Path Spring Test 2

Front 1

Type I Glycogenosis

Back 1

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)

Front 2

Pompe's Dz

Back 2

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

Front 3

trinucleotide repeat expansions in coding regions

Back 3

Huntington's Dz

expansion of CAG w/in coding region during spermatogenesis

aggregated misfolded proteins → apoptosis

polyglutamine gain of fnx → neuotoxicity → chorea & dementia

Front 4

McArdle’s Syndrome

Back 4

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

Front 5

Fragile X Syndrome

Gene, Protein, Normal Fnx, Phenotype, Inheritance

Back 5

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

Hint 5

"fragile" chrom appears broken

Front 6

Epigenetic

Back 6

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.

Front 7

Congenital

Back 7

condition that is present at birth; Huntingtons is genetic but not congenital.

Front 8

Missence mutation

Back 8

Factor V Leiden mutation, Alpha 1 antitrypsin deficiency, Sicle Cell Anemia #6 glutamic acid --> valine turns Ba globin chain into a Bs globin chain

Front 9

Nonsense mutation

Back 9

B-globin of beta thalassemia

Front 10

Defective splicing

Back 10

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

Front 11

Blood Type O

Back 11

Frameshift mutation inactivates enzyme

Front 12

CFTR

Back 12

3bp frameshift deletion: chloride/sodium channel abnormalities
(Review Cystic Fibrosis)

Front 13

Functional pleiotropy

Back 13

single mutation has multiple effects: sickle cell anemia, marfan's syndrome (fibrillin)

Front 14

Genetic heterogeneity:

Back 14

same defect produced by different mutation: deafness >20 genetic causess, 16 recessive

Front 15

Autosomal dominant disorders:

Back 15

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

Front 16

Blue sclera

Back 16

osteogenesis imperfecta

Front 17

Dominant negative

Back 17

mutant allele impairs fnx of normal allele eg osteogeneis imperfected, defective collagen chain interferes with assembly of normal proteins --> severe collagen defficiency

Front 18

Gain of Fnx

Back 18

Huntingtons trinucleotide amplification produces Huntingtin polyglutamine: toxic to neurons w/ GABA receptors

Front 19

Know table 5-1 listing autosomal dominant diseases

Back 19

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

Front 20

Know table 5-1, autosomal recessive disorders

Back 20

---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

Front 21

Autosomal Recessive Disorder Characteristics

Back 21

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

Front 22

characteristics of X-linked recessive disorders

Back 22

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

Front 23

Know table 5-3, list of X-linked recessive disorders.

Back 23

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

Front 24

What are the features of X-linked dominant Inheritance. Describe the features of the X-linked dominant example disease.

Back 24

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]

Front 25

Cori's Dz

Back 25

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

Front 26

What are the genetic and biochemical defect, accumulation and clinical features of alkaptonuria?

Back 26

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

Front 27

What are the inheritance and clinical features of neurofibromatosis, type I? Know the gene, gene product, and risks of this disease.

Back 27

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

Front 28

p & q

Back 28

p is short arm "petite"
q is long arm

Front 29

Xp21.1

Back 29

X chromosome, short arm, region 2 band 1, sub-band 2

Front 30

Robertsonian translocation

Back 30

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

Front 31

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?

Back 31

woah

Front 32

What are MiRNA and SiRNA and what are functions/potential uses ?

Back 32

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

Front 33

What are the genetic defect and clinical features of Prader-Willi syndrome? Of Angelman syndrome?

Back 33

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

Front 34

Recognize the pedigree of mitochondrial inheritance. Know the features of two mitochondrial diseases.

Back 34

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.

Front 35

male pseudohermaphroditism. What is the most common cause and what are the features of this cause? List additional causes and features where given.

Back 35

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

Hint 35

p167

Front 36

Define female pseudohermaphroditism. What is the most common cause and what are the features of this cause?

Back 36

XX female w/ AR 21 hydroxylase deficiency → congential adrenal hyperplasia → excess androgen during embryogenesis

→ normal ovaries & internal genitalia, male external genitalia

Front 37

What defines a true hermaphrodite? What are some causes?

Back 37

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

Front 38

What are the clinical features of Turner Syndrome? List types of chromosome defects

Back 38

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

Front 39

XYY sro

Back 39

Excessively Tall Male w/ Severe Acne

[Normal Intelligence, Normal Fertility]

Front 40

What are the clinical features of Klinefelter syndrome? What is the most common karyotype?
What complications are associated with this Syndrome?

