Genetic Disorders Flashcards
1
Q
Down syndrome newborn clinical manifestations
A
hypotonia flat facial features enlarged/protruding tongue small nose upward slant of eyes simian crease abnormally shaped ears hyper flexibility extra space b/w first and second toe brush field spots on iris
2
Q
Down syndrome adult clinical manifestations
A
multiple cardiac defects multiple intestinal malformations growth impairment vision abnormalities hearing loss recurrent respiratory infections behavioral issues memory loss w/increased risk of Alzheimer's at an early age
3
Q
Down syndrome increased risk
A
maternal age
4
Q
Klinefelter syndrome clinical manifestations
A
50% develop gynecomastia
may have: impaired psychosocial skills, impaired higher language skills, increased risk of Non-Hodgkin’s lymphoma/leg ulcers/lupus
will have: small testes, abnormally low sperm count, decreased sperm testosterone, abnormal arm and leg length, increased risk of male breast cancer and pulmonary disease
5
Q
Klinefelter Genetics
A
XXY
6
Q
Turner syndrome clinical manifestations
A
hearing loss hypothyroidism autoimmune disease/ autoimmune thyroiditis elevated liver enzymes primary amenorrhea osteoporosis renal structure abnormalities vision/ocular abnormalities diabetes hyperlipidemia HTN cardiac structure abnormalities aortic dissection increased CV mortality
7
Q
Turner syndrome physical characteristics
A
female appearance short, wide chest prominent neck skin folds usually sterile/low estrogen small breasts normal mental development
8
Q
Turner syndrome genetics
A
XO
9
Q
Cystic fibrosis clinical manifestations
A
thick mucus buildup in lungs and pancreatic ducts
failure to thrive impaired growth in kids chronic pulmonary infections/colonization of pseudomonas aeruginosa nasal polyps epistaxis sinusitis chronic cough hemoptysis abnormal lung parenchyma cor pulmonale pancreatitis steatorrhea CF-related DM biliary cirrhosis liver damage portal HTN
10
Q
Cystic Fibrosis males
A
98% infertile due to absence of vas deferens
11
Q
Cystic Fibrosis genetics
A
autosomal recessive
CFTR gene
F508 mutation most common
12
Q
Cystic Fibrosis pathophysiology
A
change in chloride and water transport across membranes
ions stay intracellularly so water not getting into mucus
13
Q
PKU clinical manifestations
A
severe mental retardation due to excess phenylalanine
- -impairs brain growth
- -impairs myelination
- -impairs NT synthesis
14
Q
PKU genetics
A
autosomal recessive
15
Q
PKU treatment
A
dietary restriction of phenylalanine + pharmacotherapy
16
Q
SCID clinical manifestations
A
children prone to develop severe infections due to deficient T and B cells
commonly fatal w/in one year
17
Q
SCID genetics
A
X-linked genes (multiple)
IL2RG defect
18
Q
SCID treatment
A
gene therapy
hematopoietic stem cell transplant
19
Q
SCID dx
A
look at newborn biomarkers for naive T cells
20
Q
Alzheimer’s disease clinical manifestations
A
memory deficits (recent events) language changes --verbal disfluency --anomia --reduced vocabulary --diminished comprehension --circumlocution visuospatial skills --misplace items --worsening navigation skills Reduced insight into self-decline apraxia/dyspraxia loss of executive fan mild depression/psychosis changes in olfactory fan loss of sleep combative
21
Q
Alzheimer’s disease early onset genetics
A
Autosomal dominant
APP gene
PSN1 gene
PSN2 gene
22
Q
Alzheimer’s disease late onset genetics
A
Many genes
APOE epsilon 2 (decreases risk)
APOE epsilon 3 (no affect on risk)
APOE epsilon 4 (increases risk of AD)
23
Q
Late onset Alzheimer’s disease genetic testing
A
not recommended, many genes involved and outcome isn’t certain
24
Q
Early onset Alzheimer’s disease genetic testing
A
Can be tested for 3 genes if desired, still won’t predict age of onset
