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Block 2 IQ Questions (P=MD ver.)

IQ1: TYPE 1 DIABETES MELLITUS 6
DESCRIBE THE MOLECULAR AND CELLULAR EVENTS OF INSULIN SECRETION AND REGULATION. 6
LIST AND DESCRIBE THE TISSUES WITH INSULIN RECEPTOR EXPRESSION AND EXPLAIN THE DOWNSTREAM EFFECTS OF INSULIN
BINDING TO THESE RECEPTORS. 6
DESCRIBE THE MOLECULAR AND CELLULAR EVENTS OF GLUCAGON SECRETION AND REGULATION. 6
LIST AND DESCRIBE THE TISSUES WITH GLUCAGON RECEPTOR EXPRESSION AND EXPLAIN THE DOWNSTREAM EFFECTS OF
GLUCAGON BINDING TO THESE RECEPTORS. 7
EXPLAIN THE EFFECT OF INSULIN DEFICIENCY ON BLOOD GLUCOSE. 7
DESCRIBE THE THREE FACTORS (GENETIC, VIRAL AND AUTOIMMUNE) INVOLVED IN THE ETIOLOGY OF TYPE 1 DIABETES
MELLITUS. 7
LIST AND DESCRIBE THE PATHOPHYSIOLOGY OF THE SYMPTOMS OF HYPERGLYCEMIA. 8
LIST THE MAJOR TYPES OF INSULIN USED TO TREAT DIABETES MELLITUS AND EXPLAIN HOW THEY ARE USED IN COMBINATION
TO TREAT DIABETES. 8
NAME AND BRIEFLY DESCRIBE ONE NEW TREATMENT STRATEGY BEING INVESTIGATED FOR TYPE 1 DIABETES MELLITUS. 8
IQ2: TYPE II DIABETES MELLITUS 8
LIST THE FOUR FORMAL CRITERIA FOR MAKING A DIAGNOSIS OF DIABETES MELLITUS. 8
DESCRIBE THE HYPOTHETICAL CAUSES OF TYPE 2 DIABETES MELLITUS. 9
LIST AND DESCRIBE THE PATHOPHYSIOLOGY OF THE TYPICAL SYMPTOMS OF TYPE 2 DIABETES. 9
DEFINE INSULIN RESISTANCE AND EXPLAIN THE CENTRAL ROLE PLAYED BY ADIPOSE TISSUE IN THE DEVELOPMENT OF THIS
CONDITION. 9
DESCRIBE THE INTERACTION OF GENES AND ENVIRONMENT IN THE EVOLUTIONARY CAUSATION OF TYPE 2 DIABETES MELLITUS.
10
DEFINE THE TERM METABOLIC SYNDROME. 10
DESCRIBE THE ROLE OF DIET AND EXERCISE IN THE TREATMENT OF TYPE 2 DIABETES. 10
DESCRIBE HOW MAJOR CLASSES OF DRUGS USED TO TREAT TYPE 2 DIABETES MELLITUS TRY TO CORRECT ABNORMALITIES
RELATED TO PATHOGENESIS OF TYPE 2 DIABETES MELLITUS. 10
IQ3: THYROID DYSFUNCTION 10
DESCRIBE THYROID HORMONE SYNTHESIS AND HOW IT IS REGULATED BY THE HYPOTHALAMUS-PITUITARY-THYROID AXIS. 10
LIST AND DESCRIBE THE EFFECTS OF THYROID HORMONE ON THE DIFFERENT TISSUES AND BODY SYSTEMS. 12
DESCRIBE MAJOR SYMPTOMS AND SIGNS OF THYROTOXICOSIS AND EXPLAIN HOW EXCESS THYROID HORMONE CAUSES THESE
SYMPTOMS. 12
COMPARE AND CONTRAST THE DISORDERS THAT CAN CAUSE THYROTOXICOSIS. CLASSIFY THESE DISORDERS BY THE RESULT OF
RADIOACTIVE IODINE THYROID UPTAKE AND SCAN. 12
DESCRIBE THE THERAPY FOR GRAVES DISEASE INCLUDING ANTITHYROID DRUG THERAPY INVOLVING PROPYLTHIOURACIL AND
METHIMAZOLE. 13
DESCRIBE THE MAJOR SYMPTOMS AND SIGNS OF HYPOTHYROIDISM. 13
LIST AND DESCRIBE TWO LABORATORY TESTS USED TO DIAGNOSE HYPOTHYROIDISM. 13
DESCRIBE THE MECHANISM OF ACTION, ABSORPTION, METABOLISM OF LEVOTHYROXINE. 13
IQ4: HPG AXIS & MALE SEX CELLS 13
LIST HYPOTHALAMIC, PITUITARY, GONADAL HORMONES INVOLVED IN MALE SEXUAL DEVELOPMENT 13
DESCRIBE THE HYPOTHALAMIC, PITUITARY, GONAD AXIS, ITS FEEDBACK AND REGULATION, BY DRAWING A DETAILED DIAGRAM
OF THIS SYSTEM. 14
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DESCRIBE THE NORMAL SEQUENCE OF PUBERTAL DEVELOPMENT IN THE MALE. 15
DESCRIBE THE ANATOMY AND EMBRYOLOGICAL DEVELOPMENT OF THE MALE UROGENITAL TRACT. 16
DESCRIBE THE CELLULAR COMPONENTS OF THE TESTES. 16
DESCRIBE TESTOSTERONE BIOSYNTHESIS AND LIST THE TARGET TISSUES FOR TESTOSTERONE ACTION IN THE MALE. 17
IQ5: HPG AXIS & FEMALE SEX CELLS 18
LIST THE HYPOTHALAMIC-PITUITARY-OVARIAN (HPO) HORMONES INVOLVED IN THE INITIATION OF PUBERTY AND THE
CONTROL OF THE MENSTRUAL CYCLE IN FEMALE DEVELOPMENT. 18
DRAW A DETAILED DIAGRAM OF THE HORMONAL CONTROL OF THE FEMALE REPRODUCTIVE SYSTEM TO DEMONSTRATE A CLEAR
UNDERSTANDING OF THE FEEDBACK AND HORMONAL REGULATORY MECHANISMS INVOLVED IN THE FEMALE REPRODUCTIVE
SYSTEM. 18
LIST THE FEMALE PELVIC ANATOMY NECESSARY FOR NORMAL MENSTRUATION. 19
DESCRIBE HOW ESTROGEN FROM THE OVARIES CAUSES THE DEVELOPMENT OF SECONDARY SEXUAL CHARACTERISTICS. 19
DESCRIBE HOW THE GENOTYPIC SEX DETERMINES THE GONADAL SEX, WHICH THEN DETERMINES THE PHENOTYPIC SEX. 19
IDENTIFY THE HORMONAL INTERACTIONS WHICH STIMULATE THE OVARY TO SYNTHESIZE ESTROGEN. 19
DESCRIBE THE SIMILARITIES IN THE NEUROENDOCRINE CONTROL OF MALE AND FEMALE REPRODUCTION. 20
DEFINE CHROMOSOMAL MOSAICISM AND DESCRIBE THE PHENOTYPIC EFFECT OF 45,X/46,XX MOSAIC KARYOTYPE. 20
IQ6: GESTATIONAL DIABETES 21
DESCRIBE SYMPTOMS OF PREGNANCY AND THE ASSOCIATED PHYSIOLOGIC AND HORMONAL CHANGES. 21
DESCRIBE THE HORMONAL AND PHYSICAL CHANGES THAT OCCUR IN NORMAL LABOR. 21
DESCRIBE THE EMBRYOLOGIC DEVELOPMENT OF THE FETUS AND LIST THE TIMING AND SEQUENCE OF MAJOR ORGAN SYSTEMS
(CNS, HEART, AND LIMBS). 21
IDENTIFY HOW CHANGES IN GLUCOSE METABOLISM CAN AFFECT FETAL GROWTH AND DEVELOPMENT. 22
IDENTIFY THE FETAL ANOMALIES ASSOCIATED WITH ABNORMAL GLUCOSE METABOLISM. 22
LIST FIVE FACTORS THAT INFLUENCE FETAL GROWTH. 22
DESCRIBE THE IMPACT OF DIABETES MELLITUS (DM) ON THE MOTHER DURING PREGNANCY. 22
DEFINE GESTATIONAL DIABETES MELLITUS (GDM) AND CONTRAST GDM WITH TYPE 1 AND TYPE 2 DM. 22
PROPOSE HOW THE EVOLUTIONARY CONCEPT OF MATERNAL-FETAL CONFLICT IN PREGNANCY CAN BE USED TO EXPLAIN
GESTATIONAL DIABETES. 22
DEFINE THE BIOETHICAL PRINCIPLE OF PATIENT AUTONOMY AND DESCRIBE HOW THIS APPLIES TO ADOLESCENT PREGNANCIES.
23
IQ7: GENETIC TESTING, DOWN SYNDROME (TRISOMY-21) 24
COMPARE AND CONTRAST THE MATERNAL AND PATERNAL AGE RELATED RISKS FOR FETAL ANOMALIES. 24
LIST AND DESCRIBE FOUR TESTS USED FOR PRENATAL SCREENING, INCLUDING THE HORMONES AND PROTEINS USED IN THE
TESTS AND WHY THE TESTS ARE USED. 24
DESCRIBE PROFESSIONAL GUIDELINES FOR OFFERING PRENATAL TESTING AND PATIENT AUTONOMY IN DECISION MAKING. 25
NAME AND DESCRIBE AT LEAST THREE COMMONLY USED PRENATAL DIAGNOSTIC TESTS. COMPARE AND CONTRAST THE RISKS
AND BENEFITS OF THE COMMON DIAGNOSTIC TESTS AND WHEN THEY CAN BE PERFORMED. 25
DESCRIBE HOW ULTRASOUND IS USED AS A CLINICAL TOOL IN THE IDENTIFICATION OF DEVELOPMENTAL ABNORMALITIES
INCLUDING HAVING AN UNDERSTANDING OF WHEN DEVELOPMENTAL FINDINGS ARE VISIBLE. 25
DIFFERENTIATE BETWEEN A SCREENING AND DIAGNOSTIC TEST AS THEY PERTAIN TO THE CARE OF THE PRENATAL PATIENT. 26
LIST AND DESCRIBE THE TWO DIFFERENT KARYOTYPES THAT WILL RESULT IN DOWN SYNDROME. DESCRIBE THE DIFFERENT
PARENTAL GENETIC TESTING AND COUNSELING SCENARIOS APPROPRIATE FOR EACH KARYOTYPE. 26
DEFINE THE FLUORESCENT IN SITU HYBRIDIZATION (FISH) TECHNIQUE AND EXPLAIN THE CLINICAL APPLICATION FOR THIS
TEST. 27
DESCRIBE THE TYPICAL FEATURES SEEN IN INFANTS WITH DOWN SYNDROME AND EXPLAIN HOW CHROMOSOME ANEUPLOIDY
COULD CAUSE MULTISYSTEM MALFORMATIONS. 27
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DESCRIBE A ROBERTSONIAN TRANSLOCATION AND EXPLAIN WHY THIS CHROMOSOME TRANSLOCATION CAN CAUSE DOWN
SYNDROME. CONTRAST AND DEFINE A BALANCED VERSUS UNBALANCED KARYOTYPE. 27
IQ8: DIGEORGE (22Q11.2 DELETION) 29
DEFINE MICRODELETION SYNDROME AND LIST THE GENOTYPIC AND PHENOTYPIC ABNORMALITIES ASSOCIATED WITH THE
22Q11.2 DELETION SYNDROME. 29
DESCRIBE THE NORMAL FATES OF THE CRANIAL NEURAL CREST CELLS AND USE THESE TERMS TO EXPLAIN THE EMBRYOLOGIC
RELATIONSHIP OF SOME OF THE STRUCTURES AFFECTED IN THE 22Q11.2 DELETION SYNDROME. 29
DISCUSS THE MAJOR ACTIONS OF PARATHYROID HORMONE, INCLUDING THE CLASS OF HORMONE TO WHICH IT BELONGS, WHERE
IT IS SYNTHESIZED, HOW IT IS SECRETED AND REGULATED, HOW IT IS TRANSPORTED, AND HOW IT EXERTS ITS EFFECTS. 29
DISCUSS THE MAJOR ACTIONS OF VITAMIN D, INCLUDING THE CLASS OF HORMONE TO WHICH IT BELONGS, WHERE IT IS
SYNTHESIZED, HOW IT IS SECRETED AND REGULATED, HOW IT IS TRANSPORTED, AND HOW IT EXERTS ITS EFFECTS. 29