Back 40

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

Front 41

Genetics of Sexual Differentiation

Back 41

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.

Front 42

22q11- sro

Back 42

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

Front 43

Cri du Chat Syndrome

Back 43

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

Front 44

DiGeorge Syndrome:

Back 44

vast majority of DiGeorge are del22q11
thymic hypoplasia w/ T cell immunodeficiency
Hypoplasia of parathyroids w/ hypocalcemia
congenital heart defects

Front 45

The 5 Distinct Deletion Syndromes

Back 45

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

Front 46

Trisomy 13

Back 46

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]

Front 47

Trisomy 18

Back 47

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

Front 48

Prenatal screen of Down Syndrome

Back 48

quadruple scren
↑ beta-HCG
↑ inhibin A
↓ AFP
↓ PAPPA (Pregnancy Associated Plasma Protein A)

Fetal US: nuchal lucency, cardiac and intestinal anomalies

→ amniocentesis for chromosomes

Front 49

Define proptosis. Review causes. Know orbital neoplasms, pseudotumor and its differential diagnosis.

Back 49

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

Front 50

blepharitis, blepharoconjunctivitis, hordeolum, chalazion, wen

Back 50

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

Front 51

Neoplasms of the Eyelids

Back 51

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

Front 52

5 causes of conjunctival scarring

Back 52

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

Front 53

Define and recognize morphology of pterygium

Back 53

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

Front 54

List conjunctival neoplasms.

Back 54

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

Front 55

Define keratitis. List causes. What is the most common cause of corneal ulcer? Describe morphology. What are the consequences of keratitis, corneal ulcers?

Back 55

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

Front 56

Describe band keratopathy and list causes of both types.

Back 56

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

Front 57

What are causes of keratoconus?

Back 57

bilateral progressive thickening of cornea into cone shape
Down syndrome, Marfan Syndrome, Ideopathic
[causes irregular stigmatism Tx: rigid contact lenses or corneal transplant]

Front 58

Define cataract. List causes, symptoms. What is the significance?

Back 58

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

Front 59

What is glaucoma? Contrast the two categories.

Back 59

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

Front 60

Pathogenesis of Open Angle Glaucoma

Back 60

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

Front 61

2 Types of Ophthalmitis

Back 61

Endophthalmitis: involves the vitrious

Panophthalmitis: involves retina, choroid sclera, extends into orbit and causes cellulitis & proptosis

Front 62

Define uveitis. List causes. What are symptoms of uveitis?

Back 62

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

Front 63

List the eye lesions of sarcoidosis.

Back 63

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]

Front 64

Sympathetic Ophthalmitis

Back 64

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

Front 65

Melanocytic Neoplasms of the Eye

Back 65

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%)

Front 66

What are the clinical features, prognosis, metastatic sites of malignant melanoma?

Back 66

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%)

Front 67

Adenohypophysis:

Embryonic Origin, Regulation, Cell Types

Back 67

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

Front 68

Neurohypophysis

Back 68

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

Front 69

What is the most common cause of pituitary hormone excess?

Back 69

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

Front 70

What is a fairly cause of deficiency of pituitary hormones?

Back 70

pituitary adenomas?

Front 71

most common type of familial pituitary adenomas

Back 71

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

Front 72

Define pituitary macroadenoma by size; what are the clinical features and local effects of macroadenoma? Recognize MRI of macroadenoma.

Back 72

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

Front 73

Most Common Pituitary Neoplasm:

SSx, Tx

Back 73

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

Front 74

What are the clinical features, pituitary morphology, and complications of growth hormone producing pituitary tumor?

Back 74

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

Front 75

What are the clinical features and pituitary morphology of the corticotroph adenoma?

Back 75

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

Front 76

DDx Cushing's Syndrome

Back 76

Cushing's Disease: Pituitary Adenoma (Hyperpigmentation)
Adenocortical adenoma/hyperplasia
Paraneoplastic manifestation of Small cell carcinoma of the lung
Exogenous steroids

Front 77

Nelson's Syndrome

Back 77

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)

Front 78

What are the clinical features of gonadotroph adenomas?

Back 78

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

Front 79

What are the features of thyrotroph adenoma?

