Dr. Garg's Exam 4 Master Study Guide

The vocabulary you must own

Genetics questions rest on definitions. Lock these in first. Every Punnett square and inheritance question uses them again.

Humans have 46 chromosomes, which is 23 pairs. There are 22 pairs of autosomes plus 1 pair of sex chromosomes, XX for female and XY for male. Homologous chromosomes are the matching pair, one from each parent. They carry the same genes in the same spots.

Single-gene traits vs polygenic traits

• Single-gene trait: one gene, two possible outcomes. You either have it or you do not. Cystic fibrosis and sickle cell disease work this way.
• Polygenic trait, also called multifactorial: many genes plus the environment, which gives a whole range of outcomes. Height and heart health work this way, and so do later-life diseases such as diabetes, high blood pressure, coronary artery disease, and cancer, plus some mental illness. Early-life examples are cleft lip and palate, clubfoot, hip dislocation at birth, and heart defects at birth.

Mutations

A mutation is a change in the DNA sequence that can be passed down. There are two main kinds. One is an extra or missing nucleotide, which shifts the whole sequence. The other is a substitution, where one base swaps for another. The result can be nothing at all, or a new version of the gene. That new version may be harmless, helpful, as with sickle trait that resists malaria, or harmful, as with cancer.

❓ Practice Questions

1. A person has the genotype Bb. B is brown and dominant over b, which is blue. What eye color do you see? Could this person pass on the blue allele?
   Show answer

   The phenotype is brown eyes, because the dominant B shows. And yes. This person is heterozygous, carries the recessive b, and can pass it to a child.
2. Which trait is polygenic rather than single-gene: cystic fibrosis, or adult height?
   Show answer

   Adult height. Many genes shape it, plus the environment, such as nutrition. Cystic fibrosis is a single-gene trait.
3. SATA: Which of these are true of a karyotype? (a) it shows all 46 chromosomes, (b) it finds number problems such as trisomy, (c) it finds structure problems such as translocations, (d) it reads the sequence of single genes.
   Show answer

   a, b, c. A karyotype is a picture of the chromosomes, showing number, size, and shape. It finds extra, missing, or rearranged chromosomes. It does not read the sequence of single genes, so d is wrong.

Mitosis vs meiosis: know what each one produces

Why the halving matters: a haploid egg (n) joins a haploid sperm (n) at fertilization, and that rebuilds a diploid (2n) zygote. If the gametes were not halved first, the chromosome count would double with every generation.

Nondisjunction, the key error

Nondisjunction means "failure to separate." During meiosis the chromosomes are supposed to split evenly. When they do not, one gamete ends up with an extra chromosome and another gets none. After it joins a normal gamete, the embryo ends up with one of these:

• Trisomy means one extra chromosome, for 47 in all. Examples are Trisomy 21, which is Down syndrome, and XXY, which is Klinefelter.
• Monosomy means one missing chromosome, for 45 in all. The example is Monosomy X, written 45,X, which is Turner syndrome. There is no O, because nothing sits in the missing X's place.

The risk of nondisjunction climbs with the mother's age, because the eggs are older. It is the most common cause of chromosome disorders that change the number of chromosomes. By contrast, problems with chromosome structure are deletions, duplications, inversions, and translocations.

❓ Practice Questions

1. A sperm cell forms with two copies of chromosome 21, then fertilizes a normal egg. How many copies of chromosome 21 does the zygote have? What is the condition?
   Show answer

   Three copies, for 47 chromosomes in all. That is Trisomy 21, or Down syndrome. The extra copy came from the nondisjunction error in the sperm.
2. Which kind of cell division creates genetic variety through crossing over, mitosis or meiosis?
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   Meiosis. Crossing over trades pieces of DNA, and that is why siblings are not identical. Mitosis makes matching clones.
3. Nondisjunction in meiosis most directly causes which category of disorder? Name its two possible number outcomes.
   Show answer

   Chromosome disorders of number. The two outcomes are trisomy, with an extra chromosome, and monosomy, with a missing one.

