Exam 3 Flashcards
1
Q
Types of gene mutations
A
- Point mutations
- Insertions
- Deletions
- TNRs
2
Q
With the following mutations, which require molecular analysis: a.) genome mutations, b.) chromosome mutations, c.) gene mutations
A
- Gene mutations require molecular analysis. Genome and chromosome mutations can be analyzed using molecular analysis, but also cytological techniques
3
Q
Compare and contrast the types of DNA diagnoses
A
- ) Direct: when exact DNA sequence is known
a. ) Endonuclease: PCR to amplify region of interest, Digestion using appropriate endonucleases, Separation of fragments by electrophoresis
b. ) Allele-specific extension: Label DNTPs fluorescently - ) Indirect: when DNA sequence is not known, but linkage marker nearby is known (and inherited with mutated gene(s)) a.) Endonuclease, Southern Blot and probe for detection of marker
4
Q
What is SKY?
A
- Spectral karyotyping
- Visualization of all human c/s by “painting” each pair in different fluorescent color. Used to detect rearrangements and other c/s abnormalities
5
Q
What is array-based comparative genomic hybridization (array CGH)?
A
- Genomic DNA and a reference DNA (control) are labeled with two different fluorescent dye (one green and the other red) and hybridized to slide spotted with DNA probes spanning the human genome.
- If yellow, then equal amounts of both DNAs have hybridized
- If green or red, then amplification or deletion respectively.
6
Q
Increase in methylation typically leads to what in terms of expression of a gene?
A
- Decreased expression, esp when methylation occurs at CpG island promoters.
7
Q
Deacetylation of a gene does what to its expression?
A
- Associated with decrease in gene expression
8
Q
A 4yo female presents with rashes on her palms and soles. Her nasal bridge looks flattened. Exam of her oral cavity shows deformed molars and incisors. Her front teeth are notched. Her shins exhibit and outward/anterior bowing. What is the most likely diagnosis?
a. ) CMV infection
b. ) Herpes infection
c. ) Rubella
d. ) Syphilis
e. ) Down syndrome
A
- D.) Syphilis
9
Q
Top 4 congenital malformations in the US
A
- ) Clubfoot (25/10K)
- ) PDA (17/10K)
- ) VSD (11/10K)
- ) Cleft +/- palate (9/10K)
10
Q
What is congenital atresia?
A
- Upper GI (esophagus) or lower GI is stenosed
11
Q
What is the leading cause of mental retardation is the US?
A
- Down syndrome (trisomy 21)
12
Q
Down syndrome.
a. ) Incidence
b. ) Karyotype
c. ) Pathogenesis
d. ) Clinical presentation
e. ) Complications
A
a. ) Incidence: 1/700
b. ) Karyotypes: 47 X_ (+21), 46 (14, 21q +21) = Robertsonian, 46 / 47 (+21) = Mosaic
c. ) Pathogenesis: meiotic nondisjunction, Robertsonian translocation, Mosaic type
d. ) Clinical presentation: - Mental retardation, flattened nasal bridge/facial profile, epicanthal folds, simian crease, congenital heart defects, intestinal stenosis, umbilical hernia, hypotonia, first/second toe gap
e. ) Complications: 10-20x risk of developing leukemia (AML: acute megaloblastic leukemia), almost all over 40 develop neurodegenerative changes like Alzheimers, abnormal immune response predisposition to serious infections (lung, thyroid autoimmunity)
13
Q
Describe maternal age implication in higher incidence in having a baby with DS.
A
- Risk starts increasing at age 35.
- 40 = > 5 x increase
- 45 = > 10 x increase
14
Q
Cystic Fibrosis.
a. ) Incidence
b. ) Pathogenesis
c. ) Clinical presentation
A
a. ) Incidence: 1/3200
b. ) Pathogenesis: AR
- Defect in CFTR (Cl channel) d/t mutation of 3 nts coding for Phe. This is most severe mutation. Other mutations are known. - Results in high salt concentration in exocrine glands and viscous luminal fluid of resp tract, GI and repro tracts (including vas deferens) - Viscous fluid in resp tract subjects lungs to recurrent infections and therefore fibrosis
c. ) Clinical presentation - First symptom noticed by parent is salty child - Recurrent pulmonary infection, cor pulmonale (right heart failure) malabsorption, obstructed vas deferens (sterility), chronic pancreatitis, secondary biliary cirrhosis, meconium ileus (in newborn)
15
Q
Of the following, what are the ages associated with each:
a.) neonate, b.) infant, c.) child
A
a. ) neonate = 0-28 days
b. ) infant = 28 days – 1 year
c. ) child = 1-17 years old
16
Q
What is considered term, preterm and post-term gestational age?
A
- Term = 38-42 weeks
- Preterm/premature = <37 weeks
- Post-term = >42 weeks
17
Q
Describe APGAR scoring
A
- Scale 0-10
- A: appearance (color): 0 = entirely cyanotic, 2 = no cyanosis
- P: pulse (HR): 0 = absent, 2 = >100
- G: grimace (reflex): 0 = absent, 1 = grimace/feeble cry, 2 = sneeze / cough or pulling away
- A: activity (muscle tone): 0 = none, 1 = some flexion, 2 = active movement
- R: respiration: 0 = absent, 2 = strong
Note: 0-1 corresponds to 50% likelihood of death, 4 = ~20% likelihood of death, 7+= 0%
18
Q
What is the 2nd most common cause of neonatal mortality?
A
- Prematurity
- What is the most common cause?
19
Q
Clinical signs of prematurity besides GA
A
<2.5 kg, thin skin, reduced tone/activity, extremities unflexed
20
Q
Complications of prematurity
A
- ) Hyaline membrane disease
- ) Necrotizing enterocolitis
- ) Sepsis
- ) Intraventricular hemorrhage
- ) Developmental delay
21
Q
What is prematurity vs FGR (fetal growth restriction)?
A
- Prematurity: <37 weeks gestation
- FGR (aka SGA, IUGR) = fetal weight below the 10th percentile
22
Q
Causes of FGR
A
- ) Fetal: chromosomal disorder, congenital malformation, infection
- ) Placental: placental anomalies, infection, confined mosaicism
- ) Maternal: preeclampsia, chronic HTN, malnutrition, renal disease, drugs, smoking How to tell difference?
- If fetal, there is symmetric FGR and all systems involved. If placental, there is asymmetric FGR and brain is spared.
23
Q
Complications of FGR
A
- Perinatal asphyxia
- Meconium aspiration
- Hypoglycemia
- Polycythemia
- Brain dysfunction
- Hearing/visual impairment
- Learning disability
24
Q
What is the most common birth injury?
A
- Caput succedaneum: subQ edema over presenting part of head at delivery, typically over occipitoparietal and crosses suture lines
25
Common birth injuries
- Caput succedaneum
- Subgaleal hematoma
- Skull fracture
- Intracranial hemorrhage
- Brachial plexus injury
- Facial nerve injury
- Fractures: clavicle, humerus
26
Routes of perinatal infections
1. ) Transplacental: hematogenous
2. ) Ascending: transcervical
3. ) Combined
27
Most common causes of transplacental infections
- Mnemonic = TORCH
- Toxoplasmosis, other (syphilis, listeriosis, HIV, HBV, parvo B19), rubella, CMV, herpes
28
Congenital syphilis.
a. ) Causative agent
b. ) Clinical presentation
a. ) Causative agent: T. pallidum (spirochete)
b. ) Clinical presentation: vesiculobullous rash (pemphigus syphiliticus), mulberry molars (rounded rudimentary enamel cusps on molars), Hutchinson’s incisors (notches on biting surfaces) with widely spaced teeth, Saber shin (sharp anterior bowing of tibia)
29
Why is early determination of syphilis in a pregnant mother key for prevention?
- T. pallidum doesn’t cross the placenta until the 5th month of pregnancy.
