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95 Cards in this Set
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marfan syndrome: what are the common features? |
cardio: aortic root dilation, dissection of ascending aorta, mitral valve prolapse, dilation of pulm artery or descending aorta skeletal: tall stature, long arms and legs compared to trunks, long thin digits, flat feet other features: dural ectasia, hernia, stetch marks, spontaneous pneumothorax, high arched palate, dental crowding |
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marfan syndrome: inheritance pattern |
AD with 25% new mutations |
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marfan syndrome: mutations what protein is involved? |
allelic heterogeneity, various mutations within the FBN1 gene on chromosome 15q21
protein fibrillin |
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marfan syndrome: lab tests |
diagnosis based on FH and clinical features with highest weight given to arotic root dilation and to ectopia lentis (lens displacement)
genetic testing by mutation scanning and sequence analysis
FBN1 mutation itself does not confer dx of marfans |
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how do you manage marfans? |
life time follow up for cardiac issues obtain ECHO-- assess for surgical or medical management (beta blockers) monitor skeletal abnormalities annual optho exams |
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what do you counsel marfans patients to do? |
avoid contact sports, strenuous exercise pregnant women with marfan need high risk OB and cardiac management bc of aortic dissection/rupture |
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turner syndrome: clinical features |
prenatally: 45, X karyotype associated with cystic hygroma, severe lymphedema, hydrops fetalis with high risk of fetal demise
newborn: lymphedema, webbed neck, congenital heart defects most commonly coarctation of the aorta, usually normal linear growth until 2-3
childhood: short stature, low posterior hairline, cubitus valgus, short 4th metacarpals, disproportionately short legs, broad chest, prominant ears, pigmented neci, scoliosis micrognathia
adolescence: short stature and delayed puberty, delayed eiphyseal fusion adults: intertility/anovulation
other features: inc risk for chronic otitis, hearing loss, hip dysplasia, strabismus, scoliosis, liver deisease, HTN, osteoporosis, diabetes, dyslipidemia
incresaed risk for aorticaortic dilation learning disabilities, but not intellectual disability vast majority are infertile, most will not develop secondary sexual characteristics without hormone replacement
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inheritance pattern of turners syndrome |
chromosomal incidence is 1 in 2500 femal live births, 1-2% of all conceptions |
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mutations of turner syndrome |
half have 45, X karyotype (cusaed by paternal meiotic non disjunction) also structural abnormalities |
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what lab tests do you do for turners syndrome? |
karyotyping- peripheral blood if karyotyping reveals non-mosaic 45, X karyotype, FISH for X/Y should be completed to rule out sex chromsome mosaicism
prenatal dx using CVS or amniocentesis |
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management issues with turners syndrome |
medical: peds card evalutaion with ECHO and EKG, renal ultrasound, audiology, thryoid function test, celiac disease monitoring ,formal optho exam, evaluate for scoliosis
increased risk for gonadoblastoma if karyotype includes a Y chromsome cell line |
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counseling issues for turners syndrome |
review recurrence of less htan 1% for future pregnancy most girls with turner syndrome are infertile can use GH and sex hormone replacement |
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down syndrome: clinical features |
dysmorphic features include upslanting palpebral fissues, epicanthal folds, flat nasal bridege, small, dysplastic ears, large tongue/small mouth, excess nuchal skin, short fingers, fifth finger clinodactylly, wide space between first and 2nd toes, single transverse palmar crease microcephalybrachycephaly intellectual disability with most individuals with a mild to moderate disability hypotonia, short stature congenital heart defects (commonly endocardial cushion defects, ASD, VSD) hearing problems vision problems (cataracts, refractive errors, nystagmus, strabismus) obstructive sleep apena GI atresias, hypothyroidism, seizures, hematologic problems, celiac disease |
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down syndrome: incidence inheritance pattern mutation |
incidence: 1/800 inheritance: chromosomal mutations: 95% have trisomy 21 caused by maternal meiotic nondisjunction 3-4% 14, 21 translocation is most common |
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lab tests for DS |
karyotyping peripheral blood karyotype detects almost all cases prenatal dx available using CVS or amniocentesis
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management issues for DS |
medical: echo w/ cardio referral thyroid screening hearing screeing vision cervical spine x rays
counsel about recurrence risk |
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What deletion is involved in DiGeorge syndrome? |