All three classic chromosome disorders come from nondisjunction. The exam wants the karyotype, the sex, and the telltale features of each one.

The mechanism, in one line

Down syndrome is an extra copy of autosome 21, so an extra non-sex chromosome. Klinefelter is an extra X in a male, written XXY, so testosterone runs too low and feminizing features appear. Turner is a missing X in a female, written 45,X, so the ovaries stay underdeveloped, height is short, and the heart and thyroid are affected.

❓ Practice Questions

1. A karyotype shows 47 chromosomes, with three copies of chromosome 21. Name the condition and one health risk that goes with it.
   Show answer

   Trisomy 21, which is Down syndrome. The risks include heart defects present at birth, leukemia, and diabetes.
2. A tall adolescent male has small testes, breast tissue, and infertility. Which chromosome disorder is this, and what is the karyotype?
   Show answer

   Klinefelter syndrome, 47,XXY. The extra X holds testosterone down, which brings feminizing features and infertility.
3. SATA: Which of these are features of Turner syndrome? (a) a 45,X karyotype, (b) male, (c) short height, (d) a webbed neck, (e) a narrowed aorta.
   Show answer

   a, c, d, e. Turner syndrome affects a female with 45,X. She has short height, a webbed neck, and heart defects such as a narrowed aorta. Answer b is false, because there is no Y chromosome.

This is the biggest genetics topic of all. For each pattern, know how many copies it takes, which sexes it hits, the clue in the family tree, and the common conditions.

The probabilities to know

• AD, one affected parent (Bb) with an unaffected one (bb): each child has a 50% chance of being affected.
• AD, both parents heterozygous (Bb × Bb): 75% are affected, which is 1 BB plus 2 Bb. The other 25% are not.
• AR, two carriers (Bb × Bb): 25% are affected, 50% are carriers, and 25% are neither.
• X-linked, carrier mom with an unaffected dad: 50% of the sons are affected, and 50% of the daughters are carriers.
• X-linked, affected dad with an unaffected mom: none of the sons are affected, because dad gives his sons the Y. All of the daughters are carriers.

Spotlight conditions

• Marfan (AD): a connective tissue disorder. The person is tall, with long fingers (arachnodactyly), a caved or jutting chest, and a lens that can slip out of place. The deadly part is the aorta, which can widen and tear.
• Huntington's (AD): brain cells break down in mid-adult life. It brings chorea, which looks like dance-like movements, plus fading thinking and psychiatric symptoms. Each child has a 50% risk.
• Cystic fibrosis (AR): the CFTR protein is faulty, so thick mucus builds up in the lungs, the pancreas, and the reproductive tract.
• Duchenne MD (X-linked): the protein dystrophin is missing, so muscle wastes away in young boys.

❓ Practice Questions

1. A disease shows up in every generation and hits sons and daughters the same. One affected parent tends to have about half affected children. Which inheritance pattern is this?
   Show answer

   Autosomal dominant. It passes straight down through every generation, hits both sexes, and about 50% of children are affected when one parent is heterozygous.
2. Two unaffected parents have a child with cystic fibrosis. What were the parents' genotypes? What is the chance the next child is affected?
   Show answer

   Both parents are carriers, so Bb, for this autosomal recessive disease. For each pregnancy: 25% affected, 50% carrier, and 25% neither.
3. A condition hits mostly boys. An affected man's sons are all healthy, but all his daughters are carriers. Which pattern is this? Name one example.
   Show answer

   X-linked recessive. A father gives his sons the Y, so they are spared. He gives his X to every daughter, so each one is a carrier. Examples are hemophilia, Duchenne MD, and color blindness.
4. SATA: Which of these conditions are autosomal recessive? (a) Huntington's, (b) cystic fibrosis, (c) sickle cell disease, (d) Marfan, (e) Tay-Sachs.
   Show answer

   b, c, e. Cystic fibrosis, sickle cell, and Tay-Sachs are autosomal recessive. Huntington's and Marfan are autosomal dominant.

