhood, Failure to tan, Fair Complexion, Freckles, presence of large congenital mole FHx: melanoma, xeroderma pigmentosum, albinism |
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ABC’s of malignant melanoma.
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Asymmetry
Border is irregular "Scalloped" Edges Color is mottled Diameter is >6mm (pencil thickness) Elevated above surroundings, enlarging |
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Describe behavior, location and compare prognosis of the four types of malignant melanoma. Which has the worst prognosis
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Superficial spreading malignant melanoma- most common. irregular borders, variegated pigmentation. usually on tunk & extremities. radial growth phase predominates.
Lentigo maligna melanoma: sun exposed skin, usually from Hutchinson's Freckle (lentigo maligna), long radial growth phase Acrolentigenous melanoma- occurs on hands & feet, including plantar feet. can affect dark skinned individuals Nodular melanoma- begins with vertical growth phase; poorest prognosis |
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What are prognostic factors for malignant melanoma? (memorize numbers)
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MELTUMP: melanocytic tumors of uncertain malignant potential- excise completely & follow
Good factors Depth of Invasion: <1mm >96% 5 yr survival <1.7 mm good surviva No ulceration Low mitotic rate, absence of regression Female Extremities TIL's |
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Suborrheic Keratosis
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≥ 30 yo on face, trunk & upper extemities
FGF receptor-3 implicated in sporadic type sharply outlined & raised "coin like w/ progressive increase in pigmentation. "stuck on" greasy. Micro: proliferation of basaloid cells w/ pseudo-horn cysts, hyperkeratosis, melanin pigmentation present w/in cells Dermatosis papula nigra seborrheaic keratosis of melanized skin, commonly located on face Leser-Trelat Sign: Multiple seborrheic keratoses, assoc. with internal malignancy, probably 2* to TGFalpha |
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Define acanthosis nigricans and list associations
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Thickened/hyperplastic epidermis with hyperpigmentation
velvet like texture, found in skin folds assoc. w/ malignancies & benign conditions 80% Benign: gradual dvlpt, most assoc w/ obesity, IR & Diabetes [else Pituitary, pineal tumors, OCPs, familal AD mutations in FGFR3, dvlps during puberty] Malignant assocations: Paraneolastic manifestation of adenocarcinomas, esp stomach & lungs [also breast & uterus] |
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What are associations of skin tags?
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CT covered by squamous epithelium, esp intertrigenous areas of axial body
Assoc: --Pregnancy --DM --Intestinal Polyposis |
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Wen
Define, Gross & Micro Morphology, Categorize, Complication |
Cyst
Gross: dome shaped movable nodule Micro: stratified squamous epithelial lining, filled with keartin &/ sebum Pilar or tricholemmal cyst: expansion of epithelium of the hair follicle Dermoid cyst: skin appendages in wall Epidermal inclusion cyst: down growth and cystic expansion of epidermis --multiple EIC's ≈ FAP-Gardner syndrome may rupture & produce painful granuloma |
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Review general features of skin appendage tumors. Know names and associations of those listed in handout.
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Papules/Nodules which arise form hair follicles, sebaceous glans, sweat glands
tumor types tend to occur at specific anatomica lcoations malignant are rare, often confused with met'd adenoCA incl: Cylindroma Trichoepithelioma Syringoma Tricholemmoma Eccrine Poroma Sebaceous adenoma, epitheliomas [Syrongocystadenoma papilliferum Pilomatrixoma] |
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Cylindroma
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sporatic or AD
Apocrine derived tumor, multiple, form turban tumor of scalp |
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Trichoepithelioma
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sporadic or AD
upper trunk, head multiple, basaloid cells resembling hair follicles, with CYLD gene |
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Syringoma
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multiple
eccrine gland derived tumors of lower eyelids DDx: basal cell CA |
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Tricholemmoma
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PTEN mutation
uppermost hair follcile cells cowden's syndrome: multiple hamartomas of GI tract, multiple tricholemmomas assoc. with brreast CA |
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Sebacious adenomas & epitheliomas
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associated with internal malignancy: MSH-MLH mutation (Muir-Torre Syndrome)
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Syringocyasdenoma papilliferum
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aporcine derived tumors of face & scalp aka nevus sebaceous
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Pilomatrixoma
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beta-catenin mutation
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Eccrione poroma:
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palms & soles
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What are the features of tuberous sclerosis, esp. with regard to the skin?
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AD variable expressivity
Sx: MR & Seizures Brain Lesions: Tubers: white nodules Skin Lesions: -Angiofibromas: acne-like lesions of the face -Hypopigmented lesions: ash leaf macules -Periungual fibromas -Shagreen patches: CT hamartoma [Genetic defect of either TSC1 (hamartin) or TSC2 (tuberin), which form a dimer in charge of regulating signal involved in protein synth, cell prolif, dif & migration] |
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Describe morphology and clinical course of keratoacanthoma.
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Rapidly growing squamous neoplasm in sun exposed skin of older whites
Dome shaped nodule with keratin-containing central crater probably well diffrentiated squamous cell carcinoma Micro: proliferation of squamous cells w/ central cup of keratin usually p53 mutations may spontanously regress |
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What are the causes, risks, and morphology of actinic keratosis?
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Premalignant dysplastic intraepidermal lesion
Cused by fair skin & sun exposure Similar lesion due to ionizing radiation, arenicals, hydrocarbons risk for dvlping invasive sqamous cell caricnoma Gross: brown, red or skin colored plaque w/ "sandpaper" surface cutaneous horn Micro: atpyia w/ intact BM. from basal layer alone to full thickness parakeratosis: retention ofnuclei in thickened keratin dermal elastic fiber damage |
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What are the predisposing factors, clinical behavior, gross and microscopic appearance of squamous cell carcinoma of the skin?
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Behavior: locally invasive; rarely met before >2cm (5%)
gross: scaling, indurated, ulcerated nodule; leukoplakia on mucosa micro: Polyclonal cells form epithelial or keratin "pearls"; "geographic" irregular sheets & islands of invading cells in dermis. Eosinophilic cytoplasm w/ hyperchormatic nuclei. Sun exposed skin, esp UV light: damages DNA, suppresses local immunity, Smoking, Chronic skin ulcers, Draining osteomyelitis, Old burn scars, Arsenical ingestion, Ionizing Radiation, Immunosuppression, Xerodemra pigmentosum, Precursor Lesions: actinic keratosis, Bowen's carcinoma in situ [also industrial carinogens: tars, oils, arsenic; Tobacco, betel nuts, lip CA, HPV 5&8] Mn: I-SCArRaAkBOUX (pronounced "Scarabouche" in Bohemian Rhapsody) → Immunosuppression, Sun, (Bowen's) CIS, Arsenic, Radiation, Actinic Keratosis, Burn scars, Osteomyelitis, Ulcers, Xermadosa Pigmentosa |
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What are the pathogenesis, clinical behavior, gross and microscopic morphology of basal cell carcinoma? Describe the familial syndrome, incl. gene, associated with BCC.
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see notes
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Describe the clinical appearance of benign fibrous histiocytoma. What is another name for this lesion?
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aka Dermatofibroma
tan to brown papules dimple inward on lateral compression, collar button sign = benign usually found on legs of working age women (20-50) Micro: poorly circumscribed intertwining bundles of fibroblasts & collagen in mid dermis overlain with epidermal hyperplasia; partially composed of factor 8a positive dermal dendrocytes, Hx previous injury common. |
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What is the primary malignant fibrosarcoma of the skin, its morphology and behavior?
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dermatofibrosarcoma protuberans: well differentiated fibroblast spindle cell tumor with radially arranged "storiform pattern" of proliferating nuclei
firm solid nodule on trunk translocation of collagen gene with PDGFR → tyrosine kinase activation indolent, mostly benign; tend to recur after excision; |
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What are the malignant cell type, characteristic microscopic morphology and clinical of the cutaneous T cell lymphomas?
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Malignant Cell = Sezary-Lutzner CD4+ T cells, have cerebriform nuclei & CLA expression targets which homes to skin
Band-like aggregates of lymphos in superficial dermis; invasion of epidermis = pautrier's microabscesses Spectrum of Disorders: Mycoses Fungoides: lymphoma localized to skin for years, Early: Eczema w/ red papulovesicular crusting → indurated irregular patches eventually evolves to generalized lymphoma w/ systemic spread = multiple large red nodules Sezary syndrome: leukemia, presents as whole body erythema & scaling "Red Man Syndrome" Adult T Cell Lymphoma/Leukemia variant = HTLV-1 infx: rapidly progressive |
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What is the most common type of mastocytosis and what are the clinical features ?
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Urticaria pigmentosum accts for majority
usually in early infancy; 1+ round/ovoid red-brown nons-caling papules or plaques good Px Sx from release of histamine, hepraine & other mast cell products Darier's sign: wheal & flare in surrounding area when lesion is rubbed Dermatographism: wheal & flare where skin is stroked Morphology non objective: clonal proliferation 2* to c-KIT mutation w/ receptor tyrosine kinase activation giemsa positive granules, tryptase + on immunostain |
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What are symptoms of systemic mastocytosis?
