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Genetic Syndromes

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hasanmd's version from 2018-02-09 05:01

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Prader willi and anglemans Prader willi from deletion of normally active paternal allele, Angelmans from deletion of maternal alleles - Chromosome 15 -
Prader willi characterization MEntal retardations, hyperphagia, obesity, hypogonadism, hypotonia
Angelman’s syndrome characteristicsMental retardation, seizures, ataxia, inappropriate laughter (happy puppet)
AchondroplasiaAutosomal dominant Cell-signaling defect of fibroblast growth factor (FGF) receptor 3, Results in dwarfism; short limbs, but head and trunk arc normal size. Associated with advanced paternal age.
Autosomal dominant polycystic kidney disease (ADPKD)Formerlv known as adult polvcystic kidnev disease. Always bilateral, massive enlargement of kidneys due to multiple large cysts. Patients present with flank pain, hematuria, hypertension, progressive renal failure. 90% of cases are due lo mutation in APKDI (chromosome 16; 16 letters in "polycystic kidney"). Associated w/polycystic liver disease, berry aneurysms, mitral valve prolapse, infantile form is recessive.
Familial adenomatous polyposisAutosomal dominant, colon becomes covered with adenomatous polyps after puberty. Progresses to colon cancer unless resected. Deletion on chromosome 5 (APC genes); 5 letters in polyp
Familial hypercholesterolemia (hyperlipidemia type IIA)Autosomal dominant, elevated LDL due to defective or absent LDL receptor. Heterzygotes (1:500) have choleterol of 300mg/dL, homozygotes (very rare) have 700+mg/dL, severe atherosclerotic disease early in life and tendon xanthomas (achilles) - MI may develop before age 20
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)Autosomal dominant Inherited disorder of blood vessels. Findings: telangiectasia, recurrent epitaxis, skin discoloration, AV malformations
Hereditary spherocytosisAutosomal dominant spheroid RBCs due to spectrin or ankyrin defect → hemolytic anemia, ↑MCHC, splenectomy is curative (for the hemolysis)
Huntingdon’s diseaseAutosomal dominant trinucleotide repeat disorder - Gene 4 location CAG repeats. Findings: depression, progressive dememtia, choreiform movements, caudate atrophy, ↓GABA and ACh in brain. Sx manifest b/w 20 and 50y
Marfan’s syndromeAutosomal dominant fibrillin gene mutation→ connective tissue disorder affecting skeleton, heart and eyes. Tall w/long extremities, pectus excavatum, hyperextensive joints and long, tapering fingers and toes (arachnodactyly), cystic medial necrosis of aorta→aortic incompetence and dissecting aortic aneurysms; floppy mitral valve - subluxation of lenses
Multiple endocrin neoplasiaAutosomal dominant syndromes characterized by familial tumors of endocrine glands - MEN2A and B associated with ret gene
Neurfibromatosis 1 (von Recklinghausen’s disease)Autosomal dominant, cafe-au-lait spots, neural tumors, Lisch nodules (pigmented iris harmartomas) Also marked by skeletal disorders (scoliosis), optic pathway gliomas, pheochomocytoma and ↑ tumor susceptibility. On long arm of chromosome 17; (17 letters in von Recklinghausen)
Neurofibromatosis 2Autosomal dominant: bilateral acoustic neuroma, juvenile cataracts, NF2 gene on chromosome 22 (type 2=22)
Tuberous sclerosisAutosomal dominant - facial lesions (adenoma sebaceum), hypopigmented “ash of leaf spots” on skin, cortical and retinal hamartomas, seizures, mental retardation, renal cysts and renal angiomylipomas, cardiac rhabdomyomas, ↑ incidence of astrocytoma, incomplete penetrance, variable presentation
