Diseases Flashcards
(168 cards)
1
Q
Human Papilloma Virus Infection
A
Cervical CA
HPV oncogene E6 (E6 protein) that binds p53 leading to p53 degradation via ubiquitinatiob
HPV 16 and 18 cause 70% of CAs
HPV 31, 33, 45, 52, and 58 cause 20%
2
Q
Retinoblastoma
A
Rare childhood malignancy of the eyes
classic presentation: leukocoria in child less than 3 y/o
Rutation of Rb1 tumor suppressor gene
Abnormal Rb protein leading to unregulated cell growth via E2F
Inherited forms (40% of cases):
- 1 gene mutation at birth due to germline mutation
- second somatic mutation (heterozygous child loses heterozygosity leading to CA (two-hit hypothesis))
- frequent multiple tumors at a younger age
Sporadic forms:
- 2 hits, two mutations in same cell is rare, often single tumor and occurs at later age
3
Q
Li-Fraumeni Syndrome
A
Autosomal dominant
Multiple malignancies at early age
(Sarcoma, breast, leukemia, Adrenal Gland)
“SBLA” cancer syndrome
Tumor Suppressor Gene (TP53) mutation
Mutation: cell cycle not arrested preventing DNA MISMATCH repair
Cells do not undergo apoptosis
Accumulated DNA damage results to malignancy
colon CA (< 50 y/o)
family hx: colon CA, extraintestinal CA (endometrial CA)
5
Q
Lynch Syndrome/
Hereditary Non-polyposis Colorectal Cancer (HNPCC)
A
germline mutations of DNA mismatch repair
90% due to MLH1 and MSH2 mutations
other mutations: MSH 6 and PMS2
leads to Colon CA via microsatellite instability
hallmark: cancer cells with microsatellite instability
two hit hypothesis: germline + second allele inactivation = colorectal CA
6
Q
Anaplastic Thyroid Cancer
A
P53 mutation
older patients with mean age of 65
often metastatic at time of diagnosis (90% in lungs)
most thyroid CAs are painless nodules but Anaplastic Thyroid CA is symptomatic
7
Q
Ataxia Telangiectasia
A
defective double stranded DNA repair (non-homologous end joining)
mutation at ATM gene in chromosome 11
skin, CNS, immune systems affected
sensitivity to ionizing radiation
healthy in 1st year of life
walks normally at normal age but slow development afterwards; with progressive motor coordination problems
@10 y/o -> wheelchair-bound
s/sx: recurrent sinus and respiratory tract infections
(+) telangiectasias
increased risk for CA
8
Q
Xeroderma Pigmentosum
A
defect in nucleotide excision repair (pyrimidine dimers caused by UV radiation) UV sensitivity infancy to early childhood easy sunburning, freckling ,dry skin inc. risk for skin CA
9
Q
Osteoporosis
A
screening with DEXA scan for all females >65 and for both males and females with risk factors
10
Q
Cerebral Palsy
A
permanent central motor control dysfunction
affects muscle tone, posture, movement
non-progressive
may be caused by asphyxia during labor
11
Q
Sickle Cell Anemia
A
missense mutation on 6th codon of Beta globin gene
6glutamte -> valine due to transversion of A->T
12
Q
Constitutional Growth Delay
A
delayed adolescent growth spurt but attains normal adult height
delayed puberty
variant of normal
13
Q
Familial Short Stature
A
variant of normal
parents are short hence genetic predisposition of child to be short
14
Q
Pathologic Short Stature
A
(+) pulmonary s/sx = Cystic Fibrosis
(+) dev’t delay, learning disability = Down syndrome
(+) webbed neck, wide chest = Turner Syndrome
(+) short limbs vs. torso = Achondroplasia
15
Q
Precocious Puberty
A
puberty for <8-9y/o
inc. androgens for males nad inc. estrogens for females
males usu. caused by congenital adrenal hyperplasia
16
Q
Cystic Fibrosis
A
initially presents with meconium ileus (obstruction)
(+) abdominal distension, bilious vomiting dilated bowel loops with hair-fluid levels
most common mutation is delta F508 leading to deletion of 3 bases and consequent loss of phenylalanine -> abnormal protein folding
Chromosome 7 -> CFTR gene (with allelic heterogeneity - over 1400 diff mutations described)
Sweat chloride testing is primary diagnostic test
may cause infertility due to absence of vas deferens
17
Q
Duchenne Muscular Dystrophy
A
X-linked Recessive disorder
frameshift mutation causing loss of functional dystrophin protein
more severe than Becker Muscular Dystrophy since it is frameshift (vs in-frame deletion)
exhibits germline mosaicism where parents test negative for the mutation and the child will be classified with a sporadic mutation but it is a germline mutation which is revealed by a “recurrent sporadic” mutation in other offspring
female carriers may also be affected through skewed lyonization (random X inactivation)
abnormal DMD gene (massive gene prone to mutation) that codes for dystrophin (binds actin intracellularly)
loss of dystrophin = myonecrosis
inc. creatinine kinase during early stages
also inc. aldolase, AST, and ALT
PROXIMAL ms. affected first then distal limb ms.
Lower ext. affected first before upper ext.
difficulties with running ,climbing stairs, jumping
some walk on the balls of feet or toes
(+) Gower’s Sign (+) waddling gait (+) scoliosis of lumabe spine from back and chest ms. weakness
muscle replaced with fat and connective tissue leading to calf enlargement and pseudo hypertrophy
(+) Dilated Cardiomyopathy = dec. Left ventricular Ejection fraction, systolic HF, and Myocardial Fibrosis; conduction abnormalities, arrhythmias
Muscle Biopsy (rarely done): degeneration of ms. fibers with fat and connective tissue replacement
Diagnostics: Western Blot: Absent dystrophin protein
Replaced by genetic testing with PCR
boys ages 3-5 y/o
18
Q
Duchenne Muscular Dystrophy
A
X-linked Recessive disorder
frameshift mutation causing loss of functional dystrophin protein
more severe than Becker Muscular Dystrophy since it is frameshift (vs in-frame deletion)
exhibits germline mosaicism where parents test negative for the mutation and the child will be classified with a sporadic mutation but it is a germline mutation which is revealed by a “recurrent sporadic” mutation in other offspring
abnormal DMD gene (massive gene prone to mutation) that codes for dystrophin
loss of dystrophin = myonecrosis
inc. creatinine kinase during early stages
also inc. aldolase, AST, and ALT
PROXIMAL ms. affected first then distal limb ms.
Lower ext. affected first before upper ext.