30
Outcomes of pregnancy in syphilitic women
- 1/3rd stillbirth
- 2/3rd congenital syphilis
31
Congenital rubella syndrome.
a. ) Causative agent
b. ) Clinical presentation
a. ) Causative agent: Rubella virus, 1st trimester
b. ) Clinical presentation: low birth weight, purpuric rash, microcephaly, heart defects (PDA), visual problems (cataracts)
32
Ascending infections. Causative agents, types of infections, consequence
- Pathogens = E.coli, GBS, herpes simplex II
- Infections = chorioamnionitis, funisitis, placentitis, villitis
- Consequence = preterm birth
33
Neonatal sepsis. a.) Types b.) Causes c.) Risk factors
1. ) Types:
a. ) Early-onset: 0-7 days
b. ) Late-onset: 8 days – 3 months
2. ) Causes:
a. ) Early-onset: GBS, E.Coli, Klebsiella
b. ) Late-onset: Staph, H.influenzae, Listeria, Chlamydia, Mycoplasma, Candida
3. ) Risk factors:
a. ) Early-onset: previous infant with GBS, GBS bacteuria during pregnancy, premature delivery, ruptured membrane \> 18 h, intrapartum temp \> 38 deg C
34
Causes of neonatal RDS (respiratory distress syndrome). What is the most common cause?
- Hyaline membrane disease (deficiency of alveolar surfactant) = most common cause
- Prematurity: prior to 28 weeks (~60% of infants)
- Head injury
- Sedation
- Aorta anomalies
- Umbilical cord coiling
- Amniotic fluid aspiration
35
Hyaline membrane disease
a. ) What is it?
b. ) Clinical presentation
c. ) Pathogenesis
d. ) Complications
e. ) Risk factors
a. ) What? Deficiency of alveolar surfactant
b. ) Clinical presentation: respiratory distress, cyanosis, hypoxemia, hypercapnia, metabolic acidosis. Can measure L/S (lecithin-sphingomyelin) ratio in amniotic fluid to assess for fetal lung maturity.
c. ) Pathogenesis: decreased alveolar surfactant (by type II pneumocytes) = increased surface tension = atelectasis = uneven perfusion and hypoventilation = hypoxemia and CO2 retention = acidosis = pulmonary vasoconstriction = pulmonary hypoperfusion = endothelial damage/epithelial damage = plasma leaks into alveoli = fibrin and necrotic cells (hyaline membrane) = increased diffusion gradient = vicious cycle
d. ) Complications: intraventricular hemorrhage, PDA, necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity
e. ) Risks: preterm AGA, maternal DM, C/section, male gender
36
What is bronchopulmonary dysplasia (CLD: chronic lung disease)?
- Lung disease that develops in preemies born less than 32 weeks and placed on at least 4 weeks of oxygen.
- Hyperplasia and squamous metaplasia of bronchial epithelium occurs with alveolar wall thickening, peribronchial and interstitial fibrosis. This is attributed to oxygen and inflammatory cytokines that lead to reduced numbers of alveoli.
- Can lead to respiratory failure and predisposition to RSV infection – can progress to death.
37
Necrotizing enterocolitis.
a. ) What is it?
b. ) Clinical presentation
c. ) Pathogenesis
d. ) Complications
a. ) What? Mucosal or transmural intestinal necrosis commonly affecting the terminal ileum, less commonly colon or proximal small bowel. It is a complication of prematurity and low birth weight.
b. ) Abdominal distension, ileus and bloody stool
c. ) Controversial etiology with ischemia being a top contender. Ischemia result in focal to confluent areas of bowel necrosis.
d. ) Strictures, perforation
38
Fetal hydrops.
a. ) What is it?
b. ) Two types and causes?
c. ) Describe pathogenesis of immune hydrops fetalis. Describe clinical presentation of newborn.
a. ) Edema in fetus. When generalized = hydrops fetalis, when localized = cystic hygroma.
b. ) Immune hydrops (blood incompatibility) and non-immune hydrops (infections, chromosomal anomalies, twin pregnancy, CV defects)
c. ) Mother = Rh neg, Father = Rh pos. Occurs with second Rh+ pregnancy. After first pregnancy, fetus’ blood inoculates mother’s blood at delivery. Mom’s immune system becomes sensitized to fetal RBCs with Rh+ factors on cell surface and her B cells produce anti-Rh abs. At second pregnancy, mother’s antibodies cross placenta and target and destroy fetus’ RBCs. Clinical presentation = kernicterus (bilirubin-induced brain destruction), CHF, jaundice, hemolytic anemia, hepatosplenomegaly and edema.
39
What is SIDS? Risk factors? Autopsy findings?
* Unexplained newborn/infant death under 1 year of age.
* Risk factors:
1. Maternal: young age (\< 20), maternal smoking during pregnancy, drug abuse, late / no prenatal care, short intergestational intervals
2. Infant: brain stem abnormality, prematurity/SGA, male, antecedent respiratory infections, multiple birth pregnancy
3. Environment: prone sleep position, sleeping on soft surface, hyperthermia, postnatal passive smoking
* Autopsy findings: petechiae, lung congestion (vascular engorgement), hypoplasia of arcuate nucleaus and decreased brain stem neuronal populations
40
What is the most common tumor in infants?
- Hemangioma; vascular tumor
41
Types of hemangiomas in infants
1. ) Capillary hemangiomas (strawberry, Juvenile type): skin. May grow in first few months of life, but typically spontaneously regresses leaving behind some scarring and deposits of hemosiderin pigment.
2. ) Cavernous hemangiomas: cerebellum, brain stem, pancreas, liver.
42
Types of fibrous tumors in infants
1. ) infantile myofibromatosis: most common fibrous tumor in infants, tumors in skin, muscle, bone or viscera.
2. ) aggressive infantile fibromatosis: infiltrates skeletal muscle, no metastasis, but can grow very large
3. ) infantile digital fibroma
4. ) congenital infantile fibrosarcoma
43
Teratoma in infancy.
a. ) Incidence
b. ) Location
a. ) 1/20K to 1/40K live births, more common in girls
b. ) SCT (sacrococcygeal teratomas) are most common (10% of these are associated with congenital malformations).
44
Malignant tumors of infants/children
- Neuroblastoma
- Wilms tumor
- Rhabdomyosarcoma
45
Most common solid tumor in newborn. Prognosis
- Sacrococcygela teratoma (benign, 12% of them are malignant)
- Prognosis: depends on location
46
Most common solid congenital malignancy
- Neuroblastoma
47
Neuroblastoma
a. ) What is it?
b. ) Clinical presentation
c. ) Diagnosis
d. ) Pathology
a. ) Malignant tumor of primitive sympathetic cells in adrenal medulla, sympathetic ganglia. Accounts for 10% of all childhood cancers
b. ) Most commonly abdominal mass (blueberry muffin baby) with blueish subcutaneous nodules and weight loss. Also possibly: fever, pain, ascites, respiratory distress, gait disturbance, diarrhea, proptosis, periorbital ecchymosis.
c. ) Increased catecholamines in blood, increased catecholamine metabolites in blood (VMA, HVA), blood neuron-specific enolase (NSE), NSE staining by IHC
d. ) Light microscopy: small blue round cells with rosette structure. EM microscopy: dense core neurosecretroy granules
48
Wilms tumor
a. ) What is it?
b. ) Clinical presentation
c. ) Pathology
d. ) Prognosis
a. ) The most common primary malignant tumor of the kidney in children resulting from tumor suppressor (WT) mutation and present with congenital malformations such as WAGR syndrome and Denys-Drash syndrome
- WAGR: 33% risk for Wilms tumor, aniridia, genital anomalies, retardation, germline deletion of WT1 gene
- Denys-Drash: 90% risk for Wilms tumor, nephropathy, gonadal dysgenesis, gonadoblastoma, WT1 mutation
b. ) Abdominal mass, hematuria, fever, HTN
c. ) Blue round cells, primitive tubules
d. ) Prognosis very good with nephrectomy and chemo. Diffuse anaplasia in extrarenal metastasis has less favorable outcome.
49
Most common soft tissue sarcoma in children
- Rhabdomyosarcoma
50
Rhabdoymyosarcoma (RMS).
a. ) What is it?
b. ) Locations
c. ) Histologic types. Which has best and worst prognosis?
a. ) Malignant neoplasm arising from striated muscle.
b. ) Common sites = head/neck, eyes, GU tract, extremities, trunk
c. ) Sites
1. ) Embryonal: sarcoma botryoides is a variant of this type. Develops in walls of hollow mucosal-lined structures such as nasopharynx, common bile duct, bladder and vagina. Has best prognosis.