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Poor Px
Pruritis & flushing triggered by food, EtOH & certain drugs (codeine ASA) Rhinorrhea [GI bleeds, epistaxis, malabsorption w/ diarrhea] Bone pain indicates marrow involvement |
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What are the gene; functions of the gene product, inheritance and clinical features of Marfan Syndrome?
|
Most AD (~80%), Some new mutations (~20%): 600 mutations, most missense
FIBN-1 gene: codes for fibrillin-1, constituent of microfibrils: the scaffold for elastin deposition, abundant in aorta, ligaments, ciliary zonules (lense support); loss of normal microfibril sequestering → excess of TGF-beta → abnormal vascular smooth muscle and bone growth Clinical: widely variable expressivity of: tall, arachnodactyly, ligamentous laxity, scoliosis and pectus deformities, weak suspensory ligaments: ectopia lentis (bilateral disolation/subluxation of lens), severe myopia, retinal detachment Dx: "Thumb Sign," FHx, PE, Ophthalmalogic exam, Echocardiogram, DNA testing CV: proximal aortic dissection, mitral/aortic incompetance: floppy valve w/ regurg & CHF → premature death: males in 20's, females in 30's Tx: BP control, Valve Replacement(s), Aortic Grafts → normal longevity [Addt'l morphology: dolichocephaly (long head), prominent supraorbital ridges, high arched palate, spinal deformities (kyphosis, scoliosis, lordosis), chest deformities: pectus excavatum (depressed), pectum carinatum (pigeon breast deformity)] |
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What are the features of Ehlers-Danlos syndrome?
Know collagen types affected. Which type is associated with premature death? |
6 variants of inherited CT disorders, manifest all threee patterns of inheritance (AR, AD, XL)
skin fragility, hyperextensibility, hypermobility, purpura 2* to capillary weakness, "papyraceous" cigarette paper scarring of skin w/ minimal truma: esp knee complications: easy bruising, gaping defects after minor injury, difficult surgical healing, Joint dislocation common --most common: Types I and II; AD mutation in type 5 collagen: skin & joint hypermobility + easy bruising --most common AR: Kyphoscoliosis type: lysyl hydrolase enzyme: inadequate crosslinking Hypermobility: unknown defect; Arthrochalasia: AD; Dermatosparaxis: AR internal oran lesions occur in one type: vascular, visceral rupture, ophthalmic abnormalities Vascular Type (ie Type IV): COL3A1 for type 3 collagen mutated → ruptured colon, larged arteries (death), uterus (maternal death); Only EDS w/ shortened life expectancy: ~50 |
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What are the genetic and biochemical defect, accumulation and clinical features of Tay-Sachs Disease?
|
1/30 Eastern European Jews
Chrom 15: 4 base insertion with frameshift or gene splicing → Hexosamindidase-a deficiency → GM2 gangliosidosis in the nervous system: neurons, axon cylinders, glial cells, retina Micro: neuron ballooned with cytoplasmic vacuoles containing fat, stains positive with: Sudan black B & Oil Red O PE: Cherry red spot of retina: persistence of normal macula color in pale ganglioside rich retinal cells NO HEPATOSPLENOMEGALY (contrast to: neiman pick disease) Px: Normal at birth: Sx start at 6 mo w/ Exaggerated Moro repsonse (extensor starter response to sound as baby) → Motor incoordination progresses to flaccidity → blindness, mental deterioration → dementia, complete vegitative state → Death ~2yrs Dx: heterozygote screening: hexosaminadase blood level & DNA analysis, amniocentesis |
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What are the genetic and biochemical defect, accumulation and clinical features of Niemann-Pick disease, types A and B?
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deficiency of sphingomyelinase --> accumulation of spingomyelin in phagocytic cells and neurons
Dx: sphingomyelinase activity or in bone marrow biopsy >100 mutations expressed in maternal chroms (paternally imprinted genes) Relative Freq's: C > (A+B); A>>B Fat stain + (Sudan black B & Oil Red O) Clinical Type A: severe, infantile form seen in EsEuJws: massive hepatosplenomegaly & neuologic involvment w/ severe deterioration; evident at 6mo: protuberant abdomen, failure to thrive, vomiting, fever, lymphadenopathy ± Cherry red spot of retina; Death ~1yo Clincial Type B: EsEuJws: organomegaly w/o neurologic invovlement, survive to adulthood |
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What are the biochemical defect, inheritance and clinical features of Niemann-Pick disease, C
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NPC-1 gene: cholesterol trafficking --> accumulations --> deterioation of terminal axons and dendrites --> organomegaly
clinical presentation heterogenous stillbirth, hydrops fetalis, neonatal hepatitis chronic neruologic damage w/ childhood onset hepatosplenomegaly |
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What are the genetic and biochemical defect, accumulation and clinicla features of Gaucher disease?
|
3 AR mutations of glucocerebrosidase: accumulation of glucocerebroside/glycosylceramide from breakdown of cell membrane glycolipids; Membranes of senescent RBC's WBCs are greatest source of substrate, disease strongly related to accumulation from these sources
Gaucher cells: swollen phagocytic cells, w/ PAS+ "wrinkled tissue paper" fibrillary cytoplasm & displaced neucli; in Peripheral Blood and Sinusoidal Organs: Liver, Bonmarrow, Spleen, Lymphatic ts Type I: chronic non neuropathic gaucher: Eastern European Jews, Accts for almost all cases (99%): glucocerebrosidease decreased but present, thus compatible with life-long tx; Massive splenomegaly, Most to all of Bone Marrow displaced by Gaucher cells --> Cytokine prodxn --> bone erosions -- "Erlenmeyer flask" deformity of long bones --> infarction, aseptic necrosis SSx: bone pain, massive splenomegaly --> pancytopenia (not present in early childhood) Dx: test leukocytes/fibroblasts for glucocerebrosidase activity; >150 mutations Tx: recombinant enzymes, effective, expensive, normal life expectancy |
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What are the genetic and biochemical defect, accumulation and clinical features of Fabry’s disease?
|
X linked deficiency of lysosomal alpha galactosidase A
accumulation of globosides: ceramide trihexoside mean life expectancy 41 years Global Microvascular Disease --> Renal insufficiency, Death from Cardiovascular/Cerebrovascular Disease Neopathic pain: burning pain in extremities angiokeratomas: telangectasias of skin hypohidrosis: decreased sweating & heat intolerance tortuous arteries toluidine blue staining lysosomal accumulations in podocytes Corneal opacities in heterozygotic females T: alpha galactosidase therapy |
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What are the genetic and biochemical defect, accumulation and clinical features of MPS I H, Hurler syndrome?
|
Mucopolysacharides/Glycosaminoglycans GAG's
MPS I (H): most severe form: 6yr life expectancy AR deficiency of alpha-L-iduronidase accumulation of dermatan sulfate and heparan sulfate in Phagocytes, fibroblasts, neurons, endothelium, VSMC Presentation:"Gargoyalism" Coursening facial features: frontal bossing of head, hypertelorism, deperessed nasal bridge, gapped teeth, gingival hypertrophy, thick tongue, Clouded Cornea Deranged collagen synth: joint stiffness, Short Stature,hunched posture, kyphosis, claw hand, Hepatosplenomegaly Death from MI Cells w/ Clear PAS+ cytoplasm Tx: alpha-L-iduronidase enzyme, cord blood transplants from non-relatives (risks graft v host) |
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Contrast with MPS II H, Hunter syndrome And MPS I S Scheie syndrome.
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Hunter: X linked deficiency of L-iduronate sulfatase, males only, abscence of corneal clouding, milder clinical course
accumulation of heparan sulfate and dermatan sulfate Scheie: different mutation of alpha-L-iduronidase; stiff joints, corneal clouding, but intellignece nad life expectnacy normal |
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The mucolipidoses are characterized by defect in what process? What diseases do the most resemble?
|
[Rare AR dz, incl. I-cell disease and pseudo-Hurler polydystrophy]
defect in formation of mannose-6-phosphate recognition marker newly synthezied lysosomal enzymes are secreted into ECM I cell disease: clinically similar to Hurler syndrome Early onset (infancy/birth): hurler-like + non-immune hydrops fetalis Late onset: psychomotor retardation, kyphoscoliosis, lumbar gibbus |
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Describe the morphology and general defect of ichthyosis. What is the pathogenesis of the most common type?
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Defective desquamation process: Epidermal thickening (hyperkeratosis) resmbling fish scales (ichthy)
Heterogenous group of disorders both heritable & acqd Heritable: AD, AR or XL Aqcd 2* to lipid metabolism, neuologic & bone disorders Morphology: lossof normal basket weave pattern, thickened stratum corneum Most common type: AD ichthyosis vulgaris accts for almost all cases (95%) appears in early childhood deficiency of profilaggrin synthesis, scales on extensor surfaces face & trunk Tx: topical |
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What are causes and clinical course of urticaria?
What is the macroscopic morpholoygy? |
IgE dependent mast cell degranulation
IgE independent: ideosyncratic, maybe some aspirin suppressed prostaglandin Heretidary angioedema: deficiency of C1 inhibitor Wheals 2* to dermal edema most likely 30yo+-10 individual wheals dvlp in areas exposed to pressure: trunk, extremities, ears & fade w/in 24 hours, but episodes may persist for months |
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What is eczema. List types.
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red, papulovesicular oozing & crusting skin lesion: itch that rashes
multiple causes: --Allergic contact dermatitis --Atopic dermatitis --Primary irritant --Rx related: antigens or haptens --Pheotexzematous dermatitis: UV lights --Phytophotoeczema: the synergistic combination of plants and UV Atopic dermatitis: atopy = without place often familial, assoc with hay fever & asthma exacerbated by allergens, stress, hormones, temprature |
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What are the pathogenesis and clinical features of allergic contact dermatitis (use poison ivy as an example)? What is the macroscopic and microscopic morphology?