difficulties with running ,climbing stairs, jumping
some walk on the balls of feet or toes
(+) Gower’s Sign (+) waddling gait (+) scoliosis of lumabe spine from back and chest ms. weakness
muscle replaced with fat and connective tissue leading to calf enlargement and pseudo hypertrophy
(+) Cardiomyopathy = dec. Left ventricular Ejection fraction, systolic HF, and Myocardial Fibrosis; conduction abnormalities, arrhythmias
Muscle Biopsy (rarely done): degeneration of ms. fibers with fat and connective tissue replacement
Diagnostics: Western Blot: Absent dystrophin protein
Replaced by genetic testing with PCR
boys ages 3-5 y/o
19
Q
Kallman Syndrome
A
delayed puberty GnRH deficiency (+) anosmia
20
Q
Becker Muscular Dystrophy
A
in-frame mutation leading to mutated dystrophin gene and protein (still with some not full absence of the protein)
milder than Duchenne Muscular Dystrophy since it is in-frame deletion (vs frameshift)
x-linked recessive disorder
90% from carrier mothers
less severe than Duchenne, later age of onset, remain ambulatory, survive into 30s
more males pass genes to female children
Diagnostics: Western Blot: Altered dystrophin protein vs absent in Duchenne
21
Q
Tay Sachs Disease
A
lysosomal storage disease
frameshift mutation
abnormal Hexosaminidase A
22
Q
Trinucleotide Repeat Disorders
A
Fragile X syndrome - “CGG”
Friedrich Ataxia - “GAA”
Huntington’s Disease - “CAG”
Myotonic Dystrophy - “CTG”
23
Q
Genetic Disorders that are germline mutations
and exhibit germline mosaicism
A
Osteogenesis Imperfecta
Duchenne Muscular Dystrophy
- both parents may test (-) for the mutation using conventional genetic testing (buccal swabs) since the cause is not a somatic mutation rather a germline mutation (gametes)
- spontaneous mutations may still occur
24
Q
Beta Thalassemia
A
mutation in the beta globin gene
(allelic heterogeneity) wide spectrum of disease depending on mutation
Beta0 = no function; B1 = some function
Splicing error
25
Q
Systemic Lupus Erythematosus
A
Anti-Smith antibodies (Anti-Sm) = antibody against snRNPs
26
Fanconi Anemia
Inherited Aplastic Anemia (anemia, thrombocytopenia, leukopenia)
(+) short stature
(+) abnormal thumbs
more than 13 genetic abnormalities involving DNA repair enzymes and impaired homologous recombination
DNA is hypersensitive to damage
27
Mixed Connective Tissue Disease
Anti-RNP = antibody against U1RNA
| strongly associated
28
DiGeorge Syndrome/Thymic Aplasia
CATCH 22
utilizes FISH to visualize microdeletion in 22q11 (no fluorescence)
immune deficiency
caused by absence of T-cells
presents in childhood with recurrent infections, absent thymus, loss of parathyroid glands (hypocalcemia, tetany), and congenital heart defects
HYPOCALCEMIA
29
Fetal Maternal Hemorrhage
fetal RBCs reach maternal blood due to placental failure/trauma leading to dec. fetal movement, abnormal fetal HR, stillbirth
utilize Flow Cytometry with monoclonal Ab to HbF
30
Paroxysmal Nocturnal Hemoglobinuria
utilize flow cytometry with fluorescent-labeled monoclonal antibodies that bind glycosylphosphatidyl inositol (GP1) anchored proteins, Decay Accelerating Factor (DAF/CD55), and MAC inhibitory protein (CD59) which are dec or absent in PNH
31
Inclusion Cell (I-Cell) Disease
failure of processing in the golgi apparatus leading to the loss of mannose-6-phosphate on lysosomal proteins
deficiency: UDP-N-acetylglucosaminyl-1-phosphotransferase (phosphate not added to mannose due to missing enzyme)
result: enzyme secreted outside of the cell, hydrolases missing from lysosomes and can be detected un blood/urine
lysosomes contain inclusions of undigested glycosaminoglycans and glycolipids
rare autosomal recessive metabolic disorder
lysosomal storage disease (mucolipidosis)
Onset in the first year of life presenting with growth failure, coarse facial features (enlarged skull, wide nasal bridge, flattened midface), and hypotonia/motor delay.
appear normal at birth. but with skeletal bony abnormalities seen prenatally. over the first year of life, developmental delay occurs. often have recurrent sinus and respiratory infections from soft tissue enlargement in the airways. other features: corneal clouding and hepatosplenomegaly.
pattern of skeletal abnormalities: Dystosis multiplex on xray
32
Parkinson's Disease
reduced ubiquitin-proteasome activity leading to toxic accumulations of proteins in neurons
33
Gaucher's Disease
lysosomal storage disease caused by the absence of the enzyme glucocerebrosidase within lysosomes causing accumulation of glucocerebroside
Classic bone marrow biopsy findings: nucleus pushed to the side and cytoplasm is "crumpled tissue paper"-like
clinical evidence: infiltration of gaucher cells in liver, spleen, and bone marrow.
occur at any age bt mostly before 20 y/o.
s/sx: splenmegaly, bone marrow suppression (anemia, thrombocytopenia, leukopenia), bone fractures are common
diagnosis: demonstrating reduced glucocerebrosidase activity in leukocytes.
Tx: recombinant glucocerebrosidase enzyme replacement
34
Kartagener's Syndrome
manifestation of Primary Ciliary Dyskinesia
lack of dynein arms in microtubules in cilia
TRIAD:
- Chronic sinusitis
- Bronchiectasis (dilation of large airways, chronic cough, recurrent infections)
- Situs Inversus (cilia is important for proper positioning of organs in-utero)
may cause infertility due to immotile sperm
35
Primary Ciliary Dyskinesia/
| Immotile Cilia Syndrome
autosomal recessive
Dynein (microtubule motor protein) gene mutations causing immotile cilia
recurrent Rhinosinusitis (excessive mucus production), Otitis Media, Bronchiectasis, and infertility (immotile sperm in males or dysfunctional fallopian tube cilia increasing risk of Ectopic pregnancy)
most present at age 5 y/o
May lead to Kartgener's Syndrome
36
Squamous Cell CA
classic histology: sheets of polygonal cells with "crisp" eosinophilic cytoplasm and intracellular bridges (represent desmosomes); nuclei vary in shape (pleomorphic)
Keratin producing SCCA: (+) keratin pearls
Immunohistochemistry: (+) high molecular weight cytokeratin
Non-keratin producing SCCA:
Immunohistochemistry: (+) p40 (+) p63 (+) desmoglein
37
Melanoma
```
malignant skin cancer
rare in children, 90% of cases >10 y/o
epithelioid and spindle cells
(+) vimentin (-) desmin
classic tumor marker: S100
```
38
Peroxisomal Disorder
inborn error of metabolism caused by insufficient function of peroxisomes.