variable expressivisity
common features: facial features: prominent nose with squared nasal root, small eyes, small ears cognitive-- intellectual disability, mean palatal abnormalities: velopharyngeal incompetence, submucosal cleft palate hypoparathyroidism: hypocalcemia, may lead to seizures congenital heart disease-- tetralogy of fallot, interrupted aortic arch, truncus arteriosus immune defiency: imparied T cell production resulting from thymic hypoplasia, recurrent infection, autoimmune disease can also have ADHD, autism, anxiety, depression, schizophrenia endocrine abnormalities-- hypo/er thyroidism, GH, vsion concerns, hearing loss, vertebral, GU tract |
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incidence of digeroge inheritance pattern mutations |
1/4000 chromosomal (michrodeletion)-- 10% inherited from parent mutations: 85% have 3 MB deletion, 15% have nested deletion within 22q11.2 |
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lab testing for digeorge |
FISH for 22q11.2 deletion or microarray (if phenotype is non specific) prenatal dx using cells obtained by CVS or amnio |
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management issues for digeorge |
at dx: serum ionized Ca conc PTH, TSH, CBC w/ dif, immune eval otpho, audiology, renal ultrasound, cardiac exam, chest x ray for thoracid vertebral anomalies, cervical spine films, evaluate palate |
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fragile x: clinical features |
phenotype is variable, becomes more pronounced with age physical features (more evident in late childhood/early adolescence): prominent forehead, long thin face with prominent jaw, large protuberant ears, post pubertal macroochidsm cog: mild to severe dvlp delay, males more severly affected behavior: hyperactivity, lack of eye contact, repetitive behaviors, perserverative speech, autism, social shyness increased risk for: seizures, ocular problems, recurrent otitis media, orthopedic problems, mitral valve prolapse |
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incidence of fragile x inheritance pattern mutation |
1/4000 for males and 1/8000 for females inheritance: x linked with ancipation due to CGG trinucleotide repeat expansion
mutation: expansion of CGG trinucleotide repeat in first exon of FMR1 gene on Xq27
repeat sizes: normal-- 5-44 intermediate: 45-54 premutation:55-200 full mutation: >200, highly methylated premutations ONLY expand when inherited from a carrier female daughts of males with a premutation are obligate carriers, but intellectually normal
shows anticipatioN! |
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lab testing for fragile x |
PCR assays specifically designed to detect long CGG repeats methylation specific PCR assays or southern blotting are then used to determine methylation status |
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management issues for fragile x |
medical: optho (strabismus, hyperopia, astigmatism) audiology (recurrent serous otitis) orthopedic (flat feet, scoliosis) neuro (seizures)
20% of premutation carrier females develop premature ovarian failure/insufficiency, with highest risk at repeat size 80-99
40% of premutation males and 8-16% females develop fragile X associated tremor/ataxia syndrome-- cerebellar gait ataxia, intention tremor, parkinsonism, execuitve dysfunction, onset >50 yrs |
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huntingtons: clinical features |
progressive disorder of cognition, motor, and psych disturbance. 2/3 of affected individuals initially present with neuro features (incoordination, involuntary movements) while 1/3 present with psych changes (depression, irritability) motor symptoms include gait disturbance, progressive chorea, dysarthia global decline in cognitive abilities significant personality change mean age of onset is 35-44, survival time after onset is 15018 yrs |
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inheritance pattern of huntingtons |
AD most will have affected parent, new mutations are rare disorder shows anticipation de novo cases of HD are more likely due to intermediate sized or reduced penetrance alleles in parent |
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mutations in huntingtons |
expansion of a CAG triplet repeat within HD gene of chromosome 4p-- more repeats, earlier onset normal: <26 intermediate: 27-35-- no risk to individual, but can expand to offspring reduced penetrance alleles (36-39) adult onset: 40-59 juvenile onset: above 60 expansions more likely to occur through paternal gametogenesis-- juvenile onset HD almost exclusively inherited through fathers |
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lab tests for huntingtons management issues |
lab: PCR detects repeat number
management issues: symp tx (neuroleptics, antipsychotics)
genetic testing of asymptomatic individuals is predictive rather than diagnostic dont usually test asymptomatic children |
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whats the difference between a deletrious mutation and a common polymorphism? |
polymorphism: common alteration in DNA sequence seen in >1% of popultaion (most are benign, but they may account to diff in drug response or disease risk)
mutation: any alteration in DNA sequence (deleterious mutation is associated with disease) |
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which CYP450 variants....