DESCRIBE HOW HYPOCALCEMIA COULD RESULT FROM AN UNDERDEVELOPED PARATHYROID, DISCUSSING THE TWO HORMONAL
MECHANISMS THAT CAN CAUSE HYPOCALCEMIA AND LISTING THE TYPICAL LABORATORY ABNORMALITY FOUND WITH EACH
MECHANISM. 30
NAME THE TYPE OF INHERITANCE FOUND IN THE 22Q11 DELETION SYNDROME AND ESTIMATE RECURRENCE RISKS FOR FUTURE
CHILDREN OF A: A) WOMAN OF A SINGLE CHILD WITH DELETION 22Q11. B) WOMAN AFFECTED WITH DELETION 22Q11. 30
DEFINE PLEIOTROPY AND VARIABLE EXPRESSIVITY AND EXPLAIN HOW THESE CONCEPTS ARE USED IN GENETIC COUNSELING FOR
22Q11.2 DELETION SYNDROME. 30
DESCRIBE THE ETHICAL IMPLICATIONS OF RECOMMENDING PARENTAL TESTING FOR COUPLES OF REPRODUCTIVE AGE. 31
IQ9: TAY-SACHS DISEASE (15Q22-15Q25) 31
DEFINE TAY-SACHS DISEASE (TSD) AND EXPLAIN THE MAJOR FINDINGS IN THE DISEASE, THE INHERITANCE PATTERN, AND THE
CAUSATIVE GENE. 31
LIST AND DESCRIBE FOUR COMPONENTS OF A PRECONCEPTIONAL OR PRENATAL GENETIC COUNSELING FOR ASHKENAZI JEWISH
DISEASES. 31
DEFINE THE HARDY WEINBERG EQUILIBRIUM AND CALCULATE CARRIER FREQUENCY AND THE A PRIORI POPULATION RISK FOR
TSD. 31
EXPLAIN THE SIMILARITIES AND DIFFERENCES BETWEEN THE A PRIORI RISK CALCULATIONS FOR TSD AND CYSTIC FIBROSIS
(CF). 32
DEMONSTRATE, BY WRITING OUT THE CALCULATIONS, HOW CARRIER TESTING ADJUSTS RISK FOR TSD. 32
DESCRIBE CARRIER SCREENING FOR TSD AND EXPLAIN A POTENTIAL CAUSE OF FALSE NEGATIVE SCREENING IN TSD. 32
DEFINE THE TERM FOUNDER MUTATION AND EXPLAIN HOW THIS TERM IS RELEVANT FOR TSD AND THE ASHKENAZI JEWISH
POPULATION. 32
LIST AND DESCRIBE ADDITIONAL RARE GENETIC DISORDERS FOR WHICH ASHKENAZI PATIENTS CONSIDERING HAVING
CHILDREN SHOULD CONSIDER PRE-CONCEPTION GENETIC CARRIER TESTING. 32
IQ10: FRAGILE X SYNDROME 33
CONSTRUCT A PEDIGREE FOR THE FAMILY IN THIS CASE AND DEFINE THE TERMS X-LINKED INHERITANCE AND ANTICIPATION.
33
DEFINE X INACTIVATION AND COMPARE AND CONTRAST THIS PROCESS TO IMPRINTING. 33
DESCRIBE HOW FEMALES CAN MANIFEST AN X-LINKED DISORDER. 33
DISCUSS HOW A PRIORI GENETIC RISKS FOR FRAGILE X CAN BE MODIFIED BY ADDITIONAL INFORMATION OBTAINED FROM THE
FAMILY HISTORY. 33
LIST THE TYPICAL FEATURES OF FRAGILE X SYNDROME AND NAME THE GENE RESPONSIBLE FOR THE CONDITION. 33
IDENTIFY THE GENETIC MECHANISM THAT CAUSES FRAGILE X SYNDROME AND CORRELATE THE TRIPLET REPEAT EXPANSION
WITH SPECIFIC DISEASE CHARACTERISTICS. 33
DEFINE THE TERMS PRE-MUTATION AND FULL MUTATION AND DESCRIBE THE RANGE OF PHENOTYPES ASSOCIATED WITH THESE
MUTATIONS. 34
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IQ11: BWS (11P15.5) 34
LIST THE MAIN PHENOTYPIC FEATURES OF BECKWITH-WIEDEMANN SYNDROME AND EXPLAIN HOW THESE FEATURES ARE
CAUSED BY A DEFECT IN IMPRINTING. 34
DIAGRAM THE PROCESS OF CHROMOSOMAL IMPRINTING, INCLUDING THE ACTION OF THE IMPRINTING CENTER, METHYLATION,
AND CHROMOSOMAL PARENT OF ORIGIN. 35
LIST AT LEAST THREE MOLECULAR MECHANISMS THAT CAN LEAD TO A DEFECT IN IMPRINTING AND EXPLAIN HOW THESE
MECHANISMS CAN RESULT IN BECKWITH-WIEDEMANN SYNDROME. 35
ESTIMATE THE RECURRENCE RISK FOR AN IMPRINTED DISORDER, BASED ON THE MOLECULAR MECHANISM. 36
DESCRIBE THE NORMAL PROCESS OF ABDOMINAL BODY WALL FORMATION AND THE PROCESS BY WHICH OMPHALOCELE
RESULTS. 36
REVIEW THE MECHANISM OF HYPOGLYCEMIA IN BECKWITH WIEDEMANN SYNDROME. 36
DEFINE OVERGROWTH SYNDROME AND DISCUSS THE CANCER RISKS ASSOCIATED WITH BECKWITH WIEDEMANN SYNDROME. 36
DESCRIBE POTENTIAL PHYSICAL AND PSYCHOSOCIAL RISKS TO CHILDREN ASSOCIATED WITH CONCEPTION VIA IVF. 37
IDENTIFY POTENTIAL ISSUES OF ACCESS REGARDING IVF TREATMENTS. 37
IDENTIFY WHAT A PATIENTS/COUPLES OPTIONS ARE WHEN DECIDING WHAT TO DO WITH REMAINING EMBRYOS FROM IVF
AND THE ASSOCIATED ETHICAL IMPLICATIONS. 37
IQ12: CHRONIC MYELOID LEUKEMIA T(9:22)(Q34:Q11) 37
DEFINE THE CONCEPT OF A RECIPROCAL CHROMOSOMAL TRANSLOCATION; IDENTIFY THE CHROMOSOMAL TRANSLOCATION IN
CHRONIC MYELOGENOUS LEUKEMIA AND THE TWO GENES INVOLVED. 37
LIST THE MOLECULAR STEPS THAT LEAD FROM A CHROMOSOMAL TRANSLOCATION TO THE PRODUCTION OF THE BCR/ABL
FUSION PROTEIN (TRANSCRIPTION, TRANSLATION). 37
INVASION AND METASTASIS ARE TYPICALLY IMPORTANT HALLMARK PROPERTIES OF MALIGNANCY, HOWEVER THESE
CONCEPTS ARE SOMEWHAT MORE RELEVANT TO A SOLID TUMOR MALIGNANCY SUCH AS A CARCINOMA. SINCE BLOOD CELLS
NORMALLY CIRCULATE THROUGHOUT THE BODY, DESCRIBE THE HALLMARK PROPERTIES THAT THIS DISEASE (LEUKEMIA)
DISPLAYS THAT MAKE IT FULFILL THE CRITERIA OF A MALIGNANCY. 38
DEFINE TYROSINE KINASE; DESCRIBE HOW EXPRESSION OF THE BCR/ABL TYROSINE KINASE RESULTS IN LEUKEMIA. 38
DEFINE AN ONCOGENE; CONTRAST THIS WITH THE CONCEPT OF A TUMOR SUPPRESSOR GENE. 38
DESCRIBE THE INFORMED CONSENT PROCESS FOR THE USE OF DASATINIB IN TERMS OF ITS TARGET, ITS EFFECTS AND SIDE
EFFECTS IN THE TREATMENT OF CML. 39
PROPOSE A MECHANISM OF ACQUIRED RESISTANCE FOR A TARGETED THERAPY 39
IQ13: RETINOBLASTOMA (13Q14.1-13Q14.2) 39
COMPARE AND CONTRAST THE GENETIC BASIS OF INHERITED RETINOBLASTOMA VS. RETINOBLASTOMA IN A PATIENT WITH NO
FAMILY HISTORY OF THE DISEASE. DESCRIBE THE DIFFERENCE IN THE GENETIC BASIS OF SPORADIC BILATERAL VS. UNILATERAL
RETINOBLASTOMA. 39
RECOGNIZE THE DIFFERENCE BETWEEN AUTOSOMAL DOMINANT AND AUTOSOMAL RECESSIVE INHERITANCE, AND PREDICT THE
FREQUENCY OF AFFECTED INDIVIDUALS. 39
DEFINE THE KNUDSON TWO-HIT HYPOTHESIS AND PROVIDE AN EXAMPLE OF A CANCER THAT OCCURS AS A RESULT OF THIS
PHENOMENON. 40
LIST TWO MECHANISMS FOR THE LOSS OF FUNCTION OF TUMOR SUPPRESSOR GENES AND DESCRIBE LOSS OF HETEROZYGOSITY
(LOH). 40
DESCRIBE THE ROLE OF THE RETINOBLASTOMA GENE PRODUCT RB AND CYCLIN DEPENDENT KINASES IN CELL CYCLE
REGULATION. 40
CONCEIVE A HYPOTHESIS TO EXPLAIN WHY MANY CANCERS CONTAIN MUTATIONS IN THE RB GENE, BUT GERMLINE RB
MUTATIONS RESULT PRIMARILY IN PEDIATRIC RETINOBLASTOMA. 40
RETINOBLASTOMA DO NOT REQUIRE AS MANY MUTATED GENES FOR TRANSFORMATION 40
8. EXPLAIN THE ETHICAL CHALLENGES ASSOCIATED WITH REPRODUCTIVE DECISION-MAKING IN LIGHT OF AN AUTOSOMAL
DOMINANT GENETIC DISORDER. 40
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IQ14: LYNCH SYNDROME 41
DESCRIBE AT LEAST FOUR CLINICAL CHARACTERISTICS OF A FAMILIAL CANCER SYNDROME. 41
COMPARE AND CONTRAST THE PHYSIOLOGIC FUNCTION OF AN ONCOGENE, A TUMOR SUPPRESSOR GENE, AND A CARETAKER
GENE. 41
DESCRIBE THE CLINICAL FEATURES, GENETIC HETEROGENEITY AND MECHANISM OF LYNCH SYNDROME, ALSO KNOWN AS
HEREDITARY NONPOLYPOSIS COLORECTAL CANCER (HNPCC). 41
DEFINE THE DNA MISMATCH REPAIR SYSTEM AND DISCUSS HOW INHERITANCE OF ONE MUTANT ALLELE LEADS TO
MANIFESTATION OF DEFECTIVE DNA MISMATCH REPAIR. 41
DEFINE EPIGENETIC MODIFICATION OF DNA AND DESCRIBE ITS ROLE IN PROMOTING TUMORIGENESIS. 42
DISCUSS THE REASONS WHY SOME PATIENTS ACCEPT OR DECLINE GENETIC TESTING FOR LYNCH SYNDROME WHEN THERE IS A
KNOWN PATTERN OF FAMILIAL HERITABILITY. 42
IQ15: BREAST CANCER 42
DESCRIBE THE CLINICAL FEATURES OF FAMILIES THAT CARRY MUTATIONS IN BRCA1 OR BRCA2 AND REASONS WHY CANCER
PATIENTS AND THEIR FAMILY MEMBERS MIGHT CONSIDER UNDERGOING TESTING. 42
DESCRIBE THE FUNCTION OF BRCA1 AND BRCA2. CLASSIFY THESE GENES AS TUMOR SUPPRESSOR GENES, ONCOGENES, OR
CARETAKER GENES AND EXPLAIN YOUR RATIONALE. 43
COMPARE AND CONTRAST THE MECHANISM OF TAMOXIFEN WITH AN AROMASTASE INHIBITOR FOR THE TREATMENT OF BREAST
CANCER. 43
EXPLAIN THE SIGNIFICANCE OF HER2/NEU (HER 2 OR C-ERBB2) OVEREXPRESSION IN BREAST CANCER. 43
PROVIDE AN EXAMPLE OF A THERAPY THAT TARGETS HER2/NEU AND DESCRIBE ITS MECHANISM AND CLINICAL SIGNIFICANCE.
44
EXPLAIN THE ROLES OF STAGING, SURGERY, RADIATION AND CHEMOTHERAPY FOR EARLY STAGE BREAST CANCER. 44

