Genetic Disorders Flashcards
Down syndrome newborn clinical manifestations
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
Down syndrome adult clinical manifestations
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
Down syndrome increased risk
maternal age
Klinefelter syndrome clinical manifestations
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
Klinefelter Genetics
XXY
Turner syndrome clinical manifestations
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
Turner syndrome physical characteristics
female appearance short, wide chest prominent neck skin folds usually sterile/low estrogen small breasts normal mental development
Turner syndrome genetics
XO
Cystic fibrosis clinical manifestations
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
Cystic Fibrosis males
98% infertile due to absence of vas deferens
Cystic Fibrosis genetics
autosomal recessive
CFTR gene
F508 mutation most common
Cystic Fibrosis pathophysiology
change in chloride and water transport across membranes
ions stay intracellularly so water not getting into mucus
PKU clinical manifestations
severe mental retardation due to excess phenylalanine
- -impairs brain growth
- -impairs myelination
- -impairs NT synthesis
PKU genetics
autosomal recessive
PKU treatment
dietary restriction of phenylalanine + pharmacotherapy
SCID clinical manifestations
children prone to develop severe infections due to deficient T and B cells
commonly fatal w/in one year
SCID genetics
X-linked genes (multiple)
IL2RG defect
SCID treatment
gene therapy
hematopoietic stem cell transplant
SCID dx
look at newborn biomarkers for naive T cells
Alzheimer’s disease clinical manifestations
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
Alzheimer’s disease early onset genetics
Autosomal dominant
APP gene
PSN1 gene
PSN2 gene
Alzheimer’s disease late onset genetics
Many genes
APOE epsilon 2 (decreases risk)
APOE epsilon 3 (no affect on risk)
APOE epsilon 4 (increases risk of AD)
Late onset Alzheimer’s disease genetic testing
not recommended, many genes involved and outcome isn’t certain
Early onset Alzheimer’s disease genetic testing
Can be tested for 3 genes if desired, still won’t predict age of onset
Alzheimer’s disease pathogenesis
amyloid plaques
neurofibrillary tangles
lose synaptic connections
kill neurons
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
Huntington’s disease genetics
autosomal dominant
Huntingtin gene/protein
juvenile HD almost always inherited from father
White people, mid-life onset
Huntington’s Disease and CAG repeats
higher CAG repeats=earlier onset/greater severity
negative <35
positive >40
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
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
Neurofibromatosis type 1 genetics
autosomal dominant
50% inherited, 50% de novo
Neurofibromin is tumor suppressor gene
Neurofibromatosis type 2 genetics
Autosomal dominant
merlin/schwannomin are tumor suppressor genes
Neurofibromatosis 1 and 2
NF 1 more common
Genetic testing not widely available, look at family hx
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
ESRD–end stage renal disease
loss of normal renal tissue/death of renal tubular cells
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
Polycystic Kidney Disease genetics
Usually autosomal dominant
PKD1 (85% of disease)
PKD2 (15% of disease)
some people have both
VERY RARELY autosomal recessive
PKD1
more severe symptoms and earlier onset
ESRD progression by age 60 in 50% of pts
Polycystic Kidney Disease genetic testing
available
all kidney donors should be thoroughly tested
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
Reversible clinical manifestations of hereditary hemochromatosis
cardiomyopathy arrhythmia abdominal pain hepatomegaly increased liver enzymes skin hyperpigmentation infection
Irreversible clinical manifestations of hereditary hemochromatosis
cirrhosis hepatocellular carcinoma hypogonadism DM hypothyroidism arthritis
Hereditary hemochromatosis genetics
Autosomal recessive
variable penetrance
HFE gene mutation
- -C282Y
- -H63D
Hereditary Hemochromatosis gender distributions
more common in men
if women develop, usually at later age
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
Hereditary Hemochromatosis treatment
remove blood
Hemophilia clinical manifestations in newborn
intracranial hemorrhage w/seizures
increased bleeding w/circumcision
Hemophilia clinical manifestations in kids (usually dx by age 6)
abnormal bleeding during procedure/injury
excessive bruising, hematomas, hemarthroses
Hemophilia Clinical manifestations in adults
epistaxis bleeding after coughing blood in stool hematuria delayed post-traumatic bleeding out of proportion to injury menorrhagia
Female symptomatic hemophilia
carriers can manifest mild symptoms of disease or have classic symptoms (classic presentation rare)
usually just slower clotting process
Hemophilia genetics
X-linked recessive
Missing factor VIII or IX
Fathers never pass to sons
Hemophilia A
disorder of factor VIII
classic hemophilia
most common
Hemophilia B
disorder of factor IX
Christmas disease
Hemophilia genetic testing
encouraged
Hemophilia C
factor XI deficiency
autosomal recessive
Von Willebrand’s Disease Type 1
mild to moderate bleeding, clinical variability, may go unrecognized
Von Willebrand’s Disease Type II
moderate to moderately severe bleeding of soft tissue, joints, urinary or post procedural bleeding
Von Willebrand’s Disease Type III
severe bleeding of skin and mucus membranes, hematoma, hemarthrosis, oral cavity bleeding expistaxis
Von Willebrand’s Genetics
autosomal dominant w/variable penetrance
some autosomal recessive
vWF gene, 300 mutations
vWF
involved in platelet adhesion to sub endothelium
most common inherited bleeding disorder
Sickle Cell anemia clinical manifestations in kids/infants
failure to thrive anemia splenomegaly multiple infections swelling of extremities
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
