Genetics

Question 1

Fragile X Syndrome

Answer 1

• Most common inherited and 2nd most common congenital cause of intellectual disability
• x-linked d/o c/b loss of function mutation in FMR1
• trinucleotide repeat = (CGG)n
• females with 1 abnormal X have milder and variable sx

Features:

• long, narrow face
• prominent forehead and chin
• large testes
• hyperlaxity of hand joints
• developmental delay (speech and motor) in infancy
• neuropsych sx in childhood (e.g. anxiety, ADHD, autism spectrum)

Question 2

Number 1 cause of congenital intellectual disability

Answer 2

Down Syndrome

• epicanthal folds
• upslanting palpebral features
• low-set small ears
• flat facial profile
• sandle-toe deformity
• single palmar crease
• Brushfield spots (in iris)
• duodenal atresia
• congenital heart dz (ASD)
• inc risk of ALL and Alzheimer’s dz (>35 yo)

Quad screen: dec alpha-fetoprotein, dec estriol, inc inhibin A, inc beta-hCG

Question 3

Ehlers-Danlos syndrome

Answer 3

connective tissue d/o

most common mutation = type V collagen production

sx = skin hyperelasticity and fragility, joint laxity

Question 4

Klinefelter syndrome

Answer 4

47, XXY

mild ID
tall stature
gynecomastia
small testes (often undescended)
infertility

Question 5

Marfan syndrome

Answer 5

AD, fibrillin-1 gene mutation–> connective tissue d/o

• tall stature
• arachnodactyly (long and thin fingers)
• ectopia lentis (lens displacement)
• dilation of proximal aorta –> dissectic aortic aneurysms
• inc arm:height ratio
• dec upper:lower body segment ratio
• pectus excavatum

Question 6

Prader Willi syndrome

Answer 6

paternal deletion of part of chromosome 15

infancy –> hypotonia and associated gross motor delays, hyperphagia and associated obesity

ID and behavioral problems common (e.g. autistic behaviors, OCD features)

Question 7

Wilson disease

Answer 7

dx = dec serum ceruloplasmin, inc hepatic copper

cirrhosis, CNS involvement, Kayser-Fleischer rings

Question 8

Hemochromatosis

Answer 8

dx = high serum ferritin levels

cirrhosis, pancreatic fibrosis, subsequent DM, CM (cardiomyopathy), secondary hypogonadism

Question 9

Fabry Disease

Answer 9

inherited deficiency of alpha-galactosidase A

globoside ceramide trihexoside accumulates in tissues

sx = hypohidrosis, acroparesthesia (episodic burning neuropathic pain in extremities) and angiokeratomas (punctate dark non-blanching macules and papules between umbilicus and knees)

tx = enzyme replacement therapy to avoid renal failure and death

Question 10

alpha 1 antitrypsin deficiency

Answer 10

panacinar emphysema and liver cirrhosis

alpha 1 antitrypsin = serine protease inhibitor that normally inactivates elastase and trypsin

Question 11

Lesch-Nyhan

Answer 11

sx = spasticity, choreoathetoid movement, self-mutilation

c/b HGPRT absence (which converts hypoxanthine to IMP and guanine to GMP) –> defective purine salvage pathway –> excess uric acid production and de novo purine synthesis
“He’s Got Purine Recovery Trouble”

X-linked recessive

Question 12

Niemann-Pick disease

Answer 12

spasticity

Question 13

Adenosine deaminase deficiency

Answer 13

excess ATP and dATP –> feedback inhibition of ribonucleotide reductase –> prevents DNA synthesis –> decreased lymphocyte count –> SCID

Question 14

Achondroplasia

Answer 14

AD

cell-signaling defect in fibroblast growth factor (FGF) receptor 3 –> dwarfism, short limbs, larger head, normal trunk, i.e. Tyrion Lannister

assoc. with advanced paternal age

Question 15

ADPKD

Answer 15

AD

• always b/l
• massive kidneys from cysts
• sx = flank pain, hematuria, HTN, progressive RF

85% 2/2 PKD1 mutation (chromosome 16)

assoc. conditions:
- polycystic liver dz
- berry aneurysms
- mitral valve prolapse

*infantile form = recessive

Question 16

Familial adenomatous polyposis

Answer 16

AD

colon covered with polyps after puberty –> colon cancer unless resected

mx on chromosome 5 in APC gene

Question 17

Familial hypercholesterolemia (hyperlipdemia type IIA)

Answer 17

AD

Elevated LDL due to defective or absent LDL receptor

heterozygotes (more common) = LDL ~300
homozygotes (rare) = LDL ~700+

severe atherosclerosis at young age, tendon xanthomas (esp Achilles), MI before age 20

Question 18

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)

Answer 18

AD

inherited d/o of blood vessels

findings: telangiectasiasm recurrent epistaxis, skin discolrations, AVMs

Question 19

Hereditary spherocytosis

Answer 19

AD

spectrin and ankyrin defect –> spherocytes

findings: hemolytic anemia, inc MCHC

cure = splenectomy

Question 20

Huntington’s disease

Answer 20

AD

findings: depression, progressive dementia, choreiform movements, caudate atrophy, and dec levels of GABA and ACh in the brain

sx onset = 20-50 yo

trinucleotide repeat (CAG)n on chromosome 4

“hunting 4 food”

Question 21

MEN 1

Answer 21

AD

pituitary, parathyroid, pancreas

Question 22

MEN 2A

Answer 22

AD

pheochromocytoma, parathyroid hyperplasia, medullary thyroid cancer

ret gene

Question 23

MEN 2B

Answer 23

AD

pheochromocytoma, medullary thyroid cancer, marfanoid habitus, mucosal neuromas

ret gene

Question 24

Neurofibromatosis type 1 (von Recklinghausen’s disease)