increase affect warfarin by inactivating ability to break down metabolites decrease clopidogrel efficacy by not metabolizing it to its active form decrease tamoxifen activity increase codeine toxicity by rapidly metabolizing it to morphine |
warfarin increased: CYP2C9
clopidogrel decreaesed: CYP2C19
Tamoxifen increased: CYP2D6
codeine increased: CYP2D6 |
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what does warfarin sensitivity genotyping test show? |
CYP2C9*3/*3-- VKORC1 reduced enzyme activity and negative variants in VKORC1 assoc with warfarin sensitivity
CYP2C9 is enzyme responsible for inactivation of warfarin, and CYP2C9*2, *3 are reduced metabolism variant alleles that give you inc sens to warfarin seen in 40% cauc, <10% asians, af am
(VKOR is vitamin K oxidase reductase which is important for replenishing vit K-- warfarin blocks this so that clotting factors are not formed) VKORC1*2 is associated with inc sensitivity to warfarin seen in 40-50% caucasians, 90% asians, 10-15% af am
so they have increased sensitivity to warfarin compared to pt with norml CYP2C9 genotype |
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what is clopidogrel? what enzyme activates it? what alleles have loss of activity? |
platelet inhibitor used in a-fib, coronary artery stents progdrug activated by CYP2C19 CYP2C19*2 and *3 alleles are most common variants with loss of enzymatic activity-- inc death from CV events |
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what is one enzyme that is recommended to genotype? in what population |
genotype HLA-B*5701 for HIV rx to aviod abacavir hypersensitivity |
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phenylketonuria: clinical features |
inborn error of metabolism caused by dec activity of liver enzyme phenylalanine hydroxylase, resulting in inc blood levels of AA phenylalanine
untreatd chlidren with PKU risk intellectual disability, seziures, inc irritability, musty odor, eczema elevated blood levels of phenylalanine in older children/adults with PKU put them at risk for behavioral and learning problems, regardless of good tx incidence 1/15,000- 1/20,000 |
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inheritance pattern of PKU mutations lab tests |
AR with variable expression due to varying levels of enzyme activity, other epigenetic factors
mutations: allelic heterogenetiy, with over 500 mutations in the phenylalamine hydroxylase gene on chromosome 12q23 identified
lab tests: screening labs measure phenylalanine levels from samples in newborn nursery elevated phenyl. detected on blood samples obtained at least 24 hrs after birth screen for BH4 deficiency in all neonates dx with PKU |
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management and counseling issues in PKU |
management: newborn screening for PKU, intellectual disability prevented if tx initiated before 4 wks of age with a special individualized diet low in phenylalanine if you have BH4 deficiency, biopterin replacement therapy and NT replacement therapy, dont require low phenyl diet
maternal risks: children born to women with PKU are at inc risk of birth defects and intellectual disability bc of tetragoenic effect of phenylalanine levels should remain between 120 and 360 throughout pregnancy to prevent defects |
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MCAD (medium chain acyl coenzyme A deydrogenase deficiency) clinical features |
inborn error of metabolism caused by significantly dec activity of one of enzymes involved in pathway of mitchondrial FA oxidation, resulting in accumulation of medium chain FA variable presentation (usually occur before age 5) presentation characterized by hypoketotic hypoglycemia, vomiting and lethargy triggered by prolonged fasting or intercurrent illness episodes may be accompanied by hepatomegaly, acute liver disease, seizures without tx of IV glucose, child can progress to coma and death children at risk for acquired aphasia, ADD secondary to brain injury during acute metabolic event which progresses to coma |
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MCAD (medium chain acyl coenzyme A deydrogenase deficiency) inheritance |
AR with variable with variable age of onset due to environmental factors (diet, stress, intercurrent illness) mutation: due to changes in ACADM gene with K304E being the most common mutation gene located on 1p31
lab test: newborn screening measures alcycarnitine species by tandem mass spectrometry from blood samples on filter paper perform on infants at least 24 hours old |
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nagement issues in MCAD counsleing |
detected by newobrn screen prevent symptoms by avoidance of being in catabolic state, management of illnesses which may precipitate fasting, promst hospitilization during acute metabolic decompensation