Punnett square questions are guaranteed points if you follow the same routine every time. Do not guess. Build the grid. Below, Xᵃ means a normal X and Xʰ means an X carrying the disease.

Worked example 1: autosomal recessive, carrier × carrier

Both parents are carriers, so Aa × Aa. "A" is the normal dominant allele. "a" is the recessive one that causes the disease. The affected box is shaded.

Results: 1 AA who is unaffected, 2 Aa who are carriers, and 1 aa who is affected. That is 25% affected, 50% carriers, and 25% unaffected.

Worked example 2: autosomal dominant, affected × unaffected

One parent has an AD condition and is heterozygous, so Aa. The other parent is unaffected, so aa. Here "A" causes the disease, and the shaded boxes are affected.

Results: 2 Aa who are affected, and 2 aa who are not. So 50% of the children are affected. If both parents were Aa, it would be 75% affected instead.

Worked example 3: X-linked recessive, affected father × unaffected mother

The father has hemophilia, so XʰY. The mother is not affected and not a carrier, so XᵃXᵃ. The shaded boxes are the carrier daughters.

Every daughter is a carrier, XᵃXʰ. Every son is unaffected, XᵃY. An affected father has no affected sons, but all of his daughters are carriers. He passes his Y to his sons, not his X.

❓ Practice Questions

1. Two carriers for an autosomal recessive disease (Aa × Aa) have a child. What is the chance that child is unaffected and not a carrier, so AA?
   Show answer

   25%. Only one of the four boxes, the AA box, is fully unaffected and not a carrier.
2. Two people are heterozygous for Marfan syndrome, which is autosomal dominant, so Aa × Aa. They have a child. What is the chance the child is unaffected?
   Show answer

   25%. Only the aa box is unaffected. The other 75%, which is 1 AA plus 2 Aa, are affected.
3. A carrier mother (XᵃXʰ) and an unaffected father (XᵃY) have a son. What is the chance that son has the X-linked disease?
   Show answer

   50% of sons are affected. Each son has a 1-in-2 chance of getting the mother's Xʰ.

A teratogen is anything that causes a birth defect in the fetus. The fetus is most at risk during organogenesis, which runs about days 15 to 60 after conception, or weeks 3 to 8. That is when the organs are forming.

• Before day 15: it is all or nothing. Either there is no effect, or the pregnancy is lost.
• Days 15 to 60: the highest risk of defects in body structure.
• After day 60: the exposure is more likely to affect growth or brain development than structure.

Common teratogens to recognize

❓ Practice Questions

1. During which window is the fetus at the highest risk for structural birth defects, and why?
   Show answer

   About days 15 to 60, which is weeks 3 to 8. This is organogenesis, when the organ systems are forming and are most easily harmed.
2. What does TORCH stand for?
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   Toxoplasmosis, Other, which covers syphilis, varicella, HIV, and parvovirus, Rubella, Cytomegalovirus, and Herpes simplex.
3. SATA: Which of these are known teratogens? (a) alcohol, (b) folic acid, (c) isotretinoin (Accutane), (d) mercury, (e) rubella.
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   a, c, d, e. Alcohol, isotretinoin, mercury, and rubella are teratogens. Folic acid, answer b, protects the baby, because it helps prevent neural tube defects.

The chain of command

Most hormones travel down one chain: the hypothalamus, then the pituitary, then the target gland. The hypothalamus is the control center. The front of the pituitary makes the hormones that order other glands around. The back of the pituitary stores ADH and oxytocin, which the hypothalamus makes.

• Hormones from the front of the pituitary: GH, prolactin, ACTH, which drives cortisol, TSH, which drives the thyroid, plus FSH and LH.
• Stored in the back of the pituitary: ADH, which holds on to water, and oxytocin.

Feedback loops: negative vs positive

Levels of trouble: where did the problem start?

