Genetics

Question 1

Nonsense mutation

Answer 1

Introduce stop codon within gene sequence resulting in formation of shorter nonfunctional protein.

Question 2

Silent mutation

Answer 2

Ex. UAA–> UAG (both stop codons)
Ex. UUU–>UUA (both code for phenylalanine)
Mutation does not alter protein structure, and is thus silent.

Question 3

Frameshift mutation

Answer 3

Occur with deletion, or less commonly, insertion of base pairs which are not a multiple of three therefore altering the reading frame of genetic code. Usually results in formation of shorter, nonfunctional proteins.

Question 4

Missense mutation

Answer 4

Base substitution resulting in an amino acid change, creating a dysfunctional but usually same sized protein. Eg, UUU to UCU changes translated AA from phenylalanine to serine.

Question 5

Splice site mutation

Answer 5

Formation of larger proteins that are usually nonfunctional, but often retain immunoreactivity of normal protein (binding to antibodies). Eg, nonfunctional protein contains 156 AA residues rather than the 130 AA residues seen in the functional protein. Nonfunctional protein still detected by specific Abs against the functional protein.

Question 6

Homeobox

Answer 6

A highly conserved DNA sequence, usually ~180 nucleotides in length. A gene containing a homeobox sequence is called a homeobox gene. Homeobox genes typically code for DNA-binding transcription factors which alter expression of genes involved in morphogenesis (the proper formation and placement of tissues, organs, and structural elements of the body).

Question 7

Anticipation

Answer 7

Earlier age of onset associated with larger number of trinucleotide repeats. During spermatogenesis, CAG repeats in the abnormal HD gene rapidly increase. Thus, patients who receive an abnormal gene from their fathers tend to develop the disease earlier in life. Number of trinucleotide repeats on HD gene remains the same during maternal transmission. Anticipation is common in d/o associated with trinucleotide repeats aka Fragile X, myotonic dystrophy, Friedreich ataxia.

Question 8

Deletion

Answer 8

The loss of genetic material. Examples of deletion are DiGeorge syndrome (22q11 microdeletion) and cri-du-chat syndrome (5p deletion).

Question 9

Kozak sequence

Answer 9

1. Kozak consensus sequence occurs on eukaryotic mRNA [(gcc)gccRccAUGG, where R is either A or G] and plays a role in initiation of translation (mRNA binding to ribosomes).
2. When AUG (methionine codon) positioned near the beginning of an mRNA molecule and is surrounded by the Kozak sequence, it serves as the initiator for translation.
3. The purine (A or G) in the R position, 3 bases upstream from AUG, appears to be a key factor in initiation.
4. A mutation in which G is replaced by C three bases upstream from start codon (AUG) in the Kozak sequence of the β-globin gene is associated with β-thalassemia intermedia.
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Question 10

Stop codons

Answer 10

1. UGA “U’re Going Away”
2. UAA “U Are Away”
3. UAG “U Are Gone”
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Question 11

Genetic disorders with mutations on chromosome 1

Answer 11

1. Chediak-Higashi syndrome (CHS1/LYST gene)
2. Factor V Leiden (factor V gene)
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Question 12

Genetic disorders with mutations on chromosome 2

Answer 12

1. Gilbert syndrome/Crigler-Najjar Syndrome (UGT1A1 gene) 2. HNPCC (microsatellite instability)
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Question 13

Genetic disorders with mutations on chromosome 3

Answer 13

1. von Hippel-Lindau disease (VHL gene on 3p)
2. Renal cell carcinoma (VHL gene)
3. HNPCC (microsatellite instability)
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Question 14

Genetic disorders with mutations on chromosome 4

Answer 14

1. Achondroplasia (FGFR3 gene)
2. Huntington disease (CAG repeats in HD gene)
3. ADPKD (PKD2 gene)
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Question 15

Genetic disorders with mutations on chromosome 5

Answer 15

1. Cri-du-chat (5p microdeletion)
2. Familial Adenomatous Polyposis (APC gene on 5q)
3. Gardner syndrome (APC gene)
4. Turcot syndrome (APC gene)
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Question 16

Genetic disorders with mutations on chromosome 6

Answer 16

1. Hemochromatosis (HFE gene, C282Y > H63D)
2. Congenital Adrenal Hyperplasia (21-β-hydroxylase gene)
3. ARPKD (polyductin gene)
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Question 17

Genetic disorders with mutations on chromosome 7

Answer 17

1. Williams syndrome (7q microdeletion)
2. Cystic Fibrosis (CFTR gene, ΔF508)
3. Osteogenesis imperfecta (COLIA2)
4. HNPCC (microsatellite instability)
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Question 18

Genetic disorders with mutations on chromosome 9

Answer 18

1. Friedreich ataxia (GAA repeat in frataxin gene)
2. Tuberous sclerosis (TSC1 gene)
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Question 19

Genetic disorders with mutations on chromosome 10

Answer 19

MEN 2a/2b (RET proto-oncogene)

Question 20

Genetic disorders with mutations on chromosome 11

Answer 20

1. MEN 1 (MEN1 gene)
2. Sickle cell anemia (β-globin gene, HBB)
3. Hb C disease (β-globin gene, HBB)
4. β-thalassemia (β-globin gene, HBB)
5. Oculocutaneous albinism (TYR gene)
6. Ataxia-Telangiectasia (ATM gene)
7. Wilms tumor
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Question 21

Genetic disorders with mutations on chromosome 13

Answer 21

1. Patau syndrome (trisomy 13)
2. Wilson disease (ATP7B gene)
3. Retinoblastoma (RB1 gene)
4. BRCA2 gene
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Question 22

Genetic disorders with mutations on chromosome 14

Answer 22

α-1-antitrypsin disease (A1AT gene, PiZZ genotype)

Question 23

Genetic disorders with mutations on chromosome 15

Answer 23

1. Marfan syndrome (FBN1 gene)
2. Prader-Willi syndrome (15q11-13 paternal chromosome deletion)
3. Angelman syndrome (15q11-13 maternal chromsome deletion)
4. Bloom syndrome (BLM gene)
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Question 24

Genetic disorders with mutations on chromosome 16

Answer 24

1. ADPKD (PKD1 gene)
2. α-thalassemia, (HBA1, HBA2 genes)
3. Tuberous sclerosis (TSC2 gene)
4. Mediterranean Familial Fever (MEFV gene)
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Question 25

Genetic disorders with mutations on chromosome 17

Answer 25

1. Neurofibromatosis type 1 (NF1)
2. LiFraumeni (TP53)
3. BRCA1 gene
4. Osteogenesis imperfecta (COLIA1)
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Question 26

Genetic disorders with mutations on chromosome 18

Answer 26

Edwards syndrome (trisomy 18)

Question 27

Genetic disorders with mutations on chromosome 19

Answer 27

1. Myotonic dystrophy type I (CTG repeats in DMPK gene)
2. Peutz-Jeghers syndrome (LKB1 gene)
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Question 28

Genetic disorders with mutations on chromosome 20

Answer 28

1. Pseudohypoparathyroidism (PTH receptor gene)
2. Hyper IgM syndrome (CD40 receptor gene)
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Question 29

Genetic disorders with mutations on chromosome 21

Answer 29

Down syndrome (trisomy 21)

Question 30

Genetic disorders with mutations on chromosome 22

Answer 30

1. Neurofibromatosis type 2 (NF2)
2. DiGeorge syndrome (22q11 microdeletion)
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Question 31

Genetic disorders with mutations on chromosome X

Answer 31

1. Klinefelter syndrome (XXY)
2. Turner syndrome (XO)
3. Fragile X syndrome (CGG repeats in FMR1 gene)
4. G6PD deficiency
5. Hemophilia A and B
6. Bruton’s X-linked agammaglobulinemia (Btk gene)
7. Chronic Granulomatous Disease (NADPH oxidase)
8. Wiskott-Aldrich syndrome (WAS gene)
9. Hyper IgM syndrome (CD40L gene)
10. Androgen Insensitivity Syndrome (androgen receptor gene)
11. Duchenne/Becker Muscular Dystrophy (DMD gene)
12. Ocular albinism
13. Lesch-Nyhan syndrome
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Question 33

McCune-Albright Syndrome (MAS)

Answer 33

1. Noninherited postzygotic activating mutation in GNAS1, causing constitutively active stimulatory Gs alpha subunit, leading to increased production of hormones regulated by Gs protein system (eg, estrogen/precocious puberty (LH/FSH receptors), melanogenesis (MSH receptor), hyperthyroidism (TSH receptor), hypercortisolism (ACTH R), acromegaly (GHRH R)) with no negative feedback system.
2. At least 2 of 3 features: (1) polyostotic fibrous dysplasia (PFD), (2) café-au-lait macules, and (3) autonomous endocrine hyperfunction (eg, gonadotropin-independent precocious puberty).
3. Other endocrine syndromes may be present, including hyperthyroidism, acromegaly, and Cushing syndrome.
4. Eumelanogenesis normally stimulated by MSH binding to MSH receptor, a classic GPCR. Constitutive activation of Gs alpha subunit in melanocytes results in increased brown pigmentation characteristic of café-au-lait spots. Classically, unilateral cafe-au-lait spots with a tendency to respect the midline and follow developmental lines of Blaschko (jagged “coast of Maine” borders).
5. Both LH and FSH receptors are Gs alpha−coupled receptors, and constitutive activation leads to multiple ovarian follicular cysts with excess estrogen production and precocious puberty in girls.
6. Disease lethal in utero if mutation occurs before fertilization affecting all cells with survival only in patients with mosaicism. Accounts for the lack of autosomal dominant transmission of this syndrome.
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Question 34

DiGeorge syndrome (22q11 deletion syndrome)

Answer 34

1. DiGeorge syndrome- thymus (T-cell deficiency), parathyroid (hypocalcemia), cardiac defects 2/2 aberrant development of the 3rd and 4th branchial pouches.
2. Velocardiofacial syndrome- palate, facial, and cardiac defects.
3. Chromosome 22q11 microdeletion (detected by FISH) results in failure of development of third and fourth pharyngeal pouches, which give rise to thymus and parathyroids (inferior- 3rd, superior- 4th).
4. Disruption in 3rd and 4th pharyngeal arches leads to abnormal neural crest cell migration, with facial abnormalities (cleft palate, small jaw) and cardiac malformations (eg, tetralogy of Fallot, truncus arteriosus).
5. T-cell deficiency manifests as recurrent viral, fungal, and protozoal infections. Hypoparathyroidism manifests with signs of hypocalcemia (tetany).
6. Labs reveal decreased T cell count, decreased PTH, decreased Ca2+, increased phosphate, absent shadow on CXR.
7. Small, low-set ears, wide-set eyes, hooded eyes, a relatively long face, or a short or flattened groove in the upper lip.
8. Tx fetal thymus transplant to restore T-cell immunity.
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Question 35

Williams syndrome

Answer 35

Congenital microdeletion of the long arm of chromosome 7, deleted region contains elastin gene. Presents with intellectual disability, elfin facies, hypercalcemia 2/2 increased vitamin D sensitivity, well developed verbal skills, extreme friendliness with strangers, cardiovascular problems.

