Chromosomal/storage disorders Flashcards
Robertsonian translocation
4% of downs
nonreciprocal chromosomal translocation
chromosome pairs
long arms of acrocentric chromosome fuse at centromeres –> loss of short arms
Downs: 14:21 - normal
- -> risk of Down syndrome in offspring
- not associated w/ advanced maternal age
Down syndrome - Trisomy 21
MC trisomy
Intellectual disability, flat facies, prominent epicanthal folds, simian crease, increased gap between 1st and 2nd toes
duodenal atresia
endocardial cushion defects
Increased risk of ALL, AML, and Alzheimers “ALL fall Down”
Polycythemia
Quad screen: low AFP, high b-hCG, low estriol, high inhibin A - put in Alpha order, start with Down arrow and alternate
US: increased nuchal translucency (seen in Turners too)
Maternal nondisjunction of homologous chromosomes during anaphase of meiosis I
Advanced maternal age over 35 (over 45 1:25)
Mosaicism
Edward syndrome - trisomy 18
death before 1 yo
intellectual disability, rocker bottom feet, micrognathia, clenched hands, prominent occiput
Quad: all low, normal inhibin A
can get nuchal tranlucency on US
Patau syndrome
trisomy 13
defective SHH, death before 1 yo
Intellectual disability, rocker bottom feet, microcephaly, cleft lip and palate, holoprosencephaly (single midline eye), polydactyly, congenital heart disease
Pregnancy screening: low b-hCG, low PAPP-A
US: increased nuchal translucency
Cant use triple/quad screen to dx
Double Y males
47 XYY
phenotypically normal Tall severe acne Antisocial behavior normal fertility possible association w/ autism spectrum disorders
Cri-du-chat syndrome
“cry of the cat”
Microcephaly
Moderate to severe intellectual disability syndrome
high pitched crying and mewing
epicanthal folds
cardiac abnormalities
Chr 5p deletion
William syndrome
Elfin facies, intellectual disability
Hypercalcemia d/t hypersensitivity to vit D
valve defects
Good verbal skills, friendliness with strangers
microdeletion of long arm of Chr7
22q11 deletion syndromes
DiGeorge syndrome, velocardiofacial syndrome
Cleft lip, abnormal facies
Thymic aplasia resulting in T cell deficiency
Cardiac defects
Parathyroid hypoplasia –> hypocalcemia
Autosomal dominant polycystic kidney disease
B/L enlargement of kidneys d/t multiple cysts
flank pain, hematuria, HTN, progressive renal failure
Mutation of APKD1 on Chr 16
Assoc w/ berry aneurysms
Achondroplasia
Dwarfism
defect of FGFR3 receptor
Associated with advanced PATERNAL age
AD but 75% sporadic mutation
Familial adenomatous polyposis
colon covered in polyps after puberty
-colectomy or colon CA
APC gene mutation
AD
Gardner Syndrome
AD Osteomas Lipomas Sebaceous cysts Colon polyps Colon cancer
Familial hypercholesterolemia
Type IIA hyperlipidemia
Markedly elevated LDL from defective or absent LDL receptor
Heterozygous LDL > 300
Homozygous LDL > 700 - very severe atherosclerotic disease early in life, tendonous xanthomas, xanthelasmas
-mild MI before 20
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu Syndrome)
Abnl blood vessel formation in skin, mucous membranes, organs
Telangiectasias, recurrent epistaxis, skin discolorations, arteriovenous malformations, chronic GI tract bleeding
Hereditary spherocytosis
Spheroid erythrocytes d/t defect in spectrin or ankyrin - structural framework of RBC
Increased blood viscosity
Hemolytic anemia and jaundice - hemolysis worsens w/ viral infections
Normal or slightly decreased MCV, increased MCHC d/t membrane loss and dehydration
Tx: splenectomy
Dx testing: hemolytic anemia, spherocytes on peripheral smear, osmotic fragility test
Huntington disease
Neurodegenerative disorder –> cognitive decline, psychiatric problems
Decreased GABA and ACh in brain
Cs: Cognitive decline, Caudate atrophy, Chorea, CAG repeats, Chr cuatro (4), age 40, decreased ACh
marfan syndrome
connective tissue disorder d/t fibrillin gene mutation
Pectus excavatum, hyperextensible joints, long extremities, long finger and toes (arachnodactyly)
Cystic medial necrosis of aorta - aortic valve regurgitation, aortic aneurysm, aortic dissection
Mitral valve prolapse - floppy
Subluxation of lenses
Multiple endocrine neoplasias 1
MEN1 gene
PPP - parathyroid adenomas, pituitary adenomas, pancreatic tumors
Multiple endocrine neoplasias 2A and B
RET gene mutation
2A: PPM: parathyroid adenomas, pheochromocytoma, medullary thyroid cancer
2B: PMM: pheochromocytoma, medullary thyroid cancer, mucosal neuromas
Neurofibromatosis type I (von Recklinghausen)
AD
Mutation of gene on Chr 17 - cell divsion gene