Back 79

Rare: 2* hyperthyroidism

Front 80

What are the frequency and consequences of nonfunctioning adenomas and of carcinoma?

Back 80

~25% of all pituitary tumors, produce local effects, esp hypopituitarism
carcinomas are rare and nonfunctional

Front 81

Define panhypopituitarism? What lab tests are performed to make this diagnosis? List causes.

Back 81

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

Front 82

pituitary apoplexy

Back 82

hemorrhage into pituitary gland
often 2° to adenoma

Acute onset: excruciating HA, diplopia, Hypopituitarism

Neurosurgical emergency: will cause Cardiovascular collapse

Front 83

Sheehan syndrome

Back 83

necrosis of anterior pituitary 2* to shock 2* hemorrhage from labor
hypogonadism is first sx, onset may be years delayed from event

Front 84

What are other causes of ischemic pituitary injury?

Back 84

DIC, Shock, CNS truma
Sickle Cell

Front 85

What are the hypothalmic causes of panhypopituitarism?

Back 85

Benign Tumors: gliomas & craniopharyngiomas;
Metastatic Tumors: breast & lung
Radiation for nasopharyngeal tumors
Inflammatory/Infiltrative Diseases: Sarcoidosis, TB

Front 86

What are the origin, morphology and clinical Features of the craniopharyngioma?

Back 86

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

Front 87

Know the manifestations of panhypopituitarism

Back 87

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

Front 88

What are the clincial features of central diabetes insipidus?

Back 88

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

Front 89

Hand Schuller Christian Dz

Back 89

eosinophilic granulomas (langerhans cells)

traid of
calvarial defects
exophthalmos
diabetes inspidius

± hepatosplenomegaly, lymphadenopathy, fever, skin rash

Front 90

What are the causes and labs of SIADH? Which cause is the most common?

Back 90

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

Front 91

Differentiate Between Dwarfs

Back 91

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

Front 92

Hyperkeratosis, Parakeratosis, Acanthosis, Acantholysis, Spongiosis, Paillomatosis, Exocytosis, Erosion, Ulceration, Vacuolization, Lentigenous

Back 92

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

Front 93

Understand the bolded microscopic terms. Recognize skin pathologies that are characterized
by each.

Back 93

?

Front 94

What are the effects of UV radiation on the skin, including UV-related skin cancers?

Back 94

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

Front 95

Define vitiligo. What is the likely pathogenesis and what diseases are associated with it?

Back 95

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

Front 96

What are the pathogenesis, manifestations and conditions associated with oculocutaneous albinism?

Back 96

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

Front 97

Melasma

Back 97

"Mask of pregnancy"
blotchy facial hyperpigmentation
generally resolves after delivery

[all causes: pregnancy, OCP's, hydantoins, exacerbated by sunlight]

Front 98

Ephelis

Back 98

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]

Front 99

Benign Lentigo

Back 99

Pigmented macule of hyperplastic melanocytes.

All ages, all races, unknown cause, does not fade seasonally

[contrast to Ephelis/Freckle w/o ↑ melanocytes & w/ seasonality]

Front 100

Nevocellular Nevi

Back 100

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

Front 101

What is a blue nevus? Spitz nevus? Halo nevus?

Back 101

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

Front 102

dysplastic nevi.

Back 102

darker & thicker in center, irregular peripehry

lentiginous hyperplasia w/ atpical nuclei

Often >5mm & numerous

Precursor lesion of malignant melanoma

Front 103

What are the gene and clinical features of familial dysplastic nevi?

Back 103

AD inherited CDKN2A gene complex (usually p16INK4a) or CDK4 germline mutation

50% malignant melanoma by age 60

often arises outside of moles

Front 104

What is lentigo maligna?

Back 104

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

Front 105

What are the risk factors for malignant melanoma?

Back 105

>>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

Front 106

ABC’s of malignant melanoma.

Back 106

Asymmetry
Border is irregular "Scalloped" Edges
Color is mottled
Diameter is >6mm (pencil thickness)
Elevated above surroundings, enlarging

Front 107

Describe behavior, location and compare prognosis of the four types of malignant melanoma. Which has the worst prognosis

Back 107

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

Front 108

What are prognostic factors for malignant melanoma? (memorize numbers)

Back 108

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

Front 109

Suborrheic Keratosis

Back 109

≥ 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

Front 110

Define acanthosis nigricans and list associations

Back 110

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]

Front 111

What are associations of skin tags?

