Genetics

Question 1

polygenic disease

Answer 1

caused by a number of alleles of several genes interacting.

Question 2

penetrance

Answer 2

disease is expressed in 100% of people with a particular genotype, incomplete or complete

Question 3

allele

Answer 3

homologous copies of a gene…Human have two sets of each gene, once copy on each chromosome.

Question 4

trisomy 21 phenotype

Answer 4

cardiac defects intestinal malformations vision abnormalities hearing loss recurrent respiratory infections memory loss with an increased risk of Alzheimer’s at early age. decreased muscle tone flat facial features, enlarged and protruding tongue small nose upward slant of eyes abnormally shaped ears deep palmar crease Hyperflexibility extra space between first and second toe

Question 5

klinefelter syndrome

Answer 5

XXY Most common genetic abnormality associated with PRIMARY hypogonadism. Individuals have small external genitalia and tests. 50% will develop breasts. Usually sterile, impaired spermatogenesis elevated levels of FSH and LH

Question 6

Turner Syndrome

Answer 6

XO Ovum that lacks X fertilized by Sperm with X or Normal ovum (X) fertilized by sperm lacking X or Y. Female appearance but Short, wide chest Prominent neck skin folds Usually sterile, low estrogen Small breasts Normal mental development

Question 7

autosomal dominant

Answer 7

Mutation in a SINGLE allele of autosome is enough to cause disease or abnormal phenotype In pedigree, multiple generations are affected → vertical pattern Equal male and female Only one affected parent necessary for child to be affected Each child has a 50% chance of abnormal phenotype

Question 8

autosomal recessive

Answer 8

Mutation in which TWO copies of the allele of autosome are require to manifest abnormal phenotype. Horizontal pattern in the pedigree Equal male and female pattern Both parents must be carriers in order for offspring to manifest trait Often occur in consanguinity Less common, but some autosomal recessive disorders can confer a biological advantage (i.e. sickle cell) Offspring of two carriers have 25% chance of being affected, 50% chance of being carrier, 25% chance of normal alleles

Question 9

X-linked inheritance

Answer 9

No male-to-male transmission. X-linked dominant and X-linked recessive applies to females only.

Question 10

X-linked dominant inheritance

Answer 10

A single allele of mutant X allele is all that is needed to express the phenotype. The trait is never passed from father to son. Males are more severely affected than females and the trait may be lethal in males. Affected female x normal male = ½ of sons affected and ½ daughters affected Less common than x-linked recessive inheritance

Question 11

X-linked recessive inheritance

Answer 11

Two copies of mutant allele are required to produce the disease in females (XmXm), but only one copy in males (XmY) to produce disease. Women are generally not affected by trait if heterozygous for it. The trait is not passed from father to son. X-linked recessive diseases are more common in males.

Question 12

mitochondrial inheritance

Answer 12

Mother will pass her mitochondrial DNA, including mutant DNA to all of children, male or female. inheritance only through maternal lines affected males do not pass on gene

Question 13

PKU

Answer 13

Phenylketonuria is an inherited disorder in which there is a defect in phenylalanine hydroxylase causing phenylalanine to accumulate. Leads to severe mental retardation as excess phenylalanine is thought to impair brain growth, myelination and neurotransmitter synthesis. Dietary restriction of phenylalanine and pharmacotherapy helps to mitigate impairment

Question 14

CF

Answer 14

Cystic Fibrosis results from a mutation in the CTFR gene causing changes in the chloride and water transport across membranes. Individuals with this disorder have thick mucus that is difficult to expectorate from the lungs, and also builds up in the ducts of the pancreas. The newborn is tested for the presence of increased levels of immunoreactive trypsinogen (IRT), a pancreatic protein linked to cystic fibrosis

Question 15

pre-embryonic stage

Answer 15

first stage of human development after fertilization and ends with implantation

Question 16

day 3 of pre-embryonic stage

Answer 16

morula forms

Question 17

blastocyst

Answer 17

as morula continues to divide, it will accumulate fluid in the center and become a blastocyst