2. ) Alevolar: muscles of extremities form cords or alveoli stroma. Very aggressive.
3. ) Pleomorphic: deep within muscle of extremities and trunk. Predominantly occurs in adults. Has worst prognosis.
51
What is FAS? Clinical presentation
- Physical and mental defects that develop in a fetus in association with high levels of etoh consumption during pregnancy. Causes growth retardation, microcephaly, short palpebral fissures, maxillary hypoplasia, ASD
52
State the most common cause of death in children, as well as the most common non-traumatic cause of death in children:
- under one year of age
- between 1-5 years of age
- between 5-14 years of age
1. 2. 1-5 yo: congenital malformation/deformation/chromosomal abnormalities, malignant neoplasms, disease of heart
3. 5-14 yo: malignancy is most common second to injuries
53
Define and recognize malformation, disruption, deformation, sequence and syndrome. Give appropriate examples of underlying factors which may lead to deformation by such mechanisms as in: prune belly sequence and Potter sequence.
- Malformation: primary error of morphogenesis, ie. abnormal developmental process. Examples = polydactyly, cleft lip
- Disruption: secondary destruction of an organ/body region previously normal. Examples = amniotic bands
- Deformation: extrinsic disturbance of development. Example = uterine constraint, multiple fetuses, oligohydramnios.
- Sequence: multiple congenital anomalies that result from secondary effects of a single localized aberration in organogenesis. Event may be one of the above things. Example = Potter sequence
1. ) Potter sequence: Oligohydramnios (decreased amniotic fluid) d/t variety of things = fetal compression = pulmonary hypoplasia, altered facies, positioning deficits of feet/hands, breech presentation
2. ) Prune belly: poor development of abdominal muscles (causing skin over belly to wrinkle like prune), cryptorchidism, UT problems
54
Describe type I hypersensitivity reactions and provide examples
- Reaction where injury is caused by TH2 cells, IgE antibodies, mast cells and other leukocytes.
- Examples: anaphylaxis, bronchial asthma, allergies (hay fever and food)
55
Describe type II hypersensitivity reactions and provide examples
- Reaction where secreted IgG and IgM injure cells by promoting phagocytosis or lysis and injury tissue through induction of inflammation.
- Examples: myasthenia gravis, Graves disease, Goodpasture syndrome
56
Describe type III hypersensitivity reactions and provide examples
- Reaction where IgG and IgM antibodies bind antigens usually in circulation and the antigen-antibody complex deposits in tissues and induces inflammation.
- Examples: SLE
57
Describe type IV hypersensitivity reactions and provide examples
- Reactions where sensitized T lymphocytes (TH1, TH17 and CTLs) are the cause of tissue injury.
- Examples: RA, MS
58
Types of transplantation grafts
1. Autograft: self tissue
2. Isograft: identical twins
3. Allograft: other human, different genetic background
4. Xenograft: different species
59
What is the underlying cause of transplant rejection?
- Immune damage caused by recipient’s response to allograft HLA antigens
60
Describe mechanisms of graft rejection
1. ) Cellular rejection: type IV hypersensitivity reaction
a. ) host CTLs bind and react to class I HLA Ag presented by allogeneic APCs (direct pathway), differentiate into CTLs, release perforins and granzymes leading to apoptosis of graft cells
b. ) TH cells bind and react to class II HLA Ag presented either by allogeneic APCs (direct pathway) or via host APCs (indirect pathway), release cytokines recruiting mononuclear cells, which release IFN-gamma and TNF that leads to inflammatory tissue damage.
2. ) Humoral rejection: type II and III hypersensitivity reactions
a. ) type II: abs binds to surface HLA in graft endothelium = activation of complement = acute inflammation or vasculitis
b. ) type III: abs against host Ag form immune complexes in circulation and deposit in graft endothelium or in situ = fixing of complement = necrotizing vasculitis
61
Describe the 3 types of transplant rejection in terms of
a. ) timing
b. ) mechanism
c. ) histological features
1. ) Hyperacute
a. ) timing: mins to hours (including intra-operatively)
b. ) mechanism: type III - Preformed abs (previous sensitization via pregnancy, transfusion or prior transplant) where destruction occurs via type III response – immune complex = complement activation
c. ) histological features: fibrinoid necrosis, thrombosis, ischemia
2. ) Acute
a. ) timing: days to months (1-3)
b. ) mechanism: type II, III and IV response - CD8 cells infiltrate tubular and vascular membranes - CD4 cells produce cytokines = interstitial inflammation - Anti-graft abs deposit in graft vasculature = complement activation
c. ) histological features: lymphocytic infiltrates, tubular necrosis (in case of kidneys), necrotizing vasculitis, intimal thickening (accumulation of fibroblasts, foamy macrophages, myocytes)
3. ) Chronic
a. ) timing: months (4-6) to years
b. ) mechanism: type II, III and IV response - as above, but chronically leading to proliferative lesions (d/t humoral response) and cytokine induced proliferation of vascular SM and production of collagen in EMC
c. ) histological features: vascular changes, interstitial fibrosis, tubular atrophy (in case of kidneys), chronic inflammation
62
Describe liver transplant rejection on acute vs chronic basis
1. Acute: cellular response in which portal lymphocytic infiltrates cause damage. Triad seen = portal tract inflammation, bile duct epithelial damage, endothelial damage (portal vein, hepatic artery). Cells seen: lymphocytes, plasma cells, macrophages and eosinophils.
2. Chronic: cellular response as above, but on chronic basis leads to bile duct destruction/disappearance, which is compounded by ischemia from ab-mediated damage to hepatic arterioles. Fibrosis (foam cells, myointimal hyperplasia, luminal obliteration)
63
Describe heart transplant rejection on acute vs chronic basis. Complications?
- Rejection is cell-mediated. Lymphocytic infiltrates lead to myocyte damage and necrosis. Histology resembles viral myocarditis.
- Acute: lymphocytes surrounding myocytes
- Chronic: lymphocytes stimulate allograft cells to produce GFs that promote vascular SM and ECM
- Complications = graft arteriopathy (change resembling CAD, ie. with intimal thickening, accumulation of foamy macrophages) causing silent MI as heart is denervated, infections (EBV)
64
Describe 3 complications resulting from hematopoietic cell transplants. Describe histologic features of acute/chronic GVHD.
1. ) GVHD (graft versus host disease): type IV reaction via CD4 (via cytokines) and CD8 attack recipient tissue where targets are skin, liver and GI tract
a. ) Acute: epithelial necrosis. Triad: exfoliative rash, enteritis (blood diarrhea), hepatic involvement (bile duct necrosis) = jaundice
b. ) Chronic: fibrosis of dermis with destruction of skin appendages, esophageal strictures and liver/bile duct damage manifested by jaundice.
2. ) Graft failure / rejection: some host NK cells or T cells survive irradiation and react against graft
3. ) Immunodeficiency: irradiation leads to immunodeficiency and susceptibility to serious, recurrent infections especially d/t viruses such as CMV and EBV. Autoimmune disorders can also develop.
