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Genetic Diseases Flashcards

1
Q

Prader-Willi Syndrome

A

Deletion/mutation of paternal gene on chromosome 15 (maternal copy is imprinted)

Presents as obesity, hyperphagia, intellectual disability, hypogonadism, and hypotonia

25% of cases due to maternal uniparental disomy

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2
Q

Angelman Syndrome

A

Deletion/mutation of maternal gene on chromosome 15 (paternal copy is imprinted)

Presents with inappropriate laughter, seizures, ataxia, and severe intellectual disability

5% due to paternal uniparental disomy

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3
Q

Achondroplasia

A

Autosomal dominant constitutively activating mutation of fibroblast growth factor receptor 3 (FGFR3) causing failure of endochondral ossification and linear bone growth

85% of mutations occur sporadically and are associated with advanced paternal age

Presents with short stature, macrocephaly, flat midface with prominent forehead, and shortening of the limbs

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4
Q

Huntington’s Disease

A

Autosomal dominant neurodegenerative disorder due to CAG trinucleotide repeat in Huntingtin gene on chromosome 4

Presents as progressively uncoordinated movements/chorea + psychiatric symptoms (aggression, depression, dementia); may present with genetic anticipation

Atrophy of caudate nuclei seen on imaging

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5
Q

Kartagener’s Syndrome

A

AKA Primary Ciliary Dyskinesia

Autosomal recessive defect of dynein arms on cilia Presents as chronic sinusitis + bronchiectasis + situs inversus; +/- recurrent otitis media, bronchitis, and pneumonia; also associated with infertility (male and female) and risk of ectopic pregnancy

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6
Q

Autosomal Dominant Polycystic Kidney Disease

A

85% due to autosomal dominant mutation of PKD1 (chromosome 26); remainder due to autosomal dominant mutation of PKD2 (chromosome 4)

Presents as bilateral, massive enlargement of the kidneys due to the presence of multiple cysts, hematuria, flank pain, hypertension (due to increased renin), urinary infection, progressive renal failure

Associated with increased risk of aneurysm

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7
Q

Familial Adenomatous Polyposis

A

Autosomal dominant mutation of APC gene on chromosome 5

Presents as innumerous polyps of the colon after puberty; 100% progress to adenocarcinoma without colonic resection

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8
Q

Familial Hypercholesterolemia

A

Autosomal dominant mutation of the LDL receptor

Presents with high LDL, early onset atherosclerosis, and tendinous xanthomas

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9
Q

Hereditary Hemorrhaging Telangiectasia

A

AKA Osler-Weber-Rendu Syndrome

Autosomal dominant inherited mutation of the TGF-B signaling pathway (multiple genes) involved in angiogenesis

Presents with telangiectasias, recurrent epistaxis, AVMs, hematuria, GI bleeding, skin discoloration

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10
Q

Hereditary Spherocytosis

A

Autosomal dominant mutation of proteins spectrin and/or ankyrin; RBCs appear small on smear with elevated MCHC and reticulocyte count

Presents with hemolytic anemia and splenomegaly

Treatment: Splenectomy

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11
Q

Marfan Syndrome

A

Autosomal dominant mutation of Fibrillin-1 gene (chromosome 15) causing connective tissue disease of skeleton, cardiovascular system, and eyes

Presents with long extremities, hypermobile joints, pectus excavatum, aortic/mitral valve incompetence, aortic dissection, and subluxation of optic lenses

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12
Q

MEN1 (Wermer Syndrome)

A

Autosomal dominant syndrome of mutiple endocrine tumors, affecting:

Pituitary
Parathyroid - Kidney stones
Pancreas - Gastrinoma and stomach ulcers

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13
Q

MEN2A (Sipple Syndrome)

A

Autosomal dominant syndrome of multiple endocrine tumors, including:

Medullary thyroid carcinoma
Pheochromocytoma
Parathyroid hyperplasia

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14
Q

MEN2B

A

Autosomal dominant syndrome of multiple endocrine tumors, including:

Medullary thyroid carcinoma
Pheochromocytoma
Oral mucosal neuromas

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15
Q

Neurofibromatosis Type I (Von Recklinghausen Disease)

A

Autosomal dominant mutation of NF1 on chromosome 17

Neurocutaneous presentation characterized by:

Cafe au lait spots
Axillary / inguinal freckles
Neurofibromas (Schwann cell origin + fibroblasts + mast cells)
Lisch nodules (hamartomas of the iris)

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16
Q

Neurofibromatosis Type II

A

Autosomal dominant mutation of NF2 on chromosome 22

Presents with bilateral acoustic schwannomas, juvenile onset cataracts, meningiomas, ependymomas