Question 18

inner cell mass becomes

Answer 18

embryo

Question 19

trophoblast becomes

Answer 19

placenta

Question 20

day 6 or 7 of pre embryonic stage

Answer 20

blastocyst will attach to uterine wall and begin to digest it for nourishment

Question 21

embryonic stage

Answer 21

from day 8 to week 8 uterine wall will grow over blastocyst, for protection amniotic cavity forms 3 germ layers begin to differentiate from the internal cellular mass

Question 22

fetal stage

Answer 22

from end of week 8 to week 40 organ development continues and rapid growth

Question 23

Day 16 of embryonic stage

Answer 23

all organs of the body have been formed from the 3 germ layers

Question 24

teratogenesis

Answer 24

dose dependent, can produce death, growth retardation, malformation and functional impairment

Question 25

critical period for teratogenesis

Answer 25

3-16 weeks due to potential impairment of organogenesis

Question 26

Category A medication

Answer 26

A is A-OK Well-controlled human studies have not disclosed any fetal risk

Question 27

Category B medication

Answer 27

B is Be weary Animal studies have not disclosed any fetal risk, or some risk but not confirmed, or no adequate studies available

Question 28

Category C medication

Answer 28

C is Caution! Animal studies have shown adverse effects, no studies available

Question 29

Category D medication

Answer 29

D is Don’t Some fetal risk, risk vs. benefit to patient

Question 30

Category X Medication

Answer 30

X is the worst Fetal abnormalities in animal/human studies, risk > benefit. CONTRAINDICATED

Question 31

Amelia

Answer 31

Deformity associated with Thalidamide use complete absence of a limb or limbs

Question 32

Meromelia

Answer 32

Deformity associated with thalidomide use partial absence of a limb

Question 33

Phocomelia

Answer 33

Deformity associated with thalidomide use absence of long bones with hands and feet attached to trunk with small rudimentary bones

Question 34

Kefauver-Harris Drug Amendments Act

Answer 34

in 1962, enacted as a result of Thalidomide tragedy. Prior to act, medications could be sold 60 days after application filed with FDA FDA was given 180 days to review new medications and adverse effects had to be recorded. New drugs now take 8-10 years to come to market

Question 35

Diethylstilbestro

Answer 35

DES is a potent estrogen that was used from 1940-1971 in order to prevent spontaneous abortion and premature labor. DES daughters found to have increased risk of developing vaginal cancer (rare) and at a young age, along with increased risk of cervical cancer, reproductive organ structural defects and infertility DES sons found to have smaller male reproductive organs

Question 36

Vitamin A

Answer 36

substantial Vitamin A use while pregnant fount to increase risk of cleft-palate and cleft-lip, hydrocephalus and cardiac deformities

Question 37

Isotretinoin

Answer 37

vitamin-A isomer, accutaine for acne. one of most potent teratogens currently in use spontaneous abortion in 30% of cases. malformations on par with thalidomide effects

Question 38

ACE inhibitors

Answer 38

Use in 2nd and 3rd trimester → growth retardation, renal dysfunction, fetal demise and oligohydramnios (less amniotic fluid) Lisinopril, Captopril, Ramipril, Enalapril, Captopril

Question 39

SSRI’s

Answer 39

Linked to increased risk of cardiovascular defects, May increase risk for spontaneous abortion, Inhibit serotonin signaling in heart development Fluoxetine, Sertraline, and Paroxetine

Question 40

Anticonvulsants

Answer 40

Abnormality is based on specific anticonvulsant, but includes cleft palate, cleft lip, atrial septal defects, spina bifida, developmental delay, limb abnormalities Valproic acid, Carbamazepine, Phenytoin.