The ACTH and cortisol logic, worth real points

Follow the feedback. In a primary adrenal problem, ACTH moves the opposite way from cortisol. In a secondary problem at the pituitary, ACTH and cortisol move the same way.

• Primary high cortisol, as in an adrenal adenoma: cortisol goes up, feedback kicks in, and ACTH and CRH go low.
• Secondary high cortisol, where the pituitary makes too much ACTH: ACTH is high, so cortisol is high. They rise together.
• Primary low cortisol, as in Addison's: cortisol goes down, so nothing holds the system back, and ACTH and CRH go high. That is what bronzes the skin.
• Secondary low cortisol, where the pituitary cannot make ACTH: ACTH is low, so cortisol is low. Both are low.

❓ Practice Questions

1. An adrenal adenoma puts out high cortisol on its own. What happens to ACTH and CRH, and why?
   Show answer

   ACTH and CRH both drop. High cortisol triggers negative feedback on the pituitary and the hypothalamus. This is a primary problem, since it starts in the gland.
2. Which of these is an example of positive feedback?
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   Oxytocin during labor, or the LH surge. The response feeds itself until it reaches an end point, which is delivery or ovulation. Most hormone control is negative feedback.
3. A pituitary tumor cannot make ACTH, so cortisol runs low. Is this primary, secondary, or tertiary? What is the ACTH level?
   Show answer

   It is secondary, at the pituitary. ACTH is low, so cortisol is low. Both move together, because the problem sits upstream at the pituitary.

Growth hormone (GH, also called somatotropin) comes from the front of the pituitary. It drives cell growth, protein building, the use of fat for fuel, and the growth of bone, cartilage, and muscle. The disorders come down to too little or too much. What matters most is whether the growth plates are still open.

What decides which one: gigantism and acromegaly both come from too much GH, usually a pituitary adenoma. If the excess starts before the growth plates fuse, you get gigantism, so the person is tall. If it starts after they fuse, you get acromegaly, so the person gets broader and thicker but no taller.

❓ Practice Questions

1. An adult's hands are getting bigger, the jaw juts out, and shoes no longer fit. Which GH disorder is this? Why is the person not getting taller?
   Show answer

   Acromegaly. The GH excess started after the growth plates fused, so the bones thicken and widen instead of lengthening. No new height comes from it.
2. A child has too much GH from a pituitary adenoma, before puberty. What result would you expect?
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   Gigantism. The growth plates are still open, so the long bones grow in length and the child becomes very tall.
3. A child with low GH is short but has a body in normal proportion. What is this? Name a possible cause.
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   Growth hormone deficiency, which is called proportional short stature. The height is short while the body stays in normal proportion. The cause may be unknown, present at birth, or acquired, such as damage to the pituitary.

ADH (antidiuretic hormone, also called vasopressin) tells the kidneys to hold on to water. The two disorders are mirror images. One has too little ADH, and the other has too much.

How DI looks like diabetes mellitus

DI and diabetes mellitus share the word "diabetes," which means "to pass through." Both cause heavy urine output and heavy thirst. Here is the difference. In DM the urine is loaded with glucose. In DI the urine is watery with no glucose, because the problem is with water, not with sugar.

❓ Practice Questions

1. A patient passes large amounts of very watery urine, is extremely thirsty, and has a high blood sodium. Is there too much or too little ADH? Which disorder is this?
   Show answer

   Too little ADH, so this is Diabetes Insipidus. The kidneys cannot hold water. Watery urine pours out, the blood turns concentrated with a high sodium, and thirst takes over.
2. A patient after surgery turns confused, puts out little urine, gains weight, and has a sodium of 122 mEq/L. Which ADH disorder is this?
   Show answer

   SIADH. Too much ADH holds water in, which dilutes the sodium down to a low level. That brings fluid overload and changes in thinking.
3. How is diabetes insipidus like diabetes mellitus? How does the urine differ?
   Show answer

   Both cause heavy urine output plus heavy thirst. In DM the urine is full of glucose. In DI the urine is watery with no glucose, because the trouble is with water, not sugar.