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urushiol from Rhus genus of plants: poison ivy, oak, sumac
Type IV Cell Mediated hypersensitivty rxn Toxicodendron hapten takes one hour to form complex with carrier protein in skin Requires sensiztiation via langerhans cells; Immunologic memory dvlps in LN's; Upon reexposure: Langerhans cells secrete IL1 to simulate lympho roliferation Memory T's relase cytokines which recruit inflammatory cells --> erythema, pruritis 24-48 h = spongiocytic phase of T4HS Mciroscopic morphologic: spongiosis spongiotic vesicles of proteinacous fluid form in stratum spinosum from epidermal edema vesicles rupture ooze & crust risk for bacterizal superinfection: impetiginization by Staph/Strep forms yellow crusts lymph infiltrate dermis, mast cells degranulate Inflam resolves in 2 weeks once stim removed Chronic exposure --> scaling, lichenification |
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erythema multiforme
|
CD8 hypersensitivity reaction assoc w/ infections and drugs
esp Herpes simplex, Coccy, Mycoplasma symmetrical involvement of entire body including palms; multiform lesions: macules, papules, vesicles and bullae characteristic target lesion: central necrosis + inflammation mucosal lesions are rare. parthenogenesis: CLA+ CD8 mediated apoptosis of basal cells self limited [histoplasmosis, leprosy, EBV, malignancy, SLE, dermatomyositis, majority idiopathic, Rx more commonly manifest ast Steven's Johnson Syndrome; CD4 & Langerhans found in erythematous margins] |
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5) What are two severe forms of erythema Multiforme; what are their usual associations, and What are the clinical features?
|
Stevens-Johnson Syndrome
Toxic epidermal necrolysis Stevens-Johson Syndrome: follows Rx expsoure: macular lesions w/ focal slughing at skin, lips & mucosa of GI & respiratory tract assoc. w/ fever & systemic sx potential for infection & death Toxic epidermal necrolysis also follows Rx expsoure diffuse sloughing detachment of >30% of epithelial surfaces & muscoa 35% mortality |
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6) Describe the macroscopic and microscopic morphology and pathogenesis of psoriasis.
What are some associations? |
pink plaque w/ loosely adherent silver-white scale:
Auspitz sign: point bleeding when scale is lifted; Koebner phenomenon: new lesions dvlp at trauma sites often rusty discoloration of distal lateral nail bed, oncholysis, pitting total body erythroderma possible, pustular variant looks like life threatening infx Path: Tcell response to ?. majority assoc w/ HLA Cw*0602; TH1, TH17, & CD8's acccumulate in epidermis: TNFa, IL12, IFNg and Growth Factors: keratinocyte prolif, inflam & angiogenesis Assoc: risks CVD, Psoriatic arthritis: ± deforming, usu. distal phalanges; common in HIV+ pts, Never in Asians or American Indians Morph: Munro's microabscesses: pustules within stratum corneum, Thinned stratum granulosum with perakeratotic scale, thinnest over tips of dermal papillae, acanthosis w/ elongated rete ridges, dermal inflammatory infiltrate; dilated dermal venules |
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Define seborrheic dermatitis. What is the likely cause?
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macules & papules on erthematous yellow greasy base in regions of abundant sebaceous glands: forehead, scalp, ear canal, nasolabial folds
extnesive crusting & scaling, fissures esp behind ears Probaly caused by Malassezia furfur Responds to antifungals & reducing oil in skin Dandruff in adults Cradle Cap in infants Leiner Disease: suborrheic dermitis, diarrhea, failure to thrive Common in HIV & difficult to treat Shares features w/ spongiotic dermatitis & psoriasis: parakeratotic forms scale, dermal inflammatory cell infiltrate |
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Describe the morphology, pathogenesis and Clinical features of lichen planus.
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self limiting CD8/CLA T cell hypersensitivity in mucus membranes: pruritic purle polygonal planar papules and plaques
itchy violaceosu flat topped papules form plaques with Wickham's striae (white highlights); occurs as dark brown color in melanized skins lesions typically symmetrical involving wrists, elbow & glans penis oral in majority of pts (70%) Koebner phenomenon: lesions dvlp at trauma sites regress spontaneously in 1-2 years +- post-inflammatory hyperpigmentation microscopic morphology: lymphos along dermal-epidermal jnx with destrx of basal cells --> angulating saw toothed interface dermatitis Civatte bodies: necrotic basal cells incorporated into inflamed dermis stimulated keratinocytes proliferate ( IFNg, IL6) |
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Pemphigus
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Gross: 4 types; vast majority pemphigus vulgaris, otherwise pemphigus vegetans, pemphigus foliaceous, pemphigus erythematosis,; else peraneoplastic mostly lymphoma
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Pemphigus Vulgaris
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Pathogenesis: IgG antibodies against intracellular attachments desmoglein 1, 3; cause cell bonds to lyse (acantholysis ) & bullae to dvlp
Clinical Features middle years 30+; may present with oral ulcers months before skin lesions; superficial vesicles --> crusting erosions; complications: life threatening fluid loss & superinfection Morphology Gross: mucosa & skin of face, scalp, groin trunk; Micro: suprabasal acantholytic blister within squamous epithelium Immunoflorescence fishnet-like staining for IgG w/in epidermis |
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Bullous Pemphigoid
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Pathogenesis: autoimmune process; complement-fixing antibody to basal cell-basement membrane attachment plaques, BPAG (hemidesmosomes) in lamina lucida; eosinophil products contribute to edema.
Clinical Features: elderly; tend to heal without scars Morphology Gross: large tense bullae esp inner thighs, flexor surfaces, forarms, axilla, groin & abdomen; +- intensely pruritic +- musoca; Micro: subepidermal vesicles & bullae, dermal inflam, incl. eosinophils Immunoflorescence: continuous linear basement membrane immunoglobulin & complement |
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Dermatitis Herpetiformis
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Pathogenesis: IgA & IgG anti-gliadin cross react with reticulin which anchors BM to dermis
Clinical Features: 30yo +-10; assoc w/ celiac disease & responds to gluten free diet; HLA prespsiposition Morphology Gross: pruritic plauqes & vesicles in clusters; bilateral symmetric on extensor surfaces: elbows knees upper back & buttocks Micro: granular deposites of IgA at tips of dermal papillae; microabscesses at tips of dermal paillae, subepidermal vesicles form; Immunoflorescence |
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Porphyria, Erythema Bullosa
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Epidermolysis Bullosa
Pathogenesis Clinical Features Morphology Gross Micro Immunoflorescence |
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What is the pathogenesis, in general, of epidermolysis bullosa. Which form is most serious? Why?
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heritable, nonimmune blistering disorders:
usually appear at or soon after birth bilsters dvlp at sites of pressure/rubbing/trauma unrelated pathogeneses: mutations in structural proteins Junctional EB = abnormal BM, +- Fatal |
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What are the dermatologic features and associations of porphyria?
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Vesicular nonimmune disease
prophyrins derived from hemoglobin, myoglobin & cytocromes Types: Congenital erythropoietic, Erythrohepatic protoporphyria, acute intermittent, porphyria cutanea tarda, mixed types Urticaria & vesicles that heal with a scar exacrerbated by sunlight Micro: subepidermal bullae w/ thickened dermal blood vessels |
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Describe the pathogenesis and list lesions of Acne vulgaris.
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Hormonally induced excessive prodxn of sebum
abnormal cornification accumulates in hair follicle proprionibacterium acnes, anaerobically proliferates in follicle; breaks down oils into irritating fatty acids; follicle distends & ruptures leading to inflammation Open comedones: non inflammatory "black heads" have central keratin plug Closed comedones: non inflammatory papules w/o central keratin plug Inflammatory types: papules, nodules & pustules; may erode underlying bone. |
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What disease in older adults resembles acne?
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Rosacea
pilosebacous units Celts & southern italians onset 40's & 50's episodic reddening/flushing with expsoure to heat or alcohol erythema, telangectasis, papules & tiny pustules; rhinophyma: enlarged nose |
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Describe clinical features, macroscopic morphology and associations of erythema Nodosum.
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Most common form of panniculitis
self limiting immune mediated hypersnsitivty reaction mostly of legs; poorly defined tender nodules assoc with fever & malaise; leasions flatten & heal without residiuum High serum [ACE] Associations: NO cause: common Drugs Organisms: strep, TB, Coccy Sarcoidosis Ulcerative Colitis & Crohn's Malignancy |
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What are other types of panniculitis?
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Erythema induratum
adolescents & menopausal women dermal blood vessels erythematous tender nodules which ulcerate not assoc with underlying disaese |
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What is the microscopic morphology of verrucae?
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benign papilloma w/ vacuolated (koilocytes) cells in granular layer and prominent cytoplasmic keratohyaline granules
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What are the four forms of Cushing syndrome (Fig. 24-43). Which is the most common cause of Cushing syndrome in clinical practice? Which is the most common of the endogenous types? What is Cushing DISEASE? Which form is ACTH independent? Which tumor is responsible for many cases of ectopic secretion?