Question 36

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Answer 36

1. Autosomal dominant mutation that leads to bilateral massive enlargement of the kidneys with multiple large cysts and progressive renal failure.
2. 85% of cases due to a mutation of PKD1 gene on chromosome 16 and 15% due to a mutation in PKD2 gene on chromosome 4.
3. Mutation in PKD1 leads to defective polycystic, protein involved in cell-to-cell matrix interactions.
4. Exact mechanism unknown, but thought that defective polycystic results in abnormal cell differentiation, leading to cyst formation.
5. Presents with hypertension, hematuria, palpable renal masses that eventually progresses to ESRD. CT reveals multiple large cysts in both kidneys.
6. Associated with secondary polycythemia, polycystic liver disease, berry aneurysms, and MVP.
7. Blood pressure control and low-protein diet may slow progression of ESRD.
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Question 37

Achondroplasia

Answer 37

1. AD mutation in FGFR3 gene located on chromosome 4.
2. FGFR3 (fibroblast growth factor receptor 3) gene codes for a tyrosine kinase receptor that inhibits chondrocyte proliferation at growth plates, leading to decreased cartilage proliferation and subsequent decreased bone growth.
3. FGFR3 mutation leads to constituent activity of the tyrosine kinase, so that cartilage proliferation at the growth plate is inhibited 100% of the time, resulting in short thick bones with narrow epiphyseal plates, consisting of disorganized chondrocytes.
4. Most common cause of dwarfism. Full penetrance.
5. Presents as dwarfism (short limbs with normal trunk); macrocephaly with frontal bossing, midface hypoplasia, hypotonia in early life that resolves spontaneously. May have neurological symptoms that result from small foramen magnum.
6. Tx genetic counseling for parents of affected patient regarding future offspring; sx treatment of neurologic complications.
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Question 38

Familial hypercholesterolemia

Answer 38

Autosomal dominant disorder that manifests as greatly increased circulating LDL due to a defective or absent LDL receptor. Presents as severe atherosclerosis early in life with corneal arcus, tendon xanthomas, and risk of stroke/MI.

Question 39

Mitochondrial myopathies

Answer 39

Rare disorders that present with myopathy, lactic acidosis, and CNS disease 2/2 failure in oxidative phosphorylation. Muscle biopsy classically shows “ragged red fibers.” MELAS= Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes.

Question 40

Hereditary Hemorrhagic Telangiectasia (HHT) aka Osler-Weber-Rendu syndrome

Answer 40

1. AD disorder due to mutations in TGF-β-binding proteins.
2. Mutations in TGF-β-binding proteins lead to abnormal development of vascular structures, resulting in localized dilation and convolution of venules and capillaries of skin, mucus membranes, lungs, GI tract, urinary tract.
3. Presents with branching skin lesions (telangiectasias), recurrent epistaxis, skin discolorations, arteriovenous malformations, GI bleeding, and hematuria.
4. Labs reveal normocytic normochromic anemia.
5. Tx nasal packing, cautery, estrogens to control epistaxis.
6. Seen with increased frequency in Utah Mormons.
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Question 41

Tuberous sclerosis

Answer 41

1. AD neurocutaneous disorder caused by mutation in one of several different genes, including TSC1 gene on chromosome 9 and TSC2 gene on chromosome 16. Variable expression.
2. TSC1 and TSC2 are tumor suppressor genes. Mutation of these genes leads to multiple different neoplasms.
3. Characterized by multi-organ system involvement of numerous benign hamartomas including brain hamartomas (nodules composed of disorganized neurons in the cerebral cortex, also called cortical tubers), cardiac rhabdomyomas (benign hamartoma of cardiac muscle that usually arises in the ventricle), adenoma sebaceum on face (lesion consisting of malformed blood vessels), renal angiomyolipomas (hamartoma of the kidney comprised of BVs, smooth muscle, and adipose tissue), and cysts of the bone and lung.
4. Neurologic hamartomas lead to mental retardation and seizures beginning in infancy. Red nodules on face appear between ages of 5 and 10.
5. Tx includes seizure control, regular surveillance for renal angiomyolipomas, genetic counseling.
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Question 42

Li-Fraumeni syndrome

Answer 42

1. AD mutation in TP53 gene (tumor-suppressor) on chromosome 17 leading to multiple malignancies at an early age.
2. Aka “SBLA cancer syndrome” = Sarcoma, Breast, Leukemia, Adrenal gland.
3. p53 is responsible for regulating multiple cell cycle and DNA repair processes. Essentially, p53 senses DNA damage and activates expression of DNA repair proteins as well as proteins that halt cell cycle at G1 phase while repair takes place.
4. If DNA damage too extensive, p53 can trigger apoptosis (via Bax).
5. If p53 gene mutated, cell cycle stop mechanisms are ineffective and cells with damaged DNA continue to proliferate through the cell cycle, leading to tumor formation.
6. Patients inherit only 1 copy of the mutated gene (AD), but loss of heterozygosity leads to cancer.
7. Patients are at significantly increased risk of cancers (particularly sarcomas, osteosarcomas, breast cancer, leukemia, adrenal carcinoma, and brain tumors) at an early age.
8. Tx cancers with chemotherapy/radiation. Typically significant family history of malignancy leads to genetic testing.
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Question 43

Myotonic Dystrophy (Type I)

Answer 43

1. AD trinucleotide repeat expansion disorder caused by CTG repeat expansion in DMPK gene on chromosome 19.
2. CTG repeats cause abnormal expression of myotonin protein kinase. Exact function of myotonin protein kinase unclear.
3. Histology reveals “ring fibers” (cytoplasmic band within center of fiber), fiber splitting, and necrosis of intrafusal fibers of muscle spindles.
4. Presents between age 20-30 with myotonia (inability to relax contracted muscles), cataracts, testicular atrophy, frontal balding, arrhythmias (cardiac disease), muscle wasting, and glucose intolerance.
5. Myotonia presents as muscle stiffness, weakness, and wasting of distal limb and facial muscles.
6. “My Tonia, My Testicles, My Toupee, My Ticker.”
7. Tx myotonia with phenytoin.
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Question 44

Huntington disease

Answer 44

1. AD trinucleotide repeat expansion disorder of CAG repeats in HD gene on chromosome 4. Variable penetrance.
2. Exact function of HD gene product unknown. Researchers suspect protein involved in neuronal apoptosis as neurologic system severely affected in HD.
3. GABAergic striatal neurons of the basal ganglia are damaged, leading to atrophy of the caudate nucleus and putamen. Destruction of these components of the extrapyramidal motor system leads to motor abnormalities as seen in HD.
4. Progressive disorder that presents at age 40-50 with chorea (involuntary jerky movements), cognitive impairments, depression/personality changes, and progresses to severe dementia.
5. Brain MRI demonstrates caudate atrophy and dilation of lateral and third ventricles.
6. Think “Hunting 4 CAGs” to remember that Huntington disease is caused by CAG repeats on chromosome 4.
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Question 45

Fragile X syndrome

Answer 45

1. X-linked dominant disorder caused by CGG trinucleotide repeat expansion in FMR1 gene on X chromosome, leading to decreased expression of FMR1.
2. Fragile X is the second most common cause of genetic intellectual disability (after DS).
3. Presents with severe intellectual disability with autistic characteristics, post-pubertal macroorchidism (large testes), a long face with a large jaw and large everted ears, and mitral valve prolapse. Connective tissue defect manifested by hyperextensible joints and MVP. “Fragile X= eXtra large testes, jaw, and ears.” Lifespan not affected.
4. Demonstrates anticipation, phenomenon in which number of repeats increases with each generation and results in more severe disease manifestations.
5. Affects both males and females, but females have less severe clinical manifestations.
6. Fragile X named for the fragile gap at the end of the long arm of the X chromosome in lymphocytes grown in folate-deficient medium.
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Question 46

Familial Adenomatous Polyposis (FAP)

Answer 46

AD mutation of APC gene on chromosome 5q leading to a colon covered with adenomatous polyps (500-2500) by puberty. Adenomatous polyposis coli (APC) is a large multifunction tumor-suppressing protein that acts as a “gatekeeper” to prevent development of tumors by regulating β-catenin. Patients with FAP require prophylactic colectomy as there is a 100% chance polyps will evolve into colorectal carcinoma if not resected. (Think 5 letters in “polyp” = chromosome 5).

Question 47

Chediak-Higashi Syndrome

Answer 47

1. Rare AR disorder due to a protein trafficking (microtubule) defect characterized by impaired phagolysosome formation. Phagosomes are unable to join with lysosomes due to a microtubule defect.
2. Presents with an increased risk of pyogenic infections
3. Neutropenia due to intramedullary death of neutrophils as they are unable to divide properly
4. Giant granules in leukocytes (fusion of granules from Golgi since unable to distribute evenly throughout cell)
5. Defective primary homeostasis due to abnormal dense granules in platelets that are not properly distributed throughout platelets
6. Albinism b/c pigment from melanocytes (melanosomes) cannot disperse via microtubules to surrounding keratinocytes
7. Peripheral neuropathy b/c peripheral nerves die with lack of axonal transport of nutrients from the cell body without functioning microtubules.
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Question 48

Marfan syndrome

Answer 48

1. AD mutation in FBN1 gene on chromosome 15 leading to defective fibrillin protein (scaffold protein for elastin).
2. Most mutations hereditary, but 20% sporadic.
3. Fibrillin is a glycoprotein constituent of microfibrils, present in great quantities in ECM of aorta, ligaments, perichondrium, and ocular zonules (attach lens to ciliary body).
4. Present with tall stature, long extremities, pectus excavatum, hyperextensible joints, long “tapering” fingers/toes (arachnodactyly), mitral valve prolapse, dissecting aortic aneurysm, aortic insufficiency, skeletal abnormalities (kyphosis, scoliosis), spontaneous pneumothorax.
5. Cystic medial necrosis of aorta 2/2 dilation of aortic valve and weakening of media with increased risk of intimal tear and dissection. Mitral valve prolapse 2/2 loss of connective tissue support of valvular leaflets.
6. Predisposition to lens dislocation (ectopia lentis) or subluxation of lenses upward and temporally (classic finding).
7. Think “MarFan syndrome due to FBN1 mutation on chromosome Fifteen causing a defect of Fibrillin.”
8. Tx spine brace, endocarditis prophylaxis, AVR if necessary, beta-blockers. Untreated, death is common between ages 30-40 from aortic dissection or CHF secondary to aortic regurgitation.
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Question 49

Familial Hypocalciuric Hypercalcemia

Answer 49

1. Benign AD disorder caused by a defective CaSR (calcium sensing receptor) in the parathyroid glands and kidneys leading to decreased sensitivity to calcium plasma levels.
2. In FHH, higher serum calcium levels are required to suppress the secretion of PTH, raising the set point of calcium-induced regulation of PTH secretion.
3. Sx. Mild asymptomatic hypercalcemia, reduced urinary excretion of calcium, and high normal PTH.
4. CaSRs are transmembrane GPCRs that help regulate the secretion of PTH in response to serum Ca++ levels.
5. Binding of Ca++ to CaSR leads to inhibition of PTH release.
6. Cinacalcet can cause increased sensitivity to Ca++.
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Question 50

Familial erythrocytosis

Answer 50

1. Disorder caused by mutation in 2,3-BPG binding pocket of β-globin gene of Hb A.
2. Normally 2,3-BPG binds strongly to deoxyHb A in a pocket formed by 2 β-chains.
3. Binding of 2,3-BPG reduces oxygen affinity of HbA, allowing more oxygen to diffuse into peripheral tissues.
4. 2,3-BPG binding pocket contains positively charged amino acids (histidine, lysine) to attract negative phosphate groups on 2,3-BPG.
5. Mutations that decrease the positive charge of the 2,3-BPG binding site increase Hb affinity for oxygen, rendering the Hb A similar to Hb F.
6. Lack of oxygen available to tissues leads to a reactive compensatory erythrocytosis.
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Question 51

Myeloperoxidase deficiency

Answer 51

1. AR disorder characterized by absent enzyme myeloperoxidase (MPO).
2. MPO uses peroxide (formed by NADPH oxidase and superoxide dismutase) as a substrate to make HOCl to kill bacteria.
3. MPO deficiency results in defective conversion of H2O2 to HOCl.
4. Increased risk for candida infections, however, most patients asymptomatic.
5. NBT test is normal b/c NADPH oxidase (respiratory burst) is intact, unlike in chronic granulomatous disease.
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Question 52

Kallmann syndrome

Answer 52

Mutation in KAL-1 gene or FGFR-1 gene that lead to failure of GnRH-secreting neurons to migrate from their origin in the olfactory placode to the hypothalamus. Presents with delayed puberty (central hypogonadism) and anosmia. On exam the testes are very small (1-2mL in volume) though there may be some pubic hair due to adrenarche. Puberty defined as absence or incomplete development of secondary sexual characteristics by age 14 in boys or 12 in girls.