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IQ1: Type 1 Diabetes mellitus
Describe the molecular and cellular events of insulin secretion and regulation.
NOTE: insulin is synthesized, packaged, and secreted from pancreatic beta cells
Preproinsulin made by rough endoplasmic reticulum (RER) then cleaved into proinsulin (stored in
secretory vesicles). Proinsulin is cleaved into insulin and C-peptide, but most of the insulin (60%)
is removed when it first passes through the liver. This is why C-peptide is better for Beta Cell
function test.
Glucose is the main regulator of insulin release. It enters eta cells through GLUT2 diffusion.
Glycolysis and ATP generation increases the ATP/ADP ratio, and higher ratio would allow ATP-
sensitive K+ channel to close.
K+ buildup allows for depolarization, at the membrane, opening up Ca2+ channels, allowing Ca2+
to enter the cell.. At the same time, Ca2+ is released from the ER, allowing Ca2+ at cytoplasm to
increase like crazy and signal for insulin release.


List and describe the tissues with insulin receptor expression and explain the downstream effects of
insulin binding to these receptors.
Insulin affects basically every tissue in the body, but mostly in the liver, muscle, and fat.
Insulin is anabolic!
Liver (GLUT2)
o Glycogen breakdown inhibited, and glycogen synthesis increased
o Promotes glycolysis and inhibits gluconeogenesis.
Fat storage (GLUT4)
o Glucose is increasingly transported into fat cells and allows fatty acid uptake as well,
making more triglyceride
o Lipolysis is inhibited
Muscle (GLUT4)
o 4 main effects
o Increased uptake of glucose by increasing GLUT4 receptor expression
o Increased rate of glycolysis
o Increased glycogen synthesis
o Increased protein synthesis
Note :Insulin-independent tissues where glucose uptake is independent of insulin memorize using
BRICK-L (Brain, RBC, Intestine, Cornea, Kidneys, Liver)


Describe the molecular and cellular events of glucagon secretion and regulation.
Glucagon synthesized by alpha cells in islet of Langerhans, involved in catabolic processes.
Preproglucagon made in RER then cleaved during translation to make proglucagon. Glucagon is
cleaved by proteases, but there is different cutting mechanism so that in intestinal L cells
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(neuroendocrine) GLP-1 is made instead from proglucagon.



Release is stimulated by AA, and different AA have different ability to secrete glucagon. Its
inhibited by glucose, insulin, and somatostatin (since if theres too much glucose then we dont
need any more glucose in blood, okay?)


List and describe the tissues with glucagon receptor expression and explain the downstream effects of
glucagon binding to these receptors.
Glucagon mainly affects the liver (not clear whether other tissues other than the liver is affected)
Glucagon binds to GPCR (G protein-coupled receptor) and then allows for transcription of genes
involved in nutrient metabolism like breakdown of glycogen, gluconeogenesis in liver, oxidation of
fat to get ATP, and formation of ketone bodies from fatty acid precursors (ketone bodies used for
fuel in the brain)

Explain the effect of insulin deficiency on blood glucose.
Insulin deficiency leads to hyperglycemia. Since insulin inhibits glucagon, lack of it increases
glucagon level as well. This leads to accelerated fasting state where your cells think youre lacking
energy when you are not. This induces liver to make glucose and ketone.
Polyuria occurs due to increased osmotic pressure in the nephron filtrate.
Ketoacidosis occurs due to keto acids (can lead to death)

Describe the three factors (genetic, viral and autoimmune) involved in the etiology of type 1 diabetes
mellitus.
Genetic disposition to autoimmunity attacking the beta cells (this distinguished by islet cell Ab,
insulin Ab, and GAD (glutamic acid decarboxylase) Ab. Anyways, individuals with high risk for the
TIDM tend to have elevated autoantibodies (GAD65) earlier in life
Environmental factors trigger the actual destruction of beta cells, such as virus infections, toxic
chemicals, and cytotoxins spoiled tapioca

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List and describe the pathophysiology of the symptoms of hyperglycemia.
Accelerated fasting state
Polyuria due to increased osmotic pressure
Ketoacidosis from keto acids
Polydipsia (thirst) from hyperosmolar state
Blurred vision from hyperosmolar state
Dizziness and weakness from low plasma volume
Microvascular problems like retinopathy, nephropathy, and neuropathy all from damage in small
vessels
Micro vascular complications like myocardial infarction and stroke
o we dont really know how microvascular and macrovascular complications occur (but we
assume its due to energy production abnormality)

List the major types of insulin used to treat diabetes mellitus and explain how they are used in
combination to treat diabetes.
4 types of insulin based on duration of action and biological action
Type Name Onset Peak Duration Role
Rapid acting Lispro 15-30
minutes
30-90 3-5 hr Eaten with meals at the same time
Often used with longer acting insulin
Short- acting Regular
humulin
30-1hr 2-5hr 5-8hr Meals eaten within 30-60minutes
Intermediate
Acting
NPH 1-2 hr 4-12
hours
18-24hr Insulin needs for half a day or
overnight
Often combined with rapid or short-
acting
Long acting glargine 1-1.5 hr No peak 20-24 hr Needs for one full day
Often combined with rapid or short-
actin insulin
Combination of rapid acting insulin (lisper) at meals with intermediate or long acting (NPH or
glargine) have improved results

Name and briefly describe one new treatment strategy being investigated for type 1 diabetes mellitus.
Islet cell transplantation: beta cells from the donor are implanted into a patient; minimally
invasive and mimic the physiological insulin level but the insulin secretion diminishes over time
and the dependence on constant donors and use of immunosuppressant make this treatment
option currently unfeasible.

IQ2: Type II Diabetes Mellitus
List the four formal criteria for making a diagnosis of diabetes mellitus.
Diabetes requires one or more of following
1. Symptoms of T2DM and a random blood sugar level of 200mg/dL or higher; symptoms like
blurred vision, polyuria, thirst
2. Fasting blood sugar level of 126 mg/dL or higher
3. Blood sugar level of 200mg/dL or higher two hours after an oral glucose tolerance test
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4. A1C of 6.5% or higher
Note: for pre-diabetes, number would be HbA1c between 5.7 to 6.4%, 2 hr blood sugar level as
140-199, and fasting at 100-125

Describe the hypothetical causes of type 2 diabetes mellitus.
Starts off with development of insulin resistance that slowly worsens. Pancreas compensates for
insulin resistance by increasing insulin secretion. Insulin resistance becomes worse and pancreas
cannot compensate.
Genetic (TCF7L2 allele, or identical twins, 90% chance both having the disease) and
Environmental (obesity)
Note: insulin resistance characterized by improper signaling downstream of IR (insulin binding
and tyrosine autophosphorylation not compromised in insulin resistance)
o Tyrosine phosphorylation of IRS-1 and IRS-2 (adaptor molecules transmitting signals from
the insulin and IGF-1 receptors to PI3K/Akt and Erk/MAP kinase pathways) is LOW
o Inhibitory Ser/Thr phosphorylation of IRS is high
The Ser/Thr phosphorylation of IRS caused by PKS and Jun kinases
PKC activated by free fatty acids
JUNK activated by pro-inflammatory cytokines
The Ser/Thr phosphorylation explains why obesity may increase T2DM
Since FFA level also increases cytokine release
Other causes
o High insulin levels (due to compensatory mechanism) leads to decrease in IR in target
tissues
o FFA from adipocytes increases ectopic lipid storage in muscle, liver, and beta cells,
decreasing insulin sensitivity
o Adipocytes release pro-inflammatory FFA and adipokines
Activate macrophages that release more pro-inflammatory molecules
Inflammation causes insulin resistance

List and describe the pathophysiology of the typical symptoms of type 2 diabetes.
Theres the hyperglycemia pathophysiology (refer back to IQ1)
Acanthosis Nigracans!
o Epidermal hyperplasia induced by high levels of circulating insulin
o Characteristic of initial T2DM (the compensatory role of beta cells)
o High insulin mimics IGF-1, activating insulting growth receptors on epidermal cells

Define insulin resistance and explain the central role played by adipose tissue in the development of this
condition.
Insulin resistance: when cells fail to respond to the normal actions of insulin
Potential causes
o Chronic high levels of insulin lead to decrease in insulin receptors
o FFA from adipocytes increases ectopic lipid storage in muscle, liver, and beta cells,
decreasing insulin sensitivity
o Adipocytes release pro-inflammatory FFA and adipokines that activate macrophages,
which in turn release more pro-inflammatory molecules that cause local inflammation.
Inflammation causes insulin resistance.
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o Lepton and adiponectin increase insulin sensitivity
o Elevated levels of FFAs in circulation increase insulin resistance

Describe the interaction of genes and environment in the evolutionary causation of type 2 diabetes
mellitus.
Thrifty Genotype hypothesis: insulin resistance limits the bodys intake of glucose by muscle and liver
cells. This increases fat storage, which was good for hunter-gather societies.