Question 41

NSAIDS

Answer 41

Use of NSAIDs during first trimester →increased risk of having a baby with cardiac ventricular and septal defects Use of NSAIDs during third trimester results in pulmonary hypertension in newborn. Aleve, Ibuprofen, Advil, Naproxen, Ketoprofen, Celebrex, Indocin

Question 42

Warfarin (Coumadin)

Answer 42

First trimester exposure results in skeletal abnormalities: Nasal hypoplasia Long bone development abnormalities Limb hypoplasia

Question 43

Benzodiazepines

Answer 43

used in treatment of generalized anxiety- Alprazolam, Diazepam, Lorazepam, Clonazepam, Chlordiazepoxide Neonatal withdrawal Hypotonia- decreased muscle tone Cyanosis- poor o2 “Floppy infant syndrome

Question 44

Alcohol

Answer 44

Alcohol at any gestational stage can cause developmental disabilities. Teratotogenic effects can depend on quantity of alcohol used and pattern of drinking behavior. Smallest effects recognized (LBW) at 2 drinks/day and become more evident at 4 drinks/day Most FAS occurs in mothers who are alcoholics (8-10 drinks/day) Prenatal alcohol exposure leads to abnormal brain structure and reduction of brain volume in multiple structures of brain.

Question 45

Tobacco

Answer 45

Increased risk of infertility Increased risk of placenta previa Increased risk of preterm premature rupture of membranes (PPROM) Increased risk of placental abruption

Question 46

Marijuana

Answer 46

The most commonly abused illicit drug of pregnancy≈2-3% of pregnant women No apparent effect on birth weight or gestational age No association with prematurity or congenital abnormalities No effect on overall IQ, but some increase difficulty with problem-solving skills, learning and memory deficits Heavy marijuana use seems to increase memory and learning issues.

Question 47

Cocaine

Answer 47

Spontaneous abortion Fetal demise Placental abruption Premature birth IUGR- Intrauterine growth retardation Neurobehavior issues appear within 48-72 hours of birth and include tremors, high-pitched cry, irritability, excess suck, hyperalertness, and episodes of either apnea or tachypnea.

Question 48

Opioids

Answer 48

rapidly increasing in popularity, especially heroin use. Codeine- associated with increased risk of congenital heart defects Chronic heroin use is associated with: an increased risk of fetal growth restriction abruptio placenta fetal death preterm labor intrauterine passage of meconium

Question 49

Toxoplasmosis

Answer 49

TORCH Most commonly spread through the fecal matter of cats ACOG recommends that only high-risk women (HIV) be screened or women with fetus with evidence of abnormalities related to toxoplasmosis

Question 50

Maternal toxoplasmosis symptoms

Answer 50

can be asymptomatic, or feel like the flu

Question 51

congenital toxoplasmosis

Answer 51

Chorioretinitis- inflammation in chorion Hydrocephalus- calcified lesions in brain and fluid Intracranial calcifications Learning or visual disability later in life

Question 52

Other infection

Answer 52

TORCH Primarily congenital syphilis Congenital syphilis affects one million pregnancies per year worldwide. Most cases occur in mothers with little or no prenatal care. Transmission occurs as spirochete crosses placenta or during birth. Lab work to detect syphilis is done during pregnancy.

Question 53

Rubella

Answer 53

TORCH Screening for antibodies to rubella routinely done in pregnancy Increased rates of: Fetal death Premature delivery Intrauterine growth retardation Low birth weight Purpura and petechiae (“blueberry muffin rash”)

Question 54

Cytomegalovirus

Answer 54

TORCH (CMV) is a member of the herpesvirus family, and most commonly causes a “mono like” infection in its host with fever, rhinitis, pharyngitis, myalgias headache and fatigue. It can manifest in many ways and affect many organ systems in host. ~90% of time no clinical manifestations. CMV is transmitted via placenta, or less commonly during vaginal delivery or breastfeeding Progressive hearing loss- early or late onset Jaundice Small for gestational age Hepatomegaly Petechiae and purpura

Question 55

Herpes Simplex Virus

Answer 55

TORCH Transmission to neonates can occur during delivery due to viral shedding, even when visible disease is absent. C-sections performed to avoid this