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17
Q

Tuberous Sclerosis

A

Autosomal dominant syndrome of multiple benign hamartomas with multi-system involvement, including:

Hamartomas of the CNS and skin
Angiofibromas
Rhabdomyomas
Angiomyolipomas

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18
Q

von-Hippel Lindau Disease

A

Autosomal dominant mutation of VHL tumor suppressor gene on chromosome 3 causing constitutive activation of HIF and angiogenesis, presents with:

Cavernous hemangiomas of skin & organs
Hemangioblastomas
Bilateral renal cell carcinoma
Pheochromocytoma

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19
Q

Cystic Fibrosis

A

Autosomal recessive defect of CFTR gene on chromosome 7; decreased Cl- secretion into GI tract and lungs + increased Na/H2O retention within cells leads to abnormally viscous mucous secretion; decreased Na in the ECF stimulates K/H wasting with resultant hypokalamia/alkalosis

Dx: Sweat Cl > 60 mEq/L

Complications: Recurrent pulmonary infections (pseudomonas), bronchitis, bronchiectasis, pancreatic insufficiency, malabsorption, nasal polyps, infertility (men)

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20
Q

Autosomal Recessive Diseases

A 
Albinism
ARPKD 
Cystic Fibrosis 
Glycogen Storage Diseases 
Hemochromatosis 
Kartagener Syndrome 
Mucopolysaccharidoses (except Hunter)
Phenylketonuria 
Sickle Cell Anemia
Sphingolipidoses (except Fabry)
Thalassemias 
Wilson's Disease
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21
Q

X-linked recessive disorders

A 
Bruton agammaglobulinemia
Wiskott-Aldrich Syndrome
Fabry Disease 
G6PD Deficiency
Lesch-Nyhan Syndrome 
Duchenne / Becker Muscular Dystrophy
Hunter Syndrome
Hemophilia A and B
OTC Deficiency
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22
Q

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

A

Risk of renal failure in utero - presents in infancy, associated with congenital hepatic fibrosis

Complications: Hypertension, portal hypertension, progressive renal insufficiency

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23
Q

Glycogen Storage Diseases

A

I. Von Gierke Disease (Glucose-6-Phosphatase)
II. Pompe Disease (alpha-1,4-glucosidase)
III. Cori Disease (alpha-1,6-glucosidase)
V. McArdle Disease (skeletal muscle glycogen phosphorylase)

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24
Q

Von Gierke Disease

A

Autosomal recessive deficiency of glucose-6-phosphatase (glycogen storage disease type I)

Presents as severe fasting hypoglycemia, elevated glycogen stores in liver / hepatomegaly

Treat with frequent oral glucose

25
Q

Pompe Disease

A

Autosomal recessive deficiency of alpha-1,4-glucosidase (glycogen storage disease type II)

Primarily affects cardiac/skeletal muscle and liver; cardiomyopathy leads to early death

26
Q

Cori Disease

A

Autosomal recessive deficiency of alpha-1,6-glucosidase (debranching enzyme); glycogen storage disease type III

Milder form of Von Gierke disease; gluconeogenesis is intact

27
Q

McArdle Disease

A

Autosomal recessive deficiency of skeletal muscle glycogen phosphorylase (glycogen storage disease type V)

Inability to break down glycogen in muscle leads to painful muscle cramps, exercise intolerance, myoglobinuria

28
Q

Wilson’s Disease

A

Autosomal recessive defect of hepatocyte copper-transporting protein ceruloplasmin, causing decreased copper secretion into the biliary system with resultant accumulation of copper in liver, brain, cornea, kidneys, and joints; presents with:

Cirrhosis, hepatocellular carcinoma
Basal ganglia degeneration with parkinsonism, asterixis, dementia, dyskinesia, dysarthria
Corneal deposits (Kaiser-Fleischer Rings)

Treat with penicillamine (chelating agent)

29
Q

Hemochromatosis

A

Autosomal recessive mutation of HFE gene leading to excessive iron accumulation

Labs: Elevated ferritin, iron, transferrin saturation; decreased TIBC

Presents with: Cirrhosis, diabetes mellitus, skin hyperpigmentation (‘Bronzed Diabetes’)

Treated with therapeutic phlebotomy or chelation

30
Q

Phenylketonuria

A

Autosomal recessive defect of phenylalanine hydroxylase (PAH); Phe cannot be converted to Tyr so tyr becomes essential in diet

Diagnosis: Newborn screening 2-3 days after birth; elevated phenylketones in urine

Presentation: Intellectual disability, seizures, eczema, musty body odor; maternal PKU presents in infants with microcephaly, poor growth, intellectual disability, congenital heart defects

