Genetics Flashcards
polygenic disease
caused by a number of alleles of several genes interacting.
penetrance
disease is expressed in 100% of people with a particular genotype, incomplete or complete
allele
homologous copies of a gene…Human have two sets of each gene, once copy on each chromosome.
trisomy 21 phenotype
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
klinefelter syndrome
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
Turner Syndrome
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
autosomal dominant
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
autosomal recessive
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
X-linked inheritance
No male-to-male transmission. X-linked dominant and X-linked recessive applies to females only.
X-linked dominant inheritance
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
X-linked recessive inheritance
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.
mitochondrial inheritance
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
PKU
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
CF
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
pre-embryonic stage
first stage of human development after fertilization and ends with implantation
day 3 of pre-embryonic stage
morula forms
blastocyst
as morula continues to divide, it will accumulate fluid in the center and become a blastocyst
inner cell mass becomes
embryo
trophoblast becomes
placenta
day 6 or 7 of pre embryonic stage
blastocyst will attach to uterine wall and begin to digest it for nourishment
embryonic stage
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
fetal stage
from end of week 8 to week 40 organ development continues and rapid growth
Day 16 of embryonic stage
all organs of the body have been formed from the 3 germ layers
teratogenesis
dose dependent, can produce death, growth retardation, malformation and functional impairment
critical period for teratogenesis
3-16 weeks due to potential impairment of organogenesis
Category A medication
A is A-OK Well-controlled human studies have not disclosed any fetal risk
Category B medication
B is Be weary Animal studies have not disclosed any fetal risk, or some risk but not confirmed, or no adequate studies available
Category C medication
C is Caution! Animal studies have shown adverse effects, no studies available
Category D medication
D is Don’t Some fetal risk, risk vs. benefit to patient
Category X Medication
X is the worst Fetal abnormalities in animal/human studies, risk > benefit. CONTRAINDICATED
Amelia
Deformity associated with Thalidamide use complete absence of a limb or limbs
Meromelia
Deformity associated with thalidomide use partial absence of a limb
Phocomelia
Deformity associated with thalidomide use absence of long bones with hands and feet attached to trunk with small rudimentary bones
Kefauver-Harris Drug Amendments Act
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
Diethylstilbestro
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
Vitamin A
substantial Vitamin A use while pregnant fount to increase risk of cleft-palate and cleft-lip, hydrocephalus and cardiac deformities
Isotretinoin
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
ACE inhibitors
Use in 2nd and 3rd trimester → growth retardation, renal dysfunction, fetal demise and oligohydramnios (less amniotic fluid) Lisinopril, Captopril, Ramipril, Enalapril, Captopril
SSRI’s
Linked to increased risk of cardiovascular defects, May increase risk for spontaneous abortion, Inhibit serotonin signaling in heart development Fluoxetine, Sertraline, and Paroxetine
Anticonvulsants
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.
NSAIDS
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
Warfarin (Coumadin)
First trimester exposure results in skeletal abnormalities: Nasal hypoplasia Long bone development abnormalities Limb hypoplasia
Benzodiazepines
used in treatment of generalized anxiety- Alprazolam, Diazepam, Lorazepam, Clonazepam, Chlordiazepoxide Neonatal withdrawal Hypotonia- decreased muscle tone Cyanosis- poor o2 “Floppy infant syndrome
Alcohol
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.
Tobacco
Increased risk of infertility Increased risk of placenta previa Increased risk of preterm premature rupture of membranes (PPROM) Increased risk of placental abruption
Marijuana
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.
Cocaine
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.
Opioids
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
Toxoplasmosis
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
Maternal toxoplasmosis symptoms
can be asymptomatic, or feel like the flu
congenital toxoplasmosis
Chorioretinitis- inflammation in chorion Hydrocephalus- calcified lesions in brain and fluid Intracranial calcifications Learning or visual disability later in life
Other infection
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.
Rubella
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”)
Cytomegalovirus
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
Herpes Simplex Virus
TORCH Transmission to neonates can occur during delivery due to viral shedding, even when visible disease is absent. C-sections performed to avoid this
HSV intrauterine disease
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
HSV Neonatal disease
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
Disseminated involvement
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
Alzheimers
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.
early onset alzheimers
most are autosomal dominant between 30-60 yo 1-5% total cases Amyloid precursor protein (APP gene) Presenilin 1 (PSN1) Presenilin 2 (PSN2)
Late onset alzheimers
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).
APOE
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.
Huntingtons disease
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
Cystic Fibrosis
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.