Back 111

CT covered by squamous epithelium, esp intertrigenous areas of axial body

Assoc:
--Pregnancy
--DM
--Intestinal Polyposis

Front 112

Wen

Define, Gross & Micro Morphology, Categorize, Complication

Back 112

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

Front 113

Review general features of skin appendage tumors. Know names and associations of those listed in handout.

Back 113

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]

Front 114

Cylindroma

Back 114

sporatic or AD
Apocrine derived tumor, multiple, form turban tumor of scalp

Front 115

Trichoepithelioma

Back 115

sporadic or AD
upper trunk, head
multiple, basaloid cells resembling hair follicles, with CYLD gene

Front 116

Syringoma

Back 116

multiple
eccrine gland derived tumors of lower eyelids
DDx: basal cell CA

Front 117

Tricholemmoma

Back 117

PTEN mutation
uppermost hair follcile cells
cowden's syndrome: multiple hamartomas of GI tract, multiple tricholemmomas assoc. with brreast CA

Front 118

Sebacious adenomas & epitheliomas

Back 118

associated with internal malignancy: MSH-MLH mutation (Muir-Torre Syndrome)

Front 119

Syringocyasdenoma papilliferum

Back 119

aporcine derived tumors of face & scalp aka nevus sebaceous

Front 120

Pilomatrixoma

Back 120

beta-catenin mutation

Front 121

Eccrione poroma:

Back 121

palms & soles

Front 122

What are the features of tuberous sclerosis, esp. with regard to the skin?

Back 122

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]

Front 123

Describe morphology and clinical course of keratoacanthoma.

Back 123

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

Front 124

What are the causes, risks, and morphology of actinic keratosis?

Back 124

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

Front 125

What are the predisposing factors, clinical behavior, gross and microscopic appearance of squamous cell carcinoma of the skin?

Back 125

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

Front 126

What are the pathogenesis, clinical behavior, gross and microscopic morphology of basal cell carcinoma? Describe the familial syndrome, incl. gene, associated with BCC.

Back 126

see notes

Front 127

Describe the clinical appearance of benign fibrous histiocytoma. What is another name for this lesion?

Back 127

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.

Front 128

What is the primary malignant fibrosarcoma of the skin, its morphology and behavior?

Back 128

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;

Front 129

What are the malignant cell type, characteristic microscopic morphology and clinical of the cutaneous T cell lymphomas?

Back 129

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

Front 130

What is the most common type of mastocytosis and what are the clinical features ?

Back 130

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

Front 131

What are symptoms of systemic mastocytosis?

Back 131

Poor Px
Pruritis & flushing triggered by food, EtOH & certain drugs (codeine ASA)
Rhinorrhea
[GI bleeds, epistaxis, malabsorption w/ diarrhea]
Bone pain indicates marrow involvement

Front 132

What are the gene; functions of the gene product, inheritance and clinical features of Marfan Syndrome?

Back 132

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)]

Front 133

What are the features of Ehlers-Danlos syndrome?
Know collagen types affected. Which type is associated with premature death?

Back 133

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

Front 134

What are the genetic and biochemical defect, accumulation and clinical features of Tay-Sachs Disease?

Back 134

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

Front 135

What are the genetic and biochemical defect, accumulation and clinical features of Niemann-Pick disease, types A and B?

Back 135

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

Front 136

What are the biochemical defect, inheritance and clinical features of Niemann-Pick disease, C

Back 136

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

Front 137

What are the genetic and biochemical defect, accumulation and clinicla features of Gaucher disease?

Back 137

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

Front 138

What are the genetic and biochemical defect, accumulation and clinical features of Fabry’s disease?

Back 138

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

Front 139

What are the genetic and biochemical defect, accumulation and clinical features of MPS I H, Hurler syndrome?

Back 139

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)

Front 140

Contrast with MPS II H, Hunter syndrome And MPS I S Scheie syndrome.

Back 140

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

Front 141

The mucolipidoses are characterized by defect in what process? What diseases do the most resemble?

Back 141

[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

Front 142

Describe the morphology and general defect of ichthyosis. What is the pathogenesis of the most common type?

Back 142

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

Front 143

What are causes and clinical course of urticaria?
What is the macroscopic morpholoygy?

Back 143

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

Front 144

What is eczema. List types.