all affected indiv should carry emergency letter at all times and provide this to ER
test siblings |
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neurofibromatosis type 1 clinical features |
dx by clinical criteria requires at least 2: 6+ cafe au lait spots (>15mm postpubertal or > 5 mm prepubertal) 2+ neurofibromas or 1 plexiform neurofibroma axillary or groin freckling an optic glioma 2+ lisch nodules (benign, raised iris hamartomas seen by slit lamp exam) distinctive bony lesion first degree relative with NF1
progresses with age, some features are age dependent lisch nodules and cutaenous fibromas develop late childhood to adulthood inc risk for learning problems, seizures, hypertension, malignant neoplasms |
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NF1 incidence inheritance mutations lab test
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1/3000 inheritance: AD, variable expression, nearly complete penetrance, 50% are new mutations mutations: allelic heterogeneity, NF1 gene chromsome 17q, protein is neurofibromin
lab test: dx depends on clinical features and family history genetic testing includes protein truncation testing, sequencing, FISH testing, southern blotting detects up to 95% gene sequencing alone detects 89% gene mutations more deleted, earlier onset |
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management issues of NF1 |
complications increase with age progression is cafe au lait spots at birth progressing in number, freckling, lisch nodules before adulthood and neurofibromas later in life intellectual disability presents early, if present
surgical removal of neurofibromas not recommended
discuss genetic risks-- 50% have mild manifestations, 30% have severe complications first degree relatives need examination |
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leigh syndrome and NARP clinical features |
mitochondrial DNA associated leigh and NARP are part of continuum of disorders
leigh: progressive neuro disease with motor and intellectual disability, onset typically between 3-12 months, periods of deterioration followed by plateaus with stabalization early symptoms: poor suck, vomiting, irritability, failure to thrive, loss of head control, loss of motor skills seizures, hypotonia, muscle weakness, movement disorder, ataxia, optho findings, respiratory difficulty 50% die by 3 yrs due to respiratory or cardiac failure
NARP: initial symptoms-- sensory neuropathy, muscle weakness, ataxia, ocular symptoms start with salt and pepper retinopathy which progresses to retinitis pigmentosa migraines, seizures, hearing loss common |
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narp/leigh
inheritance pattern mutation lab test |
interitance: locus heterogeneity, wiht mendelian (AR, x linked) and mitochondrial inheritance
NARP exhibits mitochondrial inheritance-- complicated by heteroplasmy (presence of more than 1 type of mitochondrial DNA) threshold effect
mutations: 50% have mutation in MT-ATP6 gene mutant loads <60% are either asymptomatic or have mild symptoms (most commonly pigmentary retinopathy or migraines) mutant loads 70-90% have NARP and those with >90% have leigh syndrome
lab testing: if suspected, you need info from FH, blood and/or CSF lactate levels, neuroimaging and molecular genetic testing to confirm the diagnosis
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management and counseling for NARP/leigh |
management: symptomatic tx, regular neurolgoicla, optho, cardiology evaluations recommended
counseling: review recurrence risk, testing can be offered to mom and maternal relatives if interested symptoms along family members variable, vaiability related to concept of mitochondrial genetic bottleneck |
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PCR: |
amplify single cell into millions of copies of region of interest rapid and inexpesnive limited-- target can only be several hundred bases-- used for sensitivity |
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multiplex ligation dependent probe amplification positives? |
quantitative method detects larger deletions or insertions affecting multiple exons and whole genes enables testing of all exons of gene in a single rxn |
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DNA sequencing postives |
allows examination of nucleotide sequence up to 500 bases detects single base changes as well as small insertions and deletions |
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limitations of PCR based mutation detection analysis |