CFTR
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.
Neurofibromatosis
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.
NF1
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%
NF2
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
Polycystic kidney disease
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
PKD1
polycystin-1
85% of disease
Increased severity of symptoms- larger kidneys and more cysts
Younger onset of symptoms
Faster progression to ESRD
PKD2
polycystin-2 15% of disease
Decreased severity of symptoms compared to PKD1
Later onset of symptoms
Hemochromatosis
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”
coagulation cascade
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
Factor X
where the extrinsic and intrinsic coagulation pathways merge
Hemophilia
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
Hemophilia A
F8 mutation
Classic hemophilia, most common 1:5-10,000
Hemophilia B
F9 mutation
Christmas disease
less common, 1:25-30,000
Female symptomatic hemophilia
Turner-like, XO
X Chromosome inactivation
Affected male mates with carrier female
Hemophilia manifestations
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
Von Willebrand factor
Involved in platelet adhesion to the subendothelium- acts as a “bridge” between platelets and the injured subendothelium
Von Willebrand disease
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
Hemophilia C
Factor 11 defeciency autosomal recessive 1:100,000 50% of diagnosed are asymptomatic- people usually do not need treatment
Sickle cell anemia
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
Sickle cell disease manifestations
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.
Familial hypercholesterolemia
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
LDLR gene
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
Marfan syndrome
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
the 4 P’s
Pallor Pulselessness Paresthesias- numb extremities Paralysis severe symptoms of arctic aneurism –> familial thoracic aortic aneurism?
Familial thoracic aortic aneurism
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
Dilated cardiomyopathy
Dilatation of at least one of the ventricles of the heart which results in impaired contraction of one or both ventricles
hypertrophic cardiomyopathy
Myocardium becomes thickened, especially in the left ventricle
disease of the sarcomere
linked to 12+ genes
mostly autosomal dominant, some de novo
restrictive cardiomyopathy
Stiffening and rigidity of the ventricles due to replacement of normal myocardium by scar tissue, no hypertrophy of ventricle
arrythmogenic cardiomyopathy
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
2 most common hereditary cardiomyopathies
Hypertrophic cardiomyopathy (HCM)- disorder of left ventricle
Arrhythmogenic cardiomyopathy/Arrhytmogenic Right Ventricular Dysplasis/Cardiomyopathy (ARVD/C)- disorder of right ventricle
breast cancer
lifetime risk for women is 10-13% most common cancer in women
hereditary breast cancer
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
BRCA1 and BRCA2 overview
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
RAD51
complexes with BRCA2 to repair damage to dsDNA. The RAD51 gene has been implicated in breast cancer as well.
BRCA1
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
BRCA2
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
ovarian cancer
lifetime risk is 1:58 most common cause of gyno cancer DEATH
hereditary ovarian cancer
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
testing in hereditary breast and ovarian cancer
HBOC preventative task force states you should see a GC and get tested if you have family hx.
management of pts with HBOC
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)
colorectal cancer
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
symptoms of colorectal cancer
blood in stool- Hematochezia unexplained weight loss cramping decrease in stool size
WARNING about Colorectal cancer
if you have an elderly patient with sudden anemia, it IS COLORECTAL CANCER until proven otherwise
hereditary CRC
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
FAP
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
How do you get FAP
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
Attenuated FAP
fewer polyps and develop later in life 70-80% risk of colon cancer, instead of 100% Adenomas are typically in right colon
Genotype phenotype association in FAP
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.
Gardner syndrome
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…
Hereditary Nonpolyposis Colorectal Cancer
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
other associated malignancies in HNPCC
*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
Amsterdam II
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
Genetics of Lynch syndrome
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
recommendations for lynch syndrome
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
Peutz-Jehgers Syndrome
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
Leukemia
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
Tendon Xanthomas
Manifestation of Familial Hypercholesterolemia
xanthelasma
Skin tags
Manifestation of Familial Hypercholesterolemia
Acute leukemia
Chronic leukemia
u- Some blast cells are present, but generally cells more mature and can carry out normal functions, develops at slower pace
CML
uncontrolled production of granulocytes, primarily neutrophils, but also basophils and eosinophils
All the phils
Philadelphia Chromosome
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
HOw do you get CML
It is not inherited.
Mutation happens in SOMATIC cell lines
Malignant melanoma
Use of indoor tanning beds = four x more likely to develop malignant melanoma
ABCD’s of nevus
FAMMM Syndrome
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
Familial Malignant Myeloma
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%