The adrenal cortex, which ACTH switches on, makes three things: cortisol, which is a glucocorticoid, aldosterone, which is a mineralocorticoid, and androgens. Cortisol raises blood sugar, holds inflammation and immunity down, and helps keep the blood pressure up. The two big disorders are opposites: too much, which is Cushing's, and too little, which is Addison's.

Why Addison's turns the skin bronze

In primary Addison's the adrenal cannot make cortisol. That means the feedback brake is gone, so the pituitary pours out high ACTH. ACTH is built from the same starting molecule as melanocyte-stimulating hormone. So high ACTH darkens the skin to a bronze color.

Addisonian crisis, the emergency

Cortisol drops suddenly, and it threatens life. You see severe low blood pressure and shock, low blood sugar, and a high potassium. What sets it off: stopping steroids all at once, so never stop without tapering. Major stress, infection, or surgery can do it too in someone whose adrenals already run low. Why tapering matters: long-term steroid pills shut down the body's own supply. Stopping all at once leaves a window with no cortisol at all, and that is the crisis.

Pheochromocytoma, in the adrenal medulla

A tumor of the adrenal medulla that pours out too many catecholamines, meaning epinephrine and norepinephrine. Learn it as the 5 P's: Pressure, meaning dangerously high blood pressure that spikes, Pain, meaning a severe headache that comes in waves, Palpitations, Perspiration, and Pallor. Three of those five stand out most and are often named together: headache, palpitations, and sweating. Treat that trio as the loudest part of the five, not as a rival list.

❓ Practice Questions

1. A patient on long-term prednisone develops a round "moon" face, fat around the middle, high blood sugar, and easy bruising. Which disorder is this?
   Show answer

   Cushing's syndrome, from too much cortisol. Here the cortisol came from the steroid medicine. The telltale signs are a moon face, a hump on the upper back, fat around the middle, high blood sugar, and thin skin that bruises.
2. Why does the skin turn bronze in primary Addison's disease?
   Show answer

   Low cortisol takes away the feedback brake, so ACTH climbs. ACTH is built from the same starting molecule as melanocyte-stimulating hormone, so high ACTH darkens the skin.
3. SATA: Which of these can set off an Addisonian crisis? (a) stopping long-term steroids all at once, (b) a major infection or surgery in someone with low adrenal function, (c) a slow steroid taper, (d) severe physical stress.
   Show answer

   a, b, d. Stopping steroids suddenly, and major stress or illness, can both set off a crisis. A slow taper, answer c, prevents it, because it gives the body's own cortisol time to come back.
4. A patient has pounding headaches that come in waves, a racing heart, sweating, and a BP that spikes to 220/120. Which adrenal tumor is this?
   Show answer

   Pheochromocytoma. It is a tumor of the adrenal medulla that releases catecholamines. Look for the 5 P's, meaning pressure, pain or headache, palpitations, perspiration, and pallor. The three that stand out here are the headache, the palpitations, and the sweating.

Thyroid hormone, which is T3 and T4, sets how fast the body runs. Hypo means everything slows down. Hyper means everything speeds up. The pituitary controls it with TSH.

Reading the labs in primary thyroid disease

In a primary thyroid problem, TSH moves the opposite way from T3 and T4, because of negative feedback. When thyroid hormone is low, the pituitary calls for more, so TSH is high. That is hypothyroidism. When thyroid hormone is high, the pituitary goes quiet, so TSH is low. That is hyperthyroidism.

Goiter

A goiter is a swollen, enlarged thyroid. It can show up in either an underactive or an overactive thyroid. The classic causes are too little iodine and Graves' disease. The size alone does not tell you the hormone level, so you still need labs.

Hypoparathyroidism, the calcium gland

The parathyroid glands raise blood calcium, using PTH. Hypoparathyroidism means low PTH, which means LOW calcium. Low calcium makes nerves and muscles fire too easily. You see tingling, muscle cramps, tetany, a positive Trousseau's sign, which is a hand spasm when a BP cuff inflates, and Chvostek's sign. A classic cause is damaging or removing them by accident during thyroid surgery, since the parathyroids sit right on the thyroid.