hallmark: elevated very long chain fatty acids,phytanic acid and pristanic acid in plasma
common features:
hypotonia, hepatomegaly, facial abnormalities
39
Melanoma
epithelioid and spindle cells
40
Adenocarcinoma
usually with well-differentiated glandular structures
41
X-linked Agammaglobulinemia/
| Bruton's Agammaglobulenemia
defects in Bruton Tyrosine Kinase gene
deficient Ab/Immunoglobulin production by B-cells
recurrent respiratory bacterial infections and GI infections
present at 6 months of age when maternal antibody levels start to go down
Recurrent respiratory and GI infections are the most common
42
Chediak-Higashi Syndrome
Autosomal Recessive
mutations in lysosomal trafficking regulator gene
microtubular dysfunction and abnormal intracellular trafficking of lysosomes
large lysosome vesicles in neutrophils
(+) albinism from abnormal melanocytes
(+) recurrent Staph and Strep infections from neutrophil abnormalities
43
Severe Combined Immunodeficiency (SCID)
abnormal adenosine deaminase gene (enzyme used in purine break down specifically for adenine; adenine converted into inosine)
T-cells and B-cells are absent or diminished
absence of adaptive immunity
recurrent infections, chronic diarrhea, and poor growth
44
Osteogenesis Imperfecta
defective Collage Type 1 production
frequent fractures, abnormal dentition, hearing loss, BLUE SCLERAE
exhibits germline mosaicism where parents test negative for the mutation and the child will be classified with a sporadic mutation but it is a germline mutation which is revealed by a "recurrent sporadic" mutation in other offspring
also exhibit pleiotropy where one gene results to multiple phenotypic effects in various organs
45
CD3
T cell marker
46
CD20
B cell marker
47
Ehlers-Danlos Syndrome
family of disorders all caused by defective collagen synthesis
predominantly affects JOINTS and SKIN
some cases have defect of Type III Collagen
Subtypes:
Classic Type
- autosomal dominant (often de novo)
- COL5A1 or COL5A2 genes (Type V collagen which interacts with other collagens)
- joint hypermobility, hyperextensible skin, easy bruising, thin, wide scars, MITRAL VALVE PROLAPSE
Vascular Type
- autosomal dominant
- COL3A1 gene (Type III collagen)
- skin and blood vessels
- thin skin, easy bruing, RUPTURE OF LARGE ARTERIES (CNA BERRY ANEURYSMS), hollow organ rupture (intestinal perforation/uterine rupture)
- Life-threatening form with 80% having vascular event at 40 y/o and death average at 48 y/o
48
Scurvy
Vitamin C deficiency
dec. hydroxylation of proline and lysine residues in collagen (Vit. C is cofactor)
defective pro-alpha chains leading to no formation of triple helix, collagen degraded
presentation: fragile blood vessels, easy bleeding/bruising, loss of teeth, impaired wound healing
(+) perifollicular hyperkeratotic papules (red and blue spots surrounding hairs of lower leg)
49
Alport Syndrome/Hereditary Nephritis
genetic Type IV collagen defect (basement membrane, lens, cochlea, basal lamina)
mutations in alpha-3, alpha-4, or alpha-5 chains
X-linked
TRIAD:
- hematuria
- hearing loss
- ocular problems
50
Scleroderma
autoimmune disorder
sclerosis (stiff, hardened tissue) of skin and other organs d/t fibroblast activation leading to excess collagen deposition
Diffuse form: (+) anti-scl70 antibodies/anti-DNA topoisomerase I antibodies
51
Aging/Wrinkles
dec. elastin and collagen synthesis
| existing collagen and elastin thicken and clump together
52
α1 Anti-trypsin Deficiency
```
inherited autosomal CODOMINANT
mutations in AAT gene
M = normal allele
S = moderately low levels of a1-AT
Z = severely low levels
MM=normal
ZZ=severe deficiency
other combinations = variable risk
```
decreased or dysfunctional α1-antitrypsin (inhibitor of enzyme elastase)
excessive elastin breakdown in neutrophils and alveolar macrophages causing destruction of alveoli leading to Emphysema, early COPD, and liver disease
53
Osteogenesis Imperfecta/ Brittle Bone Disease
family of genetic bone disorders with diff severities (some lethal in-utero)
(+) osteoporosis and (+) frequent fractures
defective or deficient collagen production
```
Clinical features:
multiple recurrent fractures even with minimal trauma
blue sclera
hearing loss (abnormal ossicles)
bone deformity
short stature
```
Dentinogenesis Imperfecta - rare in type 1, common in type 3 and 4, with discolored teeth, translucent shiny teeth, weak teeth
Subtypes:
Type 1 Form:
Autosomal dominant, most common, decreased production of Type I collagen
COL1A1 or COL1A2 genes which encode alpha chains for type I collagen -> abnormal or absent alpha chains
Type 2 form: lethal in-utero
Type 3 and 4: more severe than Type 1
dec. severity: 2341
54
Menkes Disease
"Me-KINKY" hair
X-linked
mutation of ATP7A gene involved in intestinal uptake of Cu
Copper deficiency (vs Wilson's Disease of Copper excess - ATP7B)
dec. lysl oxidase activity
```
clinical features:
Sparse, brittle, kinky hair
low body temp
CNS features (hypotonia, seizures)
poor growth and dev't delay
osteoporosis/fractures
fatal in childhood
```
55
Williams Syndrome/ Willaims-Beuren Syndrome
```
partial deletion of long arm of chromosome 7 including gene for elastin "elastin haploinsufficiency"
Elfin appearance (small nose, small chin, wide mouth, long philtrum), intellectual disability
```
```
Supravalvular Aortic Stenosis
- constriction of ascending aorta above aortic valve
- histology: loss of elastin
Pulmonary Artery Stenosis
Renal Artery Stenosis -> HTN
```
Hypercalcemia (inc. Vit. D and inc. Vit. D sensitivity)
- usually mild and asymptomatic -> CONSTIPATION
- rarely: irritability and kidney stones
56
Williams Syndrome/ Willaims-Beuren Syndrome
```
partial deletion of long arm of chromosome 7 including gene for elastin "elastin haploinsufficiency"
Elfin appearance (small nose, small chin, wide mouth, long philtrum), intellectual disability
```
```
Supravalvular Aortic Stenosis
- constriction of ascending aorta above aortic valve
- histology: loss of elastin
Pulmonary Artery Stenosis
Renal Artery Stenosis -> HTN
```
Hypercalcemia (inc. Vit. D and inc. Vit. D sensitivity)
- usually mild and asymptomatic -> CONSTIPATION
57
Marfanoid Habitus
tall and long wingspan with long fingers
Diseases:
Homocystinuria
MEN 2B
rare forms of Ehlers Danlos
58
Neurofibromatosis Type 1
neurocutaneous disorder involving structures derived from the ectoderm including the skin, nervous system and eyes
autosomal dominant
100% penetrance but with variable disease severity (tumors ,skin findings) VARIABLE EXPRESSIVITY
classic features:
cafe-au-lait spots
freckles
neurofibromas (benign tumors in cutaneous nerves leading to soft fleshy pedunculated growth on skin)
59
BRCA1 and BRCA2 Breast Cancer
Incomplete penetrance
germline gene mutations
AUTOSOMAL DOMINANT
not all women with these mutations develop CA
Implication: variable cancer risk reduction from prophylactic surgery
also in Ovaraian CA
60
Dieases that exhibit pleiotropy
```
Phenylketonuria (skin, body odor, mental disability)
Marfan Syndrome (limbs, blood vessels, eyes)
Cystic Fibrosis (lungs, pancreas)
Osteogenesis imperfecta (bones, eyes, hearing)
```
61
Turner Syndrome
```
Usually 45 XO (45%) = mostly due to sperm lacking an X
Somatic Mosaicism (45 XO/46XX) = milder (mitotic nondisjunction post-zygote)
```
```
SHORT STATURE = from lack of one SHOX gene needed for long bone growth seen in X chromosome; recombinant growth hormone treatment given during childhood
SHIELD chest, widely spaced nipples
Lymphatic obstruction during fetal dev't
webbed neck, swollen hands and feet esp. at birth
CYSTIC HYGROMA (lymph collection & cysts in head and neck) - congenital lymphatic duct defect (seen in utero through UTZ)
```
HALLMARK: female with PRIMARY HYPOGONADISM
(+) STREAK OVARIES (no to very few follicles)
dec estrogen, inc. FSH/LH, delayed puberty (-) breast dev't, (+) primary amenorrhea, infertility (Tx: donor oocytes)
Cardiovascular: (+) BICUSPID AORTIC VALVE (30%), (+) COARCTATION OF AORTA (5-10%) (+) HTN in childhood d/t coarctation or renal disease, often primary
Renal: 1/3 of cases with abnormal collecting ducts
(+) HORSESHOE KIDNEY (fused lower poles of B kidneys)
OSTEOPOROSIS (dec. estrogens)
Endocrine: (+) T2DM (2x risk than normal); (+) Thyroid disease - HYPOTHYROIDISM from HASHIMOTO'S THYROIDITIS
PREGNANT WOMEN WITH TURNERS:
- INCREASED RISK FOR AORTIC DISSECTION d/t cardiac anomalies
62
Turner Syndrome
```
Usually 45 XO (45%) = mostly due to sperm lacking an X
Somatic Mosaicism (45 XO/46XX) = milder (mitotic nondisjunction post-zygote)
```
```
SHORT STATURE = from lack of one SHOX gene needed for long bone growth seen in X chromosome; recombinant growth hormone treatment given during childhood
SHIELD chest, widely spaced nipples
Lymphatic obstruction during fetal dev't