large gains and losses will not generally be detected (except MLPA) pcr relies on efficient annealing of oligonucleotides (primers) to target DNA sequence variants within primer can interfere with annealing and thus amplification a deletion that includes region targeted by primer will not be amplified |
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massivley parallel (nextgen) sequencing |
micro/nanotechnologies used to sequence millions of rxns simultaneously results in multiple reads for targeted sequenced regions that are compared to reference genome-- tons of info, need to trust machine not good for detection of genomic structural rearrangements and repeat regions can be used for panels of genes assoc w/ dvlpmnt delay, heraing loss, hereditary cancer, somatic mutations whole exome sequencing or whole genome sequencing |
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inheritance of CF what are 3 main reasons to do molecular testing for CF? |
carrier status determination prenatal testing (method that will detect familial mutations) diagnostic testing (using a tiered approach-- panel of common mutations, sequence the coding regions, look for large duplications/deletions
oligonucleotide ligation assay measures 32 CF mutations for single multiplex rxn |
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locus heterogeneity |
this refers to the presence of a number of differetn mutant alleles at a single locus (ex: >1000 CFTR mutations have been identified) if testing targets specific known mutations, others may be missed |
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locus heterogeneity |
locus is site of gene of chromosome heterogeneity occurs when identical clinical symptoms are caused by defects at two or more genetic loci
ex: polcystic kidney disease can be caused by mutations in either PKD 1 or 2
so when testing a proband, a negative result may not rule out carrier or affected status |
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what disorders have CAG repeats?
CTG repeats?
CGG repeats? |
spinocerebellar ataxia huntington disease
CTG: myotonic dystrophy type 1
CGG repeats: fragile X syndrome (FRAXA)
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myotonic dystrophy 1 |
AD, you have progressive muscle weakness, cardiac conduction abnormalities, cataracts, frontal balding, elevated risk of diabetes, testicular atrophy normal is 5-39 CTG repeats premutation: 39-50 mild: 50-100 100-1000- classic >2000- congenital
shows genetic anticipation but size of repeat does not predict severity of disease |
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congential DM (dystrophic myopathy?)
whom is usually inherited from? |
hypotonia, intellectual disability, poor feeding, respiratory distress, bilateral facial weakness, myotonia develops at 5-10 yrs, nearly always inherited from MOTHERS
extra CUG repeat expansions in 3 prime untranslated region of DMPK takes up RNA splicing factors so you have decreased RNA stability, altered protein conformation, differential RNA distribution --> RNA toxicity model |
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where is fragile X mutation? what numbers correlate to mutation? is expansion from maternal or paternal?
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on FMR1 gene 6-45 is normal 45-55 is gray zone 55-200 is premutation >200 is affected expansion from mom |
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what is the significance of C in CG dinucleotide? |
C in CG dinucleotides are susceptible to methylation high level of methylation in a promoter can lead to transcriptional inactivation of a gene
FMR1 is hypermethylated when tract is >200 CGGs, leads to loss of expression of gene |
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what does genetic anticipation refer to with fragile X? |
it refers to the increased probability that individuals in successive generations will be affected, but not increased severity (like in huntingtons)
females who are premutation carriers have a 20% risk of primary ovarian sufficiency
males have high risk of late onset ataxia/tremor syndrome (FXTAS): intention tremor, ataxia, cognitive decline, eventual brain atrophy |
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where do repeats tend to be in huntingtons and spinocerebellar ataxia? |
CAG repeats usually in coding region of genes, resulting in tracts of poly-glutamine in protein products lengths of repeat tracts leading to these disorders are generally much shorter than pathogenic repeat in noncoding regions lengths of these repeat tracts leading to disorders are much shorter htan pathogenic repeats in noncoding regions (adult onset is 40-59 repeats)
aggregates of poly-glutamine tracts are formed in nuclei of neurons and are toxic to the cells |
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what are 2 ways to get PKU?