Define the term metabolic syndrome.
Metabolic syndrome: cluster of conditions which predisposes one to heart disease, stoke, and DM
Conditions
o Increased BP
o Visceral fat
o Cholesterol level
o Blood glucose level

Describe the role of diet and exercise in the treatment of type 2 diabetes.
Weight loss improves insulin sensitivity by
1. Decreasing adipokines (released by adipocytes)
2. Decreasing adipocytes (the ectopic and visceral)
3. Stimulate receptors to be more sensitive

Describe how major classes of drugs used to treat type 2 diabetes mellitus try to correct abnormalities
related to pathogenesis of type 2 diabetes mellitus.
Overall: manage T2DM by decreasing insulin resistance or increasing insulin level
Exercise and weight loss
Metformin (biguanide)
o Reduce gluconeogenesis
o Improve insulin sensitivity by minimizing FFA release
Thiazolidinedione (pioglitazone)
o PPAR alpha agonists
Peroxisome proliferator-activated receptors
TF that plays a role in metabolism
o Enhance insulin sensitivity in peripheral tissues
o Reduce gluconeogenesis
Sulfonylurea
o Stimulate more insulin release in beta cells (closes potassium channels)
GLP-1 like agonists (Eventide)
o Stimulate insulin secretion
o Inhibits glucagon secretion
Others: alpha glucosidase inhibitors (interfere with digestion of glucose)
IQ3: Thyroid Dysfunction
Describe thyroid hormone synthesis and how it is regulated by the hypothalamus-pituitary-thyroid axis.
Hypothalamus-pituitary-thyroid axis
11
o Hypothalamus (arcuate nucleus and median eminence) releases TRH
o TRH travels through hypophyseal portal system to anterior pituitary
o TRH activates GPCR (G-protein coupled receptor) on thyrotrophs
o Thyrotrophs release TSH
o TSH moves through systemic circulation to thyroid
o Stimulates TSH receptors on basal side
o Thyroid hormone T3, T4 released
TSH also induces hyperplasia of follicular cells (this is why TSH level could lead to
goiter or atrophy)
Thyroid hormone synthesis
o NIS symporter (Na+/I-) imports iodide ion into follicular cell from basolateral side
(Trapping)
o Iodine ion exocytosed into follicular lumen
o Thyroid peroxidase in luminal side of follicular cells convert iodine ion (I-) into iodide (I)
and cationic iodide (I+)
o Iodide attached to thyroglobulin
o Iodinated thyroglobulin endocytosed and cleaved into T4, T3, DIT, MIT
DIT and MIT = non-active
T4 and T3 are both biologically active
More T4 generated than T3
T3 more biologically active


Explain how thyroid hormone is transported in the body and what is the molecular and receptor
mechanism of its action on its target cells.
T3 and T4 bound to plasma proteins in circulation
o TBG (thyroid binding globulin) has the most significant binding capacity
o Also albumin and transthyretin (TTR)
T3 more potent but T4 released more
12
o Deiodination occur at liver and kidney (from T4 into T3, DIT, MIT, rT3)
Thyroid hormones are lipophilic, entering cells through passive diffusion or carrier mediated
transport
o T3 binds to nuclear receptor thyroid receptor, which heterodimerizes with retinoic acid
receptor (RXR)
Influence genetic transcription

List and describe the effects of thyroid hormone on the different tissues and body systems.
T3 increases O2 consumption and heat production (by stimulating Na
+
/K
+
ATPase in all tissues
except brain, spleen, and testes)
T3 increase transcription of genes that increases heart rate (chronoscopic effects) and force of
contraction (inotropic)
Sympathetic effects on heart, skeletal muscle, adipose, lymphocytes (beta adrenergic)
o This is why we use beta blockers to treat the clinical manifestations arising from increased
sympathetic response
Promotion of gut motility (leads to diarrhea)

Describe major symptoms and signs of thyrotoxicosis and explain how excess thyroid hormone causes
these symptoms.
Symptoms include palpitations, nervousness, fatigue, diarrhea, hyperkinesia (excessive abnormal
movements), sweating, heat intolerance, weight loss, thyroid enlargement, ophthalmopathy (the
eye-bulging often found in Graves disease), and muscle weakness
Symptoms mostly due to elevated BMR (T3 increases O2 consumption and heat production by
Na/K ATPase stimulation)
Cardiovascular effects due to increasing number of beta-adrenergic receptors in cardiac, skeletal
muscle, adipose, and lymphocytes

Compare and contrast the disorders that can cause thyrotoxicosis. Classify these disorders by the result
of radioactive iodine thyroid uptake and scan.
Thyrotoxicosis (excess of thyroid hormone in the body) can be diagnosed using radioactive uptake
scans for thyroid shape, size, rate of iodine uptake, and distribution of iodine activity
1. Diffuse toxic goiter (Graves Disease)
o TSH antibodies which stimulate TSH receptors
o Diffuse, enlarged thyroid
2. Toxic adenoma
o T3/T4 secreting adenoma
o Nodule is hot with diminished or absent function of contralateral lobe
o Suppressed TSH
3. Toxic multinodular goiter (Plummer Disease)
o Autonomous functioning goiters
o Secretes T3/T4 without TSH
o Absence of extranodular tissue
o Discrete regions of tracer in thyroid
4. Subacute thyroiditis
o Vital, bacterial infections
o Leakage of T4 hormone stores
13
o Suppressed RAIU due to low TSH
5. Silent thyroiditis
o Suppressed RAIU
6. Thyrotoxicosis factitia
o No RAIU since TSH is low

Describe the therapy for Graves disease including antithyroid drug therapy involving propylthiouracil
and methimazole.
Propylthiouracil (PTU)
o Inhibits thyroperodidase (prevents conversion of I
-
to I)
o Inhibits enzyme 5-deiodinase (prevents conversion of T4 to T3)
o Not recommended for children or pregnant women due to risk of liver failure/death
Methiomazole
o Inhibits thyroperoxidase (prevents conversion of I
-
to I)


Describe the major symptoms and signs of hypothyroidism.
Symptoms include bradycardia (slow heart rate), diminished oxygen consumption, constipation,
weight gain, menstrual abnormalities, muscle cramps, cold insensitivity, and myxedema (edema
from severe hypothyroidism)
Fetal hypothyroidism can lead to cretinism (mental retardation, short stature, puffy appearance,
deafness)

List and describe two laboratory tests used to diagnose hypothyroidism.
Serum TSH and fT3/T4 (free T3/T4)
By the way, hypothyroidism can be primary (thyroid failure), secondary (pituitary TSH deficiency)
or tertiary (hypothalamic deficiency in TRH)

Describe the mechanism of action, absorption, metabolism of levothyroxine.
Levothyroxine: oral medication that can treat low thyroid activity. Absorbed in GI tract and bound
to thyroxine-binding globulin (TBG) or albumin.
Levothyroxine is converted to a more active form T3 and binds to thyroid receptors to initiate
transcription.
Can be metabolized through deiodination in liver and kidney
Can be metabolized through glucuronidation and be excreted into bile

Describe the role of family history and autoimmunity in thyroid disease.
Graves and Hashimotos: both autoimmune diseased due to abnormal antibody development
against self
Autoimmunity inherited as a dominant trait
~50% of first degree relatives with autoimmune thyroiditis has thyroid antibodies in serum
IQ4: HPG Axis & Male Sex Cells
List hypothalamic, pituitary, gonadal hormones involved in male sexual development
The pathway is Gnarl LH/FSH Testosterone Estradiol or dihydrotesterone
14
GnRH
o Peptide hormone
o Released from arcuate nucleus of hypothalamus
o Moves down the hypophyseal portal system to anterior pituitary
o Pulsatile GnRH stimulates which hormone gets secreted!
FSH= low pulses
LH= high pulses
LH/FSH
o Peptide hormones released from gonadotrophs (a type of basophil)
o LH stimulates Leydigs to make testosterone
o FSH stimulates Sertoli cells to make aromatase, androgen binding protein (ABP), and
inhibin (a negative feedback regulator)
Aromatase allows testosterone to turn into estradiol
Puberty
o Initiated by large nocturnal LH pulses
o Secondary sex characteristics due to testosterone derivate (dihydrotestosterone) like
midline hair, facial hair
o Many characteristics of puberty induced by testosterone
Penis growth, testicular development, muscle growth, deepening of voice, growth
spurt

Describe the hypothalamic, pituitary, gonad axis, its feedback and regulation, by drawing a detailed
diagram of this system.
Androgens negatively feedback at the level of hypothalamus and anterior pituitary
Inhibins feed back at the level of anterior pituitary (this inhibits FSH only)
15




Describe the normal sequence of pubertal development in the male.
Stage Genital Development Pubic Hair
1 Preadolescent
Penis, scrotum, and testes are the same
size (relative to body size) as a young
child
Preadolescent
No pubic hair
2 Enlarged scrotum and testes Sparse pubic hair (mainly at base
of the penis)
3 Enlarged penis (predominantly in
length)
Further enlarged scrotum and testes
Darker, coarser, and curlier pubic
hair (spreads above the pubis)
4 Further enlarged penis (length and
diameter)
Adult type pubic hair
Covers smaller area than in most
16
Further enlarged scrotum and testes adults
5 Adult pattern Adult pattern
Note: puberty regulated by numerous hormones (GnRH, LH, FSH, testosterone, kisspeptin, leptin,
IGF-1, DHEA)

Describe the anatomy and embryological development of the male urogenital tract.
Primordial germ cells (PGC) from epiblast travels to the gonads
o Route: epiblast yolk sac endoderm gut dorsal mesentery somatic gonad
o Sexual differentiation begins upon PGC arrival to the somatic gonads
Expression of SRY gene on Y chromosome upregulates Sox9/Fgf9 expression
o Sox9/Fgf9 inhibits Wnt4, inducing testes development
Sertoli cells secrete Anti-Mullerian Hormone (AMH) that causes Mullerian duct degradation (this
was a paramesophrenic duct)
Leydig cells secrete testosterone that allows Wolffian duct development




Describe the cellular components of the testes.
Leydig cells: located in interstitial space of seminiferous tubules
o Involved in testosterone secretion in the presence of LH
o Cholesterol converted to pregnenlone using cholesterol desmolase
o Results in mainly testosterone, androstenedione, dehydroepiandrosterone (DHEA)
Sertoli cells: located in seminiferous tubules
Spermatogonium primary spermatocytes secondary spermatocytes spermatids
Blood testes barrier
o Large molecules cannot pass from blood to the lumen of seminiferous tubules
o Due to tight junctions between Sertoli cells
o Important that auto-immune reaction be prevented since sperm cells are not considered
self

17
Describe testosterone biosynthesis and list the target tissues for testosterone action in the male.
Testosterone made in Leydig cell
Biosynthesis
o LH binding to LH receptor activates adenylyl cyclase
o cAMP activates PKA (protein kinase A)
o PKA allows for new protein synthesis via CreB
o The enzymes newly synthesized convert cholesterol into testosterone
o Testosterone will move into the bloodstream to enter circulation by sex hormone binding
globulin (SHBG)
Primary target is Sertoli cells to sustain spermatogenesis
o Testosterone can be converted into estradiol via aromatase
Secondary targets: skeletal muscle, brain, prostate, liver intestines, etc.