25
Alzheimer's disease pathogenesis
amyloid plaques
neurofibrillary tangles
lose synaptic connections
kill neurons
26
Huntington's disease clinical manifestations
PROGRESSIVE
```
Chorea
gait abnormalities
slow eye movements (lose smooth movement)
irritability
anxiety
depression
disrupted social relationships
paranoia
aggression
delusions
loss of insight
inflexibility
memory loss
impaired judgement
weight loss/cachexia
```
27
Huntington's disease genetics
autosomal dominant
Huntingtin gene/protein
juvenile HD almost always inherited from father
White people, mid-life onset
28
Huntington's Disease and CAG repeats
higher CAG repeats=earlier onset/greater severity
negative <35
positive >40
29
Neurofibromatosis type 1 clinical manifestations
```
cafe au lait macules
freckling
lisch nodules
cutaneous/plexiform/nodular neurofibromas
optic gliomas
neoplasms
bony abnormalities
neurologic abnormalities
ADD
mental retardation
learning disability
seizures
macrocephaly
HTN
peripheral neuropathy
```
30
Neurofibromatosis type 2 clinical manifestations
```
neurologic lesions
bilateral vestibular schwannomas--> lead to hearing loss, tinnitus, balance dysfunction
meningioma
spinal tumors
peripheral neuropathy
schwannomas of other cranial nerves
ocular lesions
skin lesions
```
31
Neurofibromatosis type 1 genetics
autosomal dominant
50% inherited, 50% de novo
Neurofibromin is tumor suppressor gene
32
Neurofibromatosis type 2 genetics
Autosomal dominant
merlin/schwannomin are tumor suppressor genes
33
Neurofibromatosis 1 and 2
NF 1 more common
Genetic testing not widely available, look at family hx
34
Polycystic Kidney Disease Clinical Manifestations
```
Bilateral renal cysts (quadruple size of kidneys)
cysts can scar and replace normal structure, affecting kidney fxn
Renal lithiasis
Hematuria
Proteinuria
flank pain
UTI
renal infection
HTN (disturbances of renal perfusion)
ESRD
```
35
ESRD--end stage renal disease
loss of normal renal tissue/death of renal tubular cells
36
Polycystic Kidney Disease affects on other systems
```
Polycystic liver disease
Pancreatic cysts
Seminal vesicle cysts
Intracranial aneurysm
Diverticulosis/diverticulitis
Dilation of aortic root
cardiac valve abnormalities
```
37
Polycystic Kidney Disease genetics
Usually autosomal dominant
PKD1 (85% of disease)
PKD2 (15% of disease)
some people have both
VERY RARELY autosomal recessive
38
PKD1
more severe symptoms and earlier onset
ESRD progression by age 60 in 50% of pts
39
Polycystic Kidney Disease genetic testing
available
all kidney donors should be thoroughly tested
40
Hereditary hemochromatosis clinical manifestations
```
hepatomegaly
elevated liver enzymes
fibrosis/cirrhosis
increased risk of hepatocellular carcinoma
DM
arthropathy
heart disease
hypogonadism
amenorrhea
increased infection
hyper pigmented skin
```
41
Reversible clinical manifestations of hereditary hemochromatosis
```
cardiomyopathy
arrhythmia
abdominal pain
hepatomegaly
increased liver enzymes
skin hyperpigmentation
infection
```
42
Irreversible clinical manifestations of hereditary hemochromatosis
```
cirrhosis
hepatocellular carcinoma
hypogonadism
DM
hypothyroidism
arthritis
```
43
Hereditary hemochromatosis genetics
Autosomal recessive
variable penetrance
HFE gene mutation
- -C282Y
- -H63D
44
Hereditary Hemochromatosis gender distributions
more common in men
if women develop, usually at later age
45
Hereditary Hemochromatosis iron absorption/storage
iron absorption not regulated by amount of iron stores
increased iron stored in liver, pancreas, skin, heart, pituitary gland, causes end organ damage
46
Hereditary Hemochromatosis treatment
remove blood
47
Hemophilia clinical manifestations in newborn
intracranial hemorrhage w/seizures