Von Hippel-lindau diseaseAutosomal dominant - hemangioblastomas of retina/cerebellum/medulla; about half of affected individuals develop multiple bilateral renal cell carcinomas and other tumors. Associated with deletion of VHL gene (tumor suppressor) on chromosome 3 (3p)→ constitutive expression of HIF transcription factor and activation of angiogenic GFs - Von Hippel Lindau = 3 words = chromosome 3
Cystic FibrosisAutosomal recessive, defect in CFTR gene (chromosome 7) = Cl- channel → secretion of abnormally thick mucus that plugs lungs, pancreas and liver→recurrent pulm infections (pseudomonas and s.aureus), chronic bronchitis, bronchiectasis, pancreatic insufficiency (malabsorption and steatorrhea), meconium ileus in newborns. Infertility in males, Fat soluble vitamin deficiencies, Sweat test diagnosis,
Cystic fibrosis treatmentN-acetylcysteine to loosen mucous plugs (cleaves disulfide bonds in glycoproteins)
Duchenne’s MDX-linked frame-shift mutation → deletion of dystrophin gene → accelerated muscle breakdown. Weakness begins in pelvic girdle muscles and progresses superiorly. Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle; cardiac myopathy. Use of Gowers' maneuver, requiring assistance of the upper extremities to stand up, is characteristic. Onset before 5 years of age.
Dystrophin genelongest known human gene → ↑ rate of spontaneous mutation. Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle.
Becker’s MDX-linked mutated dystrophin gene. Less severe than Duchenne's. Onset in adolescence or early adulthood.
Diagnosis of muscular dystrophies↑ CPK and muscle biopsy
Fragile X syndromeX-linked defect affecting the methylation and expression of the FMRl gene. Associated with chromosomal breakage. The 2nd most common cause of genetic mental retardation (after Dowm syndrome). Findings: macro-orchidism (enlarged testes), long face with a large jaw, large everted ears, autism, mitral valve prolapse. Trinucleotide repeat disorder (CGG) - Fragile x=extra-large testes, jam, ears
Downs syndrome pregnancy quad screen↓alpha protein, ↑B-hCG, ↓estriol, ↑ inhibin A
Downs syndrome ultrasoundshows ↑ nuchal translucency
Edward’s syndrome(trisomy 18) 1:8000, Findings: severe mental retardation, rocker-bottom feet, micrognathia (small jaw), low-set ears, clenched h ands, prominent occiput, congenital heart disease. Death usually occurs within 1 year of birth .
Patau’s syndrome (trisomy 13), 1:15k, Findings: severe mental retardation, rocker-bottom feet, microphthalmia, microcephaly, cleft lip/Palate, holoProsencephaly, Polydactyly, congenital hea rt disease. Death usually occurs within 1 year of birth.
Cri-du-chat syndromeCongeniltal microdeletion of short arm of chromosome 5 (46XX or XY 5p-). Findings: microcephaly, moderate to severe mental retardation, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities.
Williams syndromeCongenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene) Findings: distinctive “elfin” facies, mental retardation, hypercalcemia, ↑ sensitivity to vitamin D), well developed verbal skills, extreme friendliness with strangers, cardiovascular problems
22q11 deletion syndromesVariable presentation - CATCH-22 - Cleft palate, Abnormal facies, Thymic aplasia→T-cell deficiency, Cardiac defects, Hypocalcemia secondary to parathyroid aplasia (due to abberant development of 3rd and 4th branchial pouches)
DiGeorge syndrome22q11 deletion - thymic, parathyroid and cardiac defects
Velocardiofacial syndrome22q11 deletion - palate, facial and cardiac defect
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Congenital Adrenal Hyperplasia (Adrenal Insufficiency)