Sickle cell anemia genetics
Autosomal Recessive
Ancestry of sub-saharan Africa (African Americans, some Hispanic Americans)
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
Familial hypercholesterolemia clinical manifestations
atherosclerosis
tendon xanthomas
xanthelasma
angina or MI possible
Familial hypercholesterolemia genetics
Autosomal dominant or recessive depending on mutation
1000 mutations on LDLR gene
homozygous form rare (heterozygous common)
Familial hypercholesterolemia genetic testing
recommended if family member presents w/FH, plasma cholesterol >310mg/dL, premature CHD, tendon xanthomas
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
Marfan syndrome major causes of mortality
aortic dilation and aortic root disease (aortic aneurysm aortic regurgitation, aortic dissection)
Marfan syndrome aortic dilation
50% of kids
60-80% of adults
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
Marfan syndrome genetics
autosomal dominant
25% de novo mutations
FBN1 (fibrillin-1 gene)
> 600 mutations
Marfan syndrome dx
Ghent criteria and family hx
Genetic testing for dx confirmation, prenatal, predictive testing
Most common connective tissue disorder
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)
Familial thoracic aneurysms and dissections genetics
Autosomal dominant
4 genes
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
Dilated cardiomyopathy
dilation of at least one ventricle, impaired contraction of one or both ventricles
Hypertrophic cardiomyopathy clinical manifestations
Dyspnea on exertion, palpitations, chest pain, syncope
ask about all of these when doing sports physicals
Hypertrophic cardiomyopathy–part of heart affected
Left ventricular hypertrophy
Impaired L ventricular contractibility
Hypertrophic cardiomyopathy genetics
Autosomal dominant
12+ genes linked (1400 mutations)
de novo mutations possible
some people inherit multiple mutations
Hypertrophic cardiomyopathy pathogenesis
mutations involve coding for thick/thin filaments of sarcomere (abnormal response of filaments to calcium signaling/ATP use in muscle fibers)
Hypertrophic cardiomyopathy genetic testing
available
difficult to predict age of onset/severity
do physical and ECG and echocardiogram prior to testing
Restrictive cardiomyopathy
stiffening/rigidity of ventricles due to replacement of normal myocardium by scar tissue (usually L ventricle)
Arrhythmogenic cardiomyopathy clinical manifestations
arrhythmias, palpitations, chest pain, syncope
Arrhythmogenic cardiomyopathy pathogenesis
desmosome dysfunction when subjected to mechanical stress, myocyte detachment and cell death, inflammation,, fibrofatty replacement of damaged myocytes
Arrhythmogenic cardiomyopathy genetics
autosomal dominant most common
8 genes
Arrhythmogenic cardiomyopathy–part of heart affected
right ventricle–fibrofatty replacement of R ventricle
Left ventricle can be involved, but less common
Arrhythmogenic cardiomyopathy genetic testing
available
difficult to predict age of onset/severity
do physical and ECG and echocardiogram prior to testing
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
Hereditary breast cancer genetics
autosomal dominant (high penetrance)
BRCA1 and BRCA2
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
Hereditary breast cancer BRCA2
49% risk by age 70
increases risk of prostate/pancreatic cancer
may increase risk of reproductive/GI cancers
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
Male breast cancer
presence of BRCA2 in men is 6% risk for breast cancer
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
Hereditary ovarian cancer
most common cause of gynecologic cancer death, second most common gynecologic malignancy
hereditary ovarian cancer clinical manifestations
belly pain/constipation (nondescript symptoms)
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
Hereditary ovarian cancer genetic testing
same as hereditary breast cancer
Hereditary ovarian cancer management
annual/semiannual transvaginal u/s, prophylactic bilateral salpingo-oophorectomy (35-40)
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)
Hereditary colorectal cancer types of polyps
adenomatous–tubular, villous, tubulovillous
non-adenomatous–hyperplastic
inflammatory
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
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)
Attenuated FAP
less polyps develops at later age 70-80% lifetime risk mean age of onset 56 adenomas typically in R colon
Gardner Syndrome
extracolonic manifestations
- -polyps of upper GI tract
- -thyroid cancer
- -childhood hepatoblastoma
- -CNS tumors
- -adrenal adenomas
- -desmoid tumors
- -sebaceous cysts
- -fibromas
- -mandibular osteomas
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
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
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
Lynch syndrome genetics
autosomal dominant
MLH1, MSH2, MSH6, PMS2 (mismatch repair genes)
risks depend on geographical/environmental factors
Peutz-Jehgers syndrome
autosomal dominant
characteristic melanocytic macule on lips/perioral/buccal regions
high risk of colon cancer, increased risk of other cancers
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
Lynch syndrome dx
family hx
Amsterdam II criteria
Genetic testing on tumor
Chronic myelogenous leukemia clinical manifestations
fatigue night sweats fever splenomegaly weight loss bleeding episodes
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)
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
CML dx
bone marrow aspiration
Familial Malignant Melanoma (FAMM) clinical manifestations
large number of atypical moles at early age, more aggressive when familial
FAMM predictors
light complexion inability to tan red hair number of atypical nevi >10 nevi on back freckles
TANNING BEDS
FAMM genetics
autosomal dominant
CDKN2A and MC1R genes
genetics+environment
FAMM genetic testing
not recommended