webbed neck, swollen hands and feet esp. at birth
CYSTIC HYGROMA (lymph collection & cysts in head and neck) - congenital lymphatic duct defect (seen in utero through UTZ)
```
HALLMARK: female with PRIMARY HYPOGONADISM
(+) STREAK OVARIES (no to very few follicles)
dec estrogen, inc. FSH/LH, delayed puberty (-) breast dev't, (+) primary amenorrhea, infertility (Tx: donor oocytes)
Cardiovascular: (+) BICUSPID AORTIC VALVE (30%), (+) COARCTATION OF AORTA (5-10%) (+) HTN in childhood d/t coarctation or renal disease, often primary
Renal: 1/3 of cases with abnormal collecting ducts
(+) HORSESHOE KIDNEY (fused lower poles of B kidneys)
OSTEOPOROSIS (dec. estrogens)
Endocrine: (+) T2DM (2x risk than normal); (+) Thyroid disease - HYPOTHYROIDISM from HASHIMOTO'S THYROIDITIS
63
McCune-Albright Syndrome
rare disorder affecting endocrine glands
sporadic mutation of GNAS gene in development (not inherited)
GNAS gene codes for alpha subunit of G3 protein that activates adenylyl cyclase resulting in continued cAMP signaling
postzygotic mutation exhibiting mosaicism (only some tissues or organs affected, clinical phenotype depends on which tissues affected)
germline occurrences of mutation are lethal with entire body affected
(+) precocious puberty (menstruation by 2 y/o)
(+) fractures and bone deformities (fibrous growth of bones)
(+) skin pigmentation (Cafe-au-lait spots, irregular borders "coast of Maine")
64
Retinitis Pigmentosa
causes visual impairment
autosomal dominant, recessive, and x-linked forms
mutations at 43 different loci can lead to disease
65
Down Syndrome
Trisomy 21
most common live born chromosomal abnormality
most common cause of intellectual disability
most commonly due to a spontaneous maternal nondisjunction during meiosis I
3% of cases are due to Robertsonian translocation of the long arms of chromosomes 14 and 21. couple with multiple spontaneous abortions with a child with trisomy is a sign that one of the parents is a carrier
rarely: mitotic error = somatic mosaicism
Key features:
dysmorphic features: flat face, flat nasal bridge, flat posterior skull, low set ears, short neck, prominent epicanthal folds, upslanted palpebral fissures, simian crease, sandal gap
BRUSHFIELD SPOTS
Intellectual disability (mild: 50-70; severe: 20-35)
Heart disease: PRIMUM ASD, VSD (ENDOCARDIAL CUSHION DEFECTS), Mitral Valve Defect
GI: Duodenal Atresia and Stenosis, inc. risk for Hirschsprung Disease
Alzheimer Disease: early onset, Amyloid Precursor Protein (APP) in chromosome 21
malignancy: inc. risk for ALL and AML (M7 subtype, megakaryoblastic leukemia)
Screening test: first trimester UTZ (nasal bones, nuchal translucency), Maternal Serum Testing (1st trimester: dec. pregnancy associated plasma protein A and inc. B-HCG; 2nd trimester: "Quad Screen"= dec. AFP and estriol and inc. B-HCG and Inhibin A)
Definitive Test: Karyotyping using Chorionic Villus sampling or Amniocentesis
66
Down Syndrome
Trisomy 21
most common live born chromosomal abnormality
most common cause of intellectual disability
most commonly due to a spontaneous maternal nondisjunction during meiosis I
3% of cases are due to Robertsonian translocation of the long arms of chromosomes 14 and 21. couple with multiple spontaneous abortions with a child with trisomy is a sign that one of the parents is a carrier
rarely: mitotic error = somatic mosaicism
Key features:
dysmorphic features: flat face, flat nasal bridge, flat posterior skull, low set ears, short neck, prominent epicanthal folds, upslanted palpebral fissures, simian crease, sandal gap
BRUSHFIELD SPOTS
Intellectual disability (mild: 50-70; severe: 20-35)
Heart disease: PRIMUM ASD, VSD (ENDOCARDIAL CUSHION DEFECTS)
GI: Duodenal Atresia and Stenosis, inc. risk for Hirschsprung Disease
Alzheimer Disease: early onset, Amyloid Precursor Protein (APP) in chromosome 21
malignancy: inc. risk for ALL and AML (M7 subtype, megakaryoblastic leukemia)
Screening test: first trimester UTZ (nasal bones, nuchal translucency), Maternal Serum Testing (1st trimester: dec. pregnancy associated plasma protein A and inc. B-HCG; 2nd trimester: "Quad Screen"= dec. AFP and estriol and inc. B-HCG and Inhibin A)
Definitive Test: Karyotyping using Chorionic Villus sampling or Amniocentesis
67
Achondroplasia
Autosomal dominant disorder of bone growth exhibiting incomplete dominance
heterozygote = Dwarfism
homozygote dominant = fatal
68
Fragile X syndrome
X-linked Dominant
abnormal FMR1 gene
"CGG" trinucleotide repeat disorder
>200 repeats = DNA METHYLATION (silencing) of FMR1 gene
2nd most common cause of intellectual disability second to Down's Syndrome
more severe in males
features of autism, long narrow face, large ears and jaw
(+) Anxiety (+) ADHD
classic feature: macroorchidism (onset at 8-12 y/o/puberty)
69
Fragile X syndrome
X-linked Dominant
abnormal FMR1 gene
"CGG" trinucleotide repeat disorder
>200 repeats = DNA methylation (silencing) of FMR1 gene
2nd most common cause of intellectual disability second to Down's Syndrome
more severe in males
features of autism, long narrow face, large ears and jaw
(+) Anxiety (+) ADHD
classic feature: macroorchidism
70
Mitochodrial Myopathies
rare disorders due to abnormal mitochondria
muscle weakness, confusion, lactic acidosis
wide range of clinical disease expression
Classic Hallmark = RED RAGGED FIBERS seen on muscle biopsy due to compensatory increase in mitochondria appearing bright red against blue background
71
Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Symptoms (MELAS)
type of mitochondrial myopathy
disorder of mitochondrial DNA
neurologic features, weakness, stroke episodes, hemianopsia, hemiparesis, hearing loss, seizures
heteroplasmy may occur (may types of mtDNA in different organs in different individuals) leading to varied phenotypes in different affected individuals
72
```
Imprinting Syndromes
(Prader-Willi and Angelman Syndromes)
```
involves chromosome15 q11-q13
PWS gene normally expressed on paternal chromosome 15 and not in maternal
UBE3A normally expressed on paternal chromosome 15 and not in maternal
```
Prader-Willi Syndrome
loss of function of PWS (paternal C15)
75% = paternal deletion
25 % = maternal uniparental disomy
most common syndromic cause of obesity
hypotonia, poor feeding, failure to thrive, hyperphagia, obesity, MILD intellectual disability, hypogonadism, delayed puberty
```
```
Angelman Syndrome
loss of UBE3A (maternal C15)
majority of cases by maternal deletion
3-5% = paternal uniparental disomy
frequent laughter and smiling "HAPPY PUPPET", arm flapping, seizures (80%), ataxia, SEVERE Intellectual disability
```
73
Acute Lymphoblastic Leukemia
10-20 x higher in Downs
Clinical features: non specific, fatigue, malaise, fever
(+) hepatosplenomegaly
infiltration of bone marrow by malignant cells -> anemia and thrombocytopenia (bruising)
bone marrow biopsy: hypercellular with lymphoblast proliferation
74
Multiple Myeloma
normal marrow cells replaced with plasma cells
plasma cell malignancy
"punched out bone lesions" LYTIC lesions -> hypercalcemia
(+) inc. immunoglobulins -> proteinuria (Bence Jones Proteins) -> nephropathy/amyloidosis
(+) inc. alkaline phosphatase (marker of inc. bone formation)
75
Chronic Myelogenous Leukemia
BCR-ABL fusion gene
typically affects adults
inc. peripheral leukocyte counts with inc neutrophils, metamyelocytes, myelocytes, basophils, eosinophils
76
Aplastic Anemia
hypocellular marrow with fatty infiltration
77
Hodgkin Lymphoma
(+) Reed Sternberg cells
78
Neural Tube Defects
inc. AFP
79
Edward Syndrome
Trisomy 18
associated with advanced maternal age
second most common trisomy in live births
3:1 female to male ratio
severe intellectual disability
physical deformities:
- CLENCHED OVERLAPPING FINGERS
- abnormal head shape with prominent occiput, small jaw and mouth
- low set ears
- rockerbottom feet
- poor intra-uterine growth -> low birth weight
congenital heart disease (50%) : VSD, PDA
GI disorders (75%): Meckel's diverticulum, Malrotation, Omphalocoele
many die in-utero, 50% die first 2 weeks, and only 5-10% survive first year of life
80
Patau Syndrome
Trisomy 13
rare; associated with advanced maternal age
severe intellectual disability and severe structural malformations
Eye abnormalities: Anophthalmia/microphthalmia
Cleft lip and palate
Post-axial polydactyly: extra digit away from midline (ulnar)
Holoprosencephaly: (prosencephalon did not separate -
> L and R did not separate-> "Alobar" brain)
Congenital Heart Disease (80%): VSD, PDA, ASD
most die in utero
median survival of 7 days
91% dies in 1st year of life
81
Prenatal Screening for Trisomy Disorders
Definitive: Karyotyping with
Fetal UTZ:
21 - NUCHAL TRANSLUCENCY; poor nasal bone growth
18 - limb and heart abnormalities
Maternal serum Testing
First Trimester
21: PAPP-A dec., B-HCG inc.