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1. Primary ACTH hypersecretion = Cushing's disease W>>M 30 +-10;
2. Ectopic ACTH secretion: Small Cell Lung Cancer, Carcinoids of Pancreas & Bronchus, Malignant Thymoma, Pheochromocytoma, Medullary Carcinoid of thyroid, Gastrinomas; 50 +-10 3. Adrenal Hyperplasia, Adenoma, Carcinoma: one side enlarged, other atrophic (feedback); 4. Exogenous? |
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Pituitary, Adrenal Morphology of Cushing Syndrome
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Pituitary: Feedback Degeneration
Crooke's hyaline degeneration of the basophils Accumulation of intermediate keratin filaments in cytoplasm Adrenals: one of 4 possibilities -Diffuse hyperplasia, accts for >half of cases: 25+ gm, thickened yellow cortex -Nodular hyperplasia: bialteral nodules scattered through cortex, more assoc w/ [ACTH]high -Adenoma/Carcinoma: Women 45+-15 ---Adenomas encapsulated <30 g no atypia ---Carcinomas unencapsulated >200g, anaplastic -Cortical atrophy 2* to exogenous glucocorticoids: bilateral atrophy |
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What are the major clinical features of Cushing syndrome (Table 24-9)?
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Obesity, Facial plethora, Rounded Face
Decreased Libido Thin Skin, Decreased Linear Growth Menstrual Irregularity Htn, Hirsutism, Depression/Liability/Psychosis Bruising, Hyperglycemia, Weakness Osteopenia/Fx Nephrolithiasis Increased Risk for Infx |
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What two laboratory tests are used to diagnose Cushing syndrome? What is done to determine the cause? What are the three general patterns of findings for the cause?
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24 hour urine free cortisol level
loss of diurnal pattern of cortisol secretion FU: [ACTH]serum, Pituitary & Adrenal CT's, Adrenal US, Dexamethasone suppression test Pituiatry: [ACTH]high, not suppressed with [Dex]low, suppressed with [Dex]high Extopic: [ACTH]high, insensitive to Dex Adrenal Tumor: [ACTH]low, insensitive to Dex |
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What are the two types of hyperaldosteronism? What three mechanisms account for the primary type (fig. 24-44)? What electrolytes are effected and what are the resultant clinical findings? What happens to the renin level? Aldosterone level?
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Primary
-Conn's Syndrome of Solitary aldosterone secreting adenoma (midlife, W>M) -Idiopathic bilateral adrenal hyperplasia -"Glucocorticoid Suppressible" Pituitary ACTH induced hyperaldosteronism Suppressed Renin, Hypokalemia, Na retention, HTN |
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What are the two adrenal causes of androgen excess? What type of inheritance are the congenital adrenal hyperplasias? Which type is the most common form?
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Androgen secreting adrenal carcinoma
Congenital metabolic errors: AR enzyme deficiency; ACTH induces production, but products shunted down androgen pathways; lack of cortisol increases ACTH. 90% of cases 21 hydroxylase deficiency. |
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What are the three syndromes associated with 21-hydroxylase deficiency? What happens to the androgen level? Aldosterone and glucocorticoid level? What findings in a neonate raise the suspicion of CAH? What is the treatment?
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Salt wasting androgenitalism: total lack of hydroxylase: no cortisol, no aldosterone, evident soon after birth from hypotension, acidosis, cardiovascular collapse;
Simple virilization adrenogenitalism: some enzymatic activity; low aldosterone level still maintains normal salt balance. Low cortisol --> increased ACTH --> hyperplasia --> increased testosterone Nonclassic androgenitalism: late onset, more common, aSx-mild |
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Neonate with salt wasting hyponatreimai, hyperkalmia, hypotension, acidosis, cardiovascular collapse:
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Salt wasting androgenitalism: total lack of hydroxylase: no cortisol, no aldosterone
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What are the two types of adrenocortical insufficiency (Table 24-10)? What are the three patterns of insufficiency?
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Primary acute adrenocortical insufficiency (adrenal crisis)
Primary chronic adrenocortical insufficiency (Addison's disease) 2* Adrenocortical insufficiency |
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Primary acute adrenocortical insufficiency occurs in what three settings?
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Massive destruction of adrenals:
-Neonates following difficult delivery -Post-surgical pts with DIC -Massive adrnal hemorrhagce complicating bactermic infx (Waterhouse-Friderichsen) -Pts on anticoagulant Tx |
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What are the four main features of the Waterhouse-Friderichsen syndrome? What age group is it more likely to occur in?
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overwhelming septicemic infx of N meningitidis
rapidly progressive hypotension with shock DIC w/ purpura massive bialteral adrnela hemorrhage with rapid adrenocortical insufficiency more common in children |
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Primary chronic adrenocortical insufficiency is also called? What are the four disorders that can cause it? What are the clinical signs and symptoms?
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Addison's disease
insidious presentaiton, won't maniefst until <10% remains autoimmune: irregularly shrunken glands TB/Fungal: granulomatous inflammation AIDS mets: lung, breast, gastric, lymphoma, melanoma: enlarged adrneals with infiltrating neoplasms SSx: weakness, easy fatigability anorexia, weight loss, N/V, diarrhea hyperpigmentation (ACTH) Decreased aldosterone activity: hyperkalemia, hyponatremia, volume depletion hpotension Stress --> adrenal crisis --> death |
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Secondary adrenocortical insufficiency is caused by? What is the difference between in ACTH and pigmentation in primary vs. secondary?
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Any hypothalamic disorder that reduces ACTH output
exogenous steroids lacks hyperpigmentation adrenals can respond to low ACTH levels |
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How are most adrenocortical adenomas found? Which adrenocortical neoplasm is more likely to be functional?
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non functinoal, incidentally; well circumscribed <2.5 cm; yellow color;
Adrenocortical carcinoma more likely to be functional; assoc. with virilism; highly malignant, 20 cm; yellow with hemorrhage, cysts, necrosis; strong tendency to invade adreal vein, vena cava & lymphatics. |
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What are the five “rule of 10’s” for pheochromocytomas? What is the dominant clinical feature with a pheo? What is the classic description of this feature? What does a pheo release that causes the symptoms? How is a pheo diagnosed in the lab?
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10% assoc. with MEN syndrome
10% extra adrenal 10%% of non familial are bilateral 10% biologically malignant 10% arise in childhood (usually familial, male) Hypertension: classically abrupt, preciptious elevation in BP assoc with tachycardia, palpitations, headache, sweating, tremor and sense of apprehension; Pheo releases catecholamines Urinary Venillylmandelic Acid, metanephrines |
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What are the five features that distinguish endocrine tumors occurring with MEN vs. sporadic endocrine tumors?
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younger age
multiple organs synchronously or metachronously preceeded by aSx endocrine hyperplasia more aggressive, more likely to recur more multifocal |
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MEN-1 has what 3P’s? Which is the most common manifestation of the 3P’s? What is the mutant gene locus?
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aka Wermer syndrome
Parathyroids<<most commonly Pancreas Pituitary tumor suppressor gene for menin |
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What are the three subclassifications of MEN-2? What three lesions characterize MEN-2A? What additional features does MEN-2B have? What is the mutant gene locus for MEN-2? Why is early diagnosis with genetic screening done on MEN-2 patients? What is the treatment option?
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MEN-2A: Pheochromocytoma, Medullary carcinoma, parathyroid hyperplasia: RET gene mutation
MEN-2B: pheochromocytoma, medullary carcinoma, neuromas, ganglioneuromas, marfanoid habitus Familial Medullary Thyroid CA |
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Define thyrotoxicosis.
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Metabolic state caused by elecated levesl of T3 and T4
Hypermetabolic state and overactive SNS |
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Define hyperthyroidism. List causes. Which is most common?
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Thyrotoxicosis due to overproduction of T3 and T4 by thyroid gland, most common cause of thyrotoxicosis
Primary -Diffuse hyperplasea, Graves disease accts for vast majority (85%) -Hyperfunctional ("toxic") multinodular goiter -Hyperfunctional ("toxic") adenoma: plummer syndrome -Iodine-induced hyperthyroidism -neonatal thyrotoxicosis assoc. w/ maternal graves Secondary: Rare TSH secreting pituitary tumor |
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What are causes of thyrotoxicosis not due to hyperthyroidism?
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Subacute granulomatous thyroid (painful)
Subacute lymphocytic thyroiditis (painless) Chronic lymphocytic thyroiditis (Hashimoto) Ectopic thyroid: struma ovarii Facticious thyrotoxicosis: exogenous thyroid hormone intake |
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What are them clinical manifestations of thyrotoxicosis / hyperthyroidism?
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--Cardiac changes manifest first: increased cardiact output from increased contractility & peripheral O2 demand, tachycardia, palpitations, cardiomegaly, arrhytmias esp A-fib, CHF in elderly; reversible, thyrotoxic dilated cariomyopathy
--Eyes: wide, staring gase & lid lag 2* to SNS activity, exophthalmos only seen in graves (proptosis) --Skin: increased blood flow: warm, moist & flusehd; sweating; infiltrating dermopathy in Graves aka pretibial myxedema present in minority of cases: skin over shins scaley, oran peel like thickening; pigmented papules or nodules --Nevrous system: tremor, hyperactivity, emotional lability, aniety, inability to concentrate, insomnia, thyroid myopathy: decrease in muscle mass, proximal muscle weakness; anxiety, heat intolerance, unexplained weight loss, multiple daily bowel movements, goiter, thyroid bruit --GI tract: hyperphagia, hyperdefication (increased bowl motility) weight loss --Skeletal system: osteoporosis w/ elevated AP;--> fx's --Oligmenorrhea/amenorrhea |
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Thyroid Storm
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Abrupt onset severe hyperthyroidism
acute elevation of catecholamines febrile, tachycardia out of proportion to fever risk of death from arrhytmia: medical emergency immidiate tx w/ beta blockers |
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Apathetic hyperthyroidism
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Elderly pts: age/comorbidities blunt sx
depression, weight loss, worsening CHF w/ A-fib |
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What is Graves’ disease, including pathogenesis, clinical features specific to this disease, and morphology of the thyroid?