Question 56

HSV intrauterine disease

Answer 56

Intrauterine disease dissemination is rare but very serious. Associated with: Infarcts of placenta Inflammation of umbilical cord Hydrops fetalis Fetal demise Skin abnormalities: skin vesicles, ulceration, scarring Ocular damage Severe CNS deformities: microcephaly

Question 57

HSV Neonatal disease

Answer 57

Skin, Eye, Mouth Manifestations (SEM)- 45% of neonatal disease, can present anytime in first 6 weeks of life Vesicles on an erythematous base Ocular infection: watery eye, crying from ocular pain, conjunctival erythema HSV keratoconjunctivitis, cataracts, chorioretinitis, vision loss Ulcerations of mouth, throat, palate and tongue Virus can spread to CNS and cause seizures and other neurological issues

Question 58

Disseminated involvement

Answer 58

HSV Neonatal occurs in 25% on neonatal HSV transmission, more severe and affects multiple organs, including the liver, lungs, adrenals, central nervous system, skin, eye, or mouth As infection progresses→ Hepatitis Hyperbilirubinemia Neutropenia/Thrombocytopenia DIC- Disseminated Intravascular Coagulation Hemorrhagic pneumonitis Necrotizing enterocolitis Meningoencephalitis and seizures Mortality exceeds 80% with untreated disseminated disease

Question 59

Alzheimers

Answer 59

Amyloid plaques- abnormal deposits of a protein called beta amyloid that is found in the space between neurons Neurofibrillary tangles- formed by clumps of tau protein, which is part of the structure of the microtubules that support the structure of the neuron As a result, the synaptic connections between neurons are lost and many neurons stop functioning and die. Eventually, atrophy of the brain occurs and functioning and memory processes decrease greatly.

Question 60

early onset alzheimers

Answer 60

most are autosomal dominant between 30-60 yo 1-5% total cases Amyloid precursor protein (APP gene) Presenilin 1 (PSN1) Presenilin 2 (PSN2)

Question 61

Late onset alzheimers

Answer 61

95% of cases in ages 65 and up Genetics of late-onset AD is much more complex and represents several genetic, environmental influences More than 20 genes have been identified, but the most firmly identified gene involved is apolipoprotein E (APOE).

Question 62

APOE

Answer 62

related to late onset alzheimers exists in 3 forms/alleles one reduces risk, one has no change and one involved in earlier onset (E4) APOE is a susceptibility gene, not a determinant gene, 40% of AD patients do not carry APOE ε4 and not every person with one or two copies of APOE ε4 will get AD…no absolutes and many other genes are being investigated.

Question 63

Huntingtons disease

Answer 63

autosomal dominant HD gene codes for a protein called Huntingtin, which is thought to be involved in neuronal function The mutated form of HD gene consists of an expanded CAG trinucleotide repeat. CAG= codon for glutamine Repeats add strings of glutamines to Huntingtin protein Higher number of CAG repeats = earlier onset and higher severity of disease. >40 will manifest the disease. worse if inherit paternally

Question 64

Cystic Fibrosis

Answer 64

affects multiple organ systems part of newborn screen Most common lethal inherited disorder among Caucasians in U.S. Autosomal recessive The cystic fibrosis transmembrane conductor regulator (CTFR) gene on chromosome 7 helps regulate chloride channels in epithelial cells. 1000+ mutations in this gene have been identified.

Question 65

CFTR

Answer 65

CFTR mutations affect the quantity and function of chloride transporters on epithelial surfaces. In healthy patients, these channels allow for chloride to be excreted and excess sodium uptake is inhibited. In patients with CF, defective transport chloride across the membrane and enhanced sodium absorption cause increase in water absorption. CF patients have thick, viscous secretions as a result of this osmotic increase in sodium and water absorption by the cell. that there is a wide variety of manifestations of CF due to variety and severity of CFTR genetic mutations.

Question 66

Neurofibromatosis

Answer 66

A neurofibroma is a benign, encapsulated tumor composed of Schwann cells that are ectodermal in origin. Neurofibromas cause tumors to grow on any part of the body and they can grow to be very large.