65
Discuss the etiology of autoimmune diseases in terms of genes, microbes, gender
- Genes:
a. ) Certain MHC (D Locus) genes confers higher susceptibility to loss of self tolerance
b. ) PTPN-22 polymorphism
- Microbes: certain infections cause cross-reactivity with self-tissue, increased expression of APC co-stimulation molecules and non-specific B and T cell stimulation (EBV and HIV)
- Gender: higher in females
66
Mechanisms that explain autoimmunity
1. ) Failure of T cell anergy
2. ) Failure of apoptosis of self-reactive cells
3. ) Failure of T cell mediated suppression (by T-regs)
4. ) Cross-reactivity/molecular mimicry (microbes)
5. ) Polyclonal lymphocyte activation
6. ) Emergence of sequestered Ag
7. ) Exposure of cryptic ag determinants
67
SLE.
a. ) Incidence and prevalence
b. ) Genetic factors
c. ) Age and sex association
d. ) Clinical criteria for diagnosis
e. ) Etiology
f. ) Pathogenesis
g. ) Lab diagnosis
h. ) Clinical presentation (include organs affected and corresponding histology)
a. ) 1/700 (1/245 black) females
b. ) HLA-DQ locus
c. ) 9:1 F:M ratio, onset bw 2nd-3rd decade of life
d. ) Malar (butterfly) rash, discoid rash, photosensitivity, oral ulcers, arthritis (2+ joints), serositis (ST elevation in all leads), renal disorder. Neurologic disorder, hematologic disorder (100% of patients), immunologic disorder, ANA abs
e. ) Genes, environment triggers (UV, viruses, drugs, hormones), immune system defect (self-reactive TH escape tolerance, defects in elimination of self-reactive B cells)
f. ) B and T cells specific for self-nuclear antigens, defective clearance of apoptotic bodies = increase burden of nuclear antigens, overall high level of AN IgG antibodies. Type II implicated in hematologic abnormalities and type III implicated in visceral lesions.
g. ) ANAs directed against 4 categories of nuclear ag including DNA, histones, proteins:RNA, nucleolar material.
- Homogenous fluorescence pattern seen in drug induced SLE (anti-histones ab).
- Rim fluorescence pattern seen in SLE with renal involvement and active flares (anti-dsDNA ab).
- Speckled fluorescence pattern seen in SLE (anti-smith ab to ribonucleoprotein).
- Nucleolar fluorescence pattern also seen in SLE.
- Antibodies specific to lupus = anti-dsDNA, anti-smith, anti-blood cells, anti-phospholipid (hyercoagulability in vivo).
h. ) Any organ, commonly skin, joints, kidneys and serous membranes. Presentation is mild dermatological and joint symptoms to life-threatening organ failure and cytopenias. Death d/t renal failure, infection and/or CAD.
- Skin (facial rash, also trunk or extremities): degeneration of basal layer, lymphocytic infiltrates, deposition of IgG and complement at junction
- Joints (hands, knees, ankles commonly): mononuclear inflammatory synovitis, no joint destruction
- Vascular changes: immune complexes deposit in vascular beds and complement activated (type III). If acute = fibrinoid necrosis of arteries/arterioles. If chronic = layered fibrous thickening (onion-skin appearance)
- Kidneys: major cause of morbidity and mortality. Lupus nephritis = glomerular changes with frank necrosis d/t immune complex induced inflammation with proliferation of endothelial/epithelial and mesangial cells. Tubulointerstitial changes also seen.
- Serosal membranes (principally involving pleurae and pericardium): Acutely, exudation of fibrin. Chronically, proliferation of fibrous tissue = adhesions.
- Heart: pericarditis, myocarditis, endocarditis (Libman-Sacks vegetations), accelerated CAD
- Lungs: pleuritis with effusion. Acutely, pneumonitis with alveolar damage, edema and hemorrhage. Chronically, interstitial and vascular fibrosis leading to pulmonary fibrosis and pulmonary HTN.
- CNS: focal deficit, seizures, psychosis. Mild histopathological changes. Vasculitis: small vessel thickening with intimal proliferation, ischemia and microinfarcts
68
Describe forms of Lupus
1. ) SLE: see above
2. ) Drug-induced: drugs such as D-penicillamine, procainamide, hydralazine, isoniazid causes a lupus-like syndrome with pos anti-histones and anti-dsDNA abs with multiple organ involvement, presence of rash, fever, arthralgias and serositis. Remission following cessation of drugs.
3. ) Chronic discoid: variety of skin lesions without systemic features
4. ) Subacute cutaneous: diffuse superficial nonscarring photosensitive lesions with mild systemic disease
69
Sjögrens syndrome
a. ) Age and sex association
b. ) Pathogenesis
c. ) Lab diagnosis
d. ) Clinical presentation (include organs affected and corresponding histology)
e. ) Complications
a. ) Female predominance, especially during middle ages
b. ) Thought that infection by superAg (eg. EBV, HepC or other microbe) triggers CD4 T cell rxn against glandular epithelial cells with induction of polyclonal B cell hyperactivitiy auto-ab production against nuclear antigens.
c. ) ANAs to ribonucleoproteins SS-A (Ro) and SS-B (La) is common. This is associated with speckled pattern. - 75% of cases also positive to RF (rheumatoid factor).
d. ) Primary form (sicca syndrome) with xerostomia (dry mouth) w/fissure, ulcers, dental caries; keratoconjunctiva sicca, nasal septa erosition, dysphagia, dyspareunia (painful intercourse) = ~40% of cases. 25% of cases have extraglandular involvement (interstitial nephritis, pulmonary fibrosis, peripheral neuropathy, synovitis). Other cases (~60%) associated with other autoimmune disorders. - Glands: activated CD4 T cells, B cells, plasma cells into ducts. Follicle formation with germinal centers. Ductal epithelial hyperplasia leads to obstruction of ducts. Acinar atrophy, fibrosis, fat replacement.
e. ) 40% increased risk of B cell lymphoma
70
Systemic sclerosis
a. ) What is it? Variants?
b. ) Age and sex association
c. ) Pathogenesis
d. ) Lab diagnosis
e. ) Clinical presentation (include organs affected and corresponding histology)
a. ) Autoimmune dz characterized by chronic inflammation, destruction of small vessels and progressive tissue fibrosis. Affects GIT, kidney, heart, lungs, musculoskeletal system. - Diffuse variant: skin involvement at onset, early visceral involvement, rapid progression - Limited variant (CREST syndrome): limited skin involvement of face, forearms and fingers with late visceral involvement. CREST = calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia
b. ) 3:1 F:M, 50-60 yo
c. ) Unknown trigger activates CD4 T cells to secrete cytokines that promote fibrogenesis (TGF-beta, IL-1, PDGF and FGF) and cause microvascular damage. Ultimately this leads to fibrosis. B cells also activated to produce ANAs. d.) Anti-Scl-70 (to topoisomerase: speckled pattern) in mostly diffuse variant case. Anti-centromere (nucleolar and centromere-specific patterns) in mostly CREST (limited variant) case.
e. ) See above for clinical presentation. Cause of death: renal, cardiac, pulmonary, GI dysfunction/failure.
- Skin: Early = edema and CD4 T cell infiltrates. Late = epidermal thinning, dermal appendage fibrosis, subcut calcifications, contractures and mask facies. Vascular endothelial damage and fibrosis (dense collagen) = ischemia and autoamputation of digits.
- GI (90% of cases): Collagen and fibrotic deposition in esophagus = esophageal dysmotility, LES dysfunction = reflux. Small bowel = mucosal thinning, loss of villi/microvilli and submucosal fibrosis = malabsorption.
- Musculoskeletal: Early = nondestructive hyperplasia and inflammation of synovium. Late = fibrosis of synovial and peri-articular CT. In 10 % of cases, myositis with lymphocytic infiltrates and fiber atrophy occurs.
- Renal (2/3rd cases): thickening of interlobular arteries by proliferation of intimal cells = deposition of collagenous or mucinous material = hyaline change. May result in HTN.
- Pulmonary (50% of cases): mild interstitial pneumonitis, alveolar fibrosis = respiratory insufficiency = pulmonary HTN = cor pulmonale
- Cardiac (1/3rd of cases): pericarditis with effusion. Perivascular lymphoid infiltrates leads to arteriolar thickening and interstitial fibrosis and restrictive cardiomyopathy.