| increased bleeding w/circumcision
48
Hemophilia clinical manifestations in kids (usually dx by age 6)
abnormal bleeding during procedure/injury
excessive bruising, hematomas, hemarthroses
49
Hemophilia Clinical manifestations in adults
```
epistaxis
bleeding after coughing
blood in stool
hematuria
delayed post-traumatic bleeding out of proportion to injury
menorrhagia
```
50
Female symptomatic hemophilia
carriers can manifest mild symptoms of disease or have classic symptoms (classic presentation rare)
usually just slower clotting process
51
Hemophilia genetics
X-linked recessive
Missing factor VIII or IX
Fathers never pass to sons
52
Hemophilia A
disorder of factor VIII
classic hemophilia
most common
53
Hemophilia B
disorder of factor IX
Christmas disease
54
Hemophilia genetic testing
encouraged
55
Hemophilia C
factor XI deficiency
autosomal recessive
56
Von Willebrand's Disease Type 1
mild to moderate bleeding, clinical variability, may go unrecognized
57
Von Willebrand's Disease Type II
moderate to moderately severe bleeding of soft tissue, joints, urinary or post procedural bleeding
58
Von Willebrand's Disease Type III
severe bleeding of skin and mucus membranes, hematoma, hemarthrosis, oral cavity bleeding expistaxis
59
Von Willebrand's Genetics
autosomal dominant w/variable penetrance
some autosomal recessive
vWF gene, 300 mutations
60
vWF
involved in platelet adhesion to sub endothelium
most common inherited bleeding disorder
61
Sickle Cell anemia clinical manifestations in kids/infants
```
failure to thrive
anemia
splenomegaly
multiple infections
swelling of extremities
```
62
Sickle cell anemia clinical manifestations in adults
```
chronic anemia
jaundice
cholelithiasis
aplastic crisis (cessation of RBC production)
tissue ischemia
severe abdominal pain
stroke
acute chest syndrome (chest pain, dyspnea, fever, renal necrosis, leg ulcers, priapism, vision loss due to infarction)
shorter life expectancy
```
63
Sickle cell anemia genetics
Autosomal Recessive
Ancestry of sub-saharan Africa (African Americans, some Hispanic Americans)
64
Sickle cell anemia pathophysiology
abnormal Hgb structure (glutamic acid replaced w/valine)--> polymerized Hgb forms long inflexible chains to form sickle cell shape of RBC
Carriers: protective against cerebral malaria
65
Familial hypercholesterolemia clinical manifestations
atherosclerosis
tendon xanthomas
xanthelasma
angina or MI possible
66
Familial hypercholesterolemia genetics
Autosomal dominant or recessive depending on mutation
1000 mutations on LDLR gene
homozygous form rare (heterozygous common)
67
Familial hypercholesterolemia genetic testing
recommended if family member presents w/FH, plasma cholesterol >310mg/dL, premature CHD, tendon xanthomas
68
Marfan syndrome clinical manifestations
overly elastic connective tissue (CV, skeletal, ocular abnormalities)
```
ectopia lentis (dislocated lens)
spontaneous pneumothorax
skin striae
recurrent incisional hernia
lumbosacral dural ectasia
```
69
Marfan syndrome major causes of mortality
aortic dilation and aortic root disease (aortic aneurysm aortic regurgitation, aortic dissection)
70
Marfan syndrome aortic dilation
50% of kids
| 60-80% of adults
71
Marfan syndrome skeletal manifestations
```
excess bone growth
dilochostenomelia
arachnodactyly
positive thumb/wrist signs
pectus carinatum/excavatum
hindfoot valus
pes planus
reduced mobility of joints
scoliosis/kyphosis
```
72
Marfan syndrome genetics
autosomal dominant
25% de novo mutations
FBN1 (fibrillin-1 gene)
>600 mutations
73
Marfan syndrome dx
Ghent criteria and family hx
Genetic testing for dx confirmation, prenatal, predictive testing
Most common connective tissue disorder
74
Familial thoracic aneurysms and dissections clinical manifestations