Describe the tissue and cellular events that lead to sperm production.
Testosterone secreted from Leydig cells signal for Sertoli cells to aid in spermatogenesis
Sertoli cells
o Provide nutrients to sperm
o Form blood-testes barrier
o Secrete fluid to transport spermatozoa from seminiferous tubules to epididymis
Pathway
o Primordial germ cells migrate to gonad
o Spermatogonia (2n) undergo mitotic division
o Some spermatogonia start first meiotic division; called primary spermatocytes (4N)
o Primary spermatocyte (4N) divide to become secondary spermatocytes (2N)
o Secondary spermatocyte (2N) undergo another division to make spermatids (1N)
o Maturation yields spermatozoa (mature sperm, 1N)

Describe environment/lifestyle factors that could affect the Hypothalamic-pituitary axis and impact male
fertility.
18
Gonadal steroids (androgens, estrogens, progestins) suppress endogenous GnRH release and
testicular function
Obesity lower concentration of SHBG so lower serum concentration of total testosterone
Environmental toxins may lower sperm counts
IQ5: HPG Axis & Female Sex cells
List the hypothalamic-pituitary-ovarian (HPO) hormones involved in the initiation of puberty and the
control of the menstrual cycle in female development.
GnRH high pulsatile release of GnRH initiates puberty
FSH/LH FSH/LH positively feedback to stimulate ovulation
Estrogen induces proliferation of endometrium
o Stimulates LH surge
Progesterone maintains uterine activity during luteal phase (luteal phase = secretory phase)


Draw a detailed diagram of the hormonal control of the female reproductive system to demonstrate a
clear understanding of the feedback and hormonal regulatory mechanisms involved in the female
reproductive system.
19


List the female pelvic anatomy necessary for normal menstruation.
Ovaries: site of follicular maturation, granulosa and theca cells
Fallopian tubes: tubular structure where egg is released
Uterus: endometrium area for implantation
Vagina: where endometrium sloughs off to and out

Describe how estrogen from the ovaries causes the development of secondary sexual characteristics.
Estrogen: breast development, widening of hips, increased fat in hips, butts, and thighs
Estradiol: acts on estrogen receptor alpha to induce transcriptional change in breast (promotes
stromal and parenchymal growth)

Describe how the genotypic sex determines the gonadal sex, which then determines the phenotypic sex.
SRY on Y chromosome: Sox9/Fgf4 positive feedback loop, inhibiting Wnt4 and leading to testes
development
Sertoli cells: secrete AMH, leading to Mullerian tract destruction
Leydig cells: secrete testosterone; facilitating development of Wolffian ducts and male phenotype
Females lack AMH and testosterone promotion of Wolffian tract degradation and Mullerian duct
development
o Female ovary is the default gonad

Identify the hormonal interactions which stimulate the ovary to synthesize estrogen.
LH stimulates theca cells to produce androstenedione from cholesterol
Androstenedione diffuses to granulosa cells
Granulosa cells respond to FSH by increasing aromatase level
Aromatase converts the diffused androstenedione to 17beta-estradiol
20


Describe the similarities in the neuroendocrine control of male and female reproduction.
Pulsatile GnRH lead to FSH/LH secretion
LH and FSH stimulates sex hormone release
o Leydig & Theca cells: secrete testosterone, respond to LH
o Sertoli & granulosa cells: secrete estrogens, respond to FSH
Inhibin B inhibits FSH release

Define chromosomal mosaicism and describe the phenotypic effect of 45,X/46,XX mosaic karyotype.
Genetic mosaicism
o Cell population with 2 or more distinct genotypes in an individual
o Due to errors in mitosis after fertilization/early embryonic development
Phenotypic variability is high
o Short stature is only phenotypic abnormality seen in all of patients
o Variable symptoms: hypertension, heart anomalies, renal anomalies, neoplasia risk
21
IQ6: Gestational Diabetes
Describe symptoms of pregnancy and the associated physiologic and hormonal changes.
Breast tenderness, fatigue, nausea, no menstruation, softening of the uterus
Sustained elevation of basal body temperature (due to hormone production by corpus luteum and
placenta)
hCG secretion (from trophoblast lineage, syncytiotrophoblast, to maintain corpus luteum
o Corpus luteum makes progesterone, estrone, and estradiol during first trimester
o Placenta after 1
st
trimester will take over the role
Progesterone made from maternal cholesterol and maintains uterine lining during pregnancy
Placental estrogen (especially estriol) important for maintaining pregnancy

Describe the hormonal and physical changes that occur in normal labor.
Events initiating labor still poorly understood
Uterine contracts (myometrium)
Cervix softens
Withdrawal of progesterone, estrogen activation, oxytocin release and PGF2alpha involved in
labor
o Withdrawal of progesterone and addition of estrogens increase gap junction and ion
channels of myometrial cells
Increased estrogen:progesterone ratio stimulates PDF2 synthesis
o PDF2 leas to thinning of cervix
Prostaglandin and oxytocin induces contractions of the uterine wall
o Cervical thinning + contraction = baby pushes out


Describe the embryologic development of the fetus and list the timing and sequence of major organ
systems (CNS, heart, and limbs).
D20: Heart starts beating as it remodels itself as it pumps
D26: anterior neuropore (opening of neural tube) by this time
22
D26-27: Upper limb buds
D28-30: lower limb buds, precursor eye structures start to form
W4: caudal neuropore closes by this time
o Heart starts beating by this time
D36-42: brain vesicles appear, hands and feet start forming, herniation of midgut, ear formation
W6: heart beats detectable
W8: spinal cord extends entire length of vertebral canal

Identify how changes in glucose metabolism can affect fetal growth and development.
Insulin similar to IGF in structure
Hyperinsulimnemia leads to increased fetal growth
Leads to macrosomia (large birth weight)

Identify the fetal anomalies associated with abnormal glucose metabolism.
Macrosomia (from increased insulin and maternal hyperglycemia)
Fetal hypoglycemia at birth
Caudal dysgenesis
Cleft palate
Neural tube defects
o Holoprosencephaly (common defect with cleft lips, closely spaced eyes, etc.)
o Anencephaly (absence of large part of the brain and skill)
o Microcephaly (small head)
o Macrocephaly (large head)
Tetralogy of Fallot

List five factors that influence fetal growth.
1. Genetics
2. Maternal Diabetes
3. Maternal Nutrition
4. Teratogens (valproic acid, retinoic acid, thalidomide)
5. Intrauterine growth restriction (limits nutrient flow to fetus due to abnormal placental
development)

Describe the impact of diabetes mellitus (DM) on the mother during pregnancy.
Typical risks with DM (retinopathy, microvascular/macrovascular complication, hypoglycemia)
Preeclampsia: hypertension in mother and proteinuria
C-section due to fetal macrosomia
Placenta abruptia: miscarriage

Define gestational diabetes mellitus (GDM) and contrast GDM with type 1 and type 2 DM.
GDM more similar to T2DM (characterized by hyperglycemia due to insensitivity_
Different from T2DM because this is a transient condition
o Insulin insensitivity is a normal state for pregnant women

Propose how the evolutionary concept of maternal-fetal conflict in pregnancy can be used to explain
gestational diabetes.
23
Fetus
o Wants to be bigger
o Secretes placental human lactogen (anti-insulin product)
Mother
o Wants to limit fetal nutrient
o Secretes more insulin
Elevated insulin levels predisposes mothers for gestational diabetes

Define the bioethical principle of patient autonomy and describe how this applies to adolescent
pregnancies.
Appreciation for patients unique values and beliefs
Want informed consent rather than paternalism
Balance between patient autonomy and fetal health
24
IQ7: Genetic Testing, Down Syndrome (Trisomy-21)
Compare and contrast the maternal and paternal age related risks for fetal anomalies.
Women
o Oocytes reach prophase I during fetal life
o Stays in Metaphase II until ovulation
o Older women: prone to nondisjunction events in oocytes (aneuploidy)
Men
o Fetal anomalies have weak association to germ line cell mutations (cancer, X-linked
mutations)
o Fetal autosomal aneuploidy not that related to paternal age

List and describe four tests used for prenatal screening, including the hormones and proteins used in the
tests and why the tests are used.
Quad test (2
nd
trimester, 15-22 weeks) composed of AFP, uE3, bhCG, Inhibin A
o MoMs (multiple of the median) calculated based off of gestational age and maternal risk
factors
o 75% DS detection, 80% NTD (neural tube defect) issues, 5% False positive
AFP
o Produced in fetal liver
o Abnormal levels highly associated with negative outcomes
o High levels (higher than 2.5 MoM)
Neural tube defects
Abdominal wall defects
Spina bifida
Tetralogy of Fallot
Turner syndrome
Fetal loss
o Low level: Down syndrome (trisomy-21), Edwards (trisomy-18) syndrome
Estriol (uE3)
Synthesized by intact feto-placental unit
Principle circulatory estrogen hormone in blood during pregnancy,
High level: adrenal hyperplasia due to 17-hydroxylase deficiency
o Low level: Down or Edwards, pregnancy loss, SLOS ichthyosis
bhCG
o Synthesized by placental cells starting very early in pregnancy
o Promotes lifespan of CL
o High levels: Down syndrome, fetal loss, hyrops fetalais
o Low level: Edwards
Inhibin A
o Produced in placenta in increasing quantity during pregnancy (mirrors fetal development)
o Found in maternal circulation during 1
st
and 2
nd
trimesters
o Levels correlate with maternal hCG and abnormal in similar conditions
25