Back 144

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

Front 145

What are the pathogenesis and clinical features of allergic contact dermatitis (use poison ivy as an example)? What is the macroscopic and microscopic morphology?

Back 145

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

Front 146

erythema multiforme

Back 146

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]

Front 147

5) What are two severe forms of erythema Multiforme; what are their usual associations, and What are the clinical features?

Back 147

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

Front 148

6) Describe the macroscopic and microscopic morphology and pathogenesis of psoriasis.
What are some associations?

Back 148

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

Front 149

Define seborrheic dermatitis. What is the likely cause?

Back 149

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

Front 150

Describe the morphology, pathogenesis and Clinical features of lichen planus.

Back 150

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)

Front 151

Pemphigus

Back 151

Gross: 4 types; vast majority pemphigus vulgaris, otherwise pemphigus vegetans, pemphigus foliaceous, pemphigus erythematosis,; else peraneoplastic mostly lymphoma

Front 152

Pemphigus Vulgaris

Back 152

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

Front 153

Bullous Pemphigoid

Back 153

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

Front 154

Dermatitis Herpetiformis

Back 154

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

Front 155

Porphyria, Erythema Bullosa

Back 155

Epidermolysis Bullosa
Pathogenesis
Clinical Features
Morphology
Gross
Micro
Immunoflorescence

Front 156

What is the pathogenesis, in general, of epidermolysis bullosa. Which form is most serious? Why?

Back 156

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

Front 157

What are the dermatologic features and associations of porphyria?

Back 157

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

Front 158

Describe the pathogenesis and list lesions of Acne vulgaris.

Back 158

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.

Front 159

What disease in older adults resembles acne?

Back 159

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

Front 160

Describe clinical features, macroscopic morphology and associations of erythema Nodosum.

Back 160

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

Front 161

What are other types of panniculitis?

Back 161

Erythema induratum
adolescents & menopausal women
dermal blood vessels
erythematous tender nodules which ulcerate not assoc with underlying disaese

Front 162

What is the microscopic morphology of verrucae?

Back 162

benign papilloma w/ vacuolated (koilocytes) cells in granular layer and prominent cytoplasmic keratohyaline granules

Front 163

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?

Back 163

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?

Front 164

Pituitary, Adrenal Morphology of Cushing Syndrome

Back 164

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

Front 165

What are the major clinical features of Cushing syndrome (Table 24-9)?

Back 165

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

Front 166

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?

Back 166

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

Front 167

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?

Back 167

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

Front 168

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?

Back 168

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.

Front 169

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?

Back 169

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

Front 170

Neonate with salt wasting hyponatreimai, hyperkalmia, hypotension, acidosis, cardiovascular collapse:

Back 170

Salt wasting androgenitalism: total lack of hydroxylase: no cortisol, no aldosterone

Front 171

What are the two types of adrenocortical insufficiency (Table 24-10)? What are the three patterns of insufficiency?

Back 171

Primary acute adrenocortical insufficiency (adrenal crisis)
Primary chronic adrenocortical insufficiency (Addison's disease)
2* Adrenocortical insufficiency

Front 172

Primary acute adrenocortical insufficiency occurs in what three settings?

Back 172

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

Front 173

What are the four main features of the Waterhouse-Friderichsen syndrome? What age group is it more likely to occur in?

Back 173

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

Front 174

Primary chronic adrenocortical insufficiency is also called? What are the four disorders that can cause it? What are the clinical signs and symptoms?

Back 174

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

Front 175

Secondary adrenocortical insufficiency is caused by? What is the difference between in ACTH and pigmentation in primary vs. secondary?

Back 175

Any hypothalamic disorder that reduces ACTH output
exogenous steroids
lacks hyperpigmentation
adrenals can respond to low ACTH levels

Front 176

How are most adrenocortical adenomas found? Which adrenocortical neoplasm is more likely to be functional?

Back 176

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.

Front 177

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?

Back 177

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

Front 178

What are the five features that distinguish endocrine tumors occurring with MEN vs. sporadic endocrine tumors?

Back 178

younger age
multiple organs synchronously or metachronously
preceeded by aSx endocrine hyperplasia
more aggressive, more likely to recur
more multifocal

Front 179

MEN-1 has what 3P’s? Which is the most common manifestation of the 3P’s? What is the mutant gene locus?

Back 179

aka Wermer syndrome

Parathyroids<<most commonly
Pancreas
Pituitary

tumor suppressor gene for menin

Front 180

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?