18: both dec.
13: both dec.
Second Trimester
21: AFP and Estriol dec.; B-HCG and Inhibin A inc.
18: all dec.
82
Myotonic Dystrophy
abnormality of the DMPK gene on chromosome 19 which codes for the enzyme myotonic dystrophy protein kinase
"CTG" repeat
onset at young adulthood 20-30 y/o
classic feature: myotonia (prolonged ms. contractions; unable to relax ms.; lock jaw, clenched fist)
characteristic facial appearance: muscle wasting with long narrow face and sunken cheeks
(+) muscle weakness (+) Intellectual Disability (severity worse with younger age of onset) (+) primary hypogonadism (+) dec testosterone (+) oligospermia, infertility, testicular atrophy (+) cataracts (+) arrhythmia (1st deg AV block, BBB, Afib, Aflutter) (+) frontal balding (+) weak respiratory ms. -> dec vital capacity, alveolar vent., respi failure, (+) glucose intolerance
Types:
Type 1: most common, abnormal DMPK gene with CTG expansion; codes for myotonic dystrophy protein kinase; abnormal gene transcribed but not translated
Type 2: rare, abnormal CNBP gene, less severe, "CCTG" repeat
83
Huntington Disease
Autosomal Dominant
GAIN OF FUNCTION mutation
Trinucleotide repeat "CAG" resulting to an HTT gene mutation that normally codes for huntingtin protein
successive generations = more severe = more repeats
degeneration of the basal ganglia (striatum)
possible mechanism: histone deacetylation = gene silencing = neuronal death in striatum
symptoms related to memory, behavior, movement
(+) chorea (jerking, writhing, involuntary movements of the arms), dementia
agitation, restlessness, disrupted social relationships
onset at 30-40s
death after 10-20 years
84
Friedrich Ataxia
autosomal recessive disorder
mutation of Frataxin gene in chromosome 9 for normal mitochonrial function
trinucleotide repeat disorder "GAA" leads to dec. Frataxin levels leading to mitochondrial dysfunction
begins in adolescence with progressive s/sx
usu. presents between 5-15 y/o
loss of position and vibratory send -> ataxia and falls
neuromuscular weakness and and abnormal reflexes
(+) cerebellar and spinal cord degeneration
associated with HYPERTROPHIC CARDIOMYOPATHY (enlarged cardiac silhouette on CXR)
Physical deformities: kyphoscoliosis and foot abnormalities (pes cavus - high arch of the foot)
85
Cri-du-Chat Syndrome
deletion of the short arm (p) of chromosome 5
severe intellectual disability with cognitive, speech and motor delays
infants cry like a cat (MEWING, HIGH-PITCHED CRY)
microcephaly, wide set eyes (hypertelorism), low set ears, small jaw, rounded face
(+) congenital heart defects (VSD, PDA, TOF)
86
Klinefelter Syndrome
usu. 47 XXY (meiotic nondisjunction either parent)
48XXXY (more severe)
46XY/47XXY somatic mosaicism (mitotic nondisjunction post-zygote)
"FEMINIZED MALE"
male with primary hypogonadism (dec testosterone, inc. LH/FSH, inc. estrogen : testosterone ratio determines severity)
small firm testes with atrophy of seminiferous tubules
delayed puberty, dec facial or body hair, female pubic hair pattern, gynecomastia (risk for Breast CA), infertility, dec. sperm count, cryptorchidism, hypospadia, micropenis
EUNUCHOID body shape (in between of male and female shape), (-) broad shoulders
long arms and legs (extra copy of SHOX gene in X chromosome for long bone growth)
Learning disability
Quiet, unassertive personality
(+) Barr body
87
Charcot-Marie-Tooth Disease
abnormal myelin synthesis
neurologic disorder sharing many features with Friedrich Ataxia
inherited, onset at adolescence with neurologic symptoms
(+) foot abnormalities like FA
NO HYPERTROPHIC CARDIOMYOPATHY compared to FA
88
Homocystinuria
```
skeletal abnormalities
lens dislocation
intellectual disability
vascular thromboses
cystathionine beta synthase enzyme defect
```
89
Familial Dysautonomia
Ashkenazi Jewish
mutation of the IKAP gene leading to loss of function of the IKAP protein
reduced sensitivity to pain, impaired tear formation, orthostatic hypotension
90
Barrett's Esophagus
squamous epithelium -> columnar epithelium in the esophagus due to gastric acid
91
Myositis Ossificans
```
heterotopic ossification
muscle metaplasia to bone
mesenchymal cells -> osteoblastic tissue
forms lamellar bone in muscles
follows trauma (hip arthroplasty)
muscles become stiff
```
92
Vitamin A Deficiency
Vit. A needed for maintenance of epithelial cells
Upper respi tract: keratinizing squamous cell metaplasia -> pulmo infections
XEROPHTHALMIA
dry eyes due to keratinized epithelial cell metaplasia (dec mucus secretion)
93
Avascular Necrosis (Osteonecrosis) of the Femoral Head
usually seen in Lupus patients esp. those taking steroids
coagulative necrosis
vascular damage to the bone blood supply leads to bone marrow necrosis and ultimately mechanical failure of the hip joint
prolonged progressive disorder necessitating hip replacement surgery
some cases caused by ischemic damage (femoral neck fracture)
many cases assoc. with lupus patients on glucocorticoid therapy
94
Non-Alcoholic Fatty Liver Disease
fat accumulation in the liver not related to alcohol
common in patients with obesity, T2DM, and Hyperlipidemia
related to insulin resistance
most are asymptomatic but some have RUQ pain, fatigue and malaise
NAFLD may lead to cirrhosis
Lifestyle changes (weight loss) = clinical improvement
95
Chronic Granulomatous Disease (CGD)
lack of normal functioning NADPH oxidase
phagocytes unable to generate H2O2 for oxidative burst
recurrent infections with catalase (+) bacteria (S. aureas, Pseudomonas, Nocardia, Serratia, Aspergillus)
(also: Candida, and E.coli) that can degrade H2O2
Can still kill catalase (-) since the organisms generate H2O2 that the phagocytes can utilize for oxidative bursts
Diagnosis:
- Dihydrorhodamine (DHR) Neutrophil Function Test -> DHR converted to green fluorescence via respiratory burst
- Nitroblue tetrazolium Test - (-) test -> neutrophils can't turn yellow dye to blue, they remain colorless
96
Chronic Granulomatous Disease (CGD)
lack of normal functioning NADPH oxidase
phagocytes unable to generate H2O2 for oxidative burst
recurrent infections with catalase (+) bacteria (S. aureas, Pseudomonas, Nocardia, Serratia, Aspergillus)
(also: Candida, and E.coli) that can degrade H2O2
Can still kill catalase (-) since the organisms generate H2O2 that the phagocytes can utilize for oxidative bursts
Diagnosis:
- Dihydrorhodamine (DHR) Neutrophil Function Test -> DHR converted to green fluorescence via respiratory burst