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Most common cause of endogenous hyperthyroidism, 1/50 women peak 30 +-10
Classic triad: --hyperthyroidism with diffuse enlargment of gland ("toxic goiter") --exophthalmos due to infiltrated ophthalmopathy --pretibial myxedema: infiltrative dermopathy of legs (minority ofcases) familal clusters esp HLA-DR3 or CTLA-4 polymorphism; assoc with Addison disease, vitiligo, SLE and Down syndrome pathogenesis: antibodies to TSHR mimics TSH; specific for graves, the cause of the eye sx stimulates growth and leads to follicular cell proliferation Ophthalmopathy: see other card Addt'lly: brui from increased blood flow, difficulty swallowing, smooth capsule, dilated follciles lined by toall epitehlial cells, scalloped colloid, inflammatory infiltrate |
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What are the lab results of hyperthyroidism in general? What lab test is specific to Graves’ dis?
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Decreased TSH
Increased T4, free T3 RAI uptake increased Radioiodine scan shows diffuse increase in uptake & enlarged gland increased AP Thyroid stimulting Ig-- specific to graves disease? +- Anemia Tx: beta blockers for sx, thyroidectomy or radioactive iodine 131 ablation Rx's propylthiouracil, methimazole Children with graves are tall for age with advanced bone age and normal sexual maturation |
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4) What are causes of hypothyroidism?
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Primary hypothyroidism: most common
thyroprivic: insufficient parenchyma 2* to surgery, radiation -----autoimmune/hashimoto is most common -----Rx's lithium, iodides, and rgus given to decrease thyroid fnx (propylthiouraciol and methimazole) goitrous: insufficent hormone synth -----Inborn errors of thyroid metabolism -----Childhood iodine deficiency -----Developmental inborn errors of metabolism (goiterou 2ndry -Pituitary tumor; apoplexy -sheehan syndrome/pituitary necrosis -suprasellar tumors eg craniopharyngioma Labs: TSH decreased, T3 & T4 decreased 3ry: -Hypothalamic tumor, damage, truma or infiltrative disease -Decreased TRH |
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What are the lab results of primary hyperthyroidism in general? Be able to interpret Labs of secondary hypothryoidism.
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think i did that elsewehre
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Define Cretinism. List causes and clinical features. Refer to hypothryoidism lab results.
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Hypothyroidism developing in fetal life & infancy:
-iodine deficiency -enzymatic deficiency for synth of T4 T3 -maldevelopment of thyroid gland fetal thyroid function replaces maternal thyroid in latepregnancy; severity of fetal defect determins degree of impairment Clinical features: severe mental retardation skeletal & cns impaired dvlpt: deafness, muteness "floppy baby" short stature coarse facial features, hoarse cry protruding tongue umbilical hernia Lab: thyroid fnx test |
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Define myxedema. List features. What lab results are present in addition to thyroid function tests?
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hypothyroidism in older child or adult
insidious onset of generalized fatigue, apathy & mental slowness which mimcis depression SOB, exercise intolerance, cold intolerance, pale cold skin, decreased appetite, weight gain, lower voice pitch, menorrhagia & infertility, constipation PE: puffiness, dry skin, hair loss, coars brittle hair, reduced axillary * pubic har, thinned lateral eyebrows, bradycardia, prolonged relaxation phase of DTR's Pathogenesis of Sx: ↓ SNS activity → ↓ CO, Accumulation of matrix substances/mycopolysaccharide in subcu ts, vocal cords, tongue; most "weight gain" is accumulation of mucopolysaccharide NOT OBESITY Lab results: Elevated TSH if primary hypothyroidism, Decreased T4 in any hypothyroidism; hyperlipidemia, increased CK, macrocytic anemia [TSH] used to monitor effectiveness of HRT; Low or normal TSH & low free T4, consider TRH stimulation test for pituitary/hypothalamic origin |
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What is the most common cause of primary hypothyroidism?
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?
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What are the pathogenesis, usual labs and specific labs, and microscopic morphology of chronic lymphocytic (Hashimoto) thyroiditis?
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Autoimmune thyroiditis with progressive gland destrux and hypothyroidism
Any age peak 55+-10; Familial & overwhelmingly female (10:1) assoc w/ autoimmune disease: RA, SLE, vitiligo, Turner & Down karyotypes, HLA-DR5, HLA- DR3 polymorphisms in immune regulatory genes CTLA4 & PTPN22 Sensitization of autoreactive CT4's → CD8 mediated death, Cytokine mediated death, Antibody dependent CMI → progressive depletion of thyrocytes Clinical course: painless, symetrical, diffuse enalrgement of thyroid, hashitoxicosis: transient hyperthyroid due to disruption of follicles & released T3 & T4; ↑ risk for B cell MALToma [? & thyroid carcinomas] Lab tests: thryoglobulin antibody, anti-TIP antibody Thyroid fnx test: evaulate for metabolic abnormality Gross morphology: diffusely enalrged encapsulated gland; cut surface: fleshy, nodular Micro: lympho infiltrate w/ germinal centers; Hurthle cells: alarge eosinic epithelial cells forming follicles |
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DeQuervain thyroiditis
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Subacute Granulomatous Thyroiditis
40yo F +-10 peaks in summer following viral URI: esp adenovirus or coxsackie HLA predisposition: viral antigen or ts damage --> cytotoxic T's --> damage follcle --> transient thyrotoxicosis followed by 2 mo of hypothyroidism: self limited normal w/in 2 mo pain in neck worse on swallowing radiates to jaw, thorat ears fever, myalgia Gross: enlarged, firm thyroid gland Micro: multinuclated giant cells esp; [+ lymphos & plasma cells] |
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Subacute lymphocytic thyroiditis
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Middle aged females
HLA related majority are self limited w/ 2 mo course thyroid diffusely enlarged but nontender |
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What is the morphology and associations of Reidel thyroiditis?
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aka Reidel struma
assoc. with ideopathic fibrosis elsewhere: retorpeirtoneal or mediastinal Morphology: fibrosis of thryoid extending into surrounding ts (indistinct capsule) |
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Categorize goiters by types; list all associations.
What is the usual metabolic state in persons with nontoxic goiters? What are consequences and complications of goiter? |
Toxic: assoc. with hyperthyroidism
Non-toxic: Impaired synthesis of thyroid hormone from iodine deficiency or enzyme defect --> increased [TSH] --> compensitaory mass increase in thyroid to maintain euthyroid state; degree of enlargement proportional to level and duration of thyroid hormone deficiency Nontoxic Simple Endemic: >10% of population affected: --areas with low iodine in soil & food: moutnaous regions like Swizterland and the Great Lakes region of N america --Dietary Goitrogens: cruciferous vegetables (cabbage family; cassava root (thiocyanate) Cretenic infants, euthyroid adults Non Toxic Simple Sporadic: young females progress to multinodular if untx'd Non Toxic Multinodular: complication of longstanding simple goiters --> recurrent hyperplasia/involution produces nodules of follicles; mostly euthyroid but Plummer syndrome may occur wherein hyperfunctioning nodule produces clinical hyperthyroidism "hot nodule" on radioiodine scan. mass effects predominate: large neck "plunging" intrathoracic extension, airway obstrx, tracheal deviation, compression of vasculature Regressive changes: hemorrhage, fibrosis, calcification, cysts |
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Thyroid Tumor Lecture
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All of it
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Gigantism:
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excess GH before epiphysial closure
disporportionate growth in long bones: long arms, long legs. All organs enlarged, usually acromegally as well. |
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Complications of somatotroph adenoma
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Hyperglycemia/DM
Osteoporosis Htn Gonadal dysfnx CHF Local effects of tumor growth increased risk for GI tumors +- Hyperprolactinemia DOC: octerotide Tx: restore GH lvels, prevent hypopituitarism: Sugery, Radiation Octreotide = somatostatin receptor ligand GH receptor antagonist: pegvisomant |
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Acromegaly
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excess GH after epiphyseal closure
enlargement of viscera: thromegaly, enalrged heart, liver, kidney,s adrenals Overgrowth of jaws, face, hands, feet Prognathism: protruding jaw Sausage fingers & toes |
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Ophthalmopathy of Graves Disease
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TSH receptor expressed on orbital tissue cells, retroorbital ts fibroblasts & eye muscles, infiltrates of T lymphos in orbit, edema and accumulation of ECM cause proptosis, exophthalmos, the muscles themselves are weak, may fail to rectress following therapy, chemosis & chorneal drying may impair vision
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Gaucher's Disease Types 2 and 3
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3 AR mutations of glucocerebrosidase: accumulation of glucocerebroside/glycosylceramide from breakdown of cell membrane glycolipids; Membranes of senescent RBC's WBCs are greatest source of substrate, disease strongly related to accumulation from these sources
Gaucher cells: swollen phagocytic cells, w/ PAS+ "wrinkled tissue paper" fibrillary cytoplasm & displaced neucli; in Peripheral Blood and Sinusoidal Organs: Liver, Bonmarrow, Spleen, Lymphatic ts Type 2: Infantile acute cerebral form: Rare, Not assoc w/ EsEuJsevere glucocerebrosidase deficiency --> severe CNS involvement: convulsions, mental deterioration Type 3: Juvenile Form, RareIntermediate in behavior |