Back 180

MEN-2A: Pheochromocytoma, Medullary carcinoma, parathyroid hyperplasia: RET gene mutation
MEN-2B: pheochromocytoma, medullary carcinoma, neuromas, ganglioneuromas, marfanoid habitus
Familial Medullary Thyroid CA

Front 181

Define thyrotoxicosis.

Back 181

Metabolic state caused by elecated levesl of T3 and T4
Hypermetabolic state and overactive SNS

Front 182

Define hyperthyroidism. List causes. Which is most common?

Back 182

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

Front 183

What are causes of thyrotoxicosis not due to hyperthyroidism?

Back 183

Subacute granulomatous thyroid (painful)
Subacute lymphocytic thyroiditis (painless)
Chronic lymphocytic thyroiditis (Hashimoto)
Ectopic thyroid: struma ovarii
Facticious thyrotoxicosis: exogenous thyroid hormone intake

Front 184

What are them clinical manifestations of thyrotoxicosis / hyperthyroidism?

Back 184

--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

Front 185

Thyroid Storm

Back 185

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

Front 186

Apathetic hyperthyroidism

Back 186

Elderly pts: age/comorbidities blunt sx
depression, weight loss, worsening CHF w/ A-fib

Front 187

What is Graves’ disease, including pathogenesis, clinical features specific to this disease, and morphology of the thyroid?

Back 187

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

Front 188

What are the lab results of hyperthyroidism in general? What lab test is specific to Graves’ dis?

Back 188

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

Front 189

4) What are causes of hypothyroidism?

Back 189

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

Front 190

What are the lab results of primary hyperthyroidism in general? Be able to interpret Labs of secondary hypothryoidism.

Back 190

think i did that elsewehre

Front 191

Define Cretinism. List causes and clinical features. Refer to hypothryoidism lab results.

Back 191

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

Front 192

Define myxedema. List features. What lab results are present in addition to thyroid function tests?

Back 192

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

Front 193

What is the most common cause of primary hypothyroidism?

Back 193

?

Front 194

What are the pathogenesis, usual labs and specific labs, and microscopic morphology of chronic lymphocytic (Hashimoto) thyroiditis?

Back 194

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

Front 195

DeQuervain thyroiditis

Back 195

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]

Front 196

Subacute lymphocytic thyroiditis

Back 196

Middle aged females
HLA related
majority are self limited w/ 2 mo course
thyroid diffusely enlarged but nontender

Front 197

What is the morphology and associations of Reidel thyroiditis?

Back 197

aka Reidel struma
assoc. with ideopathic fibrosis elsewhere: retorpeirtoneal or mediastinal
Morphology: fibrosis of thryoid extending into surrounding ts (indistinct capsule)

Front 198

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?

Back 198

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

Front 199

Thyroid Tumor Lecture

Back 199

All of it

Front 200

Gigantism:

Back 200

excess GH before epiphysial closure
disporportionate growth in long bones: long arms, long legs. All organs enlarged, usually acromegally as well.

Front 201

Complications of somatotroph adenoma

Back 201

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

Front 202

Acromegaly

Back 202

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

Front 203

Ophthalmopathy of Graves Disease

Back 203

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

Front 204

Gaucher's Disease Types 2 and 3

Back 204

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

Front 205

FMR1

Back 205

"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

Hint 205

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

Front 206

MR, Long face, macro-orchidism

Back 206

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

Hint 206

[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

Front 207

FXTAS

Back 207

Fragile X associated tremor/ataxis syndrome occurs in ~1/3 of previously aSx males starting 50's

p169

Hint 207

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

Front 208

New onset tremor & ataxia in 50 yo male w/ MR grandson

Back 208

FXTAS

CGG trinucleotide repeate expansion w/in FMR1 "familial MR" gene

most expansn during oogenesis: grandsons via daughter most affected

p169

Hint 208

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

Front 209

Vitamin D-Resistant Rickets

Back 209

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)

Front 210

X-linked Hypophasphatemia

Back 210

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)