Treated with low Phe / high Tyr diet

31
Q

Sickle Cell Anemia

A

Autosomal recessive point mutation hemoglobin beta chain (Glu to Val) carried in 8% of African American population; deoxygenation/acidosis causes polymerization of HbS and sickling of RBCs with subsequent anemia/vaso-occlusive complications, including:

Acute Chest Syndrome (vaso-occlusive disease of pulmonary vasculature; most common cause of adult mortality)
Stroke
Renal papillary necrosis / microhematuria
Autosplenectomy - increased risk of infection by encapsulated organisms
Osteomyelitis (Salmonella)
Avascular necrosis
Vaso-occlusive crisis (dactylitis, priapism)

Treated with hydroxyurea to increase production of HbF

32
Q

Fabry Disease

A

X-linked sphingolipidosis caused by mutation of alpha-galactosidase A with accumulation of ceramide

Presents with peripheral neuropathy of hands and feet, angiokeratomas, cardiovascular/renal disease

33
Q

Gaucher Disease

A

Autosomal recessive sphingolipidosis caused by mutation of glucocerebrosidase with accumulation of glucocerebroside

Presents with hepatosplenomegaly, pancytopenia, bone crises

Diagnosed by the presence of Gaucher Cells (lipid-laden macrophages with ‘crumpled tissue paper’ appearance)

Treated with recombinant glucocerebrosidase

34
Q

Niemann-Pick Disease

A

Autosomal recessive sphingolipidosis caused by mutation of sphingomyelinase, with accumulation of sphingomyelin

Presents with hepatosplenomegaly, progressive neurodegeneration, “cherry red” spot on macula

35
Q

Tay-Sachs Disease

A

Autosomal recessive sphingolipidosis caused by mutation of Hexosaminidase A with accumulation of GM2 ganglioside

Presents with progressive neurodegeneration, developmental delay, “cherry red” spot on macula; NO hepatosplenomegaly (vs. Niemann-Pick)

36
Q

Hurler Syndrome

A

Autosomal recessive mucopolysaccharidosis caused by mutation of alpha-iduronase

Presents with developmental delay, airway obstruction, hepatosplenomegaly, and corneal clouding

37
Q

Hunter Syndrome

A

X-linked recessive mucopolysaccharidosis caused by mutation of iduronate sulfatase

Presents as mild Hurler Syndrome (developmental delay, airway obstruction, hepatosplenomegaly) without corneal clouding, plus aggressive behavior

38
Q

Bruton’s Agammaglobulinemia

A

X-linked recessive mutation of BTK tyrosine kinase leading to failure of B-cells to mature

Presents with recurrent bacterial and enterovirus infections after 6 months, when maternal IgG declines

Labs: B-cell CD19 count WNL, decreased IgG of all classes

39
Q

Wiskott-Aldrich Syndrome

A

X-linked recessive mutation in WAS gene causing failure of T-cells to reorganize actin cytoskeleton

Presents with thrombocytopenic purpura, eczema, and recurrent infections

Labs: Elevated IgA, IgE; sparse/small platelets

40
Q

G6PD Deficiency

A

X-linked recessive deficiency of glucose-6-phosphate dehydrogenase, required for regeneration of NADPH; NADPH keeps glutathione in its reduced (anti-oxidant) form

Exposure to oxidizing agents (fava beans, sulfonamides, anti-malarial/anti-TB drugs) or infection (via oxidative burst) causes hemolytic anemia

Smear shows Heinz Bodies (oxidized Hb precipitated within RBCs) and bite cells (product of removal of Heinz bodies by splenic macrophages)

41
Q

Lesch-Nyhan Syndrome

A

X-linked deficiency of HGPRT enzyme in the purine salvage pathway; results in excess uric acid production and de novo purine synthesis

Presents with intellectual disability, aggression, self mutilation, hyperuricemia, gout

Treated with allopurinol

42
Q

Duchenne Muscular Dystrophy

A

X-linked frameshift mutation in DMD gene, which codes for dystrophin; dystrophin anchors the actin cytoskeleton of skeletal & cardiac myofibers to the ECM by cross-linking with transmembrane dystroglycan proteins

Presents with onset of progressive muscle weakness by age 5, pseudohypertrophy of calves; early death due to dilated cardiomyopathy

Labs: Elevated CPK
Diagnosed by muscle biopsy

43
Q

Becker Muscular Dystrophy

A

X-linked point mutation of DMD gene, which codes for dystrophin; dystrophin anchors the actin cytoskeleton of skeletal and cardiac myocytes to the ECM via cross-linking with transmembrane dystroglycan proteins

Presentation is milder than Duchenne’s with onset in adolescence or early adulthood

44
Q

Hemophilia

A

X-linked dysfunction of intrinsic coagulation cascade caused by deficiency of factor VIII (A) or IX (B)