Question 67

NF1

Answer 67

autosomal dominant due to NF1 gene mutation, which is normally a tumor suppressor gene manifestations: cafe au lait macules, freckling, Lisch nodules in iris, neurofibromas, optic gliomas (more severe), bony abnormalities, cognitive and mental retardation in 40%

Question 68

NF2

Answer 68

mutation in gene that codes for merlin, a tumor supressor (schwannomin protein) autosomal dominant Development of noncancerous tumors on the auditory and vestibular nerves of the body Tumors are known as schwannomas and are usually bilateral. Tumors can also occur in the CNS. Fewer cutaneous manifestations than NF1 Symptoms appear later in life, 20-50’s

Question 69

Polycystic kidney disease

Answer 69

Most commonly manifests as bilateral renal cysts, but is a multi-organ disease: Intracranial aneurysm- 10-20% of person with PKD- most dangerous complication autosomal dominant PKD1 or PKD2 genes

Question 70

PKD1

Answer 70

polycystin-1

85% of disease

Increased severity of symptoms- larger kidneys and more cysts

Younger onset of symptoms

Faster progression to ESRD

Question 71

PKD2

Answer 71

polycystin-2 15% of disease

Decreased severity of symptoms compared to PKD1

Later onset of symptoms

Question 72

Hemochromatosis

Answer 72

Hereditary hemochromatosis (HHC) is a disorder that causes increased intestinal absorption of iron. Subsequently, iron is stored in liver, pancreas, skin, heart and pituitary gland. Autosomal recessive sex induced phenotype, different iron intake and excretion in men and women

The HFE protein regulates the production of hepcidin, which is considered the “master” controller of iron levels in the body. Affected persons do not usually present until age 40 or later and are related to excess absorption over a period of years Potentiated by alcoholic liver disease and infectious hepatitis “bronze diabetes”

Question 73

coagulation cascade

Answer 73

intrinsic and extrinsic pathways

intrinsic will send signals that the inside of a vessel is damaged

extrinsic will send signals that there is damage done to the epidermis, or some other external structure.

Extrinsic route is shorter and the response is faster

External: immediately stop the bleeding

Internal: thoroughly stop the bleeding

Question 74

Factor X

Answer 74

where the extrinsic and intrinsic coagulation pathways merge

Question 75

Hemophilia

Answer 75

bleeding disorder, affects 1:5000 males

X-linked recessive

female carriers can show mild symptoms

1/3 of cases are de novo mutation in F8 or F9 s

everity dictated by amount of normal protein function Intrinsic coagulation pathway affected

Question 76

Hemophilia A

Answer 76

F8 mutation

Classic hemophilia, most common 1:5-10,000

Question 77

Hemophilia B

Answer 77

F9 mutation

Christmas disease

less common, 1:25-30,000

Question 78

Female symptomatic hemophilia

Answer 78

Turner-like, XO

X Chromosome inactivation

Affected male mates with carrier female

Question 79

Hemophilia manifestations

Answer 79

bleeding from forceps or vacuum use during birth, bleeding from circumcision, hemearthrosis (bleeding into joint capsule)

usually diagnosed by age 2 if not diagnosed by then and have later onset of symptoms, the severity of the disease is usually less

Question 80

Von Willebrand factor

Answer 80

Involved in platelet adhesion to the subendothelium- acts as a “bridge” between platelets and the injured subendothelium

Question 81

Von Willebrand disease

Answer 81

most common inherited bleeding disorder

will have low F8 function

mostly autosomal dominant, but can vary in penetrance men and women equally affected Type I-III, type III is the worst because no VW protein is made

Question 82

Hemophilia C

Answer 82

Factor 11 defeciency autosomal recessive 1:100,000 50% of diagnosed are asymptomatic- people usually do not need treatment

Question 83

Sickle cell anemia

Answer 83

1:72,000 in the US, higher in descendants of subsaharan africa (1:500 AA)

HBB hemoglobin gene has a point mutation, changes an AA, and you get sickled Hb from that.