Question 53

Cri-du-chat syndrome

Answer 53

1. Disorder caused by microdeletion of chromosome 5p (short arm).
2. Patients present with high-pitched cat-like cry at birth due to structural abnormalities in the larynx.
3. Sx. Severe developmental delay and intellectual disability. Distinctive facial abnormalities (round face, low-set ears, microcephaly, hypoplastic nasal bridge, epicentral folds). Cardiac abnormalities (eg, VSD) and difficulty swallowing resulting in failure to thrive.
4. Cytogenetic studies reveal deletion of chromosome 5p.
5. Supportive care with special attention to developmental needs of patient, genetic testing for any patient of childbearing age.
6. Patients have up to 10% annual morbidity and mortality rate, although most deaths occur within first year of life.
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Question 54

Patau syndrome

Answer 54

1. Trisomy 13, usually caused by meiotic nondisjunction. Few cases caused by mosaicism resulting from mitotic nondisjunction of chromosome 13 during embryogenesis. Few caused by translocation between chromosomes 13 and 14.
2. Sx severe intellectual disability, microcephaly, holoprosencephaly, rocker-bottom feet, microphthalmia, polydactyly, cleft lip/palate, congenital heart and renal defects, umbilical hernia, cutis aplasia.
3. Fatal within 1 year of birth.
4. (Patau = trisomy 13, “Puberty at age 13.”)
5. Incidence of Patau syndrome increases with maternal age.
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Question 55

Edwards syndrome

Answer 55

1. Trisomy 18, most caused by meiotic nondisjunction. Few cases caused by mosaicism resulting from mitotic nondisjunction of chromosome 18 during embryogenesis.
2. Sx severe intellectual disability, rocker-bottom feet, prominent occiput, micrognathia, low-set ears, clenched hands with overlapping 3rd and 4th fingers, congenital heart and renal defects.
3. Fatal within 1 year of birth.
4. (Edwards = trisomy 18, “Election age is age 18”).
5. Incidence of Edwards syndrome increases with maternal age.
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Question 56

Genetics of Down syndrome

Answer 56

1. Trisomy 21
2. 95% cases occur 2/2 meiotic nondisjunction (meiotic nondisjunction rates increase with advanced maternal age).
3. 4% cases occur 2/2 unbalanced Robertsonian translocation, most typically between chromosome 14 or 22. Long arm of 21 translocates to another chromosome.
4. 1% cases occur 2/2 mosaicism (no maternal association; post-fertilization mitotic nondisjunction of chromosome 21).
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Question 57

Down syndrome

Answer 57

1. Trisomy 21.
2. Sx severe intellectual disability, flat facies, prominent epicanthal folds, wide set eyes, short hands with simian crease (single palmar crease), gap between first 2 toes, duodenal/ esophageal atresia, Hirschsprung disease, Brushfield spots (white spots on periphery of iris).
3. Congenital heart defects: endocardial cushion defects leading to ostium primum atrial septal defects, VSDs and AV valve malformations (tricuspid/mitral).
4. Most common viable chromosomal disorder and most common cause of genetic intellectual disability.
5. Increased risk for ALL and AML as well as increased susceptibility to infections.
6. Associated with early-onset Alzheimer’s disease in middle age (due to 3 copies of the beta-APP gene). Beta-amyloid precursor protein creates amyloid plaques.
7. Tx surgery to repair duodenal atresia and congenital heart defects.
8. More than 80% of patients survive past age 30, but life expectancy shortened.
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Question 58

Patau syndrome

Answer 58

1. Trisomy 13, usually caused by meiotic nondisjunction. Few cases caused by mosaicism resulting from mitotic nondisjunction of chromosome 13 during embryogenesis. Few caused by translocation between chromosomes 13 and 14.
2. Sx severe intellectual disability, microcephaly, holoprosencephaly, rocker-bottom feet, microphthalmia, polydactyly, cleft lip/palate, congenital heart and renal defects, umbilical hernia, cutis aplasia.
3. Fatal within 1 year of birth.
4. (Patau = trisomy 13, “Puberty at age 13.”)
5. Incidence of Patau syndrome increases with maternal age.
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Question 59

Screening for trisomy 21

Answer 59

First trimester u/s shows increased nuchal translucency and hypoplastic nasal bone. Serum PAPP-A decreased, free beta-HCG increased. Second trimester quad screen: decreased AFP, increased beta-hCG, decreased estriol, increased inhibin A.

Question 60

Screening for trisomy 18

Answer 60

First trimester: serum PAPP-A decreased, free beta-HCG decreased. Second trimester quad screen: decreased AFP, decreased beta-hCG, decreased estriol, decreased/normal inhibin A.

Question 61

Duchenne Muscular Dystrophy (DMD)

Answer 61

1. X-linked recessive disorder caused by frameshift/nonsense mutations in DMD gene that cause a truncated dystrophin protein and absent dystrophin synthesis.
2. Dystrophin thought to anchor muscle fibers in skeletal/cardiac muscles by connecting intracellular actin cytoskeleton to transmembrane proteins α- and β-dystroglycan, which connect to the ECM.
3. Absence of dystrophin leads to muscle fiber destruction (myonecrosis), muscle atrophy, and inhibits muscle regeneration leading to fibrofatty replacement of muscle (pseudohypertrophy).
4. DMD gene is the largest protein-coding human gene, thus increasing the chances of spontaneous mutation.
5. DMD presents in males prior to age 5 with weakness beginning in pelvic girdle muscles (Gower maneuver= using arms to rise form crouching position) and progressing superiorly, eventually leading to immobilization, pseudohypertrophy of calves, dilated cardiomyopathy and/or respiratory failure.
6. Lab findings include increased serum creatine kinase and aldolase. Western blot and muscle biopsy confirm diagnosis.
7. Duchenne= deleted dystrophin
8. No treatment. Death typically occurs via respiratory failure in adolescence due to involvement of respiratory muscles.
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Question 62

Becker Muscular Dystrophy (BMD)

Answer 62

1. X-linked recessive disorder caused by non-frameshift insertion mutations in the dystrophin gene, causing dystrophin to be partially functional (rather than truncated as in DMD).
2. Presents similarly to DMD but clinically less severe and onset in adolescence or early adulthood.
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Question 63

Chronic granulomatous disease (CGD)

Answer 63

1. X-linked or autosomal recessive defects in genes encoding components of NADPH oxidase (O2–>O2*), aka oxidative burst.
2. Characterized by poor O2-dependent killing.
3. Most bacteria naturally produce a little H2O2, which can be used by neutrophils to make HOCl even if NADPH oxidase deficient. BUT Catalase + bacteria destroy H2O2, and patient cannot make own H2O2, leaving neutrophils with no HOCl to fight organisms.
4. Recurrent infections and granuloma formation with catalase+ organisms: esp Staphylococcus aureus, Pseudomonas cepacia, Serratia marcescens, Nocardia, Aspergillus, E coli.
5. Screened for with nitroblue tetrazolium test (-).
6. Tx with gamma interferon, TMP-SMX prophylaxis.
   * ***********

Question 64

Nitroblue tetrazolium test (NBT)

Answer 64

1. Used to screen for CGD.
2. Leukocytes from patient incubated with NBT dye, which turns blue of NADPH oxidase can convert O2 to O2, but remains colorless of NADPH oxidase defective and no O2 is produced.
3. NBT colorless (negative test) if CGD, NBT normal (turns blue) if MPO deficiency.
   * ***********

Question 65

von Hippel-Lindau disease

Answer 65

1. AD deletion of the VHL tumor suppressor gene on chromosome 3p.
2. VHL codes for protein involved in inhibiting RNA synthesis. Mutation of gene hinders ability to suppress RNA synthesis leading to vascular malformations and other tumors.
3. Presents with headaches, ataxia, or loss of vision. Characterized by hemangioblastomas or cavernous hemangioma (large vascular spaces filled with blood) of cerebellum, brainstem, and retina.
4. Adenomas and cysts of liver, kidneys, and pancreas.
5. Increased incidence of renal cell carcinoma, pheochromocytoma, retinal hemangioblastomas, neuroendocrine pancreatic tumors, and epididymal or broad ligament cystadenomas.
6. Tx surgical removal of tumor and radiation therapy.
   * ***********

Question 66

What organisms due patients with CGD most often get infected with?

Answer 66

1. Catalase + organisms:
2. Staphylococcus aureus
3. Pseudomonas cepacia
4. Serratia marcescens
5. Nocardia
6. Aspergillus
7. Escherichia coli
   * ***********

Question 67

Neurofibromatosis 1 (von Recklinghausen dz)

Answer 67

1. AD neurocutaneous disorder caused by mutations in NF1 gene, a tumor suppressor gene on chromosome 17. Can also occur through sporadic mutations in NF1 gene.
2. NF1 gene codes for neurofibromin, a protein that decreases the activity of p21 ras oncogene. Mutation in NF1 allows for uninhibited p21 ras oncogene activity, triggering unhindered cell growth that results in formation of neurofibromas (masses of spindle cells occurring in the dermis, peripheral nerve, or large nerve trunk).
3. Neurofibromas in dermis or iris can cause hyper pigmentation of overlying cells, leading to café au lait spots and Lisch nodules.
4. Present with neurofibromas that may cause neurologic symptoms, optic gliomas, café au lait spots (cutaneous pigmented macules), Lisch nodules (pigmented iris hamartomas), various skeletal abnormalities.
5. Increased risk for other tumors (Wilms tumor, meningiomas, pheochromocytoma, chronic myeloid leukemia).
6. 100 % penetrance, variable expressivity
7. Tx. Surgery to remove neurofibromas if disfiguring or causing neurologic abnormalities.
8. There are 17 letters in “von Recklinghausen”
   * ***********

Question 68

Wilson disease

Answer 68

1. aka Hepatolenticular degeneration: AR defect in the ATP7B gene on chromosome 13, which codes for an ATP-mediated hepatocyte copper transport membrane protein.
2. Normally, Cu absorbed in intestine and transported to liver, where hepatocytes conjugate copper to an alpha-2-globulin to form ceruloplasmin. Ceruloplasmin then circulates in plasma and is eventually broken down by lysosomes and secreted into bile.
3. Without Cu transport protein, Cu cannot be transported into hepatocytes to make ceruloplasmin.
4. Cu accumulates throughout the body, especially in the parenchymal cells of the liver, kidney, brain (esp basal ganglia) and cornea, causing increased free radical formation and damage.
5. Presents btw ages 10-30 with liver disease (hepatitis to cirrhosis), hemolytic anemia, portal hypertension, psychosis or dementia, choreiform movements (extrapyramidal motor signs similar to those in PD), Kayser-Flesher rings (thin brown rings around corneas due to Cu deposits in Descemet membrane of cornea), and renal disease (eg, Fanconi syndrome).
6. Increased risk of hepatocellular carcinoma.
7. Hypercupriuria (Cu in urine), decreased serum ceruloplasmin.
8. Tx with D-penicillamine or trientine to chelate free copper for removal from body. Oral zinc.
   * ***********

Question 69

Neurofibromatosis 2

Answer 69

1. AD disorder caused by mutation in the NF2 gene (tumor suppressor gene) located on chromosome 22.
2. Rarer than NF1 and characterized by b/l acoustic schwannomas, juvenile cataracts, multiple meningiomas, ependymomas and other neoplasms.
   * ***********