71
Rheumatoid arthritis (RA)
a. ) Age and sex association
b. ) Genetic factors
c. ) Pathogenesis
d. ) Lab diagnosis
e. ) Clinical presentation (include organs affected and corresponding histology)
a. ) 3-5:1 F:M, any age commonly 40-70s
b. ) HLA-DRB1, PTPN22
c. ) Antigenic trigger unknown. Initial synovitis with ongoing autoimmune rxn mediated by activated CD4 T cells which produce cytokines that activate macrophages and other immune cells that release degradative enzymes and promote inflammation. IL-1 leads to proliferation of synovial cells and fibroblasts. TNF leads to leukocyte recruitment. Production of rheumatoid factor, which is an IgM auto-ab to Fc region of IgG. Anti-CCP (citrulinnated peptides) or T cell response to CCP contributes to chronic RA. Ultimately pannus formation; destruction of cartilage and bone, fibrosis and ankylosis (stiffness of joint). Vasculitis d/t immune complexes (RF-IgF).
d. ) Loss of joint space via imaging, extra-articular nodules (skin, lungs, spleen, heart), rheumatoid factor
e. ) Mild discomfort to progressive disability. Features include: malaise, fatigue, pain, swelling, stiffness and deformity of small and large joints. Cause of death = amyloidosis, vasculitis, drug therapy complications: bleeding/infection.
- Joint: non-suppurative proliferative destruction synovitis, edema, synovial cell hyperplasia, stromal and perivascular infiltrates. Fibrin deposites on synovial surface. Articular cartilage erosion and osteoclastic destruction of subchondral bone
- Extra-articular lesions (25% of cases): granulomatous inflammation= central fibrinoid necrosis of collagen surrounding macrophages.
72
What is juvenile idiopathic arthritis? Include symptoms, organs involved, variants, diagnosis.
- Occurs in children less than 16 yo with 2:1 F:M ratio. Symptoms = large joint oligoarthritis – knees, wrists, elbows, ankles; pericarditis, myocarditis, pulmonary fibrosis, glomerulonephritis.
- Still’s disease variant = febrile illness with hepatosplenomegaly, rash and leukocytosis.
- ANA pos, no RF factor or nodules
73
What is MCTD? Diagnosis.
- Syndrome with overlapping features of SLE and systemic sclerosis. Distinctive d/t minimal renal disease and good response to steroid therapy.
- Anti-U1RNP (ribonucleoprotein)
74
Correlate each of the following patterns of immunofluorescent staining for ANAs with the specific antibody represented by each, and disease(s) associated with each:
a. ) homogenous (diffuse)
b. ) rim (peripheral)
c. ) speckled
d. ) nucleolar
a. Homogenous = anti-dsDNA, anti-histones – seen in drug-induced SLE
b. Rim = anti-dsDNA – seen in SLE with renal involvement and disease flares
c. Speckled = anti-histones, anti-RNPs, anti-Smith (Sm) – seen with SLE (anti-Sm), systemic sclerosis (specifically anti-Scl-70 in diffuse variant), MCTD, Sjögrens syndrome (anti-SS-A/B)
d. Nucleolar = anti-nucleolar RNA – seen with SLE, systemic sclerosis (specifically CREST/limited variant)
75
Match each of the following autoantibodies with the major autoimmune disease(s) with which it is associated:
a. ) anti-smith (Sm)
b. ) anti-dsDNA
c. ) anti-histone
d. ) anti-SS-A (Ro) and anti-SS-B (La)
e. ) anti-Scl-70
f. ) anti-centromere
g. ) anti-nuclear RNP
a. ) SLE
b. ) SLE (with renal involvement and active flares)
c. ) SLE (drug-induced)
d. ) Sjögren’s syndrome
e. ) Systemic sclerosis (diffuse variant)
f. ) Systemic sclerosis (CREST/limited variant)
g. ) Specific for SLE mostly
76
Agammaglobulinemia of bruton.
a. ) genetics
b. ) etiology
c. ) pathogenesis
d. ) immunologic defect
e. ) clinical features
f. ) methods of diagnosis
g. ) therapeutic approach
h. ) complications
a. ) genetics: XR, most common in males
b. ) etiology: mutation in tyrosine kinase gene (c/s 21)
c. ) pathogenesis: failure of normal pre-B cells to undergo further differentiation d/t defect in Bruton tyrosine kinase responsible for pro/pre-B cell signal transduction. This causes absence of mature B cells in blood and peripheral lymphoid tissue.
d. ) immunologic defect: agammaglobulinemia
e. ) clinical features:
- Following depletion of maternal abs, recurrent sinus, oropharyngeal and respiratory infections (d/t pyogenic bacteria such as Staph, strep, H.influenzae, which are normally cleared by complement via opsonization with abs).
- Susceptible to enteric viruses or protozoa d/t lack of IgA.
f. ) methods of diagnosis: lab work indicating absence of Ig
g. ) therapeutic approach: parenteral Ig replacement
h. ) complications: Increased frequency of autoimmune disorders d/t breakdown in self-tolerance or d/t chronic inflammation (d/t chronic infections).
77
Common variable immunodeficiency
a. genetics
b. etiology
c. pathogenesis
d. immunologic defect
e. clinical features
f. methods of diagnosis
g. therapeutic approach
h. complications and prognosis
a. ) genetics: unclear, equal M:F
b. ) etiology: sporadic and inherited forms, typical onset in 2nd-3rd decades of life
c. ) pathogenesis:
- intrinsic B cell differentiation defect
- abnormal T cell signaling to B cells
- Ultimately, inability of B cells to differentiate into plasma cells. Main feature = hypogammaglobulinemia usually of all Ab classes, occasionally isolated to IgG
d. ) immunologic defect: hypogammaglobulinemia
e. ) clinical features:
- Recurrent bacterial infections of sinuses and respiratory tract
- Increase enteroviral and protozoal infections d/t lack of IgA
f. ) methods of diagnosis: hypogammaglobulinemia
g. ) therapeutic approach: parenteral Ig replacement
h. ) complications and prognosis: increase incidence of autoimmune disorders (such as RA), increase risk of lymphoid cancers and gastric cancers
78
Selective IgA deficiency
a. genetics
b. etiology
c. pathogenesis
d. immunologic defect
e. clinical features
f. methods of diagnosis
g. therapeutic approach
h. complications and prognosis
a. ) genetics: ?, most common primary immunodeficiencies affecting 1/600 Americans
b. ) etiology: familial or acquired (associated with measles or toxo infections)
c. ) pathogenesis: B cell maturation failure?, cellular immunity intact
d. ) immunologic defect: serum/secretory IgA absent or low
e. ) clinical features:
- asymptomatic or recurrent GI, respiratory, GU infections
f. ) methods of diagnosis: low IgA, other isotypes normal, ~40% have anti-IgA ab
g. ) therapeutic approach: parenteral IgA replacement, those with anti-IgA abs will have anaphylactic reaction when transfused
h. ) complications and prognosis: increased tendency to develop autoimmune disorders (such as RA and SLE)
79
Hyper-IgM syndrome
a. genetics
b. etiology
c. pathogenesis
d. immunologic defect
e. clinical features
f. methods of diagnosis
g. therapeutic approach
h. complications and prognosis
a. ) genetics: X-linked pattern in 70% of cases (gene for CD40L), also AR in some cases involving mutation in CD40 gene and AID (activation induced deaminase) enzyme necessary for class switching
b. ) etiology: see genetics
c. ) pathogenesis: Failure of T cells to induce B cell isotype switching from IgM to IgG/A/E as there is a disruption in the CD40L (on TH cells):CD40 (on B cells). Also failure of T cells to activate macrophages to remove intracellular microbes.
d. ) immunologic defect: failure to isotype switch from IgM to A/G/E
e. ) clinical features: - Recurrent pyogenic infections - Infections by intracellular organisms
f. ) methods of diagnosis: IgM normal or elevated, other isotypes absent
g. ) therapeutic approach: bone marrow transplant, Ig replacement therapy
h. ) complications and prognosis - IgM reactions against blood cells = autoimmune lysis - Hyperplastic accumulations of IgM B cells in GI tract lymphoid tissue – can be fatal
80
DiGeorge Syndrome.