how do you screen for PKU? |
deficiency of enzyme phenylalanine hydroxylase or deficiency in cofactor, tetrahydrobiopterin
untreated PKU have mental retardation, autistic like behavior, hyperactivity, eczema, seizures
screened by tandem mass spectroscopy |
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how do you screen for hypothyroidism? |
screen by FIA for T4 and TSH (fluroimmune assay) confirmation requires serum T4 and TSH measurements |
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screening for sickle cell |
isoelectric focusing other hemoglobinopathies can be detected by screening method
sickle cell is due to abnromal synthesis of beta chains in hemoglobin, affected indiv have hemolytic anemia, vaso occlusive crises, functional asplenia, splenic sequestration can be lethal in infancy due to sepsis/splenic sequestration |
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galactosemia |
due to deficiency of galactose-1-phosphate uridyltransferase (GALT) enzyme
presents in first two weeks of life with juandice, lethargy, cataracts, hepatomegaly, rapidly proceeds to death if untreated
AR inheritance fluorometric assay for total galactose confirmation with GALT activity and galactose-1-phosphate testing |
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congenital adrenal hyperplasia |
family of disorders due to defects in biosynthesis of adrenal corticosteroids, 21 hydroxylase deficiency is most common type, produces ambiguous genitalia in girls fluoroimmune assay for 17-hydroxyprogesterone confirmation requires serum 17-hydroxy measurements |
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which disorders are detected by tandem mass spectometry? |
---- |
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tx of PKU
what about for moms? |
substrate reduction--on a metabolite level
dietary restriction of phenylalanine good outcome if treatment (PHE<600 micomoles/L) and compliance are adequate dietary restriciton recommended for life successful tx requires dietary intervnetion prior to 3 wks of age compliance is an issue
for moms, phenylalanine levels need to be 120-360 |
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tx for galactosemia
signs? what happens even if treated since birth? |
presents iwth jaundice, lethargy, cataracts, hepatomegaly, failure to thrive, E coli sepsis-- death if untreated any infant suspected of it should be put on galactose- free diet (soy formula) life long restriction of galactose and lactose
short stature, ovarian failure, visual-perceptual, speech, and other learning disabilites are common in patients treated from birth, in spite of dietary compliance |
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how do you tx urea cycle disorders?
signs of hyperammonemia |
specific enzyme deficiency involved in ammonia detoxification wide range of clinical severity
progressive increase in ammonia results in abnormal brain function and cerebral edema (damage/death)
signs of hyperammonemia: dec mental awareness, vomiting, combativeness, slurred speech, unstable gait, unconciousness
tx: dec endogenous protein breakdown by giving non-protein calories, limit dietary protein, removal of plsama ammonia by hemodialysis,
increase waste nitrogen excretion (diversion)-- through arginine, citrulline, sodium benzoate, sodium phenylacetate or phenylbutyrate |
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how do you treat gaucher disease? |
lysosomal storage disorder caused by def of enzyme glucocerebrosidase, result in glycolipids primary in macrophages and in CNS
clinical features: enlarged spleen and liver, anemia, thrombocytopenia, skeletal involvment (osteoporosis, bone infarcts), neuro dz in severe form
giving n-butyldcoxynojirmycin inhibits synthesis of glucosylceramide |
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how do you tx glycogen storage disorder? |
GSD type 1 is characterized by hypoglcyemia 2-3 hrs after eating secondary to inability to release free glucose from liver (results in hepatomegaly, poor growth, lactic acidosis, hyperlipidemia, easy bruising, possibly seizures
tx with frequent feedings with glucose or glucose polymers-- raw cornstarch |
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biotinidase deficiency
what does it cause? tx? |
seizures, ataxia, hypotonia, developmental delay, skin rash, alopecia
treated with oral biotin in free, unbound form |
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how does chaperone therapy work? what is it used to treat? |
chaperones aid in normal folding of proteins 30% of normal proteins do not become functionally active bc they misfold and/or aggregate and are degraded by proteasome
increase in enzyme activity from chaperone is small, but is sufficient to improve or normalize metabolic activity
used in tx of homocystinuria and lysosomal storage disorders |
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what is stop-codon-read through therapy? |
premature stop codons are common in pts with metabolic disorders aminoglycoside antibiotics and other chemical compounds allow the ribosome to read through or bypass the premature stop signals in mRNA and continue the translation process to make a full length and functional protein
PTC124 drug now exists-- acts on premature, but not natural stop codons works in pts with cystic fibrosis and muscular dysrtophy |
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where does recombinant enzymre replacement therapy work? |
lysosomal storage disorders enzymatic correction possible at hte cellular level in LSD fibroblasts (release correction factors) efficient mannose 6 phosphate receptor mediated enzyme uptake occurs in fibroblasts
also used in gaucher disease (glucocerebrosidase and cerezyme) also for mucopolysacrrhardisses (MPS)-- due to breakdown of glycosaminoglycans (GAG) recombinant enzyme helps the somatic skeletal disease but not the CNS symptoms-- prevention more important than tx
official list: gaucher disease, fabry disease, MPS, pompe, niemann pick |
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what hepatic based metabolic disorders are sutiable for liver transplantation? |
alpha 1 antitrypsin wilsons urea cycle disorders organoacidopathies CF |
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what are hematopoietic stem cell transplantation used for? |
tx for LSD and MPS
microglia of CNS are of bone marrow origin, source of enzyme in brain after HSCT-- can reduce neuro progression recommended for MPS 1 under 2 yrs of age not recommneded with MPS 2 or 3
has CNS benefit for MLD and krabbes |
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when are most structural birth defects determined? what is most important stage of life? |
during first 2 months after conceptions (weeks 3-8) gastrulation |
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what is a malformation?