Presents with macrohemorrhage, hemarthroses, easy bruising

Labs: Elevated PTT

Treatment: Recombinant clotting factor

45
Q

Ornithine Transcarbamoylase Deficiency

A

X-linked urea cycle disorder; excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway)

Findings: Elevated orotic acid in blood and urine, decreased BUN

Presents in first few days of life with symptoms of hyperammonemia

46
Q

Friedrich Ataxia

A

Autosomal recessive trinucleotide (GAA) repeat in frataxin gene on chromosome 9; frataxin is an iron-binding protein important in mitochondrial function; deficiency causes degeneration of multiple spinal tracts

Presents in childhood with kyphoscoliosis, staggering gait, frequent falls, nystagmus, dysarthria, loss of DTRs, muscle weakness, loss of vibratory/proprioceptive sensation

Early death due to cardiomyopathy

47
Q

Myotonic Dystrophy

A

Autosomal recessive trinucleotide (CTG) repeat in DMPK gene on chromosome 19

Presents with facial paralysis, ptosis, and myotonia

Associated with cardiac conduction abnormalities and heart block

48
Q

Alport Syndrome

A

X-linked mutation of Type IV collagen causing thinning/splitting of glomerular basement membrane

Presents with glomerulonephritis (nephritic syndrome) + deafness

49
Q

Cri-du-chat Syndrome

A

Congenital microdeletion of 5p

Infants present with microcephaly, intellectual disability, high pitched mewing/crying, epicanthal folds, and ventricular septal defect (VSD)

50
Q

Alkaptonuria

A

Autosomal recessive defect of homogentisate oxidase (HGD) gene in the degradative pathway of tyrosine to fumarate

Accumulation of homogentisic acid is toxic to cartilage; presents as darkening of connective tissue, brown pigmentation of sclerae, urine that turns black with exposure to air, and arthralgias

51
Q

Fanconi’s Anemia

A

Autosomal recessive mutation of DNA repair proteins

Presents with hematoogical anomalies (aplastic anemia, pancytopenia); also associated with syndromic features (short stature, structural abnormalities of limbs / eyes, abnormal pigmentation of skin) and cognitive disability

Complications: Hemorrhage, infection; increased risk of myelodysplasia / AML

Treatment: Hematopoietic growth factors, bone marrow transplantation

52
Q

Ehlers-Danlos Syndrome

A

A heterogenous group of connective tissue disorders characterized by skin hyperextensibility, joint hypermobility, and vascular fragility

Hypermobile type is most common - presents with frequent dislocation/subluxation of joints

Vascular form is most serious, caused by mutation of Type III collagen; associated with easy bruising, aneurysm, and organ rupture

53
Q

Turner Syndrome

A

Can be monosomic (45, XO) or mosaic (45, XO/46, XX)

Most common cause of primary amenorrhea; due to ovarian dysgenesis (“streak ovary”) resulting in low estrogen and elevated LH/FSH

Presents with short stature, shield chest, webbed neck, lymphedema of hands and feet

Associated with bicuspid aorta, pre-ductal coarctation of the aorta, lymphatic defects, horseshoe kidney

54
Q

Edward’s Syndrome

A

Trisomy 18

Presents with severe intellectual disability, micrognathia (small jaw), low-set ears, clenched fists, congenital heart disease; most die within 1 year of birth

Diagnosis: Maternal serum screening shows decreased AFP, bHCG, and Estriol with normal Inhibin A; screening is confirmed with amniocentesis and fetal karyotype

55
Q

DiGeorge Syndrome

A

Caused by a deletion of chromosome 22 with failure of 3rd and 4th pharyngeal pouches to develop into thymus and parathyroids

Presents as CATCH-22: Cardiac abnormalities, abnormal facies, thymic agenesis, cleft palate, hypocalcemia / hypoparathyroidism; also increased frequency of viral and fungal infections due to lack of T cells

Findings: Decreased T cells, decreased PTH, hypocalcemia, absent thymic shadow on CXR

56
Q

Hereditary Non-polyposis Colorectal Cancer (HNPCC)

A

AKA Lynch Syndrome

Autosomal dominant mutation of DNA mismatch repair genes

80% progress to colorectal cancer, always involving the proximal colon

57
Q

Gardner Syndrome

A

Variant of familial adenomatous polyposis (FAP); autosomal dominant mutation of APC gene on chromosome 5

Characterized by innumerous colonic polyps + osseous and soft tissue tumors

58
Q

Turcot syndrome

A

Variant of FAP; autosomal dominant mutation of APC gene on chromosome 5

Characterized by innumerous colonic polyps + malignant CNS tumor

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