a. genetics:
b. etiology
c. pathogenesis
d. immunologic defect
e. clinical features
f. methods of diagnosis
g. therapeutic approach
h. complications and prognosis
a. ) genetics: ~ 90% show micro-deletion of band on c/s 22 (CATCH-22), part of spectrum of disorders, 1:1 M:F
b. ) etiology: partial or complete interruption of 3rd/4th pharyngeal pouch development
c. ) pathogenesis: aplasia or hypoplasia of thymus = T cell deficiency, also aplasia or hypoplasia of parathyroids = hypoparathyroidism = hypocalcemia
d. ) immunologic defect: T cell deficiency
e. ) clinical features:
- abnormalities of face (low-set ears, midline clefts, small mandible) and cardiac (VSD, right subclavian from pulmonary artery)
- hypocalcemia
- viral and fungal infections common
f. ) methods of diagnosis: normal Ig levels, low/no T cell numbers
g. ) therapeutic approach: if hypoplasia of thymus, immune defect resolves by age 5. If aplasia, requires thymus transplant.
h. ) complications and prognosis: cardiac anomalies usually result in morbidity and mortality
81
SCID (severe combined immunodeficiency).
a. genetics
b. etiology
c. pathogenesis
d. immunologic defect
e. clinical features
f. methods of diagnosis
g. therapeutic approach
h. complications and prognosis
a. ) genetics: 50-60% of cases XR mutation in gamma-chain subunit of cytokine receptor, AR form with defects in adenosine deaminase or class II MHC expression
b. ) etiology: defect of gamma-chain of cytokine receptor, defect in adenosine deaminase, failure of class II MHC expression
c. ) pathogenesis: Defect in gamma-chain subunit in cytokine receptor = failure of IL function = impaired lymphocyte development, proliferation and function. ADA = accumulation of lymphotoxic metabolites. Failure of class II MHC = impaired T cell recognition of antigen.
d. ) immunologic defect: severe T cell defect (more common), more rare = T and B cell defect
e. ) clinical features:
- Early onset (~3 months) with thrush, diaper rash and failure to thrive
- Recurrent infections from all microbe classes
f. ) methods of diagnosis: ? low B / T cell count ?
g. ) therapeutic approach: bone marrow transplantation, gene therapy for ADA, vector for gamma-chain of cytokine receptor
h. ) complications and prognosis: Bubble boy
- Opportunistic infection causing death typically within first year
82
Wiskott-Aldrich Syndrome
a. genetics
b. etiology
c. pathogenesis
d. immunologic defect
e. clinical features
f. methods of diagnosis
g. therapeutic approach
h. complications and prognosis
a. ) genetics: X-linked defect in WASP gene (WA syndrome protein)
b. ) etiology: WASP gene defect
c. ) pathogenesis: WA protein responsible for maintenance of cytoskeleton and linkage of membrane receptors to cytoskeleton. This leads to progressive depletion of T and B cells.
d. ) immunologic defect: impairment of both cellular and humoral immunity (Ab levels normal or elevated with exception of IgM, which is low), abs all decrease over time
e. ) clinical features: immunodeficiency, thrombocytopenia, eczema
- Hemorrhagic diathesis (tendency)
- Recurrent respiratory infections
- Pyogenic bacteria, virus and fungi infections
f. ) methods of diagnosis: see immunologic defect
g. ) therapeutic approach: bone marrow transplant
h. ) complications and prognosis: death without transplant, increase in lymphoid malignancies
83
Discuss AIDs in terms of:
a. ) Definition and diagnostic criteria
b. ) Risk factors
c. ) Etiology
d. ) Pathogenesis
e. ) Immunologic defects
f. ) Clinical presentation
g. ) Associated infections and neoplasms
h. ) Therapeutic approaches
i. ) Complications and prognosis
a) Definition and diagnostic criteria: HIV infection that targets immune system and CNS causing immunosuppression, allowing for opportunistic infections, rare neoplasms and neurologic abnormalities
b) Risk factors: homosexual/bisexual males, heterosexual contact, IV/subcut drug users, recipients of transfused blood/blood products
c) Etiology: HIV infection
d) Pathogenesis:
1. ) mechanisms of T cell loss
- Virus replication in infected CD4 cells leads to death of cell (cytopathic effect)
- T cell activation leads to activation-induced apoptosis
- Expression of HIV peptides on CD4 cells leads to CTL-induced apoptosis
- Ultimately: decreased response to soluble antigens, decreased lymphokine secretion, decreased killing of tumor cells by NK cells, decreased specific cytotoxicity, depressed Ig production in response to new antigen, macrophages(decreased chemotaxis, reduced IL-1 secretion, poor antigen presentation)
e) Immunologic defects:
- CD4 T cell lymphopenia
- Polyclonal B cell activation with hypergammaglobulinemia; however, impaired B cell response to new ag
- Altered macrophage function with decrease MHC II expression and ag presentation
f) Clinical presentation
- Early = viremia, fever, sore throat, myalgias
- Middle/chronic = lymphadenopathy, weight loss, night sweats, fatigue, fever +- rash
- Final/crisis = fever, fatigue, weight loss, opportunistic infections, neoplasms
g) Associated infections and neoplasms
- Toxo (brain), pneumocystosis (lungs), candidiasis, cryptococcosis, coccidiomycosis, histo, mycobacteriosis, CMV (lungs), HSV, VZV
- Neoplasms: KS (HHV-8), B cell lymphoma, lymphomas of brain, invasive carcinomas of cervix and anus
h) Therapeutic approaches: inhibitors (fusion/RT/integrase/protease)
i) Complications and prognosis: opportunistic infections, neoplasms
84
What is amyloidosis?
- Group of disorders characterized by EC deposition and accumulation of abnormal, misfolded protein material generically termed amyloid. These depositions may occur locally in one organ or tissue or systemically in many organs.
85
What is amyloid? Components of each.
- Amyloid is abnormally misfolded protein with beta-pleated sheet configuration that consists of:
a. ) Fibrils (majority) with +15 distinct types. Most common are amyloid light chain type and amyloid associated types.
b. ) P component (glycoprotein)
86
What is the AL amyloid protein? Where is it found?
- It is the fibrillar component of amyloid derived from plasma cells and seen with monoclonal B cell proliferation or plasma cell disorders (in some cases of multiple myeloma) as a result of limited immunoglobulin light chain (lambda – L) proteolysis.
- Found in heart, GI tract, peripheral nerves, skin and tongue.
87
What is the AA amyloid protein? Where is it found?
- It is the fibrillar component of amyloid derived from limited proteolysis of the SAA protein (acute phase protein) normally produced by the liver in times of chronic inflammatory states.
- This is seen in RA, renal cell carcinoma, IBD, Hodgkin’s lymphoma and subcut drug abuse. Systemic distribution, tends to involve kidneys, liver, spleen, LNs and adrenals.
88
What is the ATTR protein? Where is it found?
- It is the fibrillar component of amyloid derived from aggregation of mutant transthyretin protein, which in normal form is responsible for thyroxine and retinol transport.
- Seen in polyneuropathy (in peripheral nerves) and in senile systemic amyloidosis.
89
What is alpha-beta2 microglobulin? Where is it found?
- Beta-2 microglobulin is normal serum protein and component of MHC class I. The amyloid protein tends to deposit in synovial tissues, joints and tendon sheaths leading to destructive arthropathy in ppl undergoing hemodialysis
90
What is Abeta protein?
- Amyloid beta protein is found plaques and cerebral vessel walls in Alzheimer’s dz leading to cerebral hemorrhage in some cases.
91
Describe amyloid in terms of:
a. ) distribution (organ and architecture)
b. ) gross appearance
c. ) microscopic and ultrastructural appearance
d. ) tinctorial properties
a. ) many organs involved, including kidney, spleen, liver, heart
b. ) iodine stain of gross specimens reveals brown color
c. ) When staining with Congo red and subjecting to polarized light, shows apple green. H&E shows pink material. EM shows non-branching fibrils in parallel and interlacing patterns. Specific organs: kidneys shows glomerular deposits; spleen shows follicular deposits or sinusoidal deposits; liver shows deposits in space of Disse; heart shows subendocardial or interstitial deposits.
d. ) ???
92
Describe clinical course of amyloidosis
- Depends on extent of deposits and organs involved.