Question 70

Androgen Insensitivity Syndrome

Answer 70

1. X-linked recessive loss of function mutation in androgen receptor
2. In an XY patient with a defective androgen receptor, cells do not respond to androgen signals and embryo does not develop external male sex organs.
3. Manifests as presence of inguinal mass in infancy, later found to be undescended testes in a phenotypic female.
4. If disorder not discovered in childhood, may come to light when the patient presents with primary amenorrhea.
5. XY on karyotype in phenotypic female
6. Normal levels of testosterone and dihydrotestosterone
7. Hormone replacement therapy (estrogen if patient identifies with female gender).
   * ***********

Question 71

3β-hydroxysteroid dehydrogenase deficiency

Answer 71

1. Rare AR mutation that results in a deficiency of 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD).
2. 3-beta-HSD converts pregnenolone to progesterone and 17-hydroxypregnenolone to 17-hydroxyprogesterone and DHEA to androstenedione.
3. Without 3-beta-HSD–> deficiency of aldosterone, cortisol, and adrenal androgens.
4. Lack of mineralocorticoid activity leads to severe “salt wasting” in urine, leading to extreme hypovolemia and hypotension, usually leading to hypovolemic shock early in life.
5. Hyponatremia, hyperkalemia, elevated ACTH, low cortisol.
6. Tx involves glucocorticoid, mineralocorticoid, and sex hormone replacement therapy. Most patients suffer early death.
   * ***********

Question 72

Becker Muscular Dystrophy (BMD)

Answer 72

1. X-linked recessive disorder caused by non-frameshift insertion mutations in the dystrophin gene, causing dystrophin to be partially functional (rather than truncated as in DMD).
2. Presents similarly to DMD but clinically less severe and onset in adolescence or early adulthood.
   * ***********

Question 73

11β-Hydroxylase deficient CAH

Answer 73

1. AR mutation that results in deficiency of 11β-hydroxylase, a Congenital Adrenal Hyperplasia (CAH) syndrome
2. 11β-hydroxylase converts 11-deoxycorticosterone to corticosterone in aldosterone synthesis and 11-deoxycortisol to cortisol in cortisol synthesis.
3. Without 11β-hydroxylase, there is a cortisol and aldosterone deficiency as well as a buildup of aldosterone and cortisol precursors (eg, progesterone and pregnenolone).
4. These precursors are shunted towards synthesis of DHEA and androstenedione, leading to an excess of adrenal androgens.
5. 11-deoxycorticosterone has weak mineralocorticoid activity and will therefore lead to hypertension through salt and water retention as it builds up.
6. Manifests as masculinization of external genitalia of female infants, hypertension, precocious puberty with premature appearance of pubic and axillary hair, suppression of gonadal function in females.
7. Low cortisol levels, elevated ACTH, hyperplasia of adrenal cortex 2/2 increased ACTH levels.
8. Increased ACTH released from pituitary in response to negative feedback form decreased cortisol levels.
9. Tx with replacement of glucocorticoids, tx of masculinization with anti androgen therapy, treatment of hypertension.
   * ***********

Question 74

17α-hydroxylase deficient CAH

Answer 74

1. AR mutation that results in deficiency of 17α-hydroxylase (CYP17A1), a Congenital Adrenal Hyperplasia (CAH) syndrome
2. 17α-hydroxylase involved in synthesis of adrenal androgens and cortisol (converts pregnenolone to 17-OH-pregnenolone and progesterone to 17-OH-progesterone).
3. 17α-hydroxylase deficiency leads to deficiency of cortisol and adrenal sex hormones, with a build up of progesterone and pregnenolone, which shunt towards synthesis of aldosterone and other mineralocorticoids.
4. Manifests as hypertension, fluid retention, lack of onset of puberty (eg, no pubic hair growth, menses), infertility in XX individuals, ambiguous genitalia and cryptorchidism in genetic males, failure of the ovaries to function at puberty in genetic females.
5. Hypokalemia, metabolic alkalosis, low cortisol levels, elevated ACTH levels, bilateral adrenal hyperplasia.
6. Tx replacement of GCs and adrenal sex hormones, tx of hypertension.
   * ***********

Question 75

Baby boy goes into hypovolemic shock within several hours of his birth. Despite best efforts at resuscitation, child dies during first week of life. A genetic test done at autopsy shows a mutation that would have resulted in complete deficiency of aldosterone, cortisol, and adrenal androgens explaining that child died from a rare enzyme deficiency that interferes with normal steroid synthesis in the adrenal cortex.

Answer 75

3β-hydroxysteroid dehydrogenase deficiency

Question 76

9 year old girl with occasional complaints of headaches, otherwise healthy. BP of 176/104, pubic and axillary hair, masculinized female external genetalia.

Answer 76

11β-Hydroxylase deficient CAH

Question 77

Lactose intolerance

Answer 77

1. Reduced genetic expression of lactase-phlorhizin hydrolase enzyme
2. Lactase-phlorhizin hydrolase is rate-limiting step of lactose digestion.
3. Lactose hydrolyzed by intestinal lactase to glucose and galactose on the brush border microvillus membrane of intestinal absorptive cells.
4. Lactose not absorbed by small bowel 2/2 absence or deficiency of lactase enzyme is passed rapidly into colon, leading to entry of water into colon by osmosis and development of osmotic diarrhea.
5. Manifests as diarrhea, abdominal pain, bloating and flatulence after ingestion of lactose-containing products. Stools often bulky, frothy, watery, and with decreased pH. Lactose hydrogen breath test reveals increased hydrogen in lactase deficient individuals.
6. Tx. Reduce dietary lactose intake or use commercial enzyme substitute. Alternative calcium sources.
7. Prevalence of 10-20% Caucasians, 80-95% native americans, 65-75% AAs, 90% among Asian Americans, 50% among Hispanics.
8. Primary lactose intolerance is due to age-dependent decline after childhood. Absence of lactase-persistence allele common in people of Asian, African, or Native American descent.
9. Secondary lactose intolerance can occur due to loss of the brush border after gastroenteritis, autoimmune disease, etc.
   * ***********

Question 78

21β-Hydroxylase deficient CAH

Answer 78

1. AR mutation on chromosome 6 that results in deficiency of 21β-Hydroxylase, a Congenital Adrenal Hyperplasia (CAH) syndrome
2. 21β-Hydroxylase involved in synthesis of aldosterone (converts progesterone to 11-deoxycorticosterone) and cortisol (converts 17OH-progesterone to 11-deoxycortisol).
3. 21β-Hydroxylase deficiency leads to deficiency of cortisol and aldosterone, with a build up of progesterone and 17OH-progesterone, which shunt towards synthesis of DHEA and androstenedione (excess of adrenal androgens).
4. Manifests as hypotension, masculinization of external female genitalia, precocious puberty with premature appearance of pubic and axillary hair, suppression of gonadal function in females, hypovolemia 2/2 “salt wasting”
5. Hyperkalemia, hyponatremia, low cortisol levels, elevated ACTH levels, bilateral adrenal hyperplasia.
6. Tx replacement of GCs and MCs; symptomatic tx of masculinization with antiandrogen therapy
   * ***********

Question 79

Bloom syndrome

Answer 79

1. AR mutation in BLM gene on chromosome 15.
2. BLM codes for protein in DNA helicase family. DNA helicase involved in unwinding DNA helix as well as stabilizing DNA strands during replication.
3. If DNA helicase faulty, DNA replication defective and mutations occur during DNA replications.
4. Sx include short stature, butterfly-shaped rash on cheeks, distinct facial features (narrow face with bird-like facies, small mandible), telangiectasias of skin and eyes (scleral telangiectasias).
5. Pts also suffer from hypogonadism, immunodeficiency (recurrent respiratory and GI infections), increased susceptibility to malignancy.
6. Decreased levels of IgA and IgM on labs.
7. Tx avoid sun exposure; tx cancers with chemotherapy or radiation. Genetic testing.
   * ***********

Question 80

Mediterranean Familial Fever

Answer 80

1. AR disorder that results from mutation in MEFV gene on chromosome 16.
2. MEFV gene codes for pyrin.
3. Exact function of pyrin unknown, but thought to be involved in inhibition of IL-8 and/or chemotactic factor C5a.
4. Patients with MFF have decreased pyrin levels, thus when inflammatory response triggered, lack of pyrin results in excessive inflammatory activity of cytokines, leading to inflammation in viscera and joints.
5. Patients present with 2-4 day long episodes of fever, abdominal pain (peritoneal inflammation), chest pain (pleural/pericardial inflammation), muscle and joint pain (synovial inflammation) and rashes on lower extremities.
6. Tx colchicine (to tx inflammation); steroids or etanercept (TNF-alpha inhibitor) for more severe attacks.
7. Disorder more common in patients of Mediterranean descent.
   * ***********

Question 81

Chediak-Higashi Syndrome

Answer 81

1. AR disorder that results from mutation in CHS1/LYST gene on chromosome 1.
2. CHS1/LYST gene codes for protein responsible for regulation of lysosomal content transportation to other cells, including neutrophils, neurons, and melanocytes (i.e., microtubule defect)
3. Defective CHS/LYST protein leads to abnormal function of phagolysosomes, leading to impaired cytotoxic function of neutrophils (recurrent infections), impaired melanosome transport to keratinocytes (resulting in albinisim), and impaired nutrient transportation on neuronal axons (neuropathy).
4. Patients present in early childhood with recurrent pyogenic infections (Staph and Strep cellulitis, sinusitis, pneumonia) and oculocutaneous albinism. Hepatosplenomegaly and bleeding disorders (platelet dysfunction) often noted.
5. If patients survive to early adulthood, develop debilitating neurologic disease (neuropathies, ataxia, cognitive decline, seizures).
6. Labs reveal neutropenia, thrombocytopenia, elevated bleeding time, hypergammaglobulinemia.
7. Tx prophylactic antibiotics and G-CSF, steroid courses or BM transplant has been used to tx severe disease.
   * ***********

Question 82

Diseases 2/2 mutations in DNA repair

Answer 82

1. Bloom syndrome (BLM gene, chromosome 15, DNA helicase mutation)
2. Li-Fraumeni syndrome (TP53 gene, chromosome 17, p53 mutation)
3. Xeroderma Pigmentosum (nucleotide excision repair pathway)
4. HNPCC/Lynch syndrome (microsatellite instability, chromosomes 2, 3, 7, DNA mismatch repair gene mutations)
5. Retinoblastoma (Rb gene, chromosome 13)
6. Ataxia-Telangiectasia (ATM gene, chromosome 11, inability to sense damaged DNA by radiation)
   * ***********

Question 83

Hyper IgM syndrome

Answer 83

1. X-linked defect in gene encoding for CD40 ligand (on T-cells) or more rarely AR defect in gene that codes for CD40 on chromosome 20.
2. CD40L is a receptor present on activated T cells. When CD40 ligand binds to CD40 molecule on B-cell surface, immunoglobulin class switching and B cell maturation occurs.
3. If CD40L defective (or if more rarely CD40 is defective) immunoglobulin class-switching is severely hindered, resulting in elevated levels of IgM and decreased levels of IgG and IgA.
4. Presents by age 2 with recurrent URIs and PNAs as well as cellulitis, osteomyelitis, and sepsis. HSM and LAD often noted.
5. Complications include increased rates of lymphomas, HCC, or neuroendocrine carcinomas.
6. Labs reveal elevated IgM, low IgA and IgG, pancytopenia.
7. Tx with IVIg infusion or G-CSF injections to prevent infections. BM transplant for severe disease.
   * ***********