Autosomal recessive

Heterozygous carriers said to have the sickle cell trait, and are shown to be more resistant to malaria

Part of newborn screening

Question 84

Sickle cell disease manifestations

Answer 84

shorter life expectancy

have failure to thrive

anemia

splenomegaly

vaso-occulision–> swelling of extremities

hemolysis

Jaundice from breakdown of bilirubin

Aplastic crisis- shutdown of RBC production post viral infection.

Question 85

Familial hypercholesterolemia

Answer 85

most cases are polygenic, but monogenic mutations in the LDLR gene have been found. Inherited autosomal dominant or recessive, depending on the specific mutation tendon xanthomas

xanthelasma

Atherosclerosis

Question 86

LDLR gene

Answer 86

low-density lipoprotein receptor

If the receptor is abnormal, it cannot do its job properly and there is more LDL floating around, not getting taken up by the cell for energy.

Homozygous form is rare = 1 in million →atherosclerosis of childhood, serum cholesterol 8x normal

Heterozygous form = 1 in 500 → LDL 2-3 x normal

Question 87

Marfan syndrome

Answer 87

inherited or de novo mutation in fibrillin-1 gene

autosomal dominant

Fibrillin-1 encodes for glycoprotein fibrillin→principal component of the microfibril →part of the structure of collagen

Microfibrils particularly abundant in aorta, periosteum, alveolar walls, skin

Aortic root disease is the main cause of morbidity and mortality in Marfan Syndrome and needs to be carefully evaluated and monitored! often have other skeletal abnormalities, including scoliosis

other symptoms are Arachnodactyly and Dolichostenomelia (arm span > body height)

Ghent criteria for diagnosis, along with genetic testing

Question 88

the 4 P’s

Answer 88

Pallor Pulselessness Paresthesias- numb extremities Paralysis severe symptoms of arctic aneurism –> familial thoracic aortic aneurism?

Question 89

Familial thoracic aortic aneurism

Answer 89

autosomal dominant 4 genes identified Patients with familial TAA tend to present at an earlier age than sporadic TAA ~ average age of 56 vs. 64 y/o

Question 90

Dilated cardiomyopathy

Answer 90

Dilatation of at least one of the ventricles of the heart which results in impaired contraction of one or both ventricles

Question 91

hypertrophic cardiomyopathy

Answer 91

Myocardium becomes thickened, especially in the left ventricle

disease of the sarcomere

linked to 12+ genes

mostly autosomal dominant, some de novo

Question 92

restrictive cardiomyopathy

Answer 92

Stiffening and rigidity of the ventricles due to replacement of normal myocardium by scar tissue, no hypertrophy of ventricle

Question 93

arrythmogenic cardiomyopathy

Answer 93

Right ventricular myocardium replaced with scar tissue.

Abnormal rhythms follow.

1:1000 incidence

8 associated genes

autosomal dominant inheritance

Pathogenesis related to: desmosome dysfunction when subjected to mechanical stress myocyte detachment and cell death

Inflammation

fibrofatty replacement of damaged myocytes

Question 94

2 most common hereditary cardiomyopathies

Answer 94

Hypertrophic cardiomyopathy (HCM)- disorder of left ventricle

Arrhythmogenic cardiomyopathy/Arrhytmogenic Right Ventricular Dysplasis/Cardiomyopathy (ARVD/C)- disorder of right ventricle

Question 95

breast cancer

Answer 95

lifetime risk for women is 10-13% most common cancer in women

Question 96

hereditary breast cancer

Answer 96

Approximately 5-10% of breast and ovarian cancer are attributed to genetics genetics is 3rd strongest predictor or risk after age and gender increased risk in some groups: ashkenazi jews

Question 97

BRCA1 and BRCA2 overview

Answer 97

Autosomal dominant inheritance pattern with high penetrance both are tumor suppressor genes function to preserve structure of chromatids and chromosomes BRCA1 and BRCA2 involved in the repair of breaks in DNA Cells deficient in BRCA1 or BRCA2 have been shown to have increased translocations, inversion, deletions and fusions of nonhomologous chromosomes ≈50 percent of all patients with inherited early-onset breast cancer and most patients with inherited ovarian cancer carry a BRCA1 or BRCA2 mutation

Question 98

RAD51

Answer 98

complexes with BRCA2 to repair damage to dsDNA. The RAD51 gene has been implicated in breast cancer as well.