Question Answer
What causes CAHdeficiency in one of the five enzymes involved in cortisol production
End result of CAHexcess androgens + cortisol deficiency +/- aldosterone deficiency
How do most newborns with CAH presentsalt-losing, virilizing variant with urinary salt wasting with hyperK and hypoNa
Adrenal gland normally converts progesterone into whatcortisol, aldosterone and androgens
Physical exam clues to CAHhyperpigmentation of genitals/nipples; females: fusion of labia, cliteromegaly; males: small phallus, hypospadius
Classic electrolyte abN of CAHhypoNa, hyperK (often with metabolic acidosis)
Rx of hyperkalemia in infants10% calcium gluconate 1cc/kg plus sodium bicarb 1mEq/kg
When should a hyperkalemic infant be treatedwith ECG changes, otherwise just reverse underlying cause (tolerate hyperkalemia much better)
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Section

Question Answer
What is the gene and inheritance of Cystic fibrosis?AR. defect in CFTR gene on Chr 7, del F508, secretes CL- in lungs and resorbs it from sweat
What is the pathophys of Cystic fibrosis?defective Cl- channel causes secretion of thick mucus that plugs, lungs, pancreas and liver
What signs are seen in Cystic Fibrosis?recurrent pulmonary infectrio, chronic bronchits, bronchiectasis, pancreatic insufficiency, nasal polyps, meconium ileus in newborns
What are some Sx of Cystic fibrosis?infertility in males, fat soluble vitamin deficiency ( A,D,E,K)
How is Cystic fibrosis diagnosed?increased concentration of Cl- ions in sweat test
How is cystic fibrosis treated?n-acetylcysteine to loosen mucous plugs
What is the pneumonic for X linked recessive disease?Be Wise, fool's GOLD Heeds Silly Hope. Brutons agammaglobulinemia, Wiskott-Aldrich, Fabry's. G6PD deficiency, Ocular albinism, Lesch0Nyhan Syndrome Duchennes, Hunters, Hemophilia A and B
How often are female carriers of an X linked recessive disorder affect?rarely, due to X chromosome deactivation
What is the pathophyisology of Duchenne MD?X linked frameshift mutation, deletion of dystrophin gene---> muscle breakdown
What is the role of dystrophin?helps anchor muscle fibers, largest human gene so larger chance of spontaneous mutation
What are the sn and Sx of Duchenne MD?weakness in pelivic girlde, calf hypertrophy, cardiomyopathy.
How is the dx of Duchenne MD made?increased CPK, biopsy. Gowers maneuver is characteristic with onset before age 5
What is Becker's MD?x linked mutated dystrophine gene, less sever than ducheens, onset is in adolescence or early adulthood
What is the pathophys of Fragile X syndrome?X linked defect affecting methylation and expression of FMR1 gene. Trinucelotide repeat (CGG)
What are the findings in fragile X syndrome?macroorchidism, long face large jaw, large ears, autism, mitral valve prolapse. Fragile X= EXTRA large testes, jaw, ears
what are 4 major trinucelotide repeat disorders?Huntiningtons, myontonic dystrophy, Friedreich's ataxia, fragile X (Try hunting for my Fried Egg)
What is the mnemonic for trinucleotide repeats disorders?X-Girlfriends First Aid Helped Ace My Test (Fragile X = CGG), Freidrich's ataxia = GAA, Huntingotns (CAG) Myontonic (CTG)
What is the pathophys of Down Syndrome?trisomy 21, most common cause of congential retardation
What are the findings of Down's syndrome?reatradation, flat facies, prominent epicanthal fold, simian crease, duodenal atresia, congential heart disease.
What are 2 diseases associated with Down Syndrome?increased risk of ALL, Alzheimer's
What causes Down Syndrome?95% meiotic nondisjunction (assoc with advanced maternal age), 4% robertsonian
How is the dx of Down syndrome made in utero?decreased alpha fetoprotein, increased Beta hCG, decreased estriol, increased inhibin A. Nuchal translucency on US
What is the pathophys of Edwards' Syndrome?Trisomy 18, death w/in 1 yr
What are the findings in Edwards' Syndrome?severe retardation, micrognathia, low set ears, clenched hands
How is the Dx of edwards' syndrome made in utero?decreased alpha fetoprotein, decreased Beta hCG, decreased estriol, normal inhibin A
What is the Pathophys of Patau's syndrome?trisomy 13, death w/in 1 year
What are the findings in Patau's syndrome?cleft liP/Palate, holoprocencephaly, polydactyly, CHD
How is the Dx of Patau's syndrome made in utero?normal estriol, normal inhibin A, normal Beta hCG, normal alpha fetoprotein
What is a robertsonian translocation?long arms of 2 acrocentric chromosomes fuse at centromere and short arms are lost. no phenotype isf balanced. unbalanced can be fatal
What is the pathophys of cri-du-chat syndrome?congential microdeletion of short arnm of Chr 5.
What are the findings of cri-du-chat syndrome?microencephaly, moderate to severe retardation, high pitched crying/mewing, epicanthal folds
What is the pathophys of Williams Syndrome?congential microdeletion of long arm of Chr 7 (elastin gene)
What are the findings in williams Syndrome?elfin facies. retardation, hypercalcemia (increased sensitivity to vit D), well developed verbal skills, friendliness with strangers
What is the findins of 22q11 deletion syndromes?variable. include Cleft palate, Abnormal facies, Thymic aplasia---> t cell deficinec ,catdiac defect, hypocalcemia CATCH-22
What are the Sx of Di George Syndrome?thymic, parathyroid, cardiac defects 22q11 deletion
What are the Sx of velocardiofacial Syndromes?palate, facial, cardiac defects
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Psych drug effects

Question Answer
haloperidoltypical antipsycotic
-azinestypical antipsycotics
high potency neurolepticshaloperidol, trifluoperazine, fluphenazine
low potency neurolepticsthiordiazine, chlorpromazine
SE of high potency neurolepticsEPS
SE of low potency neurolepticsanti-muscarinic
clozapineatypical
risiperdoneatypical
olanzapineatypical
quetiapineatypical
atypical antipsycoticsclozapine, risiperdone, olanzapine, quetiapine
typical antispsycoticshaloperidol, trifluoperazine, fluphenazine, thioridazine, chlopromazine
thioridazine SEretinal deposits
chlorpromazine SEcorenal deposits
halperidol SEEPS Sx
ziprasidone SEprolonged QT
olanzapine SEweight gain
clozapine SEagranulocytosis and seizures, weight gain
carbamazepine SEagranulocytosis
valproic acid SELiver
lamotrigine SESJ syndrome
phenobarbitol SEacute intermittent porpyria
phenytoin SEgingival hyperplasia, lymphadenopathy, hirsuitism and acne
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