Question 84

Wiskott-Aldrich Syndrome

Answer 84

1. X-linked recessive disorder caused by mutation in Wiskott-Aldrich syndrome (WAS) gene.
2. WAS codes for Wiskott-Aldrich syndrome protein (WASp), a protein present in hematopoietic cells and involved in normal actin cytoskeleton functioning in T-lymphocytes and myeloid lineage cells.
3. Defective WASp leads to impairment of T-cell function and abnormal interaction with antigens. Defective T-cell functioning leads to altered B-cell function, resulting in immunodeficiency and autoimmunity.
4. Thrombocytopenia 2/2 reduced platelet survival from immune mediated mechanism or faulty platelet migration.
5. Clinical triad of recurrent pyogenic infections, eczema, and thrombocytopenia (bleeding).
6. Predisposition to autoimmune diseases, lymphomas, and leukemias.
7. Labs reveal thrombocytopenia, decreased number and function of T cells.
8. Tx supportive with prophylactic antibiotics, platelet transfusions as needed. IVIg, BM transplant, splenectomy considered for severe cases.
   * ***********

Question 85

X-linked agammaglobulinemia

Answer 85

1. X-linked recessive disorder caused by mutation in Btk gene.
2. Btk involved in cell signaling that leads to maturation of B-cell precursors.
3. Mutated Btk prevents B-cells precursors from maturing into naive B-cells, leading to absence of B cells in serum.
4. Presents with recurrent pyogenic bacterial infections (otitis media; sinusitis; pneumonia) in BOYS after 6 months of age (when maternal IgG levels begin to decline).
5. Cell-mediated immunity (T-cell function) is normal.
6. Labs reveal low levels of all classes of Igs, absence of serum B cells, absent or poorly defined germinal centers in lymph nodes and tonsils.
7. Tx with pooled gamma globulin.
   * ***********

Question 86

Oculocutaneous albinism type I

Answer 86

1. AR mutation in TYR gene on chromosome 11.
2. TYR gene codes for tyrosinase, an enzyme involved in melanin production. Catalyzes rate-limiting step converting tyrosine to DOPA as well as DOPA to DOPA-quinone. If tyrosinase defective, melanin cannot be produced, resulting in hypopigmentation of the skin, hair, and retina.
3. Ocular abnormalities (hypopigmentation of retina, strabismus, nystagmus, decreased visual acuity as a result of misrouting of optic nerves from retina to the lateral geniculate nucleus).
4. Complications include increased risk for actinic keratoses and skin cancers.
5. Tx protection from sun exposure, regular eye examinations.
   * ***********

Question 87

Xeroderma Pigmentosum

Answer 87

1. AR disorder caused by mutations in nucleotide excision repair pathway of DNA repair.
2. UV light causes formation of pyrimidine dimers in DNA. These dimers can lead to chromosomal abnormalities, mutation formation, DNA-strand breakage, and apoptosis.
3. Nucleotide excision repair system acts to eliminate pyrimidine dimers.
4. When nucleotide excision repair system defective, pyrimidine dimers build up in DNA, causing multiple DNA abnormalities in sun-exposed tissues (skin) or tissues that rely heavily on the nucleotide excision repair system (neurologic system).
5. Onset of disease usually between ages 1-2 with sx including extreme photosensitivity with severe sunburns, freckling on sun-exposed areas, premature aging of skin, variable occurrence of neurologic degeneration (mental deterioration, hearing loss), and ocular abnormalities.
6. 2000-fold increase in development of all forms of skin cancer.
7. Tx. avoid sunlight. Tx skin cancers.
   * ***********

Question 88

Osteogenesis imperfecta

Answer 88

1. Genetic disorder caused by mutations in COLIA1 (chromosome 17) or COLIA2 (chromosome 7) genes, which result in deficient synthesis of type I collagen.
2. Four variants of disorder, each of which is associated with different mutations in type I collagen.
3. Mostly AD inheritance (types I and IV) with some AR inheritance in types II and III).
4. Type I collagen comprises bone, teeth, skin and other tissues in ears and eyes.
5. Deficient type I collagen results in abnormal bone formation and pathologic bone changes (thinning of trabecular) that predispose to multiple fractures from minimal trauma.
6. Blue sclera: decreased collagen in the eye leads to transparent sclera, which appear blue due to underlying choroid veins.
7. Patients may also present with hearing loss 2/2 abnormal bone formation of stapes, stapedius, and incus as well as dental imperfections.
8. Type II is a particularly severe form of the disorder, fatal within the first week of life.
9. Tx involves pneumatic bracing and avoidance of trauma.
   * ***********

Question 89

Ocular albinism

Answer 89

1. X-linked recessive disorder caused by a mutated membranous glycoprotein in eye melanocytes.
2. Presents with only ocular symptoms of albinism: hypopigmentation of retina, strabismus, decreased visual acuity as a result of misrouting of optic nerves from retina to the lateral geniculate nucleus.
   * ***********

Question 90

Mitochondrial myopathies (MERRF, MELAS)

Answer 90

1. MELAS = Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes.
2. Maternally inherited disorders caused by point mutations in the tRNA gene of mtDNA.
3. MERRF presents during adolescence with ataxia, myoclonic epilepsy with seizures, muscle weakness, hearing loss, and progressive mental status decline.
4. MELAS presents in childhood with stroke-like episodes of blindness and hemiparesis, vomiting, hearing loss, seizures, lactic acidosis.
5. Tx for MERRF involves seizure control. Eventually results in encephalopathy and death.
6. Tx for MELAS involves symptomatic treatment. Eventually results in dementia and death before age 20.
7. mtDNA genes are involved in production of cellular apparatus of oxidative phosphorylation. Defects in any component can lead to defective ox-phos.
8. Defective ox-phos leads to mitochondrial proliferation with consequent destruction of muscle fibers (“ragged-red fibers”) and can lead to neuronal damage of spinal cord, cerebellum, and motor cortex.
9. NADH accumulates, leading to inhibition of pyruvate dehydrogenase and resulting in accumulation of lactate.
   * ***********

Question 91

Disorders characterized by mutations in mtDNA

Answer 91

1. MERRF
2. MELAS
3. Kearns-Sayre syndrome: ophthalmoplegia, heart block, retinal degeneration.
4. Chronic progressive external ophthalmoplegia: myopathy, ophthalmoplegia
5. Leigh disease: necrotizing encephalopathy
6. Barth syndrome: myoglobinuria, cardiomyopathy
7. LHON: acute bilateral central vision loss that leads to blindness
   * ***********

Question 92

Ehlers-Danlos syndrome (EDS)

Answer 92

1. Disorder with 10 different variants, all associated with defective synthesis of collagen with variable modes of inheritance (AD, AR, X-linked). Common mutations: lysyl-hydroxylase and pro-collagen peptidase enzymes.
2. Defective pro-alpha-1 collagen chains of collagen type III in EDS IV (vascular subtype).
3. Defective lysyl hydroxylase in EDS type VI.
4. Abnormal weak collagen leads to hyperextensible joints (weak tendons), skeletal abnormalities (abnormal bone formation), susceptibility to organ injury 2/2 fragile skin and vessel walls.
5. Presentations vary: thin hyperextensible skin, hypermobile joints complicated by dislocation, easy bruising, MVP (type I), uterine or intestinal wall rupture (type IV), scoliosis (type VI), ocular globe fragility with resulting blindness (VI), congenital hip dislocation (VII), periodontal disease (VIII), and development of premature osteoarthritis (I, VII).
6. Tx Vitamin C supplementation (involved in collagen synthesis), symptomatic care for osteoarthritis, routine eye examinations.
   * ***********

Question 93

Retinoblastoma

Answer 93

1. AD condition caused by homozygous deletion in both alleles of Rb gene, tumor suppressor gene located on chromosome 13.
2. Disease transmitted as AD condition even though homozygosity required for disease, b/c more than 90% of heterozygous carriers develop the disease. Sporadic cases can rarely occur.
3. Activated Rb halts the cell cycle in G1 phase by inhibiting E2F transcription factors. Mutated Rb leads to loss of G1 checkpoint and cell cycle continues unhindered into S phase.
4. Uninhibited progression to S phase 2/2 Rb mutation leads to cell apoptosis in most tissues, except for in retinoblasts. Instead, neoplastic changes accumulate in retinoblast and tumor arises.
5. Presents in young children with diminished visual acuity, eye pain, strabismus, intraocular mass on fundoscopitc exam, and white “cat’s eye” pupillary reflex (loss of red reflex).
6. Patients will develop bilateral retinoblastoma with risk of metastasis to brain, spinal cord, bone, and lymph nodes. Also at increased risk for osteosarcoma and other cancers.
7. Tx Surgery (enucleation if necessary) and radiation. Tumor fatal once it has spread beyond the eye.
8. Prototype of Knudson “two-hit” hypothesis: two mutations required for disease to occur. One deletion inherited, second mutation somatic.
   * ***********

Question 94

Leber hereditary optic neuropathy (LHON)

Answer 94

1. Maternally inherited disorder caused by mutation in mtDNA, encoding for components of electron transport chain.
2. Many different mutation in mtDNA can lead to LHON, with most involving alteration of complexes I and III.
3. Mechanism unknown, though some speculate that retinal ganglion cells damaged by oxidative stress or ischemia that results from defective oxidative phosphorylation.
4. Presents between age 15 and 35 with central vision loss that is acute in onset and affects both eyes, eventually leading to blindness within 1 year.
5. Occasionally, patients may have other neurological sx (dystonia, intellectual disability, ataxia, hearing loss) or cardiac conduction defects.
6. Tx supportive.
   * ***********

Question 95

Charcot-Marie-Tooth disease

Answer 95

1. CMT disease is the most common inherited neurologic disorder. 7 major types of CMT disease, each with multiple subtypes. Most common forms of CMT disease are CMT type 1 and type 2, both are mostly inherited as AD.
2. Collection of diseases resulting from a mutation in one of several genes involved in nerve myelination and function.
3. CMT-1: associated with a collection of mutations (chromosomes 1, 8, 10, 16, 17) involved in formation and stabilization of myelin. Mutation leads to abnormal myelin formation and subsequent myelin breakdown.
4. Schwann cells proliferate at abnormal rate in response to demyelination in attempt to remyelinate the nerve, leading to a thickened layer of myelin around the nerve, like an “onion bulb”.
5. CMT-2: associated with a collection of defects (chromosomes 1, 3, 7, 8, 12) that result in neuronal cell death and degeneration.
6. CMT-1: distal muscle weakness, sensory neuropathy, pes caves deformity, decreased DTRs, “stork leg” deformity (2/2 calf muscle atrophy), scoliosis, enlargement of peripheral nerves such that palpable (“onion bulb” thickening).
7. CMT-2: predominantly sensory neuropathy, tremor.
8. Tx supportive, surgery if needed for joints.
   * ***********

Question 96

Friedreich Ataxia

Answer 96

1. AR disorder caused by a GAA trinucleotide repeat expansion in the gene on chromosome 9 that codes for frataxin, leading to decreased expression of the frataxin gene.
2. Frataxin maintains normal mitochondrial functions as well as iron homeostasis.
3. Decreased levels of frataxin lead to iron accumulation in mitochondria and decreased mitochondrial function, eventually causing cell death. Neuronal and cardiac tissues are particularly sensitive to frataxin deficiencies, thus damage to nervous system and heart are prominent.
4. Presents in childhood with ataxic gait that progressively worsens until torso and arms are involved and patient requires a wheelchair. Sx include dysarthria, sensory neuropathy, absent DTRs, kyphoscoliosis, cardiac disease (hypertrophic cardiomyopathy in particular).
5. Tx supportive for neurologic degeneration, tx of cardiac disease if present. Most patients become wheelchair bound within 5 years of diagnosis and die prematurely.
   * ***********