Describe professional guidelines for offering prenatal testing and patient autonomy in decision making.
1. Identify the decision makers (assume that patient have authority and capacity to choose among
alternatives or refuse treatment)
2. Collect data and establish facts
3. Identify all medically appropriate options
4. Evaluate options (according the patients values and principles involved)
5. Identify ethical conflicts and set priorities
6. Select the options that can be best justified
7. Reevaluate the decision after action

Name and describe at least three commonly used prenatal diagnostic tests. Compare and contrast the
risks and benefits of the common diagnostic tests and when they can be performed.
Ultrasound
o No risk to the fetus
o Limited information attained (used for nuchal test though)
o Early information regarding gross abnormalities in development
CVS (chorionic villus sampling
o Pre-placental tissue (chorionic villus) extracted and sent for genetic testing
o 10
th
and 12
th
gestational week
o Use of needle with ultrasound guidance (transabdominally or transvaginally)
o Can be done in 1
st
trimester
o Greater risk of miscarriage than amniocentesis
Amniocentesis
o Sample of amniotic fluid removed (contains fetal skin cells)
o 15
th
and 20
th
gestational week
o use of needle with ultrasound guidance (transabdominally)
o lower miscarriage risk
o Can determine AFP level for neural tube defect
o Done at 2
nd
/3
rd
trimester (so cant terminate the baby)

Describe how ultrasound is used as a clinical tool in the identification of developmental abnormalities
including having an understanding of when developmental findings are visible.
Helps visualize anatomical features of the fetus (indicates developmental abnormalities) and
allows for reason to further test. Its not a diagnostic tool, but a screening tool
Tests
o Nucal translucency
Visible in first trimester
26
Accumulation of fluid on back of babys neck
May mean abnormal lymphatic development, abnormal cardiac function, anemia, or
abnormal collagen
o Fetal skin fold thickness
Second trimester
Presence of Trisomy 21
o Nasal bone length, humerus/femur length, pyelactasis (dilation of renal pelvis), echogenic
cardiac focus, echogenic bowel
Second trimester
Soft markers for Down syndrome (absence of these dont rule out Down syndrome)
o Neural tube defect
Direct visualization of incomplete closure of body wall
Anencephaly (absence of the cranial vault can be diagnosed after 10 weeks
gestation), hydrocephaly (accumulation of fluid in the brain), spina bifida

Differentiate between a screening and diagnostic test as they pertain to the care of the prenatal patient.
Screening: tests maternal blood for conditions conceptus is AT RISK FOR
o Less invasive
o Higher false positives
o Quad screen/ultrasound
Diagnostic test: makes DIAGNOSIS
o More invasive, can put fetus at risk
o CVS, amniocentesis

List and describe the two different karyotypes that will result in Down syndrome. Describe the different
parental genetic testing and counseling scenarios appropriate for each karyotype.
Nondisjunction

o Three whole copies of Chromosome 21 is visible
o Inform parents that non-disjunction increases with age (should tell them risk based on age-
related data)
Robertsonian translocation

o Two copies of Chromosome 21, but with RT containing the q arm of Chromosome 21 is
seen
o Inform parents for RT testing
27
o Inform possibility of elevated risks for having other children with RT
o Potential health risk to the parent

Define the fluorescent in situ hybridization (FISH) technique and explain the clinical application for this
test.
Performed on condensed chromatin during metaphase
Tag cells with fluorescent probes (specific for DNA or RNA sequence of interest)
Allows for high resolution detection of duplication, deletion, transpositions that karyotypes do
NOT have enough resolution for

Describe the typical features seen in infants with Down syndrome and explain how chromosome
aneuploidy could cause multisystem malformations.
Down syndrome (Trisomy-21) is most viable of the trisomies and occur 1 in 1000
Symptoms
o Mental impairment (individuals can achieve some level of independence depending on
range)
o Higher risk of congenital heat disease
o Higher risk of cancer
o Gastrointestinal issues
o Vision problems
o Hearing problems (also chronic ear infection)
o Irregular speech
o Dementia and mental illness later in life
Physical malformation
o Stunted growth
o Loose skin at the back of neck
o Low muscle tone
o Flat nose
o Slanted eyes
o Protruding tongue
o Umbilical hernia
o Flat head

Describe a Robertsonian translocation and explain why this chromosome translocation can cause Down
syndrome. Contrast and define a balanced versus unbalanced karyotype.
Robertsonian translocation occur between two acrosomal chromosomes (chromosomes with
small p arm)
o Possible only on 13, 14, 15, 21, 22 (ones with short p arms)
o Long arm goes with long arm; short arm goes with short arm
o Then the RT individual could gain extra genetic material since the long arm material came
along for the ride
o In Down syndrome often frequent as translocation between 13&21, and 21&22
Balanced form
o Robertsonian translocation takes the place of two acrocentric chromosomes
o Results in no problems for the person carrying it
Unbalanced form
28
o Robertsonian translocations produce chromosome imbalance
o Causes syndrome of multiple malformations and mental retardation


29
IQ8: DiGeorge (22q11.2 Deletion)
Define microdeletion syndrome and list the genotypic and phenotypic abnormalities associated with the
22q11.2 deletion syndrome.
Microdeletion syndrome is caused by chromosomal deletions spanning several genes (too small to
be detected by conventional cytogenic techniques)
Most commonly, 3MB deletion at 22q11.2
o Affects TBX1 gene which regulates neural crest cell migration
Called T-box protein 1, and is a transcription factor
o The varying spectrum of this disease attributed to haploinsufficiency from multiple,
contiguous genes within the deleted region
CATCH-22 for 22q11.2 DiGeorge Syndrome
o Cardiac defects (tetralogy of Fallot, truncus arteriosus, ventricular/atrial septal defect)
o Abnormal face (cleft palate)
o Thymic aplasia (impaired immune function)
o Cleft palate
o Hypocalcemia (lacks parathyroid)

Describe the normal fates of the cranial neural crest cells and use these terms to explain the embryologic
relationship of some of the structures affected in the 22q11.2 deletion syndrome.
Cranial neural crest cells migrate to branchial arches
Upon migration generate frontal, maxillary, and mandibular bones
Cleft palate occurs due to improper closure of primary and secondary palates
Cardiac neural crests aid in septation of outflow tract (pulmonary trunk and aorta)
Thymus and parathyroid gland develop in 3
rd
and 4hth branchial arches

Discuss the major actions of parathyroid hormone, including the class of hormone to which it belongs,
where it is synthesized, how it is secreted and regulated, how it is transported, and how it exerts its
effects.
PTH is a peptide hormone synthesized by chief cells in parathyroid gland and increases calcium
level in blood
o Regulation by calcium receptors on the parathyroid gland
o Inhibited by high serum calcium
In bone: resorption
In kidney
o Increase Ca2+ reabsorption
o Decrease in phosphate reabsorption (decreases phosphate level)
o Increase 1-alpha-hydroxylase to make more active vitamin D, (1,25-dihydroxy vitamin D3)
Active vit D can stimulate intestinal absorption of Ca
2+
and phosphate
Active vit D also stimulates reabsorption of Ca
2+
and phosphate in kidneys

Discuss the major actions of vitamin D, including the class of hormone to which it belongs, where it is
synthesized, how it is secreted and regulated, how it is transported, and how it exerts its effects.
90% of vitamin D is generated in the skin (and 10% through diet)
Process
30
o Start off with 7-dehydrocholesterol
o UV converts it to D3 (cholecalciferol)
o D3 is then turned into 25-OH D3 in the liver (this is also the step when you ingest Vit D3 or
Vit D2) by 25-alpha hydroxylase
o 25-OH D3 then moves to kidney to be changed into 1,25-DiH D3 by 1-alpha hydroxylase
o 1,25-DiOH D3 is a steroid!

Stimulates
o Intestinal absorption of Ca2+ and phosphate
o Reabsorption of Ca2+ and phosphate in the kidneys
o Bone resorption increased
Basically works with PTH in these roles

Describe how hypocalcemia could result from an underdeveloped parathyroid, discussing the two
hormonal mechanisms that can cause hypocalcemia and listing the typical laboratory abnormality found
with each mechanism.
Underdeveloped parathyroid glands cause low PTH secretion from the PT gland (primary
hyperparathyroidism)
Mechanisms affecting serum calcium level is PTH mediated and vit D mediated
o PTH mediation: high to normal P level due to P reabsorption in the kidney but low serum
Ca
2+

o Vit D mediation: low P and low Ca
2+
intestinal absorption (low 1,25-DiOH D3 level)

Name the type of inheritance found in the 22q11 deletion syndrome and estimate recurrence risks for
future children of a: a) Woman of a single child with deletion 22q11. b) Woman affected with deletion
22q11.
22q11.2 deletion is autosomal dominant! (90% microdeletions are de novo, 10% are familial)
Case A: Not sure if the case is de novo or is because a woman has mutation in her eggs do a
genetic test.
Case B: 50%

Define pleiotropy and variable expressivity and explain how these concepts are used in genetic
counseling for 22q11.2 deletion syndrome.
Pleiotropy: one gene affects multiple different and unrelated traits
31
Expressivity: range of signs/symptoms that occur in different people with the same genetic
condition
Note: there are other genetic environmental factors that affect the 22q11.2 phenotype

Describe the ethical implications of recommending parental testing for couples of reproductive age.
Designer babies (what are we testing for, and what traits are we selecting for?)
Complex disease gene variants (T2DM, BRCA1/2, Alzheimers)
Implication on abortion rates
IQ9: Tay-Sachs Disease (15q22-15q25)
Define Tay-Sachs disease (TSD) and explain the major findings in the disease, the inheritance pattern, and
the causative gene.
Gangliosidosis characterized by neurological deterioration
o Ganglioside usually broken by hexosaminidase in neuronal lysosomes
o Lowered activity due to HEXA gene mutation causes ganglioside buildup
o Ganglioside buildup leads to neuronal death
Symptoms: seizures, paralysis, swallowing problem, cherry-red spot in the eyes of infantile-onset
TSD
Autosomal recessive condition involving HEXA gene
o Age of onset inversely correlated with HEXA enzymatic activity
o Types
Infant Juvenile Adult
Onset of
symptoms
3-6 months 2-10 years old 30-40 years old
Age of
death/prognosis
2-4 years 10-15 years old Paralysis occurs


List and describe four components of a preconceptional or prenatal genetic counseling for Ashkenazi
Jewish diseases.
Offer carrier screening prior to conception (TSD, Canavan, CF, familial dysautonomia)
Screen the AJ first (if only one is AJ) - if that person is a carrier offer screening to the other partner
Individuals with positive family history for TSD should be offered carrier screening
Screened positive? Then refer then the person to genetic counseling for prenatal diagnostic
options