Front 211

Type V Glycogenosis

Back 211

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

Front 212

muscle phosphorylase deficiency

Back 212

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

Front 213

22 yo w/ muscle cramps & dark urine 2° to exercise

Back 213

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

Front 214

2 most frequent causes of MR

Back 214

1. Down Syndrome
2. Fragile X Syndrome

Front 215

Huntington's Dz

Back 215

expansion of CAG w/in coding region during spermatogenesis

aggregated misfolded proteins → apoptosis

polyglutamine gain of fnx → neuotoxicity → chorea & dementia

Front 216

Acid Maltase Deficiency

Back 216

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

Front 217

Massive Cardiomegaly w/ clear glycogen deposits in Myocytes

Back 217

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

Front 218

2 mo w/ SOB & massive cardiomegaly

Back 218

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

Front 219

Glucose-6 phosphatase deficiency

Back 219

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)

Front 220

Von Gierke Dz

Back 220

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)

Front 221

Sickly 2 yo, consistent failure to thrive w/ convulsions & hepatosplenomegaly

Liver biopsy shows PAS+ vacuoles

Back 221

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

Front 222

Type III Glycogen Storage Dz

Back 222

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

Front 223

female w/ normal breasts, bind pouch vagina, no uterus, amenorrhea

Back 223

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

Front 224

complete androgen insensitivity sro

Back 224

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

Front 225

Leber hereditary optic neuropathy

Back 225

progressive bilateral loss of cenral vision early adulthood onset 25+-10, cardiac conduction defects

Mitochondrial Dz

Hint 225

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

Front 226

23 yo w/ bilateral loss of central vision

EKG reveals Wenckebach

Back 226

Leber hereditary optic neuropathy


progressive bilateral loss of cenral vision early adulthood onset 25+-10, cardiac conduction defects

Mitochondrial Dz

Hint 226

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

Front 227

MELAS

Back 227

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

Hint 227

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

Front 228

WAGR Syndrome

Back 228

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

Front 229

motor and cognitive dvlpt delays

exercise intolerance, vision problems, cardiomyopathy

Stroke like episodes w/ progressive dementia

Back 229

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

Hint 229

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

Front 230

26 yo Male CC: Infertility

Long Legs, Small Penis, No Facial Hair, Gynecomastia

Back 230

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

Front 231

Common Features of Sex Chrom Abnormalities

Back 231

Abnormal Sexual Dvpt w/ Infertility
Subtle problems difficult to recognzie until puberty
more X's = more cognitive impairment

Front 232

XIST gene

Back 232

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.]

Front 233

22 yo Male

CC: Severe Acne
PE: Tall
Dx: Genetic Abnormality

Back 233

XYY

Normal Intelligence, Normal Fertility

Front 234

Prenatal Screen:
low PAPPA, low hCG

Back 234

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)

Front 235

Baby born with Cleft Lip, Cleft Palate, Polydactyly, Rocker Bottom Feet

Back 235

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]

Front 236

Chimera

Back 236

individuals of 2+ zygotes (us. in vitro fertilization)
→ anomalous blood grouping results
→ families w/ HLA incompatability
→ sex reversal or intersex (possible true hermaphrodite)

Front 237

5p-

Back 237

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

Front 238

TBX1

Back 238

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

Front 239

Velocardiofacial syndrome

Back 239

vast majority VCFS del22q11
Prominent nose, retrognathia
cardiac malformations

Front 240

child born with heart defect

now frequently sick

Positive for Chvostek's Sign

Back 240

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

Front 241

pinguecula

Back 241

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)

Front 242

Infant Dies at 2 Mo

Horseshoe Kidney on Autopsy

Back 242

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

Front 243

Pathogenesis of Closed Angle Glaucoma

Back 243

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]

Front 244

Back 244

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)

Front 245

extremely painful, taut, firm eye

Back 245

Closed angled glaucoma: pierpheal zone of iris adheres to trabecular meshwork & blocks egress;

medical emergency

Front 246

Mutton fat droplets in cornea

Back 246

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]

Front 247

fibrovascular proliferation extending from inner canthus onto cornea

Back 247

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

Front 248

hypopyon

Back 248

exudate of fluid from ciliary body/iris visible by penlight

indicative of corneal ulceration?