Question 97

Ataxia-Telangiectasia

Answer 97

1. AR disorder caused by mutation in ATM gene on chromosome 11.
2. ATM gene product involved in sensing DNA damaged by radiation and signaling p53 to delay cell cycle to allow for DNA repair.
3. ATM gene mutation leads to inactivated p53 and cell cycle continuation despite DNA damage, allowing for replication of damaged DNA. Damaged DNA leads to abnormal cellular development of neurologic, vascular and immune systems.
4. Cerebellum particularly affected (loss of Purkinje and granule cells) accounting for ataxia.
5. Presents in early childhood with cerebellar ataxia and eventual wheelchair confinement, decreased DTRs, dysarthria, and telangiectasias of face and conjunctiva.
6. Some patients have immunodeficiency leading to recurrent respiratory infections or various endocrinologic abnormalities.
7. Complications include predisposition to developing cancers (breast, lymphoma, leukemia).
8. Labs reveal increased alpha-fetoprotein levels.
9. Tx Vitamin E (antioxidant) and folic acid supplementation, avoid radiation when possible. Most patients do not live past 25 and many die much earlier.
   * ***********

Question 98

Pseudohypoparathyroidism

Answer 98

1. AR disorder caused by mutation in gene for PTH receptor on chromosome 20.
2. Normally, PTH binds to PTH receptors in bone, kidneys, and intestine. Gs activates AC and increases cAMP production, leading to downstream effects that increase calcium and decrease serum phosphate.
3. Type 1: deficiency in Gs leads to decreased coupling of PTH receptor to AC, such that activation of PTH receptor does not activate target cell.
4. Type 2: regulation of Gs altered so levels of cAMP produced by PTH stimulation inadequate to activate cell.
5. In both forms, target cell is not activated by PTH binding to PTH receptor as though PTH were not present.
6. Presents with symptoms of hypocalcemia: tetany or other signs of neuromuscular irritability, prolonged QT interval on EKG, Trousseau sign (carpal spasm 2 min after inflation of BP cuff above systolic BP), Chvostek sign (twitching of facial muscles on superficial tapping of facial nerve).
7. Albright hereditary osteodystrophy (type 1): short stature, intellectual disability, shortened 4th and 5th metacarpal and metatarsal bones, obesity.
8. Labs reveal hypocalcemia, increased PTH levels, increased serum phosphate levels.
9. Tx calcium and vitamin D supplements. GH tx.
   * ***********

Question 99

17 year old girl with no development of breasts or axillary/pubic hair. Has not experienced menarche. BP of 180/100, normal appearing female external genitalia, lack of breast development. Labs reveal increased K+ (hyperkalemia) and HCO3- (alkalemia).

Answer 99

17α-hydroxylase deficient CAH

Question 100

MEN 2a syndrome

Answer 100

1. AD disorder caused by mutation in RET proto-oncogene on chromosome 10.
2. RET proto-oncogene is a tyrosine kinase receptor involved in cellular growth signaling. Mutations in protein result in constitutively active receptor, promoting uncontrollable growth and neoplasia.
3. MEN2a: pheochromocytoma, parathyroid hyperplasia, medullary thyroid carcinoma.
4. Sx: hypercalcemia with increased levels of PTH (primary hyperparathyroidism), hypertension, pounding headaches, heart palpitations (pheochromocytoma), increased 24 hr urinary VMA, metanephrine, and catecholamine levels.
5. Surgical removal of pheochromocytoma/thyroid carcinoma. Genetic screening of family members for preventative thyroidectomy in MEN 2a and 2b.
   * ***********

Question 101

MEN 1 syndrome

Answer 101

1. AD disorder caused by mutation in MEN1 gene on chromosome 11.
2. Exact function of MEN1 gene product unknown. Mutations in gene linked to tumor formation.
3. MEN1 triad: parathyroid hyperplasia/adenoma, pituitary adenoma, pancreatic islet cell tumors (which often manifests as Zollinger-Ellison syndrome (peptic ulcers secondary to gastrinoma).
4. Tx symptomatically.
   * ***********

Question 102

MEN 2b syndrome

Answer 102

1. AD disorder caused by mutation in RET proto-oncogene on chromosome 10.
2. RET proto-oncogene is a tyrosine kinase receptor involved in cellular growth signaling. Mutations in protein result in constitutively active receptor, promoting uncontrollable growth and neoplasia.
3. MEN2b: pheochromocytoma, medullary thyroid carcinoma, mucocutaneous neuromas of skin, eyes, GI tract.
4. Surgical removal of pheochromocytoma/thyroid carcinoma. Genetic screening of family members for preventative thyroidectomy in MEN 2a and 2b.
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Question 103

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

Answer 103

1. AR disorder caused by mutation in gene that codes for polyductin on chromosome 6.
2. Polyductin is present in the cilia of renal epithelial cells and is thought to be involved in cell-to-cell signaling of renal tubular differentiation.
3. Presents with hypertension, growth failure, bilateral abdominal masses, and progressive renal failure during childhood. Congenital hepatic fibrosis develops in older children. Imaging shows multiple renal cysts at birth.
4. Tx of hypertension, dialysis for ESRD. Disease course variable but most patients die during childhood.
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Question 104

Alport syndrome

Answer 104

1. X-linked dominant disorder with mutation in type IV collagen. (AR and AD variations exist).
2. Type IV collagen is important component of cochlea, anterior lens capsule of eye, and forms the scaffolding of the glomerular basement membrane.
3. Defective type IV collagen leads to irregularities in the GMB and results in malfunctioning of glomerular filtration barrier, leading to eventual sclerosis.
4. Alport syndrome triad: nephritis, sensory deafness, and ocular damage (cataracts, lens dislocation, corneal dystrophy).
5. Often presents with hematuria and RBC casts during adolescence.
6. Usually progresses to renal failure by middle age.
7. Tx ACE inhibitors, renal transplantation.
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Question 105

2 year old girl is brought to your pediatric clinic for evaluation of delay in walking with repetitive falling. Patient was slow to walk initially and now is only able to walk for several feet before falling down. Absent DTRs in legs, mild scoliosis and ataxic gait. Cardiac workup reveals signs of hypertrophic cardiomyopathy. What is the mechanism of disease causing this disorder?

Answer 105

GAA trinucleotide repeat expansion at the gene locus on chromosome 9 that codes for frataxin.

Question 106

Peutz-Jeghers syndrome

Answer 106

Autosomal dominant mutation in LKB1, a tumor suppressor gene. PJS is characterized by multiple hamartomatous (nonneoplastic) polyps of the colon and small intestine, melanotic macule in the mouth, lips, hands, and genetalia. There is no increased risk for colon cancer but increased risk of gastric, breast, gynecologic, pancreatic, or lung cancer. Tx involves regular screening for gynecologic and GI cancers.

Question 107

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) aka Lynch syndrome

Answer 107

Autosomal dominant condition caused by defect in DNA mismatch repair genes on chromosomes 2, 3, or 7, leading to microsatellite instability (MSI). HNPCC is characterized by colonic adenomas in early adulthood with an increased risk for CRC and other cancers (especially endometrial cancer). Tx is surgical resection.

Question 108

Hereditary hemochromatosis (HHC)

Answer 108

1. AR condition involving a mutation in HFE (high Fe) gene on chromosome 6 (C282Y > H63D) that results in excessive absorption of iron in the intestinal mucosa due to abnormal iron sensing.
2. Elevated levels of circulating iron deposit in tissues, especially the liver, pancreas, heart, adrenals, joints and skin. Iron is toxic to organs, causing DNA damage by free radical formation, leading to tissue damage and fibrosis.
3. Fibrosis in the pancreas leads to decreased insulin production and results in diabetes.
4. Fibrosis in the liver leads to cirrhosis.
5. Fibrosis in the adrenals leads to an increase in ACTH release from the pituitary through a loss of negative feedback. Increasing ACTH levels also increases MSH (MSH and ACTH are created by the same precursor molecule), resulting in increased melanin deposition in the skin and hyperpigmentation.
6. Presents in northern European males after age 50 with the classic triad of cirrhosis, diabetes mellitus, and skin hyperpigmentation (“bronze diabetes”).
7. Other sx include arthropathy (calcium pyrophosphate deposition), hepatomegaly, hypogonadism, and dilated cardiomyopathy (reversible). Increased risk for HCC, a common cause of death.
8. Labs reveal mildly elevated LFTs, increased serum iron, decreased TIBC, transferrin saturation >80%, and increased serum ferritin.
9. Tx weekly phlebotomy and chelation with deferasirox, deferoxamine, and oral deferiprone. Neonatal screening for increased transferrin saturation.
10. STRONG association of HHC with HLA-A3 haplotype due to linkage disequilibrium.
11. Hemosiderin can be identified on liver MRI or biopsy with Prussian blue stain.
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Question 109

Gardner syndrome

Answer 109

Autosomal dominant condition associated with a mutation of APC gene on chromosome 5. Characterized by adenomatous polyps along with osteomas and soft tissue tumors. Associated with increased risk for CRC.

Question 110

Crigler-Najjar Syndrome, type I and II

Answer 110

1. Fatal AR (type I) or nonfatal AD with variable penetrance (type II) condition associated with absent UDPGT activity.
2. Type I: Presents early with jaundice, kernicterus (bilirubin deposition in the brain), and unconjugated hyperbilirubinemia. Fatal within 2 years of birth. Tx. with plasmapheresis and phototherapy.
3. Type II: Presents with jaundice and unconjugated hyperbilirubinemia. Kernicterus rarely occurs. Nonfatal. Responds to phenobarbital, which increases liver enzyme synthesis.
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Question 111

Gilbert syndrome

Answer 111

1. Benign AD or AR condition associated with a variety of mutations of the UGT1A1 gene on chromosome 2, which codes for the enzyme UDP-glucuronosyl-transferase (UDPGT).
2. UDPGT is the liver enzyme responsible for conjugating bilirubin, thus making it water soluble and allowing for urinary excretion.
3. Deficient UDPGT causes unconjugated, water insoluble bilirubin to build up in the serum, hindering excretion.
4. Gilbert syndrome mutations cause only mildly decreased UDPGT conjugating activity and impaired bilirubin uptake, resulting in either mild jaundice with unconjugated (indirect) hyperbilirubinemia or often asymptomatic. No overt hemolysis associated with increased bilirubin.
5. Very common. No clinical consequences. Bilirubin increases with fasting or stress.
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Question 112

Dubin-Johnson Syndrome

Answer 112

1. Benign AR condition resulting from defective bilirubin transport out of the liver due to a mutated canalicular membrane carrier.
2. Presents with intermittent jaundice, RUQ and epigastric pain, mildly elevated LFTs, and conjugated hyperbilirubinemia.
3. Gross pathology reveals a black liver.
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Question 113

Rotor Syndrome

Answer 113

1. AR disorder resulting in defective uptake and excretion of bilirubin by hepatocytes.
2. Usually asymptomatic, but may have bouts of intermittent jaundice. Conjugated hyperbilirubinemia.
3. No black liver on gross pathology.
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Question 114

Physiologic neonatal jaundice

Answer 114

1. At birth, UDPGT is immature leading to decreased conjugation of bilirubin, causing an unconjugated (indirect) hyperbilirubinemia.
2. Presents with jaundice or kernicterus (bilirubin deposition in the brain, especially basal ganglia).
3. Occurs after first 24 hours of life and usually resolves without treatment in 1-2 weeks.
4. Tx. phototherapy (non-UV) isomerizes unconjugated bilirubin to a water-soluble form that can be excreted.
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Question 115

α1-antitrypsin deficiency (A1AD)