Define the Hardy Weinberg Equilibrium and calculate carrier frequency and the a priori population risk
for TSD.
Given no evolutionary influences, Hardy-Weinberg states
o p
2
+ 2pq + q
2

o p = 1 - q
a priori population risk for TSD is ~1/3600 for AJ
o Therefore, q
2
= 1/3600. q=1/60, p=1-q=59/60
o Carrier frequency = 2pq=(1/60)*(59/60)*2=1/30
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Explain the similarities and differences between the a priori risk calculations for TSD and cystic fibrosis
(CF).
Both are autosomal recessive so calculations should hold
a priori risk in AJ is 1/3600 for TSD and 1/2500 for CF

Demonstrate, by writing out the calculations, how carrier testing adjusts risk for TSD.
Risk = (Carrier probability of father) * (Carrier probability of mother) * (probability of autosomal
recessive condition given both parents are carriers)
o Probability of autosomal recessive condition given both parents are carriers is typically
o Family history information can influence the carrier probability
Positive sibling = increase carrier chance to 2/3
Positive cousins= increase carrier risk to 1/4
Carrier testing can increase carrier probability of father/ mother to 1 or 0
o Due to false negatives, one should be careful to remove all risk if carrier test comes back
negative


Describe carrier screening for TSD and explain a potential cause of false negative screening in TSD.
DNA test screen for HEXA common mutation set
o Not that useful for rare HEXA mutations; carrier DNA can present as negative even if
theyre HEXA deficient
Biochemical enzymatic activity test for HEXA activity

Define the term founder mutation and explain how this term is relevant for TSD and the Ashkenazi Jewish
population.
Founder mutations are found in DNA or one or a few of the individuals that founded a distinct
population
o Arise from sample bias, since small group of individuals do not represent the population
frequency arising from random variation
o Mating between founders propagate the mutation within the group
AJ has mutation in the 4-bp insertion in exon 11 of HEXA) with allelic frequency of 80%

List and describe additional rare genetic disorders for which Ashkenazi patients considering having
children should consider pre-conception genetic carrier testing.



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IQ10: Fragile X Syndrome
Construct a pedigree for the family in this case and define the terms X-linked inheritance and
anticipation.
Anticipation: tendency of certain genetic disorders to have family members presenting with
earlier symptoms or more severe symptoms in each successive generation
X-linked inheritance: genes are located in the X chromosome
o Sons cannot receive X from father (all affected mother can transmit to son vertically)
o Carrier females can have affected brothers
o All daughters of affected males are carriers

Define X inactivation and compare and contrast this process to imprinting.
X chromosome inactivation: form of dosage compensation in women where one chromosome is
inactivated to create hypermethylated Barr bodies
Genomic imprinting: monoallelic gene expression in a parent of origin fashion
Imprinting depends on parental origin; X chromosome inactivation is random and not depended
on parent of origin

Describe how females can manifest an X-linked disorder.
While females manifest X-linked disorder due to presence of two X chromosome copies, the
mutated X could be inactivated in a random or skewed fashion (mutated X preferentially
inactivate) that could affect the dosage amount

Discuss how a priori genetic risks for Fragile X can be modified by additional information obtained from
the family history.
Bayesian Analysis: the carrier risk of mother is adjusted given information about the status of her
current sons in X-linked recessive conditions
Steps
1. List out all possible scenarios
2. Calculate risks of mother being a carrier and the risk of sons being a carrier
3. Multiply the two numbers to get joint probability
4. Choose pedigree of interest and sum the joint probabilities
5. Divide the previous number by the sum of joint probabilities for all pedigree scenarios.

List the typical features of Fragile X syndrome and name the gene responsible for the condition.
The Fragile X syndrome is due to FMR1 gene (Fragile X mental retardation protein, or FMRP, with
CGG repeats) that was involved in repressing translation of target mRNAs
Intellectual disability (IQ<70), prominent ears, hypotonia, large testes, autistic behaviors
Increased risk for primary ovarian insufficiency (POI) in female permutation carriers, with
menopause before 40
Fragile X associated tremor/ataxia (FXTAS) found in both men and women with premutations,
with ataxia and Parkinsonism at age >50
Females have fewer and milder abnormalities since they inherit two X chromosomes

Identify the genetic mechanism that causes Fragile X syndrome and correlate the triplet repeat expansion
with specific disease characteristics.
Premutation (55-200 repeats in 5 UTR of FMR1)
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o Primary ovarian insufficiency or fragile X-associated tremor/ataxia
o FMR1 mRNA expression increased in some permutation carriers
o This may involve some form of RNA toxicity
Fragile X syndrome (>200 repeats)
o FMR1 promoter is methylated and transcriptionally silent

Define the terms pre-mutation and full mutation and describe the range of phenotypes associated with
these mutations.
Premutation: mutated alleles with repeat lengths which are unstable and prone to
expansion/shrinkage
Full mutations: mutated alleles with repeat lengths where full disease state manifests
Repeat lengths must transition between stage
o Normal alleles cannot become full mutation in the next generation
IQ11: BWS (11p15.5)
List the main phenotypic features of Beckwith-Wiedemann syndrome and explain how these features are
caused by a defect in imprinting.
Beck is with wide WOMMEN
o Wilms tumor (embryonal tumors during childhood, such as hepatoblastoma,
neuroblastoma)
o Organomegaly (macroglossia, macrosomia, visceromegaly)
o Muscle hemihyperplasia
o Midline defects (omphalocele, umbilical hernia, cleft palate)
o Ear creases/pits
o Neonatal hypoglycemia
Genes involved
Function Normal Expression
H19 DMR (or IC1) When methylated, allows IGF2
expression
Methylation on Pat
H19 Limits body weight and cell
proliferation
Mat
IGF2 Growth promoting gene Pat
KCNQ1OT1 (or
IC2)
Silences KCNQ locus when expressed Methylation on Mat
(Expressed in Pat)
CDKN1C (or p57 KIP2)
Growth suppressing gene
Inhibitor of cyclin D kinase
Mat
KCNQ1 Potassium channel Mat
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BWS due to the deregulation of the two gene regions: (KCNQOT1/CDKN1C, and H19/IGF2)
o Normally CDKN1C maternally expressed and IGF2 paternally expressed
o Too much IGF
Neonatal growth factor
Macroglosia, macrosomia, visceromegaly
Highest risk for development of neoplasia seen in patients overexpressing IGF2
o Too little CDKN1C
Inhibitor of cyclin D kinase, which regulates cellular division/differentiation
Omphalocele, cleft palate

Diagram the process of chromosomal imprinting, including the action of the imprinting center,
methylation, and chromosomal parent of origin.
H19/IGF locus
o IC1 acts as imprinting center
o When methylated, H19 is silenced and IGF2 is expressed
KCNQ1OT1
o Methylation inhibits KCNQ1OT1 expression
o Expression of KCNQ1 and CDKN1C expression occurs on mother
The two scenarios depend on methylation of the ICR
o Controls expression of long non-coding RNAs
Expression of normal correlates with silencing of coding genes (IGF2, CDKN1C, and KCNQ1)


List at least three molecular mechanisms that can lead to a defect in imprinting and explain how these
mechanisms can result in Beckwith-Wiedemann syndrome.
1. Abnormal IC1/IC2 methylation
Hypermethylation of IC1 on maternal side will lead to expression of IGF2
36
Hypomethylation of IC2 on maternal side will lead to expression of KCNQ1OT1, silencing
CDKN1C and KCNQ1
2. Paternal Uniparental Disomy
Overexpression of IGF2 and under-expression of CDKN1C
3. CDKN1C gene mutation
Loss of function causes symptoms associated with BWS
Most of these cases are familial

Estimate the recurrence risk for an imprinted disorder, based on the molecular mechanism.
4. Abnormal IC1/IC2 methylation
LOW in offspring
Methylation reset during gametogenesis
5. Paternal Uniparental Disomy
LOW in offspring
Non-disjunction events during meiosis I and II infrequent
6. CDKN1C gene mutation
Only maternal CDKN1C is expressed, so mutation in maternal CDKN1C gene leads to the risk
High as 50%

Describe the normal process of abdominal body wall formation and the process by which omphalocele
results.
Abdominal wall muscles derive from somatic mesoderm
o At 6 weeks, midgut herniates into the umbilicus and rotates
o Rotation allows proper spatial organization
o Gut should be retracted by 11 weeks
Omphalocele arises from failure of midgut retraction by 11 weeks
o Omphalocele: has amnion covering and is near umbilical base
o Gastroschisis: occurs following midgut retraction and guts are not covered by amnion

Review the mechanism of hypoglycemia in Beckwith Wiedemann syndrome.
Hypoglycemia in BWS is usually transient and caused by hyperinsulinemia
Insulin works on muscle, fat, and liver to sequester glucose and build tissues
o Muscle: increased glucose intake (GLUT4), increased protein synthesis, increased glycogen
synthesis
o Fat: lipolysis decreases, fatty acid and glucose intake increases
o Liver: decreased gluconeogenesis and glycogenoloysis, increased fat/VLDL/protein
synthesis, increased glycogen synthesis

Define overgrowth syndrome and discuss the cancer risks associated with Beckwith Wiedemann
syndrome.
Overgrowth syndrome: syndromes characterized by abnormally heightened growth rates
BWS associated with increased embryonal tumor risks
o Wilms tumor: high IGF2 expression
o Neuroblastoma
o Hepasblastoma
Risk of cancer highest in patients with paternal uniparental disomy
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Describe potential physical and psychosocial risks to children associated with conception via IVF.
ART may affect epigenetics of early embryogenesis and cause birth defects
Associated with increased risk for BWS/Angelmans syndrome (maternal imprinting disorders)
but NOT Prader-Willi syndrome (Paternal imprinting disorder)

Identify potential issues of access regarding IVF treatments.
1. Barrier to access: cost of IVF process (upwards of 20,000 for Tx, Rx and storage of eggs)
2. Geographic barrier: most fertility clinics are localized in highly populated areas
3. Age limit: restrict upper age to 45 for the mother

Identify what a patients/couples options are when deciding what to do with remaining embryos from
IVF and the associated ethical implications.
Storage
Thaw & Discard
Donate to research
Embryo adoption
Compassionate transfer

IQ12: Chronic Myeloid Leukemia t(9:22)(q34:q11)
Define the concept of a reciprocal chromosomal translocation; identify the chromosomal translocation in
chronic myelogenous leukemia and the two genes involved.
Reciprocal chromosomal translocation occurs when there are breaks between two chromosomes
and then the genetic mutation is mutually exchanged without deletion or duplication
CML involves translocation of t(9:22)(q34:q11), creating BCR-ABL mutant gene in the
Philadelphia chromosome (small Chr22 remainder)


List the molecular steps that lead from a chromosomal translocation to the production of the BCR/ABL
fusion protein (transcription, translation).
1. Chromosomal translocation
2. Binding of transcription factors to recruit RNA polymerase II to BCR.ABL fusion gene
3. Transcription of gene
4. Splicing of mRNA
38
5. Nuclear export
6. Translation by ribosomes