Front 249

dendritic corneal ulcer

Back 249

herpes simplex

most common cause of corneal ulcer
unilateral, recurrent, produces dendritic ulcer
sequelae: corneal scar & vision loss

Front 250

blurred vision in left eye

Hx: traumatic injury to right eye 2wka

Back 250

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

Front 251

ADH

Back 251

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

Front 252

Wermer's Sro

Back 252

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

Front 253

MEN1

Back 253

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

Front 254

Pt cannot see outer half of both visual fields

HA, N/V

Back 254

Pituitary Macroadenomas (>1cm): hormonally silent but cause local effects:
Bitemoral hemianopsia
± ↑ intraCranial Pressure: HA, Nausea, Vomitting

Enlarged sella turica on imaging

Front 255

Galactorrhea, ↓ Libido, Infertility

Back 255

Fnxl Prolactinoma w/ Hyperprolactinemia:

Amenorrhea, Galactorrhea, Loss of Libido, Infertility

Imaging: "pituitary stone" dystrophic calcification

Tx: Dopamine Agonists: Bromocriptine or Cabergoline

Front 256

GNAS1

Back 256

GTPase deficient alpha subunit of Gs

oncogenic expansion → GH producing pituitary tumor

Front 257

Pt CC: Pituitary Insufficiency

PE: darkened elbow creases

Hx: Bilateral Adrenalectomy 2° to Bilateral Adrenal Hyperplasia

Back 257

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)

Front 258

hemorrhage into pituitary gland

Back 258

pituitary apoplexy

often 2° to adenoma

Acute onset: excruciating HA, diplopia, Hypopituitarism

Neurosurgical emergency: will cause Cardiovascular collapse

Front 259

Young Child with Fever, Hepatosplenomegaly, Bulging Eyes, and Urinary Frequency

Back 259

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

Front 260

CC: Short Stature
PE: Proportionality, Myxedema
Hx: Delayed Sexual Dvlpt

Back 260

Pituitary Dwarfism: Proportional Dwarfism w/ delayed sexual dvlpt ± thyroid, adrenocrtical insufficency
majority are idiopathic w/ normal anatomy
Tx: GH before epiphyseal plate closure

Front 261

CC: Short Stature
PE: Cauliflower Ears, Hitch-Hiker's Thumb

Back 261

Diastrophic Dwarfism

AR sro of short limbs, cauliflower ears, short 1st metacarpal (hitch-hikers thumb) ± deafness;

Front 262

CC: Short Stature
PE: Proportionality, Absent Distal Clavical

Back 262

Pyknodysostosis: AR sro of generalized developmental disorder w/ proportionate dwarfism; ↑ bone density and fragrility, short digits, small face, absent distal end of clavical

Front 263

CC: Short Stature
PE: Enlarged Head, Short Limbs

Back 263

Achondroplasia

AD LOF in Fibroblastic Growth Receptor 3

normal trunk, enlarged head, short limbs

80% new mutations

Front 264

Nevus

Back 264

any congenitla lesion of skin

Front 265

Desmopressin

Back 265

ADH analogue aka DDAVP

used to Dx & Tx Diabetes Inspidius

Front 266

DDAVP

Back 266

Desmopressin

ADH analogue
used to Dx & Tx Central Diabetes Inspidus

Front 267

ΔGenes of Malignant Melanoma

Back 267

Heterogenous

BRAF & p16INK4A esp common

also

↑ PI-3K/AKT signalling
PTEN silencing
c-KIT activation

Front 268

Leser-Trelat Sign

Back 268

Multiple seborrheic keratoses

assoc. with internal malignancy,

probably 2* to Tumor Prodxn ofTGFα

Front 269

Multiple seborrheic keratoses

Back 269

Leser-Trelat Sign

assoc. with internal malignancy,

probably 2* to Tumor Prodxn ofTGFα

Front 270

Dermatosis papula nigra

Back 270

seborrheaic keratosis of melanized skin, commonly located on face

Front 271

seborrheaic keratosis of melanized skin

Back 271

Dermatosis papula nigra

commonly located on face

Front 272

CC: Seizures

PE: Erythematous Macules on Face, Hypopigmented macules elsewhere

Back 272

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

Front 273

Non tender, rapidly growing erythematous papule with dark, firm, depressed central region

Back 273

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

Front 274

basal cell carcinoma

Back 274

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

Front 275

Gorlin's Syndrome

Back 275

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

Front 276

35 yo Female

CC: expanding mass lesion on Leg

PE: dark tan papule dimples inward when compressed laterally

Back 276

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.

Front 277

Dermatofibroma

Back 277

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.

Front 278

Sudden onset Rash:
symmetrical involvement of entire body including palms;

macules, papules, vesicles and bullae

lesions have central necrosis and peripheral inflammation

Back 278

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]