❓ Practice Questions

1. A patient is tired, cold, constipated, and gaining weight, with a heart rate of 54 and a goiter. The T4 is low. In primary disease, what will the TSH be?
   Show answer

   High, above normal. In primary hypothyroidism the low T3 and T4 take away the feedback, so the pituitary pushes TSH up, trying to wake the failing gland.
2. SATA: Which of these are signs of hyperthyroidism? (a) losing weight, (b) feeling too hot, (c) a slow heart rate, (d) tremor and anxiety, (e) diarrhea.
   Show answer

   a, b, d, e. Hyperthyroidism speeds everything up. Answer c is wrong, because you would expect a fast heart rate, not a slow one.
3. After thyroid surgery, a patient has tingling lips and a hand spasm when the BP cuff inflates. Which gland was likely hurt, and which electrolyte is low?
   Show answer

   The parathyroid glands were damaged, so PTH is low, and that means low calcium. Low calcium makes nerves and muscles fire too easily, which gives a positive Trousseau's sign and tetany.

Insulin, made by the beta cells of the pancreas, lets glucose into the cells and brings blood sugar down. Without working insulin, glucose piles up in the blood while the cells go hungry.

What insulin normally does

• It moves glucose into cells, in muscle, fat, and liver, so they have fuel.
• It helps the body store glycogen, fat, and protein. It is the hormone of the fed state.
• It lowers blood sugar. That is the opposite of what glucagon, cortisol, and epinephrine do.

The classic signs, the "polys"

Polyuria means lots of urine. Glucose spills into the urine and drags water with it. That leads to dehydration, which brings polydipsia, meaning heavy thirst. Polyphagia means heavy hunger, because the cells cannot use the glucose. Add weight loss, since the body burns fat and muscle, plus blurry vision from swelling in the lens, and tiredness.

DKA vs HHS, the two crises

Long-term complications, and diabetes in pregnancy

• Long-term complications split into two groups. The large-vessel ones are heart attack, stroke, and poor circulation in the legs. The small-vessel ones are damage to the eyes, which can cause blindness, damage to the kidneys, which can lead to kidney failure, and damage to the nerves, which brings numbness and ulcers. Add slow wound healing and frequent infections.
• Gestational diabetes is insulin resistance during pregnancy. The placenta blocks insulin, and late in pregnancy the mother cannot keep up. The problems include a large baby, called macrosomia, too much amniotic fluid (polyhydramnios), injury during birth, low blood sugar in the newborn, and a higher future risk of Type 2 for both mother and child.

❓ Practice Questions

1. A thin 16-year-old comes in breathing deep and fast, with fruity breath, a glucose of 480 mg/dL, ketones in the urine, and a low blood pH. Which type of diabetes is this, and which crisis?
   Show answer

   Type 1 DM in DKA. With no insulin, the body burns fat, which makes ketones, and the blood turns acidic. The patient compensates with Kussmaul breathing, and the breath smells fruity.
2. An older adult with Type 2 diabetes has a glucose of 820 mg/dL, severe dehydration, and confusion, with no real ketones. Which emergency is this?
   Show answer

   HHS. There is still enough insulin to block ketone production, but the glucose climbs extremely high. That pulls water out, so the patient becomes badly dehydrated, the blood turns thick, and thinking changes.
3. List three things insulin does.
   Show answer

   It moves glucose into cells. It helps the body store glycogen, fat, and protein. And it lowers blood sugar.
4. SATA: Which of these are known risk factors for Type 2 diabetes? (a) extra weight, (b) little physical activity, (c) an immune attack on the beta cells, (d) family history, (e) older age.
   Show answer

   a, b, d, e. Extra weight, little activity, family history, and age all drive Type 2. An immune attack on the beta cells, answer c, is Type 1.