Invasion and metastasis are typically important hallmark properties of malignancy, however these
concepts are somewhat more relevant to a solid tumor malignancy such as a carcinoma. Since blood cells
normally circulate throughout the body, describe the hallmark properties that this disease (leukemia)
displays that make it fulfill the criteria of a malignancy.
Six Hallmarks of Cancer
1. Evading apoptosis
2. Limitless replicative potential
3. Self-sufficiency in growth signals
4. Insensitivity to anti-growth signals
5. Angiogenesis
6. Invasion/metastasis
In leukemia, cells display malignant characteristics not involved in the formation of a single solid
tumor
o Limitless replicative potential, evasion of apoptosis, self-sufficiency in growth signals, and
insensitivity to antigrowth signals

Define tyrosine kinase; describe how expression of the BCR/ABL tyrosine kinase results in leukemia.
Phosphorylates tyrosine residues of proteins
BCR.ABL translocation leads to overactive ABL tyrosine kinase activity
Overactive TK activates RAS by phosphorylating GDP into GTP
o RAF MekErkTranscription of genes involved in survival and proliferation
o Ras activates AKT, which sequesters BAD to prevent apoptosis
o Activation of MYC



Define an oncogene; contrast this with the concept of a tumor suppressor gene.
Oncogenes: mutated genes which provide a proliferative advantage for cells
o Often overexpressed in transformed cells
o Proto-oncogenes are endogenous genes that become oncogenic
39
Often cell growth/division regulators
Tumor suppressors: genes that keep cells from caner
o Gatekeeper proteins: protects cells from transformation and growth
o Caretaker proteins: stabilizes the genome
o Landscapers: stops neoplastic growth by making environment not good for unregulated
cell proliferation

Describe the informed consent process for the use of dasatinib in terms of its target, its effects and side
effects in the treatment of CML.
Purpose
o Engages the patient in their own care
o Reduces discontent/litigation when there are complications
o Protects the patients autonomy
Important facts to convey
o Diagnosis
o Proposed treatment or procedure
o Alternative treatment options along with risks and benefits
o Risks and benefits of the proposed treatment
o Risks of refusing treatment
Make sure to communicate with patients at a level they can understand!

Propose a mechanism of acquired resistance for a targeted therapy
Targeted protein has a mutation which prevents the drug from binding
Imatinib cant target BCR-ABL due to T315I mutation
IQ13: Retinoblastoma (13q14.1-13q14.2)
Compare and contrast the genetic basis of inherited retinoblastoma vs. retinoblastoma in a patient with
no family history of the disease. Describe the difference in the genetic basis of sporadic bilateral vs.
unilateral retinoblastoma.
Inherited retinoblastoma
o Loss of Rb allele is passed onto the proband
o Second somatic mutation is required for transformation
o Results in multifocal tumors (multiple circumscribed masses)
o Bilateral retinoblastoma always inherited
o Only 15% of unilateral cases are heritable
Non-inherited retinoblastoma
o Requires two somatic mutations on the wild-type Rb allele
o Extremely rare, and can be either unilateral or bilateral

Recognize the difference between autosomal dominant and autosomal recessive inheritance, and predict
the frequency of affected individuals.
Autosomal dominant means inheriting one copy of a specific allele will lead to the phenotypic
effect encoded in the specific allele
Autosomal recessive means a phenotypic effect is only observed when an individual has two
copies of a specific allele
40

Define the Knudson two-hit hypothesis and provide an example of a cancer that occurs as a result of this
phenomenon.
In Knudsons two-hit hypothesis, tumors form when two events knockout both alleles of the same
gene in the same cell.

List two mechanisms for the loss of function of tumor suppressor genes and describe loss of
heterozygosity (LOH).
Mutations in the gene which inactivates its activity
o Mutations which results in loss of ability for Rb to sequester E2F
Mutations in the gene which leads to underexpression of tumor suppressors
o Mutation in promoter of Rb which prevents its transcription
LOH is characterized by loss of the entire gene and surrounding chromosomal region.
o Uniparental disomy for a chromosome is a mechanism for LOH

Describe the role of the retinoblastoma gene product Rb and cyclin dependent kinases in cell cycle
regulation.
Rb is a tumor suppressor involved in G1/S checkpoint
Phosphorylation of Rb by Cyclin/CDK complex induces release of E2F
E2F is able to function as a transcription factor to push the cell into the S phase of the cell cycle.



Conceive a hypothesis to explain why many cancers contain mutations in the Rb gene, but germline Rb
mutations result primarily in pediatric retinoblastoma.
Retinoblastoma do not require as many mutated genes for transformation
Explain the ethical challenges associated with reproductive decision-making in light of an
autosomal dominant genetic disorder
Most cells have multiple tumor suppressing systems while the retina cells rely mostly on the Rb
tumor suppressor

8. Explain the ethical challenges associated with reproductive decision-making in light of an autosomal
dominant genetic disorder.
Assuming the parent is heterozygous, the risk of passing the autosomal dominant allele is 50%.
Given this high risk, one must consider the implications of passing on this allele to the child.
o Should the parents be able to terminate a conceptus with the mutant allele?
41
o How can we decide which genetic conditions are serious enough to warrant consideration
of genetic counseling?
IQ14: Lynch Syndrome
Describe at least four clinical characteristics of a familial cancer syndrome.
1. Early age of onset
2. Multiple independent primary tumors in the same individuals
3. Family history of cancer
4. Time from benign tumors to invasive tumors are shortened in familial cancer syndromes

Compare and contrast the physiologic function of an oncogene, a tumor suppressor gene, and a caretaker
gene.
Oncogenes: control cellular growth, division, and proliferation
Tumor suppressors: protect cells from cancer by regulating cell cycle, and apoptosis
Caretaker genes: protein products involved in maintaining genomic integrity like repairing
damaged DNA

Describe the clinical features, genetic heterogeneity and mechanism of Lynch Syndrome, also known as
Hereditary Nonpolyposis Colorectal Cancer (HNPCC).
Clinical features
o Increased risk for colon and endometrial cancers
Risks for other cancers are also increased, but colon and endometrial are most
common
o Early onset of cancers
o Multiple independent primary tumors in the same individual
o TGF receptor type II mutation is a tumor suppressor commonly observed in colon cancer
of lynch patients
TGFRII is a serine threonine kinase receptor which suppresses growth in normal
cells
Genetic heterogeneity
o A tumor on average, has ~80 non-silent mutation
15-20 of these drive cancer development
due to the genomic instability characteristic of Lynch syndrome
Mechanism
o Lynch syndrome is passed down generations in an autosomal dominant fashion
o Inactivating mutations in mismatch repair genes predisposes individuals to cancer (Mainly
MLH1, MSH2, and MSH6)
o There must be a second hit on the wild-type allele for microsatellite instability to occur
(Knudsons hypothesis)

Define the DNA mismatch repair system and discuss how inheritance of one mutant allele leads to
manifestation of defective DNA mismatch repair.
MMR fixes single nucleotide mismatches, small insertion/deletion mistakes
Inherited mutant allele plus second hit to MMR genes can disrupt DNA recognition and repair
complexes
42
o MLH1, MSH2, MSH6

Define epigenetic modification of DNA and describe its role in promoting tumorigenesis.
Epigenetic DNA modifications
o Affect gene expression without changing nucleotide bases
o DNA methylation silences transcription
o Histone acetylation upregulates transcription
o Histone methylation can silence transcription (H3K27me3) or activate it (H3K4me1)
Common to sporadic colorectal cancers, promoter methylation at MMR genes inhibits its
expression
Combined with a LOH event, this can cause 2 hits on MMR proteins and cause sporadic colon
cancer

Discuss the reasons why some patients accept or decline genetic testing for Lynch Syndrome when there
is a known pattern of familial heritability.
Reasons for testing
o Informative for other family members
o Appropriate therapy can be pursued to extend life
o Can make the necessary preparations prior to conceiving
Reasons against testing
o Positive results causes anxiety and psychological distress
o Tests can come back as a false positive
o Survivor Guilt
o Quality of life diminishes with constant colonoscopies, colectomy procedures.
o Ignorance is bliss
IQ15: Breast Cancer
Describe the clinical features of families that carry mutations in BRCA1 or BRCA2 and reasons why
cancer patients and their family members might consider undergoing testing.
Clinical features
o Early onset of breast and ovarian cancer
o Breast cancer in men of the family
o Bilateral breast tumors
Why pursue testing?
o Positive results can better prepare patients to identify the tumor early (More frequent
screening protocols, double mastectomy)
o May aid in therapeutics
PARP inhibitors
43



Describe the function of BRCA1 and BRCA2. Classify these genes as tumor suppressor genes, oncogenes,
or caretaker genes and explain your rationale.
BRCA1, BRCA2 are critical for homologous recombination which is required for meiosis and
double strand break DNA repair pathways
BRCA1 and BRCA2 are involved in DNA repair
o Caretaker genes

Compare and contrast the mechanism of tamoxifen with an aromastase inhibitor for the treatment of
breast cancer.
Tamoxifen: A SERM which acts as an ER antagonist in breast tumors to shut down ER signaling
Aromatase inhibitors: Inhibits aromatase in adipocytes to decrease peripheral estrogen synthesis
Both pathways reduce endogenous estrogen signaling, shutting down the proliferative action of
estrogen.
o Estrogen binds ERs, induces transcription of genes involved in growth (Cyclin D, Igf1)

Explain the significance of HER2/neu (her 2 or c-erbB2) overexpression in breast cancer.
ErbB2 overexpression upregulates the oncogenic effects of EGF signaling
44
More HER2 available means increased heterodimerization with EGFR1
RAS-GTP RafMek MAPK pathway is increased

Provide an example of a therapy that targets HER2/neu and describe its mechanism and clinical
significance.
Trastuzumab
o Monoclonal antibody highly specific for HER2
o Acts as an antagonist to prevent EGF binding
o Induces an immune cytotoxic response targeting adjacent HER2+ tumors

Explain the roles of staging, surgery, radiation and chemotherapy for early stage breast cancer.
Staging (TNM staging)
o Look at tumor size (T), nodal metastases (N), and distant metastases (M) to stage the
tumor (I-IV scale)
o Determines prognosis and treatment plan
Surgery: remove tumors and tissue surrounding the tumor
Radiation: targeted to site of the tumor to kill all cells in a localized area by inducing irreparable
DNA damage
o Ionizing: causes direct damage to DNA (SSB and DSBs)
o Non-ionizing: ionizes water to form radicals which cause SSB and DSBs
o Radiation is given in small doses to allow for regular tissues to recover
Chemotherapy: similar to radiation therapy; causes irreparable DNA damage
o Antimetabolite 5-fluorouracil
DNA analogues which inhibit DNA replication and transcription
o Alkylating agents Cyclophosphamide
Induces intra and inter-strand crosslinks, SSB, and base errors
o Microtubule inhibiting agents vincristine
Inhibits DNA replication by preventing microtubule assembly