Question 99

BRCA1

Answer 99

mutation may increase risks for cancers of : cervix, uterus, fallopian tube, primary peritoneum, pancreas, esophageal, stomach, and prostate BRCA1 is associated with higher lifetime risk of development of cancer than BRCA2 Mean age at diagnosis lower with BRCA1 than BRCA 2 (age 43 vs. 47) BRCA1 overall increased risk of cancer by age 70

Question 100

BRCA2

Answer 100

mutation has been consistently shown to increase risk of prostate and pancreatic cancer mutation may increase risks for cancer of: stomach, gallbladder, bile duct, esophagus, stomach, fallopian tube, primary peritoneum, and skin First childbirth at later ages associated with increased breast cancer risk in BRCA2 carriers Men carriers of BRCA2 have higher risk of developing BC than if they were to carry BRCA1

Question 101

ovarian cancer

Answer 101

lifetime risk is 1:58 most common cause of gyno cancer DEATH

Question 102

hereditary ovarian cancer

Answer 102

only 5-10% of ov. ca. is hereditary BRCA1 carriers have a 70% chance of developing ov.ca. by age 70 lower risk w brca2

Question 103

testing in hereditary breast and ovarian cancer

Answer 103

HBOC preventative task force states you should see a GC and get tested if you have family hx.

Question 104

management of pts with HBOC

Answer 104

Clinical breast exam 2-4 x annually starting at age 25 Annual mammogram beginning ages 25-35 with consistent location and prior films Annual breast MRI Elective bilateral mastectomy – 90-95% risk reduction Annual or semiannual transvaginal US Annual CA-125 level Prophylactic bilateral salpingo-oophorectomy ages 35-40 (95% risk reduction in ovarian CA and 50% reduction in breast CA)

Question 105

colorectal cancer

Answer 105

rates higher in males and African Americans global incidence can vary due to environment, genetics and diet–> highest in New Zealand, Australia, NA and europe. lifetime avg. risk is 5% and usu. after 50 higher incidence in lower socioeconomic people due to obesity, smoking, inactivity, lower screening rates

Question 106

symptoms of colorectal cancer

Answer 106

blood in stool- Hematochezia unexplained weight loss cramping decrease in stool size

Question 107

WARNING about Colorectal cancer

Answer 107

if you have an elderly patient with sudden anemia, it IS COLORECTAL CANCER until proven otherwise

Question 108

hereditary CRC

Answer 108

15-30% of CRC is hereditary Two hereditary colorectal cancer syndromes: Familial adenomatous polyposis (FAP) Hereditary nonpolyposis colorectal cancer (HNPCC)- lynch syndrome. Still get polyps, just fewer of them

Question 109

FAP

Answer 109

Familial Adenomatous Polyposis have a nearly 100% lifetime risk of colon cancer average age of onset of colon cancer is 39 Manifest with adenomatous polyps very early in life colectomy is recommended, usually before age 20

Question 110

How do you get FAP

Answer 110

usually it is autosomal dominant Near complete penetrance 25% of cases are de novo mutations caused by mutation in APC gene (Adenomatous Polyposis Coli) can also be autosomal recessive, but this is less common. due to MYH gene mutation

Question 111

Attenuated FAP

Answer 111

fewer polyps and develop later in life 70-80% risk of colon cancer, instead of 100% Adenomas are typically in right colon

Question 112

Genotype phenotype association in FAP

Answer 112

mutations in middle of gene associated with the classic FAP. Whereas, attenuated FAP (AFAP) is associated with mutations that are typically in the ends of the APC gene.