Answer 115

1. AR disorder caused by a mutation of the gene for A1AT on chromosome 14, leading to lower than normal levels of α1-antitrypsin. Co-dominant trait.
2. Multiple different alleles for α1-antitrypsin gene, but most common allele combination associated with clinical A1AD is PiZZ genotype.
3. α1-antitrypsin is a liver-synthesized protease inhibitor that inhibits neutrophil elastase. Neutrophils at sites of inflammation release elastase to destroy pathogens and affected tissue. If α1-antitrypsin is deficient, neutrophil elastase is uninhibited and causes damage to delicate tissues such as the lung and liver.
4. In the lung, elastase destroys elastin in the alveolar walls, leading to panacinar emphysema.
5. In the liver, mutated α1-antitrypsin is misfolded, unable to be secreted by hepatocytes and instead accumulates in the hepatocyte endoplasmic reticulum, leading to variable hepatic disease with PAS+ globules.
6. Sx of emphysema: dyspnea, cyanosis, barrel chest, use of accessory respiratory muscles.
7. Sx of hepatic disease: intermittent attacks of hepatitis or development of cirrhosis. Increased risk for HCC.
8. Decreased FEV1/FVC ratio of PFTs, elevated LFTs.
9. Tx avoid cigarette smoking and alcohol use (as these worsen emphysema and cirrhosis). Bronchodilators as needed and symptomatic tx of liver disease. OLTx if needed.
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Question 116

Kartagener syndrome (Primary Ciliary Dyskinesia)

Answer 116

1. Rare AR disorder that results in a defect in dynein arms within cilia.
2. Dynein arms are responsible for ciliary movement, therefore, defective dynein arms result in deregulated movements of cilia on respiratory epithelium, fallopian tubes, sperm tail.
3. Impaired ciliary motility in respiratory epithelium results in decreased clearance of bacteria, leading to recurrent pneumonia and sinusitis.
4. Male and female infertility due to immotile sperm and dysfunctional fallopian tube cilia. Also increased risk of ectopic pregnancy.
5. Defect in left-right dynein (involved in L/R asymmetry) can lead to dextrocardia and situs inversus during embryogenesis (seen in 50% of patients).
6. Bronchiectasis manifested by productive cough, hemoptysis, cyanosis, clubbing and decreased FEV1/FVC ratio. Dilated bronchioles with “signet ring” appearance on CT.
7. Tx of bronchiectasis with antibiotics, bronchodilators, and surgical resection.
8. Dx. Low nasal nitric oxide levels, genetic testing, bronchoscopy and electron microscopic visualization of ciliary abnormalities.
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Question 117

Cystic fibrosis Dx and Sx

Answer 117

1. Elevated sweat chloride concentration (Cl- >60 mEq/L) is diagnostic of CF.
2. If sweat test equivocal, measurement of nasal transepithelial potential difference (more negative in CF) and genetic testing for CFTR mutations can confirm diagnosis.
3. Immunoreactive trypsinogen (IRT) used increasingly for newborn screening.
4. Present with nasal polyps, clubbing, contraction alkalosis, hypokalemia, recurrent pulmonary infections (eg, S aureus in early infancy, P aeruginosa in adolescence), chronic bronchitis, bronchiectasis (reticulonodular pattern on CXR), malabsorption with steatorrhea due to pancreatic insufficiency, ADEK vitamin deficiency, biliary cirrhosis, meconium ileus in newborns.
5. Thick mucus plugs and obstructs various secretory ducts (bile canaliculi, bronchioles, pancreatic ducts) causing biliary cirrhosis, bronchiectasis and pancreatic insufficiency.
6. CBAVD in men and subfertility in women (amenorrhea, abnormally thick cervical mucus).
7. Tx chest physiotherapy, albuterol, aerosolized dornase alfa (DNase), hypertonic saline to facilitate mucus clearance. Azithromycin as anti-inflammatory agent. Pancreatic agents for insufficiency.
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Question 118

Cystic Fibrosis pathogenesis

Answer 118

1. AR disorder most commonly due to 3-base pair deletion of phenylalanine at position 508 (ΔF508) of CFTR gene on chromosome 7.
2. ΔF508 is found in approximately 70% of CF cases, and causes a misfolded CFTR protein.
3. CFTR gene encodes an ATP-gated Cl- channel, that secretes Cl- in the lungs, pancreas, liver and GI tract and reabsorbs Cl- in sweat glands.
4. Mutation causes impaired posttranslational processing (eg, improper folding and glycosylation) of CFTR.
5. Misfolded protein is detected by the RER and targeted for proteasome degradation, preventing the CFTR channel from reaching the cell membrane.
6. Complete absence of CFTR in the apical membrane of affected epithelial cells causes decreased Cl- secretion (or decreased Cl- reabsorption in the sweat glands).
7. Increased intracellular Cl- results in compensatory Na+ reabsorption via epithelial Na+ channels leading to H2O reabsorption and abnormally thick mucus.
8. In sweat glands, misfolded protein leads to less reabsorption of Cl- from sweat leading to an increased concentration of Cl- in sweat of CF patients.
9. Increased Na+ reabsorption also causes a more negative transepithelial potential difference.
10. Mucus in lungs combines with high concentrations of DNA due to destroyed neutrophils that chronically flood inflamed lungs, causing further increased viscosity of sputum.
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Question 119

Familial Hypertrophic Cardiomyopathy

Answer 119

1. AD disorder with variable expression caused by mutation in one of the components of the cardiac sarcomere (eg, Beta-myosin heavy chain (most common), myosin-binding protein C, cardiac troponin T, α-tropomyosin).
2. Hypertrophy of the interventricular septum and myocardium, resulting in a small banana-shaped left ventricular lumen with reduced volume.
3. Reduced LV filling during diastole leads to low CO, manifesting as dyspnea and syncope.
4. Sudden death can occur from LV outflow obstruction caused by a mitral valve leaflet swinging towards the interventricular septum during systole.
5. Hypertrophied myocardium is susceptible to ischemia, leading to the common complaint of angina.
6. Sx dyspnea, angina, syncope, palpitations, arrhythmias, sudden death in a young athlete.
7. Histology reveals haphazard arrangement of hypertrophied myocytes.
8. Tx beta blockers and avoidance of strenuous exercise.
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Question 120

Glanzmann thrombasthenia

Answer 120

1. AR disorder resulting in deficiency or dysfunction of glycoprotein IIb/IIIa receptor on platelet surface.
2. GIIb/IIIa receptor complex responsible for binding fibrinogen to platelet surface, allowing for cross-linking between adjacent platelets causing platelet aggregation.
3. Defect in GIIb/IIIa receptor results in inability to aggregate properly.
4. Presents with excessive bleeding (often dental bleeding, epistaxis, or menorrhagia).
5. Labs reveal normal platelet count, PT and aPTT with a prolonged bleeding time.
6. Tx supportive tx of bleeding episodes with platelet or RBC transfusions. Avoid antiplatelet medications.
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Question 121

Bernard-Soulier Syndrome

Answer 121

1. AR disorder resulting in absence or deficiency of glycoprotein Ib receptor on platelet surface.
2. G1b receptor responsible for binding vWF to platelet surface, allowing for platelet adhesion to injured endothelial surface. Deficiency of G1b receptor prevents platelet adhesion from happening.
3. Presents with excessive bleeding (often dental bleeding, easy bruising, epistaxis, or menorrhagia).
4. Labs reveal low platelet count and prolonged bleeding time. PT and aPTT are normal.
5. Tx supportive tx of bleeding episodes with platelet or RBC transfusions. Avoid antiplatelet medications.
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Question 122

von Willebrand disease

Answer 122

1. AD disease marked by a deficiency in vWF.
2. Most common hereditary bleeding disorder, affecting 1% of population.
3. Lack of vWF impairs platelet adhesion to damaged endothelium during vascular injury, resulting in deficient platelet plug formation.
4. vWF is also a carrier protein for factor VIII, so deficient vWF results in functional deficiency of factor VIII, impairing intrinsic pathway of coagulation.
5. Presents with mucosal bleeding (epistaxis, gingival bleeding, menorrhagia).
6. Labs reveal prolonged aPTT, prolonged bleeding time, and normal PT. Normal thrombin time.
7. Tx ddAVP (desmopressin) prior to surgery or factor VIII replacement if necessary. Avoid aspirin and other anticoagulants.
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Question 123

α-Thalassemias

Answer 123

1. AR disorders caused by deletion of 1 or more of the 4 alleles (HBA1, HBA2) coding for the α-globin chain of Hgb on chromosome 16.
2. Excess β chains can form Hgb H in adults, while excess γ chains can form Hemoglobin Barts (tetrameric γ chains) in newborns.
3. Four variants exist: (1) α-thalassemia trait (3 normal alleles, asymptomatic); (2) α-thalassemia minor (2 normal alleles, mild anemia); (3) Hemoglobin H disease (1 normal allele, severe hemolytic anemia, splenomegaly); (4) hydrops fetalis (no normal alleles, stillborn fetus).
4. Labs reveal hypochromic, microcytic RBCs and target cells on peripheral smear.
5. No tx for α-thalassemia trait. Transfusions as needed for α-thalassemia minor and Hgb H disease.
6. α-thalassemia more common in people of Southeast Asian ancestry.
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Question 124

β-Thalassemias

Answer 124

1. AR disorders caused by point mutations in 1 or 2 alleles of the β-globin gene (HBB) of Hgb on chromosome 11.
2. Excess α chains combine with γ and δ chains to form Hgb A2 (α2δ2) and Hgb F (α2γ2).
3. Two variants exist: (1) β-thalassemia minor (heterozygosity, mild anemia); (2) β-thalassemia major (homozygosity, severe hemolytic anemia, increased Hgb F, splenomegaly, bony abnormalities, hemosiderosis (from chronic transfusions), heart failure (from hemosiderosis)).
4. Labs reveal hypochromic, microcytic RBCs and target cells on peripheral smear.
5. No tx for β-thalassemia minor. Transfusions and/or bone marrow transplant for β-thalassemia major.
6. β-thalassemia more common in people of Mediterranean ancestry.
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Question 125

Hemoglobin C disease

Answer 125

1. Hb C disease is an AR disorder most commonly caused by a single AA substitution at position 6 in β-globin chain of Hgb, where GLUTAMIC ACID (acidic, negatively charged) is replaced by LYSINE (basic, positively charged).
2. Since lysine is charged, although with opposite polarity to glutamic acid, hydrophobic interactions between Hb molecules do not occur (as in Hb S disease).
3. Presence of lysine causes HbC to have decreased mobility on electrophoresis.
4. Patients with hemoglobin C disease (different mutation in β-chain) or sickle cell trait (heterozygous for Hgb S gene) tend to have milder versions of sickle cell anemia.
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Question 126

Sickle Cell Anemia

Answer 126

1. AR disorder most commonly caused by point mutation in gene coding for β-globin chain (HBB) on chromosome 11.
2. Mutation causes single AA substitution of GLUTAMIC ACID (hydrophilic negative charge) —-> VALINE (hydrophobic neutral), in 6th position of β-globin chain, resulting in formation of hemoglobin S (HbS).
3. Glu–>Val substitution leads to alteration of region on β-globin surface that interacts with complementary site on another β-globin molecule.
4. Hydrophobic interactions between adjacent Hb molecules cause aggregation/polymerization under anoxic conditions.
5. Hgb S polymerizes at low blood oxygen tension (caused by infection, exercise, or dehydration), causing the RBC shape to become distorted and inflexible (“sickled”) and more susceptible to hemolysis.
6. Present with chronic hemolytic anemia, indirect hyperbilirubinemia, jaundice, painful vaso-occlusive crises, autosplenectomy, aplastic crises (usually provoked by parvovirus B19 infection) and increased susceptibility to osteomyelitis with Salmonella (infections with encapsulated organisms).
7. Labs reveal anemia, elevated indirect bilirubin, reticulocytosis, crescent-shaped RBCs and Howell-Jolly bodies on peripheral blood smear.
8. Tx with IV fluids, oxygen, pain control during vaso-occlusive crises, blood transfusions, hydroxyurea (increases Hgb F levels).
9. Hemoglobin S gene carried by approximately 8% of African Americans and provides resistance to Plasmodium falciparum malaria.
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Question 127

Turcot syndrome

Answer 127

Autosomal dominant condition associated with a mutation of APC gene on chromosome 5. Characterized by adenomatous polyps and CNS tumors. Associated with increased risk for CRC.