4 Ps: pallor, pulselessness, paresthesias, paralysis
aortic aneurysm/dissection
usually asymptomatic, incidental finding (symptomatic aneurysms are extremely dangerous)
75
Familial thoracic aneurysms and dissections genetics
Autosomal dominant
4 genes
76
Familial thoracic aneurysms and dissections genetic testing
check for Marfan syndrome first
genetic testing available for all 4 genes (screen first degree relatives)
important to know before getting pregnant
ascending aorta involved 80% of time
77
Dilated cardiomyopathy
dilation of at least one ventricle, impaired contraction of one or both ventricles
78
Hypertrophic cardiomyopathy clinical manifestations
Dyspnea on exertion, palpitations, chest pain, syncope
ask about all of these when doing sports physicals
79
Hypertrophic cardiomyopathy--part of heart affected
Left ventricular hypertrophy
Impaired L ventricular contractibility
80
Hypertrophic cardiomyopathy genetics
Autosomal dominant
12+ genes linked (1400 mutations)
de novo mutations possible
some people inherit multiple mutations
81
Hypertrophic cardiomyopathy pathogenesis
mutations involve coding for thick/thin filaments of sarcomere (abnormal response of filaments to calcium signaling/ATP use in muscle fibers)
82
Hypertrophic cardiomyopathy genetic testing
available
difficult to predict age of onset/severity
do physical and ECG and echocardiogram prior to testing
83
Restrictive cardiomyopathy
stiffening/rigidity of ventricles due to replacement of normal myocardium by scar tissue (usually L ventricle)
84
Arrhythmogenic cardiomyopathy clinical manifestations
arrhythmias, palpitations, chest pain, syncope
85
Arrhythmogenic cardiomyopathy pathogenesis
desmosome dysfunction when subjected to mechanical stress, myocyte detachment and cell death, inflammation,, fibrofatty replacement of damaged myocytes
86
Arrhythmogenic cardiomyopathy genetics
autosomal dominant most common
8 genes
87
Arrhythmogenic cardiomyopathy--part of heart affected
right ventricle--fibrofatty replacement of R ventricle
Left ventricle can be involved, but less common
88
Arrhythmogenic cardiomyopathy genetic testing
available
difficult to predict age of onset/severity
do physical and ECG and echocardiogram prior to testing
89
Hereditary breast cancer risk factors
```
family hx of breast/ovarian cancer
Ashkenazi Jews, Dutch, Icelandic, Swedish, Japanese, French Canadian
First childbirth at later ages
Oral contraceptive use
Phenotypic variability
```
BRCA1 and BRCA2 mutations
90
Hereditary breast cancer genetics
autosomal dominant (high penetrance)
BRCA1 and BRCA2
91
Hereditary breast cancer BRCA1
higher lifetime risk of cancer development
earlier onset
57% risk by age 70
may increase risk of other reproductive/GI cancers
92
Hereditary breast cancer BRCA2
49% risk by age 70
increases risk of prostate/pancreatic cancer
may increase risk of reproductive/GI cancers
93
Hereditary breast cancer management
clinical breast exams 2-4x annually starting age 25
annual mammograms starting 25-35 (consistent location w/prior films)
annual breast MRI
elective bilateral mastectomy
annual CA-125 level
Prophylactic bilateral salpingo-oophorectomy
94
Male breast cancer
presence of BRCA2 in men is 6% risk for breast cancer
95
Hereditary breast cancer genetic testing
test individual for gene then test family members
should be done in conjunction w/genetic counseling
positive, negative, ambiguous (10%) results
96
Hereditary ovarian cancer
most common cause of gynecologic cancer death, second most common gynecologic malignancy
97
hereditary ovarian cancer clinical manifestations
belly pain/constipation (nondescript symptoms)
98
hereditary ovarian cancer genetics
lifetime risk of general population = 1/58