- If in circulation, can lead to ischemic atrophy or organ
- In kidneys: leads to nephrotic syndrome and renal failure
- Cardiac: conduction disturbance, restrictive cardiomyopathy, CHF
- GI: macroglossia, dysphagia, speech abnormalities, malabsorption
- Presentation as localized tumor can be misdiagnosed for tumor - Systemic has poor prognosis
93
Give examples of each of the following types of genetic disorders:
a. ) Autosomal dominant
b. ) Autosomal recessive
c. ) Sex-linked recessive
d. ) Chromosomal disorders
e. ) Multifactorial disorders
a. ) AD: Marfan, ED variants, NF type 1 and 2, Huntingtons
b. ) AR: Alkaptonuria, lysosomal storage dz, glycogen storage dz, CF, PKU
c. ) Sex-Linked: fragile X
d. ) Chromosomal: Edwards (18), Patau (13), Turner (45 XO), Klinefelter (XXY)
e. ) Multifactorial: Prader-Willi (paternal 15), Angelmann (maternal 15)
94
Marfan syndrome.
a. ) What is it?
b. ) Genetic mechanism of inheritance
c. ) Pathogenesis
d. ) Clinicopathologic correlation
e. ) Diagnostic criteria
a. ) CT defect d/t mutation in fibrillin-1 gene with defects involving eyes, skeletal muscle and CV system primarily.
b. ) AD (c/s 15)
c. ) Fibrillin-1 is the glycoprotein constituent of microfibrils in elastic fibers of CT. Mutation leads to stiffening of aortic wall, increased TGF-beta1 activity, inflammation, MMP upregulation, elastolysis and cell disarray.
d. ) Ectopia lentis (displaced lens = nearsightedness), pectus carinatum/excavatum, arachnodactyly (spider fingers), joint hypermobility, arm span\>height, MV prolapse (parachute valve), aortic valve incompetence, dissection (d/t cystic media degeneration), CHF.
e. ) Diagnostic criteria: 4 features skeletal, ocular, CV, genetic findings
95
Ehlers-Danlos syndrome.
a. ) What is it?
b. ) Genetic mechanism of inheritance
c. ) Types, pathogeneses and clinicopathologic correlation
a. ) Collagen synthesis or structural defect
b. ) Types I-IV and VIIa/b = AD; types VI and VIIc = AR; type V = X-linked
c. )
- Type I, II (classic): COL5A1/2 gene defect encoding defective alpha-chains of type 5 collagen, which normally serves to stabilize the collagen structure. Clinical presentation = skin, joint hypermobility, atrophic scars, easy bruising.
- Type III: unknown gene defect. Clinical presentation = joint hypermobility, pain, dislocations.
- Type IV (vascular): defect in COL3A1 gene. Clinical presentation = thin skin, arterial/uterine rupture, bruising, small joint hyperextensibility.
- Type VI (kyphoscoliosis): lysyl-hydroxylase defect leading to decrease in amount of type 3 collagen. Clinical presentation = hypotonia, joint laxity, congenital scoliosis and ocular fragility.
- Type VIIa/b (arthrochalasia): defect in COL1A1/2 gene. Clinical presentation = severe joint hypermobility, mild skin changes, scoliosis, bruising.
- Type VIIc (dermatosprasis): defect in pro-collagen N-peptidase. Clinical presentation = severe skin fragility, cutis laxa (skin inelastic and hangs off), bruising. Histological findings with EH Syndrome = disorganized elastic fibers, also bear paw collagen under EM.
96
Neurofibromatosis.
a. ) Genetic mechanism of inheritance
b. ) Types, pathogeneses and clinicopathologic correlation
a. ) Disease characterized by skin growths and tumors
b. ) AD with 100% penetrance and variable expressivity (some with only café-au-lait macules). One of the highest known mutation rates, ~ 50% of cases are result of new mutation
- Type 1: mutation of NF1 gene (tumor suppressor protein = neurofibromin on c/s 17) leads to inability to inactivate p21 GTP-Ras (oncoprotein). Clinical presentation = axillary/inguinal freckling, café-au-late macules, Lisch nodules (benign growths on iris), neurofibromas\* (benign peripheral nerve tumors), bone lesions and optical gliomas. If severe, malignant tumors occur from plexiform neurofibromas, such as malignant peripheral nerve sheat tumors, pheochromocytoma, Wilms tumor, rhabdomyosarcoma, leukemia). Diagnostic criteria: 2 or more of symptoms above (with \>2 of the fibromas or Lisch nodules).
- Type 2: mutation in NF2 gene (c/s 22, tumor suppressor protein = merlin/schwannomin) leads to sporadic tumors. Clinical features = bilateral vestibular schwannomas^ (acoustic neuromas) affecting branch of 8th CN – pts often present with tinnitus, hearing loss, balance issues. Also can cause low-grade CNS tumors, meningiomas, ependymomas and gliomas. CALMs, cutaneous neurofibromas and juvenile cataracts can also be seen.
\* cell of origin = Schwann cell, but contain multiple cell types from peripheral nerve, not just Schwann cells. Resection is therefore difficult. Histologically: spindle cells.
^ Histologically: Antoni A: fibrotic dense tissue interspersed with Antoni B: myxoid less dense CT with Verocay body, which consists of an anuclear area palisaded by cells
97
Alkaptonuria.
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a. ) Mode of inheritance: AR
b. ) Enzyme deficiency: deficiency in homogentisic acid oxidase
c. ) Accumulating metabolite: homogentisate – in collagen (CT), tendons, cartilage
d. ) Key clinical manifestation: blue/black pigmentation in ears nose, black urine (alkalized, oxidized), degenerative arthropathy (severe osteoarthritis) early age
e. ) Histological feature(s): yellow-brown (ochronotic) pigment in CT
98
Name the glycogen storage diseases
- Type I: Von Gierke’s
- Type II: Pompe’s
- Type III: Cori dz (not responsible for on this exam)
- Type IV: Andersen dz (not responsible for on this exam)
- Type V: McArdle dz
99
Name the lysosomal storage diseases
- Tay Sachs
- Gaucher dz
- Niemann-Pick
- Mucopolysaccharidoses (Type I: Hurler, Type II: Hunter)
100
Tay-Sachs dz
a) Mode of inheritance
b) Enzyme deficiency
c) Accumulating metabolite
d) Key clinical manifestation
e) Histological feature(s)
a. ) Mode of inheritance: AR
b. ) Enzyme deficiency: hexosaminidase A (c/s 15)
c. ) Accumulating metabolite: GM2 ganglioside
d. ) Key clinical manifestation: lysosomal storage disease
- Normal at birth – retardation, blind, uncoordinated, limp, enlarged brain and head, death prior to age 4, cherry red spot on macula.
- High incidence in Ashkenazi Jew population.
e. ) Histological feature(s):
- Light microscopy: swollen/ballooned neurons with pale granular material
- EM: membranous concentric bodies
101
Gaucher dz
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a. ) Mode of inheritance: AR
b. ) Enzyme deficiency: glucocerebrosidase (c/s 1)
c. ) Accumulating metabolite: glucocerebroside
d. ) Key clinical manifestation: lysosomal storage disease (most common)
- Type I (most common): non-neuronopathic, hepatosplenomegaly, lymphadenopathy, skeletal problems including excruciating bone pain and fractures d/t osteonecrosis, anemia, thrombocytopenia
- Types II (most severe, rare) and II (rare): neuronopathic; Parkinsonian manifestations, hydrocephalus, cardiac valve issues, neurologic degeneration, hydrops fetalis
- High incidence in Ashkenazi Jew population
e. ) Histological feature(s):
- Huge macrophages (non-foamy as non lipid) in spleen, liver and bone marrow with wrinkled tissue paper appearance that is eosinophilic under H&E
102
Niemann-Pick dz
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a. ) Mode of inheritance: AR
b. ) Enzyme deficiency:
- Type A and B: sphingomyelinase (c/s 11 – Dad’s imprinted, Mom’s has missense mutation)
- Type C: no enzyme defect, deficiency in cholesterol transport (NPC1 or NPCS2 gene mutation, more commonly NPC1)
c. ) Accumulating metabolite:
- Type A and B: sphingomyelin
- Type C: GM1/2 gangliosides + cholesterol
d. ) Key clinical manifestation: lysosomal storage disease
- Type A (severe): infantile death usually within 3 years, neurologic signs (shrunken gyri/widened sulci with ballooning of neurons), cherry red spot, hepatosplenomegaly, lymphadenopathy
- Type B: survive into adulthood, hepatosplenomegaly, no CNS involvement
- Type C: hydrops fetalis, stillbirth, neonatal hepatitis, hepatosplenomegaly (improves into adulthood) progressively worsening neurological damage into adulthood presents as ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, psychomotor deterioration
- High incidence in Ashkenazi Jew population
e. ) Histological feature(s):
- EM: foamy/vacuolated cytoplasm with concentric lamellated myelin figures known as zebra bodies
103
What is the difference between Niemann-Pick type A and Tay-Sachs?