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FMR1
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"Familial MR" gene normal fnx: FMRP binds mRNA and regulate synaptic protein synth (esp proteins which ↨ synapse fnx); most expressed in CNS and gonads
Fragile X is CGG expans'n w/in UTR; Normal <50 → >200 → methylatn & LOF IQ <60, Long face,macro-orchidism, [macrognathism, large everted ears, hyperextensible joints, high arched palate, mitral valve prolapse] p169 |
Premutatns: 50-200; most expansn during oogenesis: grandsons via daughter most affected
aSx Carrier Males: Anticipation: Brothers have 9% risk, grandsons have 40% risk ---FXTAS: Fragile X associated tremor/ataxis syndrome occurs in ~1/3 starting 50's Affected Females (~half = MR & Premature Ovariand Failure) --Odd for X-linked |
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MR, Long face, macro-orchidism
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Fragile X Syndrome
"Familial MR" gene normal fnx: FMRP binds mRNA and regulate synaptic protein synth (esp proteins which ↨ synapse fnx); most expressed in CNS and gonads Fragile X is CGG expans'n w/in UTR; Normal <50 → >200 → methylatn & LOF p169 |
[macrognathism, large everted ears, hyperextensible joints, high arched palate, mitral valve prolapse]
Premutatns: 50-200; most expansn during oogenesis: grandsons via daughter most affected aSx Carrier Males: Anticipation: Brothers have 9% risk, grandsons have 40% risk ---FXTAS: Fragile X associated tremor/ataxis syndrome occurs in ~1/3 starting 50's Affected Females (~half = MR & Premature Ovariand Failure) --Odd for X-linked |
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FXTAS
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Fragile X associated tremor/ataxis syndrome occurs in ~1/3 of previously aSx males starting 50's
p169 |
FMR1 "Familial MR" gene normal fnx: FMRP binds mRNA and regulate synaptic protein synth (esp proteins which ↨ synapse fnx); most expressed in CNS and gonads
Fragile X is CGG expans'n w/in UTR; Normal <50 → >200 → methylatn & LOF IQ <60, Long face,macro-orchidism, [macrognathism, large everted ears, hyperextensible joints, high arched palate, mitral valve prolapse] Premutatns: 50-200; most expansn during oogenesis: grandsons via daughter most affected aSx Carrier Males: Anticipation: Brothers have 9% risk, grandsons have 40% risk ---FXTAS: Fragile X associated tremor/ataxis syndrome occurs in ~1/3 starting 50's Affected Females (~half = MR & Premature Ovariand Failure) --Odd for X-linked |
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New onset tremor & ataxia in 50 yo male w/ MR grandson
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FXTAS
CGG trinucleotide repeate expansion w/in FMR1 "familial MR" gene most expansn during oogenesis: grandsons via daughter most affected p169 |
FMR1 "Familial MR" gene normal fnx: FMRP binds mRNA and regulate synaptic protein synth (esp proteins which ↨ synapse fnx); most expressed in CNS and gonads
Fragile X is CGG expans'n w/in UTR; Normal <50 → >200 → methylatn & LOF IQ <60, Long face,macro-orchidism, [macrognathism, large everted ears, hyperextensible joints, high arched palate, mitral valve prolapse] Premutatns: 50-200; most expansn during oogenesis: grandsons via daughter most affected aSx Carrier Males: Anticipation: Brothers have 9% risk, grandsons have 40% risk ---FXTAS: Fragile X associated tremor/ataxis syndrome occurs in ~1/3 starting 50's Affected Females (~half = MR & Premature Ovarian Failure) --Odd for X-linked |
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Vitamin D-Resistant Rickets
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aka X-linked hypophasphatemia
point mutation of vitamin D receptor PHEX → ↑ renal tubular excretn of phosphate → hypophosphatemia → childhood osteomalacia w/ genu varum Unusual for being XD inheritance: males cannot pass to sons, all daughters affected (?would think modified based on lyon/barr body distribution) |
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X-linked Hypophasphatemia
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aka Vitamin D-Resistant Rickets
point mutation of vitamin D receptor PHEX → ↑ renal tubular excretn of phosphate → hypophosphatemia → childhood osteomalacia w/ genu varum Unusual for being XD inheritance: males cannot pass to sons, all daughters affected (?would think modified based on lyon/barr body distribution) |
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Type V Glycogenosis
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McArdle’s Syndrome
deficiency of muscle phosphorylase produces myopathic glycogenolysis adult onset: muscle cramps & weakness w/ exercise: myocytolysis & rhabdomyolysis → ↑ [ammonia]serum, myoglobinuria, abnormal lack of ↑ [lactate]serum Px: normal longevity p155; Mn: McArdle-McVardle, the M stands for Muscle |
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muscle phosphorylase deficiency
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Type V Glycogenosis aka McArdle’s Syndrome
myopathic glycogenolysis adult onset: muscle cramps & weakness w/ exercise: myocytolysis & rhabdomyolysis → ↑ [ammonia]serum, myoglobinuria, abnormal lack of ↑ [lactate]serum Px: normal longevity p155; Mn: McArdle-McVardle, the M stands for Muscle |
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22 yo w/ muscle cramps & dark urine 2° to exercise
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Type V Glycogenosis aka McArdle’s Syndrome
myopathic glycogenolysis adult onset: muscle cramps & weakness w/ exercise: myocytolysis & rhabdomyolysis → ↑ [ammonia]serum, myoglobinuria, abnormal lack of ↑ [lactate]serum Px: normal longevity p155; Mn: McArdle-McVardle, the M is for Muscle |
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2 most frequent causes of MR
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1. Down Syndrome
2. Fragile X Syndrome |
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Huntington's Dz
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expansion of CAG w/in coding region during spermatogenesis
aggregated misfolded proteins → apoptosis polyglutamine gain of fnx → neuotoxicity → chorea & dementia |
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Acid Maltase Deficiency
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Pompe's Dz: lysosomal α-1,4--glucosidase deficiency
(aka acid maltase); Type II Glycogen Storage Dz, technically also a lysosomal storage dz Glycogen in lever, heart, SkM w/ Muscle Hypotonia Micro: clear glycogen deposits in muscle Pediatric form: Massive cardiomegaly → early death Mn: -P-ompe's trashes the -P-ump Adult form: only SkM involved |
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Massive Cardiomegaly w/ clear glycogen deposits in Myocytes
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Pompe's Dz: lysosomal α-1,4--glucosidase deficiency
(aka acid maltase); Type II Glycogen Storage Dz, technically also a lysosomal storage dz Glycogen in lever, heart, SkM w/ Muscle Hypotonia Pediatric form: Massive cardiomegaly → early death Mn: -P-ompe's trashes the -P-ump Adult form: only SkM involved |
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2 mo w/ SOB & massive cardiomegaly
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Pompe's Dz: lysosomal α-1,4--glucosidase deficiency
(aka acid maltase); Type II Glycogen Storage Dz, technically also a lysosomal storage dz Glycogen in lever, heart, SkM w/ Muscle Hypotonia Pediatric form: Massive cardiomegaly → early death Mn: -P-ompe's trashes the -P-ump Adult form: only SkM involved |
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Glucose-6 phosphatase deficiency
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Type I Glycogenosis, Von Gierke Dz
Hepatic/renal enlargement PAS+ glucogen storage vacuoles in many cells Severe Hypoglycemia: failure to thrive, stunted growth, convulsions Hyperuricemia (gout) Xanthomas Bleeding (platelet dysfnx) |
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Von Gierke Dz
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Glucose-6 phosphatase deficiency
Type I Glycogenosis Hepatic/renal enlargement PAS+ glucogen storage vacuoles in many cells Severe Hypoglycemia: failure to thrive, stunted growth, convulsions Hyperuricemia (gout) Xanthomas Bleeding (platelet dysfnx) |
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Sickly 2 yo, consistent failure to thrive w/ convulsions & hepatosplenomegaly
Liver biopsy shows PAS+ vacuoles |
Glucose-6 phosphatase deficiency
Type I Glycogenosis, Von Gierke Dz Hepatic/renal enlargement PAS+ glucogen storage vacuoles in many cells Severe Hypoglycemia: failure to thrive, stunted growth, convulsions Hyperuricemia (gout) Xanthomas Bleeding (platelet dysfnx) DDx: Cori's Type 3, milder form from debranching α-1,6-glucosidase deficiency, GNG remains |
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Type III Glycogen Storage Dz
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Cori's Dz
debranching enzyme [ α-1,6-glucosidase ] deficiency accumulation of glycogen in liver, heart, muscle A milder version of Von Gierke Type I GSDz, as GNG remains intact Similar Sx: hepatomegaly hypoglycemia: stunted growth, failure to thrive, convulsions |
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female w/ normal breasts, bind pouch vagina, no uterus, amenorrhea
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male pseudohermaphroditism
Multiple causes, usually X-linked defective androgen receptor → Testicular feminization aka complete androgen insensitivity sro Else: --WT gene (chrom 11): Transcriptl Activator for Gonadal & Renal Differentiation (Also part of Deny's Drash & WAGR Syndromes) --Defective testicular hormone synth: 17-ketosteroid reductase, 5 alpha reductase |
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complete androgen insensitivity sro
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most common cause of male pseudohermaphroditism
X-linked defective androgen receptor → Testicular feminization Y chrom & testes present but w/ ambiguous-to-female external genitalia or genital ducts Phen: female w/ normal breasts, bind pouch vagina, no uterus, amenorrhea |
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Leber hereditary optic neuropathy
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progressive bilateral loss of cenral vision early adulthood onset 25+-10, cardiac conduction defects
Mitochondrial Dz |
Features of Mitochondrial Dz's:
Mitos entirely inherited from mother, never from father Heteroplasmy: coexistant wild & mutatnt mtDNA Genes for respiratory chain enzymes: most effected organs: CNS, SkM, CarM, Liver, Kidneys Variable expression |
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23 yo w/ bilateral loss of central vision
EKG reveals Wenckebach |
Leber hereditary optic neuropathy
progressive bilateral loss of cenral vision early adulthood onset 25+-10, cardiac conduction defects Mitochondrial Dz |
Features of Mitochondrial Dz's:
Mitos entirely inherited from mother, never from father Heteroplasmy: coexistant wild & mutatnt mtDNA Genes for respiratory chain enzymes: most effected organs: CNS, SkM, CarM, Liver, Kidneys Variable expression |
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MELAS
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Mitochondrial Dz
Mitochondrial encephalopathy, lactic acidosis, and stroke like episodes motor and cognitive dvlpt delays Stroke like episodes → progressive dementia assoc. w/ exercise intolerance (lactic acidosis), visual abnormalities (ecephalopathy), and cardiomyopathies |
Features of Mitochondrial Dz's:
Mitos entirely inherited from mother, never from father Heteroplasmy: coexistant wild & mutatnt mtDNA Genes for respiratory chain enzymes: most effected organs: CNS, SkM, CarM, Liver, Kidneys Variable expression |
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WAGR Syndrome
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Wilm's Pediatric Renal Tumor
Aniridia Genitourinary Abnormalities (Male Pseudohermaphroditism) & Mental- Retardation Defective WT1 gene, an activating transcription factor important in Renal and Gonadal Differentiation |
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motor and cognitive dvlpt delays
exercise intolerance, vision problems, cardiomyopathy Stroke like episodes w/ progressive dementia |
MELAS, a Mitochondrial Dz characterized by
Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke like episodes motor and cognitive dvlpt delays Stroke like episodes → progressive dementia assoc. w/ exercise intolerance (lactic acidosis), visual abnormalities (ecephalopathy), and cardiomyopathies |
Features of Mitochondrial Dz's:
Mitos entirely inherited from mother, never from father Heteroplasmy: coexistant wild & mutatnt mtDNA Genes for respiratory chain enzymes: most effected organs: CNS, SkM, CrdM, Liver, Kidneys Variable expression |
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26 yo Male CC: Infertility
Long Legs, Small Penis, No Facial Hair, Gynecomastia |
Klinefelter SRO: Y + ≥2X, mostly 47XXY's
2° to parental non-disjunction; maternal Ndj 2° to age Androgen Receptor (located X) contains CAG trinucleotide repeat polymorphism; shorter CAG both more active & preferentially silenced (physiologic in normal XX to use least active androgen receptor) → Sx hypogonadism w/ severe oligospermia to aspermia, common cause of male infertility Phen: Long Legs, ↓ IQ (≠MR) & Eunuch-like (gynecomastia, small penis, no virilization) ↑ # X's = ↓ IQ ↑ FSH, ↑ E ± ↓ T Risks: ↑ 20x extragonadal germ cell tumors & breast CA p165 |
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Common Features of Sex Chrom Abnormalities
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Abnormal Sexual Dvpt w/ Infertility
Subtle problems difficult to recognzie until puberty more X's = more cognitive impairment |
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XIST gene
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Lyon Hypothesis: Inactivation of either paternal or maternal X chromosome happens randomly in each cell at gestation day 16; all females are mosaics.
XIST gene inactivates one X chrom by coating it with non-coding RNA; [Pseudoautosomal region: 25% of X genes remain active on both chroms: these have normal, non-sex determining functions & a homologous region on Y.] |
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22 yo Male
CC: Severe Acne PE: Tall Dx: Genetic Abnormality |
XYY
Normal Intelligence, Normal Fertility |
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Prenatal Screen:
low PAPPA, low hCG |
Patau syndrome (Trisomy 13)
uniformly fatal w/in first year, vast majority <1mo ultimate cause: maternal age Phen: Cleft Palate, Cleft Lip, Polydacyly, Microcephalus w/ Narrow forehead, closely spaced eyes ± cyclopia, MR, umbilical hernia, rocker bottom feet, IUGR, Inside: Congenitla heart disease, renal defects Mn: Think P's: cleft Palate, cleft liP, Polydactyly, holoProsencephaly (forebrain dvlpt failure) |
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Baby born with Cleft Lip, Cleft Palate, Polydactyly, Rocker Bottom Feet
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Patau syndrome (Trisomy 13)
uniformly fatal w/in first year, vast majority <1mo ultimate cause: maternal age Phen: Cleft Palate, Cleft Lip, Polydacyly, Microcephalus w/ Narrow forehead, closely spaced eyes ± cyclopia, MR, umbilical hernia, rocker bottom feet, IUGR, Inside: Congenitla heart disease, renal defects Mn: Think P's: cleft Palate, cleft liP, Polydactyly, holoProsencephaly (forebrain dvlpt failure) Prenatal Screen: low PAPPA, low hCG [Pregnancy Assoc. Plasma Protein A] |
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Chimera
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individuals of 2+ zygotes (us. in vitro fertilization)
→ anomalous blood grouping results → families w/ HLA incompatability → sex reversal or intersex (possible true hermaphrodite) |
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5p-
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Cri du Chat Syndrome:
High pitch "Cry of Cat" for First Year Low Birth Weight, Microcephaly w/ severe MR Hypotonia, Round Facies Failure to thrive, ± reach adulthood |
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TBX1
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Deletion of TBX1 (T-box) gene: no PAX9 transcription factor, normally expressed in pharyngeal mesenchyme for 3rd & 4th pharyngeal pouches: dvlpt of palate, parathyroids, thymus
Lost in 22q11 deletion Conotroncal (outflow) defects, facial dysmorphism, developmental delay, ± T cell immmunodeficiency psychiatric comorbidities: ADD, Bipolar & Schizophrenia Velocardiofacial Sro: Cleft Palate, Prominent nose w/ Retrognathism, Outflow abnormalities, Learning Disabled DiGeorge Sro: T cell immunodef, HypoCa2+, Outflow abnormalities, mild facial abnormalities |
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Velocardiofacial syndrome
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vast majority VCFS del22q11
Prominent nose, retrognathia cardiac malformations |
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child born with heart defect
now frequently sick Positive for Chvostek's Sign |
DiGeorge Sro: mostly 22q11deletions
Loss of Deletion of TBX1 (T-box) gene: no PAX9 transcription factor, normally expressed in pharyngeal mesenchyme for 3rd & 4th pharyngeal pouches: dvlpt of palate, parathyroids, thymus thymic hypoplasia w/ T cell immunodeficiency Hypoplasia of parathyroids w/ hypocalcemia congenital heart defects |
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pinguecula
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Yellowish raised lesion of conjunctiva astride nasal limbus (corner) of cornea but does not involve cornea (ctrst to pterygium), caused by actinic (solar) damage, composed of degenerating elastin & collagen; yellow color is from solar elastosis)
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Infant Dies at 2 Mo
Horseshoe Kidney on Autopsy |
Trisomy 18 Edwards Sro usually nondisjunction or mosaic
IUGR small face to head ratio w/ micrognathia prominent occiput, low set ears, flat helices enlarged first finger: overlapping fingers congenital heart disease horseshoe kidney rocker bottom feet (slide 52) mental retardation mean survival 2 mo, overwelming majority |
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Pathogenesis of Closed Angle Glaucoma
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Closed Angle Glaucoma: aqueous fluid cannot access mesh-work
1° = shallow anteior chamber, common in asians pupillary block: iris in apposition to lens every time lens is dilated iris bombe: aqueous humor pressure makes iris bulge 2° = growth of membranes cover trabecular network -Neovascular glaucoma: ischemia, necrotic tumors (retinoblastoma) [Trauma/Surgery, Ciliary Body Tumors, Et C] |
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Yellowish raised lesion of conjunctiva astride nasal limbus (corner) of cornea but does not involve cornea (ctrst to pterygium), caused by actinic (solar) damage, composed of degenerating elastin & collagen; yellow color is from solar elastosis)
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extremely painful, taut, firm eye
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Closed angled glaucoma: pierpheal zone of iris adheres to trabecular meshwork & blocks egress;
medical emergency |
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Mutton fat droplets in cornea
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Sarcoidosis in the eye
Granulomatous uveitis: noncaseating; asteroid bodies Calcific band keratopathy Mutton fat keratitic precipitates retinal candle wax drippings (perivascular inflmmation) Mikulicz dry eyes w/ lacrimal involvement [Sarcoidosis characterized by widespread non-caseating granulomas & elevated [ACE], esp in black females, manifests as restrictive lung disease w/ interstitial fibrosis] |
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fibrovascular proliferation extending from inner canthus onto cornea
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pterygium
caused by sun exposure, manifests in adults ± bilateral, but dose not cross midline Histologically identical to pinguecula, may calcify. Unlike pinguecula: dissects into Bowman's layer (acellular layer beneith BM on anterior surface of corna) ± visual impariment, astigmatisms |
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hypopyon
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exudate of fluid from ciliary body/iris visible by penlight
indicative of corneal ulceration? |
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dendritic corneal ulcer
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herpes simplex
most common cause of corneal ulcer unilateral, recurrent, produces dendritic ulcer sequelae: corneal scar & vision loss |
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blurred vision in left eye