Question 128

Hereditary spherocytosis

Answer 128

1. AD disorder caused by mutations in various erythrocyte membrane proteins (eg, spectrin, ankyrin, band 3 protein, protein 4.1) that normally bind the cytoskeleton to the cell membrane.
2. Membrane of RBC supported by protein scaffold that allows RBC to maintain biconcave shape and be deformable to fit through capillaries and splenic fenestrations.
3. Spectrin is a major component of the RBC membrane scaffolding. Deficient or mutated membrane proteins lead to membrane blebs progressively removed during RBC circulation, leading to bite cells and spherocytes, as well as extravascular hemolytic anemia. RBC loses biconcave shape, resulting in less deformable spherical shape and decreased surface-to-volume ratio.
4. Spherical cells unable to pass through splenic fenestrations, become trapped in spleen and are hemolyzed.
5. Presents with jaundice, scleral icterus, splenomegaly, pigment gallstones due to chronic hemolysis.
6. Labs reveal hemolytic anemia, spherocytes on smear, increased MCHC, increased erythrocyte osmotic fragility, reticulocytosis, normal MCV, normal hemoglobin.
7. Tx splenectomy (eliminates site of hemolysis), folic acid supplementation. Persistence of spherocytosis after splenectomy.
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Question 129

Hemophilia A

Answer 129

1. X-linked recessive disorder caused by deficiency of factor VIII.
2. Deficiency of factor VIII interferes with intrinsic pathway of coagulation cascade, resulting in ineffective coagulation.
3. Presents with spontaneous hemarthrosis and bleeding into muscles.
4. Labs reveal prolonged aPTT, normal PT, bleeding time and thrombin time.
5. Tx replace factor VIII. Order clotting factor assay to determine which factor deficient.
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Question 130

Hemophilia B

Answer 130

1. X-linked recessive disorder caused by deficiency of factor IX.
2. Deficiency of factor IX interferes with intrinsic pathway of coagulation cascade, resulting in ineffective coagulation.
3. Presents with spontaneous hemarthrosis and bleeding into muscles.
4. Labs reveal prolonged aPTT, normal PT, bleeding time and thrombin time.
5. Tx replace factor IX. Order clotting factor assay to determine which factor deficient.
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Question 131

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Answer 131

1. X-linked recessive disorder caused by a deficiency in G6PD, enzyme that catalyzes oxidation of G6P to 6-phosphogluconate in HMP shunt pathway while reducing NADP+ to NADPH.
2. Deficiency of G6PD leads to decreased formation of NADPH, a required cofactor in glutathione reduction.
3. Glutathione scavenges oxidative metabolites and converts harmful H2O2 to water.
4. G6PD deficiency presents as hemolytic anemia with oxidative stress (infection, fava beans, sulfamethoxazole, primaquine, anti-TB drugs).
5. Patients may report history of jaundice, gallstones (from increased hemolysis and breakdown of heme into unconjugated bilirubin), fatigue, splenomegaly.
6. More prevalent among African-Americans and people of Mediterranean descent, associated with protection from malaria.
7. Tx. discontinuation of precipitating agent, oxygen and bed rest.
8. Eg, 36 year old Mediterranean man presents with increased fatigue and weakness. Recently started anti-TB prophylaxis medications a week before. Patient is tachycardic and jaundiced, with mild splenomegaly. Labs reveal low Hgb, low Hct, and elevated indirect bilirubin.
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Question 132

Fanconi anemia

Answer 132

1. Rare AR condition resulting in the mutation of one of eight Fanconi anemia genes (termed genes FA-A through FA-H).
2. Exact action of Fanconi anemia gene products unknown, likely involved in DNA repair or removal of free radicals. Mutations in these proteins leads to increased DNA damage to sensitive cells, such as those involved in hematopoiesis.
3. Patients present between ages 3 to 14 with cafe au lait spots on the trunk and neck, stunted growth with resulting short stature, hypogonadism. May have skeletal anomalies such as dysplastic thumbs and radii, congenital heart, eye or kidney defects, microcephaly, and intellectual disability.
4. Increased sensitivity of tissues to alkylating agents results in increased risk of cancer.
5. Labs reveal aplastic anemia (pancytopenia with hypocellular bone marrow on biopsy), increased chromosome fragility.
6. Stem cell transplantation is curative.
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Question 133

What are the lab findings of G6PD deficiency?

Answer 133

1. Normocytic, normochromic anemia
2. Indirect (unconjugated) bilirubinemia
3. Decreased serum haptoglobin levels (haptoglobin a scavenger for free Hgb)
4. Peripheral smear with spherocytes and Heinz bodies (hemoglobin precipitates within RBCs from oxidative stress)
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Question 134

Factor V Leiden

Answer 134

1. AD mutation in gene for factor V on chromosome 1.
2. Protein C is one of the major regulators of the coagulation cascade. After binding to protein S, protein C degrades factors Va and VIIIa ceasing coagulation.
3. Factor V Leiden mutation results in production of mutated factor V resistant to degradation by protein C, manifesting in a hypercoagulable state.
4. Patients with factor V Leiden are at an increased risk for deep venous thrombosis and pulmonary embolism. Risk is increased with pregnancy, recent surgery, cancer and use of OCPs.
5. Consider anticoagulant therapy with coumadin; avoid combined oral contraceptive (COC) use.
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Question 135

Turner Syndrome

Answer 135

1. Partial or complete monosomy of X chromosome (XO karyotype with no Barr body).
2. Sx short stature, broad chest, widely spaced nipples, cystic hygroma of neck, short neck with webbed-neck appearance, low back of neck hairline, low-set ears, lymphedema of extremities, horseshoe kidney, coarctation of aorta and other congenital heart defects.
3. May present with swollen hands and feet at birth 2/2 lymphatic obstruction during embryogenesis.
4. Primary amenorrhea, replacement of ovaries with fibrous strands (no ova or follicles), and infantile genitalia and breasts. Labs reveal decreased estrogen production, increased FSH and LH levels.
5. Patients with Turner’s syndrome are at increased risk for DM, hypertension, Hashimoto thyroiditis, and osteoporosis.
6. Tx GH injections to treat short stature, estrogen replacement.
7. Patients have decreased life expectancy due to CV abnormalities.
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Question 136

Klinefelter syndrome

Answer 136

1. Disorder characterized by 2 or more X chromosomes with one or more Y chromosomes (most commonly 47, XXY karyotype with a single Barr body).
2. Most commonly caused by maternal meiotic nondisjunction. May be due to mosaicism or paternal meiotic nondisjunction as well.
3. Small atrophic testes, tall stature, lack of secondary male characteristics, gynecomastia, male infertility (2/2 reduced spermatogenesis). Occasionally mild intellectual disability.
4. Labs reveal decreased testosterone, increased FSH and LH levels.
5. Tx with testosterone replacement after puberty. Does not tx infertility.
6. XYY syndrome results in tall males with severe acne but no other clinically significant manifestations. Of interest, studies have found an increased frequency of XYY syndrome among criminals.
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Question 137

Angelman syndrome

Answer 137

1. Genetic disorder most often caused by a deletion or mutation of a critical region (q11-13) on the maternally derived chromosome 15q. These same genes on the paternally derived chromosome 15 are usually silenced through imprinting.
2. 5% of cases are due to paternal uniparental disomy (UPD) with 2 paternally inherited chromosomes that are imprinted (and thus silenced) in the 15q11-13 region and no maternal chromosome.
3. “Happy puppet”, ataxic gait, inappropriate laughter, seizures, intellectual disability.
4. Patients require lifelong supervision and care.
5. “Angelman misses mom.” Aka missing critical region of genes on “mother” chromosome or UPD without chromosome from “mother”.
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Question 138

Barr body

Answer 138

1. Barr bodies are condensed, inactive X chromosomes found in the nucleus of somatic cells of individuals with more than one X chromosome (XXY, XX, XXX but not XO).
2. They are rendered inactive in a process called lyonization, which randomly inactivates one X chromosome.
3. XXY individuals (Klinefelter) are male and have a Barr body. XXX individuals are female and have 2 Barr bodies. XO individuals are are female with no Barr bodies.
4. XY males have no Barr bodies. XX females have one Barr body.
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Question 139

Prader-Willi syndrome (PWS)

Answer 139

1. Genetic disorder most often caused by a deletion or mutation of a critical region (q11-13) on the paternally derived chromosome 15q. These same genes on the maternally derived chromosome 15 are silenced through imprinting.
2. 25% of cases are due to maternal uniparental disomy (UPD) with 2 maternally inherited chromosomes that are imprinted (and thus silenced) in the region 15q11-13 and no paternal chromosome.
3. PWS is characterized by low muscle tone (hypotonia), short stature, incomplete sexual development (hypogonadism), cognitive disabilities, behavior problems, and a chronic feeling of hunger that can lead to excessive eating (hyperphagia) and life-threatening obesity leading to diabetes.
4. Patients require lifelong supervision and care.
5. “Prader lack fader.” Aka PWS lacks “father” chromosome (if UPD) or lacks critical region of chromosome from “father”.
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Question 139

Autosomal recessive

Answer 139

1. Often due to enzyme deficiencies
2. Usually only 1 generation.
3. Commonly more severe than AD disorder
4. Often present in childhood.
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Question 140

Autosomal dominant

Answer 140

1. Defects in structural genes
2. Many generations affected, both male and female
3. Pleiotropic (multiple “unrelated” effects)
4. Variable expressivity
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Question 141

X-linked dominant

Answer 141

1. Transmitted through both parents
2. Affected mothers transmit to 50% of daughters and sons.
3. Affected fathers transmit to all daughters but not to sons.
4. Ex. Rett syndrome, Fragile X, Alport syndrome, hypophosphatemic ricks (vitamin D-resistant, increased phosphate wasting at proximal tubule).
   * ***********

Question 142

X-linked recessive

Answer 142

1. Sons of heterozygous mothers have a 50% chance of being affected.
2. No male-male transmission
3. Skips generations.
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Question 143

What are some X-linked recessive disorders?

Answer 143

1. Oblivious And Calm Females Will Often Give Her Boys Her x-Linked Disorder.
2. O= Ornithine transcarbamylase deficiency
3. A = Androgen Insensitivity Syndrome
4. C= Chronic Granulomatous Disease
5. F= Fabry disease
6. W= Wiskott-Aldrich syndrome
7. O= Ocular albinism
8. G= G6PD deficiency
9. H= Hunter syndrome
10. B= Bruton’s x-linked agammaglobulinemia
11. H= Hemophilia A & B
12. L= Lesch-Nyhan Syndrome
13. D= Duchenne and Becker Muscular Dystrophy
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Question 144

Trinucleotide repeat expansion disorders

Answer 144

1. Fragile X (XLR) = CGG repeats on X chromosome
2. Friedrich AtAxia (AR) = GAA repeats on chrom 9
3. Huntington disease (AD) = CAG repeats on chrom 4
4. MyoTonic dystrophy (AD) = CTG repeats on chrom 19
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Question 145

Mitochondrial inheritance

Answer 145

1. Transmitted only through mother
2. All offspring of affected females may show signs of disease
3. Variable expression due to heteroplasty
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Question 146

Robertsonian translocation

Answer 146

1. Commonly involves chromosome pairs 13, 14, 15, 21, 22
2. Occurs when long arms of 2 acrocentric chromosomes (centromeres near the ends) fuse at the centromere and the 2 short arms are lost.
3. If gametes form a balanced translocation, no abnormal phenotype results.
4. If gametes form an unbalanced translocation, miscarriage, stillbirth, due to monosomy or trisomy are likely.
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