BRCA1 lifetime risk by age 70 = 40%
BRCA2 lifetime risk by age 70 = 18%
5-10% of cases are hereditary
99
Hereditary ovarian cancer genetic testing
same as hereditary breast cancer
100
Hereditary ovarian cancer management
annual/semiannual transvaginal u/s, prophylactic bilateral salpingo-oophorectomy (35-40)
101
Hereditary colorectal cancer clinical manifestations
```
hematochezia/melena
unexplained weight loss
prolonged diarrhea/constipation
cramping abdominal pain
decrease in caliber/size of stools (pencil thin)
vomiting
abdominal distention
decreased energy
```
anemia of unexplained origin (esp in elderly pts)
102
Hereditary colorectal cancer types of polyps
adenomatous--tubular, villous, tubulovillous
non-adenomatous--hyperplastic
inflammatory
103
Hereditary colorectal cancer genetics
15-30% of CRC is familial (single or multi gene)
more common in males and African Americans
genetic cancers more common in R colon
104
Familial adenomatous polyposis (FAP) clinical manifestations
adenomatous polyps (15% develop by age 10, 90% by age 30)
100% lifetime risk of colon cancer (39 avg age of onset)
105
Attenuated FAP
```
less polyps
develops at later age
70-80% lifetime risk
mean age of onset 56
adenomas typically in R colon
```
106
Gardner Syndrome
extracolonic manifestations
- -polyps of upper GI tract
- -thyroid cancer
- -childhood hepatoblastoma
- -CNS tumors
- -adrenal adenomas
- -desmoid tumors
- -sebaceous cysts
- -fibromas
- -mandibular osteomas
107
FAP genetics
autosomal dominant most common
APC gene, near complete penetrance (tumor suppressing gene ensuring correct # of chromosomes present prior to replication)
Autosomal recessive less common (MYH, MUTYH gene)---involved in error correction, less obvious in fhx
25% of cases are de novo
108
FAP genetic testing
offered to pts and family members (APC and MYH genes)
if genetic testing unavailable, should do yearly colonoscopies starting at age 12
109
Lynch syndrome clinical manifestations
few polyps (<100) but fatter, larger, more rapid transformation to cancer
R side of colon
associated w/other malignancies
cancer can develop at different sites in colon at different times
110
Lynch syndrome genetics
autosomal dominant
MLH1, MSH2, MSH6, PMS2 (mismatch repair genes)
risks depend on geographical/environmental factors
111
Peutz-Jehgers syndrome
autosomal dominant
characteristic melanocytic macule on lips/perioral/buccal regions
high risk of colon cancer, increased risk of other cancers
112
Lynch syndrome management
colonoscopy every 1-2 years beginning at age 25 or 5 years prior to age of youngest dx
upper endoscopy every 2-3 years
pelvic exam, TVUS, CA-125, bx
prophylactic total abdominal hysterectomy
113
Lynch syndrome dx
family hx
Amsterdam II criteria
Genetic testing on tumor
114
Chronic myelogenous leukemia clinical manifestations
```
fatigue
night sweats
fever
splenomegaly
weight loss
bleeding episodes
```
115
CML genetics
not inherited
```
philadelphia chromosome (9 and 22 translocations)
cells don't die
increased tyrosine activity=abnormal cell division/growth and impaired apoptosis
```
male predominance (55)
116
CML pathogenesis
uncontrolled production of granulocytes (primarily neutrophils, "-phils")
proliferation starves out space needed for bone marrow
lose cells that promote clotting, fight infection, carry oxygen
117
CML dx
bone marrow aspiration
118
Familial Malignant Melanoma (FAMM) clinical manifestations
large number of atypical moles at early age, more aggressive when familial
119
FAMM predictors
```
light complexion
inability to tan
red hair
number of atypical nevi >10
nevi on back
freckles
```
TANNING BEDS
120
FAMM genetics
autosomal dominant
CDKN2A and MC1R genes
genetics+environment
121
FAMM genetic testing
not recommended
