Genetic Diseases Flashcards
Prader-Willi Syndrome
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
Angelman Syndrome
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
Achondroplasia
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
Huntington’s Disease
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
Kartagener’s Syndrome
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
Autosomal Dominant Polycystic Kidney Disease
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
Familial Adenomatous Polyposis
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
Familial Hypercholesterolemia
Autosomal dominant mutation of the LDL receptor
Presents with high LDL, early onset atherosclerosis, and tendinous xanthomas
Hereditary Hemorrhaging Telangiectasia
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
Hereditary Spherocytosis
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
Marfan Syndrome
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
MEN1 (Wermer Syndrome)
Autosomal dominant syndrome of mutiple endocrine tumors, affecting:
Pituitary
Parathyroid - Kidney stones
Pancreas - Gastrinoma and stomach ulcers
MEN2A (Sipple Syndrome)
Autosomal dominant syndrome of multiple endocrine tumors, including:
Medullary thyroid carcinoma
Pheochromocytoma
Parathyroid hyperplasia
MEN2B
Autosomal dominant syndrome of multiple endocrine tumors, including:
Medullary thyroid carcinoma
Pheochromocytoma
Oral mucosal neuromas
Neurofibromatosis Type I (Von Recklinghausen Disease)
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)
Neurofibromatosis Type II
Autosomal dominant mutation of NF2 on chromosome 22
Presents with bilateral acoustic schwannomas, juvenile onset cataracts, meningiomas, ependymomas
Tuberous Sclerosis
Autosomal dominant syndrome of multiple benign hamartomas with multi-system involvement, including:
Hamartomas of the CNS and skin
Angiofibromas
Rhabdomyomas
Angiomyolipomas
von-Hippel Lindau Disease
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
Cystic Fibrosis
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)
Autosomal Recessive Diseases
Albinism ARPKD Cystic Fibrosis Glycogen Storage Diseases Hemochromatosis Kartagener Syndrome Mucopolysaccharidoses (except Hunter) Phenylketonuria Sickle Cell Anemia Sphingolipidoses (except Fabry) Thalassemias Wilson's Disease
X-linked recessive disorders
Bruton agammaglobulinemia Wiskott-Aldrich Syndrome Fabry Disease G6PD Deficiency Lesch-Nyhan Syndrome Duchenne / Becker Muscular Dystrophy Hunter Syndrome Hemophilia A and B OTC Deficiency
Autosomal Recessive Polycystic Kidney Disease (ARPKD)
Risk of renal failure in utero - presents in infancy, associated with congenital hepatic fibrosis
Complications: Hypertension, portal hypertension, progressive renal insufficiency
Glycogen Storage Diseases
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)
Von Gierke Disease
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
Pompe Disease
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
Cori Disease
Autosomal recessive deficiency of alpha-1,6-glucosidase (debranching enzyme); glycogen storage disease type III
Milder form of Von Gierke disease; gluconeogenesis is intact
McArdle Disease
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
Wilson’s Disease
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)
Hemochromatosis
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
Phenylketonuria
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
Sickle Cell Anemia
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
Fabry Disease
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
Gaucher Disease
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
Niemann-Pick Disease
Autosomal recessive sphingolipidosis caused by mutation of sphingomyelinase, with accumulation of sphingomyelin
Presents with hepatosplenomegaly, progressive neurodegeneration, “cherry red” spot on macula
Tay-Sachs Disease
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)
Hurler Syndrome
Autosomal recessive mucopolysaccharidosis caused by mutation of alpha-iduronase
Presents with developmental delay, airway obstruction, hepatosplenomegaly, and corneal clouding
Hunter Syndrome
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
Bruton’s Agammaglobulinemia
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
Wiskott-Aldrich Syndrome
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
G6PD Deficiency
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)
Lesch-Nyhan Syndrome
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
Duchenne Muscular Dystrophy
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
Becker Muscular Dystrophy
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
Hemophilia
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
Ornithine Transcarbamoylase Deficiency
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
Friedrich Ataxia
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
Myotonic Dystrophy
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
Alport Syndrome
X-linked mutation of Type IV collagen causing thinning/splitting of glomerular basement membrane
Presents with glomerulonephritis (nephritic syndrome) + deafness
Cri-du-chat Syndrome
Congenital microdeletion of 5p
Infants present with microcephaly, intellectual disability, high pitched mewing/crying, epicanthal folds, and ventricular septal defect (VSD)
Alkaptonuria
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
Fanconi’s Anemia
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
Ehlers-Danlos Syndrome
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
Turner Syndrome
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
Edward’s Syndrome
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
DiGeorge Syndrome
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
Hereditary Non-polyposis Colorectal Cancer (HNPCC)
AKA Lynch Syndrome
Autosomal dominant mutation of DNA mismatch repair genes
80% progress to colorectal cancer, always involving the proximal colon
Gardner Syndrome
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
Turcot syndrome
Variant of FAP; autosomal dominant mutation of APC gene on chromosome 5
Characterized by innumerous colonic polyps + malignant CNS tumor