- Nitroblue tetrazolium Test
97
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
most common inherited red cell enzyme disorder
deficiency of glucose 6 phosphate dehydrogenase leads to limited supply of glutathione leading to free radical damage to RBCs leading to acute hemolytic anemia
Glucose ------(Hexokinase)-------> Glucose-6-P ------(G6PD)-------->6 phosphogluconate
G6PD generates NADPH from NADP +
NADPH is used by Glutathione reductase that reduced oxidized glutathione (GSSH) to glutathione (GSH) that can reduce free radicals
RBCs generate H2O2 upon exposure to triggers
need NADPH to degrade H2O2
X-linked disorder (males)
most common human enzyme disorder
high prevalence in Africa, Asia, Medeterranean
may protect against Malaria
Recurrent hemolysis (may present as dark urine) after exposure to triggers
classic trigger: fava beans (contain vicine that is converted to divicine which is a free radical that depletes glutathione further), infections, and drugs (antibiotics - sulfa drugs, dapsone, nitrofurantoin, INH; anti-malarials - quinidine, primaquine; Aspirin; Acetaminophen)
diagnosis: dec. levels of NADPH in red cells; Fluorescent Spot Test (detects NADPH generation; positive is blood spot fails to fluoresce)
Blood Smear:
(+) Heinz Bodies - oxidized Hbg precipitated in RBCs
(+) Bite cells - phagocytic removal by splenic macrophages
TX: avoid triggers
98
Reperfusion Injury
Return of blood flow to a previously ischemic tissue may cause paradoxical damage due to the sudden increase in oxygen -> inc. free radicals
antioxidants were depleted during the injury
damaged mitochondria cannot completely reduce oxygen
99
Carbon Tetrachloride (CCl4)
industrial solvent used in dry cleaning
liver is highly sensitive to damage
CCl4 converted to CCl3 free radical by CYP450 system
resulting to lipid peroxidation, inhibition of lipoprotein synthesis/secretion, and accumulation of lipids
result: FATTY LIVER
100
Lipofuschin
yellow brown insoluble intracellular pigments seen in aging cells
made from oxidized lipids (lipid peroxidation) that accumulates in lysosomes
101
Myeloperoxidase (MPO) deficiency
rare immunodeficiency syndrome
>95% are asymptomatic due to normally functioning respiratory burst
symptomatic patients may have a coexisting disorder contributing to immunodeficiency such as DM
Recurrent Candidal infections are most common
Diagnosis: staining neutrophils for MPO enzyme
decreased myeloperoxidase that converts hydrogen peroxide to hypochlorous acid (3rd step in the respiratory burst)
hypochlorous acid is a type of hypohalous acid or hydroxyl halide radicals (produced in the 3rd step of respiratory burst) can amplify the killing capacity of cells
102
Autoimmune Lymphoproliferative Syndrome (ALPS)
defective FAS - FAS ligand binding (extrinsic pathway for apoptosis)
poor negative T-cell selection in the thymus
auto-reactive T-cells escape apoptosis
overproduction of lymphocytes -> lymphadenopathy, hepatomegaly, splenomegaly
hepatomegaly and lymphadenopathies apparent by 1 y/o
Autoimmune disorders (by 4 y/o): Immune mediated hemolytic anemia or thrombocytopenia
(dec hematocrit, inc. bilirubin, positive coombs test) -> antibody mediated hemolytic anemia
high risk for LYMPHOMA
103
Follicular Lymphoma
subtype of Non-Hodgkin Lymphoma
B-cell malignancy
overexpression of BCL-2 (prevents apoptosis) = uncontrolled cell growth
104
Familial Adenomatous Polyposis
APC gene mutation (normally responsible for intercellular attachment)
adenomatous polyps in normal mucosa
most sporadic colon CA and in all familial polyposis syndromes except HNPCC
105
Multiple Endocrine Neoplasia Type I
| MEN 1
MEN1 mutation
| "3P's": Parathyroid, Pituitary, and Pancreatic Adenomas
106
Multiple Endocrine Neoplasia Type II
| MEN 2
RET mutation
| "TPP": Medullary Thyroid CA, Pheochromocytoma, Parathyroid hyperplasia (MEN2A)
107
von Hippel-Lindau Syndrome
VHL gene mutation
| Hemangioblastomas, Renal Clear Cell CA, Pheochromocytoma
108
Calciphylaxis
rare, dangerous skin complication of ESRD (CKD)
CKD --> hyperphosphatemia --> binds to calcium --> hypocalcemia
Calcium-Phosphate crystals deposit in walls of blood vessels on the skin --> ischemic necrosis of the skin
can cause:
smooth muscle osteogenesis, vascular wall calcification, inc. BP, small vessel thrombosis, painful nodules and skin necrosis
Tx: Phosphate binders
109
Chronic Kidney Disease
HYPERphosphatemia
HYPERmagnesemia
HYPERkalemia
HYPOcalcemia
110
Mitral Annular Calcification
common incidental finding on 2D Echo
results from endothelial dysfunction and chronic inflammation leading to dystrophic calcification
many similarities with atherosclerosis including inc. prevalence in elderly
almost always asymptomatic but rare, severe cases may impair mitral valve function
can lead to mitral valve regurgitation, mitral stenosis, and heart failure
111
Hamartoma vs Choristoma
Hamartoma
- mature disorganized cells in the RIGHT PLACE
- Lung Hamartoma (disorganized lung tissue)
- BENIGN
Choristoma
- mature, well-differentiated cells in the WRONG PLACE
- Meckel's Diverticulum (gastric tissue at ileum)
- BENIGN
112
Pulmonary Hamartoma
```
most common benign tumor of the lung
10% of pulmonary nodules
lesions typically contain disorganized but normal tissue from the organ including fat, epithelial cells, fibrous tissue and cartilage
some may have calcifications
grow slowly over the years
excellent prognosis
```
113
Drug Induced Lupus
signs of inflammation + arthritis (usu. polyarticular and symmetrical)
milder form of lupus
malar rash is less common
renal failure, CNC involvement and bone marrow suppression are rare
autoimmune reaction with anti-histone antibodies
(vs classic lupus with anti-ds dna antibodies)
H1 histone linker protein
114
Mixed connective tissue disease
anti-U1 ribonucleoprotein antibodies
115
Celiac Disease
Anti-tissue transglutaminase antibodies
116
Lesch-Nyhan Syndrome
X-linked absence of HGPRT (in purine salvage pathway where hypoxanthine and guanine are converted into IMP and GMP which can be reused to form AMP or GMP for DNA and RNA)
excess de novo purine synthesis as compensation (inc. PRPP and IMP)
excess uric acid formation (JUVENILE GOUT) (hindi sila nasasalvage. puro excretion -> inc. uric acid)
Classic feature: SELF-MUTILATING BEHAVIOR (biting, scratching) and AGGRESSION
neurologic signs: hypotonia, chorea, dystonia, intellectual impairment
Hyperuricemia (24 hour urine uric acid inc.)