Answer 24

AD

cafe au lait spots, neural tumors, Lisch nodules (pigmented iris hamartomas), scoliosis, optic pathway gliomas

long arm of chromosome 17

Question 25

NFT2

Answer 25

b/l acoustic schwannomas, juvenile cataracts NF2 gene on chromosome 22

Question 26

Tuberous sclerosis

Answer 26

AD facial lesions (adenoma sebaceum, hypopigmented "ash leaf spots", cortical and retinal hamartomas, sz, ID, renal cysts, renal angiomyolipomas, cardiac rhabdomyomas, inc incidence of astrocytomas incomplete pentrance 4 systems affected = CNS, skin, cardiac, renal

Question 27

von Hippel-Lindau disease

Answer 27

AD hemangioblastomas or retina/cerebellum/medulla multiple b/l RCC and other tumors deletion of VHL gene (tumor suppressor) on chrom 3p --> constitutive expression of hypoxia inducible factor HIF-1 (TF) and activation of angiogenic GFs and EPO --> inc vascular endothelial growth pheochromocytomas can occur in conjunction

Question 28

Cystic Fibrosis

Answer 28

AR defect in CFTR on chromosome 7 (commonly del of Phe 508) --> misfolding and degradation of channel before reaching cell surface sx= chronic bronchitis, recurrent PNA (s. aureus, pseudomonas), bronchiectasis, pancreatic insufficiency (steatorrhea, malabsorption), nasal polyps, meconium ileus, infertility in males due to absent vas deferens b/l, fat-soluble vit deficiencies (ADEK), failure to thrive ``` dx = Cl sweat test showing Cl elevation tx = N-acetylcysteine to loosen mucus plugs (cleaves S-S bonds in mucus glycoproteins) ```

Question 29

CFTR

Answer 29

- Cl secretion in lungs and GI tract - Cl reabsorption from sweat most commonly a deletion at position 508 of codon coding for phenylalanine can also be c/b frameshift mx

Question 30

X-linked recessive d/o

Answer 30

"Be Wise, Fool's GOLD Heeds Silly HOpe" ``` Bruton's agammaglobulinemia Wiskott-Aldrich syndrome Fabry's disease G6PD deficiency Ocular albinism Lesch-Nyhan syndrome Duchenne's (and Becker's) muscular dystrophy Hunter's Syndrome Hemophilia A and B, Ornithine transcarbamoylase deficiency ```

Question 31

Duchenne's muscular dystrophy

Answer 31

x-linked frameshift mutation --> del of dystrophin gene (fxn = anchor muscle fibers) --> accelerated muscle breakdown sx = weakness in pelvic girdle muscles and progresses superiorly, calf pseudohypertrophy, cardiac myopathy, Gower's maneuver dx = inc CPK and muscle biopsy onset before 5 yo k

Question 32

Becker's muscular dystrophy

Answer 32

mx in dystrophin gene but less severe than Duchenne onset = adolescence or early adulthood

Question 33

Trinucleotide repeat expansion disease

Answer 33

"Tried HUNTING for MY FRIED eggs(X)" "X-Girlfriend's First Aid Helped Ace My Test" Fragile X - CgG --> c guy's giant junk Friedreich's ataxia - CaA Huntington's disease - CaG --> hunting to cage Myotonic dystrophy - CtG --> can't try to game too weak

Question 34

Edward's syndrome

Answer 34

trisomy 18 severe ID, rocker-bottom feet, micrognathia, low-set ears, clenched hands, prominent occiput, congenital heart disease death by 1 yo quad screen: dec alpha-fetoprotein, dec beta-hCG, dec estriol, nl inhibin A

Question 35

Patau's syndrome

Answer 35

trisomy 13 severe ID, rocker-bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, congenital heart disease death by 1 year 1st trimester screen: dec free beta-hCG, dec PAPP-A, inc nuchal translucency

Question 36

Cri-du-chat syndrome

Answer 36

Congenital microdeletion of short arm of chromosome 5 (46, XX or XY, 5p-) microcephaly, moderate to severe ID, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities (VSD)

Question 37

Williams syndrome

Answer 37

Congenital microdeletion of long arm of chromosome 7 including elastin gene distinct elfin facies, ID, hypercalcemia (inc sensitivity to vit D), well-developed verbal skills, extreme friendliness with strangers, CV problems

Question 38

22q11 deletion syndromes

Answer 38

CATCH-22 thanks to microdeletions and aberrant development of 3rd and 4th branchial pouches ``` Cleft palate Abnormal facies Thymic aplasia --> TC deficiency Cardiac defects Hypocalcemia 2/2 parathyroid aplasia ``` DiGeorge = thymic, parathyroid, and cardiac defects Velocardiofacial syndrome - palate, facial, and cardiac defects

Question 39

Robertsonian translocation

Answer 39

nonreciprocal commonly involves pairs 13, 14, 15, 21, 22 long arms of 2 acrocentric chrom (i.e. centromeres near ends) fuse at centromere and 2 short arms lost

Question 40

Bruton's X-linked agammaglobulinemia

Answer 40

p/w recurrent sinopulmonary infections, Giardia lamblia gastroenteritis, failure to thrive, low of all Ig levels, inc risk of pyogenic (encapsulated) bacT infection mx in Bruton tyrosine kinase --> failure of BM pre-B cells (CD19+, CD20+) to develop into mature BCs (CD19+, CD20+ CD21+).