a. ) Tay-Sachs clinical presentation
- Normal at birth – retardation, blind, uncoordinated, limp, enlarged brain and head, death prior to age 4, cherry red spot on macula.
b. ) Niemann-Pick Type A clinical presentation
- Type A (severe): infantile death usually within 3 years, neurologic signs (shrunken gyri/widened sulci with ballooning of neurons), cherry red spot, hepatosplenomegaly, lymphadenopathy
104
Mucopolysaccharidoses
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a. ) Mode of inheritance: MPSI (Hurler) is AR, MPSII (Hunter) is XR
b. ) Enzyme deficiency:
- MPS I (Hurler): alpha-L-iduronidase
- MPS II (Hunter): L-iduronosulfate sulfatase
c. ) Accumulating metabolite: MPS (GAGs) such as heparan sulfate, dermatan sulfate, keratan sulfate etc.
d. ) Key clinical manifestation: lysosomal storage disease
- Hurler (very severe): gargoyle children, progressive mental retardation, cardiac abnormalities, hepatosplenomegaly, skeletal deformities, brain lesions, subendothelial arterial deposits (fast progression of CAD that usually causes death by age 6-10), corneal clouding
- Hunter (mild): no corneal clouding, presence of physical deformity, mild mental retardation
e. ) Histological feature(s)
- RES and SM accumulation of MPS shows cleared cytoplasm in liver, spleen, BM, LNs, BVs and heart
105
Pompe dz
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a) Mode of inheritance: AR
b) Enzyme deficiency: lysosomal glucosidase (aka acid maltase) – (c/s 17)
c) Accumulating metabolite: glycogen
d) Key clinical manifestation: glycogen storage dz
- Infantile onset, floppy baby, failure to thrive, macroglossia, EKG changes, progressive cardiomyopathy, cardiomegaly, neonates die from cardiorespiratory failure by age 12-24 months.
e) Histological feature(s):
- accumulation of glycogen in all organs, depending on preparation of microscopic material, may appear as white empty spaces or pink if PAS stained
106
Von Gierke
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a) Mode of inheritance: AR
b) Enzyme deficiency: G-6-Phosphatase
c) Accumulating metabolite: glycogen
d) Key clinical manifestation: glycogen storage dz – hepatorenal
- hepatomegaly, renomegaly, convulsions, hyperlipidemia (xanthomas) and hyperuricemia (gout)
e) Histological feature(s):
- accumulation of glycogen in liver, kidney and depending on preparation of microscopic material, may appear as white empty spaces or pink if PAS stained
107
McArdle syndrome
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a) Mode of inheritance: AR
b) Enzyme deficiency: muscle glycogen phosphorylase
c) Accumulating metabolite: glycogen
d) Key clinical manifestation: glycogen storage dz – myopathic
- Exercise intolerance, muscle weakness, cramps after exercise without rise in serum lactate
e) Histological feature(s):
- accumulations of glycogen in muscle and depending on preparation of microscopic material, may appear as white empty spaces or pink if PAS stained
108
Fragile X syndrome
a. ) Mode/mechanism of inheritance
b. ) Pathogenesis
c. ) Key clinical manifestation
a. ) XD
b. ) Pathogenesis:
- TNR-expansion (CGG in UTR of FMR-1 gene encoding for FMR-1 protein on X c/s): 200 TNRs = classic fragile X syndrome
- Interestingly, pre to full mutation only occurs through female meiosis
- Exhibits amplification
c. ) Moderate mental impairment, autism/ASD (autism spectrum disorder), low IG, behavior problems, long characteristic face\*: prominent jaw/protruding ears, high-arched palate, macro-orchidism
\* females have milder features
109
Huntington dz
a. ) Mode/mechanism of inheritance
b. ) Pathogenesis
c. ) Key clinical manifestation
a. ) AD
b. ) Pathogenesis:
- TNR-expansion (CAG in exon of HD gene encoding for huntingtin protein on c/s 4): = 36 TNRs = may or may not HD, \>=40 = HD, \>=60 = onset of HD prior to age 21
- Exhibits amplification
c. ) Progressive neurodegenerative disorder (caudate nuclei atrophy) manifesting in motor, cognitive and psychiatric changes with mean age of onset between 35 and 44 years of age. Survival is typically bw 15-18 years.
- Early = subtle coordination changes, minor chorea, difficulty in mental planning, often depressed/irritable mood
- Following = chorea prominent, difficulty with voluntary activity, dysphagia, dysarthria
- Late = motor disability is severe, often totally dependent, mute and incontinent
110
Patau syndrome
a. ) Karyotype
b. ) Pathogenesis
c. ) Key clinical manifestation
a. ) 47 (+13) or 46 (mosaicism w/13)
b. ) Non-dysjunction = full copy or Robertsonian translocation
c. ) Most children die within first year of life, microcephaly, mental retardation, microphthalmia (or cyclopsia), polydactyly, rocker bottom feet, cardiac defects, umbilical hernia, renal defects, cleft lip
111
Edward’s syndrome
a. ) Karyotype
b. ) Pathogenesis
c. ) Key clinical manifestation
a. ) 47 (+18)
b. ) Non-dysjunction in meiosis
c. ) Heart abnormalities, kidney malformations (horse-shoe), low set ears, prominent occiput, mental retardation, micrognathia, short neck, overlapping fingers, rocker bottom feet.
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Turner syndrome
a. ) Karyotype
b. ) Pathogenesis
c. ) Key clinical manifestation
a. ) 45 XO or mosaicism
b. ) Absence of X or Y from sperm
c. ) Most are miscarried (fetal hydrops), prenatally: cystic hygroma (failure of lymphatics to form and drain properly); birth: webbed neck, puffy hands and feet, low set rotated ears, poor suck, failure to thrive; bicuspid valve, VSD, coarctation of aorta, low posterior hairline, cubitus valgus, short 4th metacarpals, widely spaced nipples, short stature, triangle-shaped face, streaked ovaries (stroma, no follicles), failure of feminization (secondary sex characteristics), failure to menstruate. IQ normal.
\*\*If any girl presents to office with short stature and failure to thrive, think Turner
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Klinefelter syndrome
a. ) Karyotype
b. ) Pathogenesis
c. ) Key clinical manifestation
a. ) 47, XXY
b. ) Non-dysjunction on maternal or paternal end
c. ) Tall stature, slightly feminized physique, mildly impaired IQ, tendency to lose chest hair, female-type pubic hair pattern, frontal baldness absent, poor beard growth, gynecomastia, osteoporosis, hypogonadism, increase risk for breast CA d/t hyperestrogenism, most are infertile
114
Prader-Willi Syndrome
a. ) Genetic mechanism of inheritance/pathogenesis
b. ) Key clinical manifestation
a. ) Inheritance of deletion of PWS/AS genes on paternal c/s 15, inheritance of imprinted (methylated) PWS gene / non-imprinted AS gene from maternal c/s 15
b. ) Truncal obesity, hypogonadism, small hands, overeat, dull/docile, prone to outburst of extreme violence with major psychoses in adult life
115
Angelman syndrome
a. ) Genetic mechanism of inheritance/pathogenesis
b. ) Key clinical manifestation
a. ) Inheritance of deletion of PWS/AS genes on maternal c/s 15, inheritance of imprinted (methylated) AS gene / non-imprinted PWS gene from maternal c/s 15
b. ) Wide stance, spasticity, happy, severely retarded, microcephaly, large jaws, severe ataxia (jerky movements), paroxysmal laughter, no speech