Cafe-au-lait spots, neural tumors, Lisch nodules (pigmented iris hamartomas), scoliosis
Neurofibromatosis type II
B/L acoustic neuroma (CNVIII)
hearing loss, tinnitus, balance problems, cataracts, other neural tumors
Chr 22 mutaiton
Tuberous sclerosis
Mutation of hamartin or tuberin gene
Facial lesions - adenoma sebaceum hypopigmented ash-leaf spots cortical and retinal hamartomas seizures intellectual disability cardiac rhabdomyomas astrocytomas
incomplete penetrance
von Hippel-Lindau disease
Hemangioblastomas of retina, cerebellum, medulla
50% b/l renal cell carcinoma
Pheochromocytomas
Deletion of VHL gene –> expression of HIF and activation of angiogenic growth factors
Fragile X syndrome
2 MC genetic cause of intellectual disability, #3 over all
X linked, trimucleotide repeat disorder CGG
Mutation of FMR1 gene (fragile mental regardation)
-codes for FMRP - cytoplasmic protein in brain and testes involved in mRNA translocaiton of axons and dendrites
Intelectual disability, macro-orchidism, long face, large jaw, everted ears, mitral valve prolapse
Friedreich ataxia
AR, trinucleotide repeat GAA
Mutation of frataxin - mitochondrial protein in iron detoxifying and storage
degeneration of sensory neurons, hypertrophic cardiomyopathy, DM
staggering gait, frequent falling, nystagmus, dysarthria, pes cavus, hammer toes
presents in childhood with kyphoscoliosis
Trinucleotide repeat disease
more repeats w/ each generation
genetic anticipation
-increased disease severity and/or decreased age of onset w/ successive generations
Cystic fibrosis
Defect in CFTR on Chr 7
recurrent pulmonary infection (Pseudomonas), bronchiectasis, pancreatic insufficiency, meconium ileus, infertility in males (absence of vas deferens), fat soluble vitamin deficiencies, salty taste
Dx: sweat chloride test >60 mEq/L
Tx: N-acetylcysteine (cleaves disulfide bonds in mucus glycoproteins –> loosening mucus), Abx (fluoroquinolones), pancreatic enzymes, fat soluble vitamines
Fabry disease
X linked recessive
alpha-galactosidase –> accumulation of ceramide trihexoside
Pain - damage to peripheral nerves (neuropathy)
renal failure
HTN
cardiomyopathy
angiokeratomas - painless papules - lower abd, back, groin
Early childhood
Lipid accumulation in GI tract vessels –> ischemia and pain
“My Fabrite activity is Ceramics, we made a GalaXy”
Gaucher disease
AR
MC lysosomal storage disease
deficient glucocerebrosidase –> accumulation of glucocerebroside - lipid like in macrophages of spleen, liver, kidney, bone marrow, brain
HSM, painful bony lesions, anemia, fatigue, thrombocytopenia (d/t enlarged spleen)
Prominent blue cytoplasmic fibrils - crumpled tissue paper - macrophages
“Oh my Gauch, he’s such a Bro” in crying voice
Niemann-Pick disease
AR
Deficient sphingomyelinase –> accumulation of sphingomyelin - lipid like
HSM, thrombocytopenia
ataxia, dysarthria, dysphagia
Gradual worsening of intellectual function
Cherry red spot on macula and foam cells
Ashkenazi Jews
“Pick you big nose w/ your splinger”
Tay-Sachs disease
AR
Deficient hexosaminidase A –> accumulation of GM2 ganglioside
Worsening mental and physical abilities
death by 4
cherry red spot on macula
Infantile type sx begin at 6 mo
no HSM!
Ashkenazi Jews
“A Gang of 6 (hexo) small Jews”
Krabbe disease
AR
deficient galactocerebrosidase –> accumulation of galactocerebroside
Affects myelin sheath --> peripheral neuropathy seizures optic atrophy weakness developmental delay
Globoid cell “glob of krab meat”
Sx at 3-6 months
Death by 2 yr
“Galactic krab”
Metachromatic leukodystrophy
AR
Deficient Arylsulfatase –> accumulation cerebroside sulfate
Affects myelin sheath, muscle wasting, weakness, progressive vision loss, dementia
Sx after 1 yr
Hurler syndrome
Gargoylism
AR
Deficient alpha-L-iduronidase –> accumulation of heparan sulfate and dermatan sulfate
Normal at birth
–> progressive deterioration, coarse facial features, HSM, intellectual disability, poor growth (resembles dwarfism), corneal clouding –> vision loss
Hurler-Scheie and Scheie lesser forms, later onset
Hunter syndrome
X linked recessive “X marks the spot for Hunters”
Deficient iduronate sulfatase –> accumulation of heparan sulfate and dermatan sulfate
Milder form of Hurlers
later onset of 1-2 years
no corneal clouding “need vision to hunt”
Aggressive behavior
X linked recessive disorders
“Oblivious Female Will Give Her Boys Her (x)Linked Disorders”
Ocular albinism Fabry disease Wiskott-Aldrich G6PD deficiency Hunter syndrome Bruton agammaglobulinemia Hemophilia A/B Lesch-Nyhan Syndrome Duchene muscular dystrophy