HGPRT enzyme activity <1.5% of normal is diagnostic
Classic presentation: male child with motor s/sx, self mutilation and gout
117
Gout
excess uric acid usu. d/t excess uric acid production
high cell turnover (trauma, chemotherapy); consumption of purine-rich food (meat and seafood)
sometimes due to decreased uric acid excretion
monosodium urate crystals deposition in the joints => neutrophil activation => release of cytokines and inflammatory mediators
Tx: Allopurinol to prevent recurrence d/t xanthine oxidase inhibition -> dec. uric acid
NSAIDs = symptomatic control
118
Respiratory Syncytial Virus (RSV) Bronchiolitis
most common cause of bronchiolitis and respiratory tract infections in children less than 2y/o
causes wheezing, inc. work of breathing (retractions and nasal flaring)
Tx: Ribavirin
119
Ornithine Transcarbomylase (OTC) Deficiency
key urea cycle enzyme
carbamoyl phosphate + ornithine = citrulline
deficiency in OTC leads to inc. carbamoyl phosphate = inc. orotic acid
elevated orotic acid in urine and hyperammonemia
ammonia = encephalopathy
baby with lethargy/coma
120
Orotic Aciduria (UMP Synthase Deficiency)
results in orotic aciduria and megaloblastic anemia
dec. UMP synthase activity (orotic acid + PRPP = UMP)
Key findings:
orotic aciduria, megaloblastic anemia with no response to B12/folate, growth retardation
Tx: Uridine (bypass UMP synthase)
121
orotic aciduria (differentiate cause)
+ megaloblastic anemia = UMP Synthase Deficiency (pyrimidine synthesis problem)
+ hypoammonemia = OTC Deficiency (urea cycle problem)
122
Folate Deficiency
ultimately lead to dec. dTMP synthesis and DNA synthesis
RNA production is intact
MACROCYTIC ANEMIA
Neural Tube Defects in-utero
123
Megaloblastic Anemia
anemia + inc. MCV
HYPERSEGMENTED NEUTROPHILS
dec. reticulocyte count
commonly caused by defective DNA production:
- Vit. B12 Deficiency (neurologic symptoms, inc. methymalonic aicd)
- Folate Deficiency (neural tube defects)
- Orotic Aciduria (dec. UMP synthase)
- Drugs (Methotrexate, Hydroxyurea, 5-FU)
- Zidovudine (HIV NRTI)
124
Vitamin B12 Deficiency
Vit. B12 is used to regenerate THF from the methyl folate trap (where some N5, N10 THF is converted into N5 methyl THF)
dec. THF = dec. dTMP = dec. DNA synthesis
```
MEGALOBLASTIC ANEMIA
NEUROLOGIC DYSFUNCTION (DEMYELINATION)
```
125
Pyruvate Dehydrogenase Deficiency
```
X-linked or autosomal recessive
abnormal mitochondrial metabolism
lactic acidosis (NO HYPOGLYCEMIA), microcephaly, neurologic deficits, hypotonia
usually presents in infancy and is worsened by carbohydrates (like orange juice) which are shunted into lactate
```
126
Vit B12 vs Folate Deficiency
RBCS = both dec. # and both inc. size/MCV
Methylmalonic acid is inc. ONLY in Vit. B12 deficiency. normal in folate deficiency
Homocysteine is inc. in both since both require to reduce homocysteine to methionine
127
Basal Cell Carcinoma
waxy/pearly nodule with central ulceration
Tx: includes 5-FU
128
Pyruvate Kinase Deficiency
Autosomal recessive
RBCs most affects as they have no mitochondria, thus relying on lactate formation for ATP from pyruvate
(PEP->pyruvate)
dec. pyruvate -> ATP is lost -> membrane failure of RBCs -> phagocytosis in the spleen
hemolytic anemia
peripheral blood smear classically shows burr cells (echinocytes)
presents in the NEWBORN as EXTRAVASCULAR HEMOLYSIS, Splenomegaly
severity ranges based on enzyme activity
neonatal hemolytic anemia with jaundice, hepatosplenomegaly, negative coomb's test
129
Essential Thrombosis (ET)
myeloproliferative disorder of megakaryocyte proliferation => inc. platelet counts
(+) erythromelalgia (redness and burning pain of hands and feet; also seen in polycythemia vera)
Hydroxyurea reduced platelet count on ET and reduced thrombosis rates
ADR: megaloblastic anemia
130
Glucokinase Deficiency
rare form of monogenic diabetes caused by a single gene mutation
hyperglycemia is mild
usu. asymptomatic, rarely associated with vascular complications of classic type 1 and 2 DM
diet alone is sufficient
commonly detected during pregnancy (pregnancy is diabetogenic state)
deficiency of Glucokinase leads to persistently low levels of G6P in the beta cells of the pancreas. the body treats this as hypoglycemia hence decreasing insulin production leading to hyperglycemia
DEC. INSULIN and HYPERGLYCEMIA
131
Pyruvate Carboxylase Deficiency
enzyme converts Pyruvate to Oxaloacetate for gluconeogenesis
very rare
presents in infants as failure to thrive
leads to inc. pyruvate and lactate levels
sometimes inc. alanine levels
fasting hypoglycemia WITH KETOSIS
other fatty acid disorders such as MCAD, and Carnitine Deficiency may have fasting hypoglycemia WITHOUT KETOSIS (HYPOKETOTIC HYPOGLYCEMIA)
132
Glycogen Synthase Deficiency
| Glycogen Storage Disease Type 0
results in low levels of glycogen stores
converts glucose to glycogen
leads to fasting ketotic hypoglycemia WITHOUT hepatomegaly
NO inc. in pyruvate and alanine
(+) POSTPRANDIAL HYPERGLYCEMIA and postprandial lactic acidosis
133
Glycogen Synthase Deficiency
| Glycogen Storage Disease Type 0
results in low levels of glycogen stores
converts glucose to glycogen
leads to fasting ketotic hypoglycemia WITHOUT hepatomegaly
NO inc. in pyruvate and alanine
(+) postprandial hyperglycemia and postprandial lactic acidosis
134
Pyruvate Dehydrogenase Deficiency
converts pyruvate into acetyl coA
deficiency leads to accumulation of pyruvate -> hyperalaninemia and lactic acidosis
no hypoglycemia
135
Klebsiella Pneumonia
lung abscess
localized liquefactive necrosis
gram negative
infection in patients with impaired host defenses including heavy alcohol users
136
Polyarteritis Nodosa
vasculitis of MEDIUM vessels
key features:
- evidence of systemic inflammation (ESR, wbc, fever)
- skin lesions (vesicles, nodules, purpura)
- neurologic s/sx (focal neuropathies)
- renal failure
immune complex mediated deposition in blood vessels (TYPE III HYPERSENSITIVITY)
strongly associated with HEP B (30%)
no specific blood tests for the disease
diagnosis: BIOPSY -> FIBRINOID NECROSIS filled with thrombus
137
Acute Viral Hepatitis
apoptosis of hepatocytes caused by CD8+ T-cells
| "SPOTTY NECROSIS" - scattered areas but still apoptosis is the major pathological process
138
Pleural Effusion
Exudative (infection, malignancy) or Transudative (HF, low albumin) based on Light's Criteria
LIGHT'S CRITERIA
Exudative IF:
- plueral protein:serum protein ratio > 0.5
- pleural LDH: Serum LDH ration > 0.6
- pleural LDH greater than 2/3 ULN of LDH
139
Pertussis
Whooping Cough
caused by Bordetella pertussis
(+) leukemoid reaction
140
Amyloid A (Secondary) Amyloidosis
caused by Serum Amyloid A Proteins (apolipoproteins)
| occurs in chronic inflammatory conditions (RA, Ankylosing Spondylitis, IBD)
141
Sarcoidosis
(+) granulomas
| Hypercalcemia
142
Pulmonary Histoplasmosis
fungal pneumonia caused by Histoplasma
Ohio and Mississippi River Valleys
Fungal spores in soil contaminated by bird or bat droppings
mostly asymptomatic or with mild pulmonary s/sx
no diagnostic CXR findings but hilar lymphadenopathy is common
granulomatous inflammation (INF Gamma and IL-2)
143
Calciphylaxis
```
seen in Chronic Hyperphosphatemia in CKD
excess phosphat taken up by vascular smooth muscles cells leading to SMOOTH MS. OSTEOGENESIS
Vascular wall calcification
increased SBP
small vessel thrombosis
painful nodules and skin necrosis
```
144
Nephrocalcinosis
Calcium Deposition in kidney tubules due to inc. urinary excretion of calcium and phosphate
seen in hypercalcemia and hyperphosphatemia (Sarcoidosis, Hyperparathyroidism)
common in patients with kidney stones
often asymptomatic
may cause polyuria/polydipsia -> Nephrogenic Diabetes Insipidus
Impaired urinary concentrating ability -> collecting duct cannot resorb water normally leading to polyuria -> volume depletion-> polydipsia
145
Keloid
raised scars that grow beyond borders of original wound
excessive healing or scarring
15x more common in dark skin (African-American, Spanish, Asian)
contain Type I and III collagen
disorganized collagen not parallel to the epithelium (which is the normal pattern)
more common in earlobe, deltoid, upper back
rare on eyelids, palms and soles
high recurrence with surgical removal
TX: corticosterois, 5-FU injection
146
Hypertrophic scar
excessive scarring but remains within original wound borders
Mostly Type III collagen that is parallel to the epithelium and not disorganized
developed about 4 weeks post injury
may occur anywhere and often regress spontaneously
147
Hamartoma
"H for HOME"
abnormal tissue in normal location
benign, mature but disorganized cells
i.e.