Hx: traumatic injury to right eye 2wka |
sympathetic ophthalmitis
rare complication of penetrating injury to 1 eye → exposed pigment antigen of uveal melanocytes, retinal epithelial & neural cells → granulomatous inflamation of both eyes 2 weeks after injury in the sympathetic eye: --Loss of accomodation --Blurred Vision --Photophobia Tx: removal of blind eye & long term immunosuppression |
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ADH
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neurohypophyseal hormone
released 2° to ↑ plasma oncotic pressure or ↓ BP (atrial receptors, not ANP); inhibited by hypervolemia/atrial distention V1 receptors: vasoconstriction V2 receptors: mvmt of aquaporins to lumenal surface of collecting ducts, water resorptn |
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Wermer's Sro
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MEN1 KO's ("Multiple Endocrine Neoplasia")
Menin is a tumor suppressor transcription regulator Wermer's MEN1 Sro: 1° Hyperparathyroidism Pancreatic Zol-Ell Gastrinomas, Insulinomas Pituitary: Fnx GH, Prolactin & ACTH adenomas |
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MEN1
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Menin is a tumor suppressor transcription regulator
("Multiple Endocrine Neoplasia") Wermer's Sro MEN1 KO's 1° Hyperparathyroidism Pancreatic Zol-Ell Gastrinomas, Insulinomas Pituitary: Fnx GH, Prolactin & ACTH adenomas |
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Pt cannot see outer half of both visual fields
HA, N/V |
Pituitary Macroadenomas (>1cm): hormonally silent but cause local effects:
Bitemoral hemianopsia ± ↑ intraCranial Pressure: HA, Nausea, Vomitting Enlarged sella turica on imaging |
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Galactorrhea, ↓ Libido, Infertility
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Fnxl Prolactinoma w/ Hyperprolactinemia:
Amenorrhea, Galactorrhea, Loss of Libido, Infertility Imaging: "pituitary stone" dystrophic calcification Tx: Dopamine Agonists: Bromocriptine or Cabergoline |
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GNAS1
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GTPase deficient alpha subunit of Gs
oncogenic expansion → GH producing pituitary tumor |
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Pt CC: Pituitary Insufficiency
PE: darkened elbow creases Hx: Bilateral Adrenalectomy 2° to Bilateral Adrenal Hyperplasia |
Nelson's Syndrome
Pituitary adenoma enlarges from pre-existing microadenoma after removal of adrneal glands for bilateral hyperplasia: macroadenoma local effects, Pituitary Insufficiency with hyperpigmentation, markedly on flexor surfaces (from MSH) |
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hemorrhage into pituitary gland
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pituitary apoplexy
often 2° to adenoma Acute onset: excruciating HA, diplopia, Hypopituitarism Neurosurgical emergency: will cause Cardiovascular collapse |
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Young Child with Fever, Hepatosplenomegaly, Bulging Eyes, and Urinary Frequency
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Probably Hand-Schuller-Christian Dz:
Eosinic Granulomatous Inflammation in Bones erodes into adjacent soft ts Traid of: 1. Calvarial Defects 2. Exophthalmos 3. Diabetes Inspidus PE: ± Hepatosplenomegaly, lymphadenopathy, fever, skin rash |
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CC: Short Stature
PE: Proportionality, Myxedema Hx: Delayed Sexual Dvlpt |
Pituitary Dwarfism: Proportional Dwarfism w/ delayed sexual dvlpt ± thyroid, adrenocrtical insufficency
majority are idiopathic w/ normal anatomy Tx: GH before epiphyseal plate closure |
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CC: Short Stature
PE: Cauliflower Ears, Hitch-Hiker's Thumb |
Diastrophic Dwarfism
AR sro of short limbs, cauliflower ears, short 1st metacarpal (hitch-hikers thumb) ± deafness; |
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CC: Short Stature
PE: Proportionality, Absent Distal Clavical |
Pyknodysostosis: AR sro of generalized developmental disorder w/ proportionate dwarfism; ↑ bone density and fragrility, short digits, small face, absent distal end of clavical
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CC: Short Stature
PE: Enlarged Head, Short Limbs |
Achondroplasia
AD LOF in Fibroblastic Growth Receptor 3 normal trunk, enlarged head, short limbs 80% new mutations |
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Nevus
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any congenitla lesion of skin
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Desmopressin
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ADH analogue aka DDAVP
used to Dx & Tx Diabetes Inspidius |
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DDAVP
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Desmopressin
ADH analogue used to Dx & Tx Central Diabetes Inspidus |
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ΔGenes of Malignant Melanoma
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Heterogenous
BRAF & p16INK4A esp common also ↑ PI-3K/AKT signalling PTEN silencing c-KIT activation |
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Leser-Trelat Sign
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Multiple seborrheic keratoses
assoc. with internal malignancy, probably 2* to Tumor Prodxn ofTGFα |
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Multiple seborrheic keratoses
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Leser-Trelat Sign
assoc. with internal malignancy, probably 2* to Tumor Prodxn ofTGFα |
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Dermatosis papula nigra
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seborrheaic keratosis of melanized skin, commonly located on face
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seborrheaic keratosis of melanized skin
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Dermatosis papula nigra
commonly located on face |
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CC: Seizures
PE: Erythematous Macules on Face, Hypopigmented macules elsewhere |
tuberous sclerosis
AD defect of either TSC1 (hamartin) or TSC2 (tuberin), which form a dimer in charge of regulating signal involved in protein synth, cell prolif, dif & migration variable expressivity Brain Tubers: white nodules → MR & Seizures Skin Lesions: -Angiofibromas: acne-like lesions of the face -Hypopigmented lesions: ash leaf macules -Periungual fibromas -Shagreen patches: CT hamartoma |
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Non tender, rapidly growing erythematous papule with dark, firm, depressed central region
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keratoacanthoma
Rapidly growing squamous neoplasm in sun exposed skin of older whites Dome shaped nodule with keratin-containing central crater probably well diffrentiated squamous cell carcinoma Micro: proliferation of squamous cells w/ central cup of keratin usually p53 mutations may spontanously regress |
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basal cell carcinoma
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Most common skin tumor: 1 million/year in US (1/300 pts!) sun exposed areas of lightly pigmented people esp head & neck, oddly not usually on dorsum of hand
Predisposing factors: Sun, Gorlin's Nevoid Basal Cell Syndrome (PTCH KO) PTCH gene: tumor suppressor receptor for SHH (embryogenic polarity signal) SMO (smoothed) 2nd messenger dissoc. from PTCH on SHH binding Mutant PTCH does not bind SMO → dysregulated growth Gross: nodular telangiectactic "rodent ulcer" w/ tumor undermining. sclerotic/morphea form: difficult to remove. ± pigmented, multifocal. Micro: invading sheets of dark staining cells with palisading peripheral nuclei (pointed) Px: Locally aggressive, mets are rare; tend to recur, slow growth with deforming invasion; Curable by resection: margins must be free of tumor Rx: SMO inhibitor vismodegib: for locally advanced or metastatic inoperable tumor |
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Gorlin's Syndrome
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PTCH gene: tumor suppressor receptor for SHH (embryogenic polarity signal)
SMO (smoothed) 2nd messenger dissoc. from PTCH on SHH binding Mutant PTCH does not bind SMO → dysregulated growth AD: Knudson's 2 hit → multiple basal cell tumors early in life assoc. w/ cryptoorchidism Meigs syndrome: Ovarian Fibromas, Right Hydrothorax Medulloblastoma Odontogenic Cysts Palmar pits |
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35 yo Female
CC: expanding mass lesion on Leg PE: dark tan papule dimples inward when compressed laterally |
Benign Fibrous Histiocytoma aka Dermatofibroma
tan to brown papules dimple inward on lateral compression, collar button sign = benign usually found on legs of working age women (20-50) Micro: poorly circumscribed intertwining bundles of fibroblasts & collagen in mid dermis overlain with epidermal hyperplasia; partially composed of factor 8a positive dermal dendrocytes, Hx previous injury common. |
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Dermatofibroma
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aka Benign Fibrous Histiocytoma
tan to brown papules dimple inward on lateral compression, collar button sign = benign usually found on legs of working age women (20-50) Micro: poorly circumscribed intertwining bundles of fibroblasts & collagen in mid dermis overlain with epidermal hyperplasia; partially composed of factor 8a positive dermal dendrocytes, Hx previous injury common. |
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Sudden onset Rash:
symmetrical involvement of entire body including palms; macules, papules, vesicles and bullae lesions have central necrosis and peripheral inflammation |
Erythema Multiform
CD8 hypersensitivity reaction assoc w/ infections and drugs esp Herpes simplex, Coccy, Mycoplasma symmetrical involvement of entire body including palms; multiform lesions: macules, papules, vesicles and bullae characteristic target lesion: central necrosis + inflammation mucosal lesions are rare. parthenogenesis: CLA+ CD8 mediated apoptosis of basal cells self limited [histoplasmosis, leprosy, EBV, malignancy, SLE, dermatomyositis, majority idiopathic, Rx more commonly manifest ast Steven's Johnson Syndrome; CD4 & Langerhans found in erythematous margins] |
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