Question 113

Gardner syndrome

Answer 113

a subset of FAP have colon adenomatous polyps, PLUS polyps in the upper GI tract, stomach and duodenum also can have thyroid cancer, CNS tumors, childhood hepatoblastoma, and others…

Question 114

Hereditary Nonpolyposis Colorectal Cancer

Answer 114

Lynch syndrome colorectal cancer develops from relatively few polyps the polyps are flatter, larger, undergo rapid transformation to cancer colon cancer often occurs in the right side of the colon average age of onset is 45 Progress from a normal colonoscopy to cancer in 2-3 years

Question 115

other associated malignancies in HNPCC

Answer 115

*Uterine cancer Ovarian cancer Gastric cancer Small bowel cancer Biliary tract cancer Upper urinary tract cancer Pancreatic cancer Skin cancer Brain cancer 7-10% of Lynch family members have had more than one cancer at time of diagnosis uterine cancer is most common, and occurs 10 years earlier than average if you have HNPCC

Question 116

Amsterdam II

Answer 116

a criteria to identify carriers of Lynch syndrome. genetic testing not always needed. 3-2-1 at least 3 relatives with an HNPCC associated cancer 2 successive generations need to be affected 1 family member diagnosed before 50

Question 117

Genetics of Lynch syndrome

Answer 117

autosomal dominant inheritance due to a defect in one of the mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) Specific gene affected can alter phenotypic expression

Question 118

recommendations for lynch syndrome

Answer 118

family hx is most important if genetic testing is done and mutation is present, relatives need to have colonoscopies every 1-2 years starting @ 25 upper endoscopies every 2-3 years Screening for endometrial cancer and ovarian cancer with pelvic exam, CA125, TVUS, endometrial biopsy at age 25-35

Question 119

Peutz-Jehgers Syndrome

Answer 119

Melanocytic macules on lips, perioral and buccal regions Increased GI polyps Increased risk of colon, breast, stomach, small bowel, pancreatic CA- 38-66% Autosomal dominant disorder

Question 120

Leukemia

Answer 120

malignant progressive disease in which the bone marrow and other blood-forming organs produce increased numbers of immature or abnormal leukocytes. These suppress the production of normal blood cells, leading to anemia and other symptoms

Question 121

Tendon Xanthomas

Answer 121

Manifestation of Familial Hypercholesterolemia

Question 122

xanthelasma

Answer 122

Skin tags

Manifestation of Familial Hypercholesterolemia

Question 123

Acute leukemia

Question 124

Chronic leukemia

Answer 124

u- Some blast cells are present, but generally cells more mature and can carry out normal functions, develops at slower pace

Question 125

CML

Answer 125

uncontrolled production of granulocytes, primarily neutrophils, but also basophils and eosinophils

All the phils

Question 126

Philadelphia Chromosome

Answer 126

first genetic abnormality associated with human cancer

Reciprocal translocation between the long arms of chromosomes 9 and 22. Leads to increased level of tyrosine kinase activity –> Abnormal cell growth

Philadelphia chromosome present in 90-95% of all CML patients

Question 127

HOw do you get CML

Answer 127

It is not inherited.

Mutation happens in SOMATIC cell lines

Question 128

Malignant melanoma

Answer 128

Use of indoor tanning beds = four x more likely to develop malignant melanoma

ABCD’s of nevus

Question 129

FAMMM Syndrome

Answer 129

familial atypical multiple mole syndrome

Large number of atypical moles at an early age
More aggressive disease progression when familial

Lifetime risk can approach 100%

Family history of cutaneous melanoma in at least two first-degree relatives

Question 130

Familial Malignant Myeloma

Answer 130

CDKN2A (Cylin-dependent kinase inhibitor 2A)

uresponsible for decelerating cells progression from G1 phase to S phase

uCDKN2A mutations can also predispose to development of pancreatic cancer- risk=11-17%