Lung Hamartoma - disorganized lung tissue
Developmental Anomalies
148
Choristoma
normal tissue in abnormal location
benign, mature well-differentiated tissue in the wrong place
i.e.
Meckel's Diverticulum (gastric tissue in ileum)
149
Tumor Spread
| Carcinoma vs Sarcoma
Sarcomas = hematogenous route (liver and lungs most common sites)
```
Carcinomas = lymphatic route
EXCEPT:
- Choriocarcinoma (early hematogenous spread)
- Renal Cell CA (renal vein)
- Hepatocellular CA (portal vein)
- Follicular Thyroid CA
```
150
Mesothelioma
CA highly linked to Asbestos
151
Glycogen Storage Diseases
Type i - von Gierke Disease (Glucose 6 phosphatase deficiency)
Type II - Pompe Disease (lysosomal acid maltase deficiency)
Type III - Cori Disease (debranching enzyme deficiency)
Type V - McArdle's Disease (muscle glycogen phosphorylase deficiency)
152
von Gierke disease
Glycogen Storage disease type I
glucose-6-phosphatase deficiency (Type Ia)
glucose transporer deficiency (Type Ib)
presents during infancy (2-6 mos)
SEVERE HYPOGLYCEMIA BETWEEN MEALS
lethargy, seizures, lactic acidosis, hepatomegaly (excess glycogen)
muscles are unaffected since they can utilize G6P
elevated serum alanine may also occur through the alanine cycle being disrupted
Diagnosis: DNA testing; Liver biopsy (no longer used)
TX: Cornstarch (glucose polymer) and other starch containing food (rice, potatoes); maintain normal serum glucose with frequent consumption of glucose polymers that are slowly absorbed
AVOID SUCROSE, LACTOSE, FRUCTOSE and GALACTOSE (they cannot be used outside the liver as fuel. but the liver cannot convert them to glucose due to the enzyme deficiency; can feed into glycolysis pathways and cannot be metabolized to glucose via gluconeogenesis; worsens the accumulation of G6P)
153
Pompe Disease
Glycogen Storage disease type II
Lysosomal Acid Maltase (alpha 1-4, glucosidase) deficiency
accumulation of glycogen in lysosomes
classic form presents during infancy
severe disease often leads to death in infancy/childhood
NO HYPOGLYCEMIA BETWEEN MEALS because liver can still breakdown glycogen
enlarged muscles, hypotonia, liver enlargement
HYPERTROPHIC CARDIOMYOPATHY
death from heart failure
ENLARGED TONGUE
Classic Infantile Form:
- glycogen accumulates in the heart and muscle lysosomes
- no direct effects of the liver
- may present with cardiomegaly and hypotonia
- HF may cause Pulmonary edema and Liver Congestion
- presents in the first few months of life
blood work: creatinine kinase is elevated
154
Cori Disease
Glycogen Storage disease type III
Debranching enzyme deficiency
similar to von Gierke except that this has MILDER HYPOGLYCEMIA, NO LACTIC ACIDOSIS, and AFFECTS MUSCLES
accumulation of LIMIT DEXTRINS -> hepatomegaly
classic presentation:
infant/child with hypoglycemia/hepatomegaly, hypotonia/ms. weakness, possible cardiomyopathy with hypertrophy
155
McArdle Disease
Glycogen Storage disease type V
Muscle glycogen phosphorylase deficiency
usually presents in adolescence or childhood
EXERCISE INTOLERANCE, cramps, fatigue
poor endurance, muscle swelling and weakness
muscle damage with exercise (Rhabdomyolysis)
MYOGLOBINURIA (DARK URINE) and Creatinine Kinase release AFTER EXERCISE
156
Wernicke-Korsakoff Syndrome
irreversible encephalopathy associated with chronic alcohol use and thiamine (B1) deficiency
among chronic alcohol users, only 13% develop this syndrome and they are found to have abnormal transketolase enzyme in fibroblasts
the pathophysiology is still not completely understood
157
Budd Chiari Syndrome
thrombosis of the hepatic vein leading to liver enlargement and ascites
seen in hypercoagulable states and in patients with HCCA
158
Insulinoma
potential cause of hypoglycemia in an adult
most cases occur at 30-50 y/o
extremely rare in children
159
Medium Chain Acyl-coA Deficiency (MCAD)
fatty acid disorder
| urinary dicarboxylic acids
160
Fibroadenoma
most common benign tumors in young women
small firm mobile masses
hormone -responsive during menstrual cycle
fibrosing stroma over normal glandular tissue
161
Intraductal papilloma
benign solitary lesion lining lactiferous ducts
premenopausal women with serosanguinous unilateral nipple discharge (r/o invasive papillary CA d/t presence of blood discharge)
rarely undergo malignant transformation
branching fibrovascular core extending from a dilated duct
Tx: ice pack, stop breast feeding, tight-fitting support bras, if no improvement -> Excision to prevent abscess formation
162
Paget Disease of the Breast
unilaterally with eczematous overlying skin and underlying intraductal carcinomas
(+) Paget cells - large cells with halo-like clearings
163
Infiltrating lobular carcinoma
irregular masses with cells in clusters or linear formation
histologic hallmark: monomorphic infiltrating cells usually only one cell wide
common in postmenopausal women
164
Invasive Ductal CA
most common breast mass in older women
| (+/-) skin changes - dimpling (impinging on suspensory ligaments), peau d' orange (edema), nipple discharge
165
Paroxysmal Nocturnal Hemoglobinuria
rare form of hemolytic anemia that us caused by a defective protein known as glycosylphosphatidylinositol (GPI) anchor (encoded by the PIG-A gene) normally on the RBC membrane that prevents the attachment of complement and subsequent lysis
Dx: combine patient RBCs with acidic solution and compare to control -> inc. hemolysis
while sleeping -> dec. RR -> slight respi acidosis -> complement mediated lysis
166
Familial Hypercholesterolemia
may cause infertility due to atherosclerosis of the vessels of the male genitalia causing erectile dysfunction
167
Bacterial Meningitis
S. agalactiae - peripartum infection (group B strep, b-hemolytic, bacitracin resistant)
168
Budd Chiari Syndrome
near complete obstruction
169
opioid Withdrawal S/Sx
Triad: piloerection, rhinorrhea and lacrimation, and yawning
opposite s/sx of opioid intoxication