examples? |
non-progressive, congential morphologic anomaly of single organ or body part due to an alteration of primary developmental program
intrinsically abnormal developmental process inborn error of morphogenesis
ex: cardiovascular: VSD, conotruncal defects cleft lip/cleft palate neural tube defects (anencephaly, meningomyelocele, encephalocele) craniosyntoses (premature closure of one of the cranial sutures) |
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deformation
when does it most likely occur? |
altered position or shape of body part due to an aberrant mechanical force that distorts and otherwise normal structure (caused by mechanical forces) ex: bowed legs, tibial torsion, clubfoot (talipes deformities), dislocated hip, craniofacial asymmetry, positional plagiocephaly (abn shape head)
frequently a third trimester phenomenon associated with fetal crowding
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disruption |
non-progessive, congential morphologic anomaly due to breakdown of body structure that had a normal devleopmental potential
extrinsic breakdown or interference with normal developmental process amniotic bands |
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dysplasia
types of dysplasia |
morphologic anomaly arising prenatally or postnatally from dynamic or ongoing ateraltion of cellular consitution, tissue organizaiton, or function within a specific organ or tissue type ex: skeletal dysplasia: abn bone and jiont: osteogenesis imperfecta, achondroplasia-- most are mendelian some teratogens (warfarin/coumadin cause strippled epiphyses)
may have assoc malformations: cleft palate, polydactylyl, craniosynostosis may have assoc deformations: talipes, long bone bowign |
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achondroplasia |
short arms and leg bones but average sized trunk |
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2 collagenopathies |
short trunk high myopia cleft palate
stickler syndrome |
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ectodermal dysplasia |
affects skin, sweat pores, hair, teeeth, nails, hearing most are mendelian (single gene) disorders may have minor anomalies/dysmorphic features (sparse/absent hair, everted lower lip, thin nails) |
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what are minor anomalies?
which traits are AD? what do 3+ traits suggest? |
minimal health consequence but may have modest impact on appearance calvaria shape, ear sieze, eye spacing, scalp hair patterning, palmar creases
AD traits: preauricular tags/pits, polydactyly, clinodactyly (curving of fingers), transverse palmar crease
3+ suggests defect in morphogenesis |
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what is a sequence?
3 specific examples |
single primary defect with secondary or tertiary anomalies
one or more secondary morphologic anomalies konwn or presumed to cascade from a single malformation, deformation, disruption, dysplasia
ex: pts with neural tube defect have clubfoot, hydrocephalus that arise secondary to NTD
potter sequence: renal ageneisis, oligohydramnios, lung hypoplsia, fetal compression wiht deformities (flat face ,talipes)
turner syndrome: upper lymphatic channels fail to develop normally-- dsitends jugular lymphatic sac (fetal edema-- swelling of face and hands, overgrowth of skin, webbed neck, ear anomalies, puffy hands and feet, deep set nails |
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syndrome: |
more than one tissue, organ system, region of body-- associated with minor or major anomalies that are not secondary effects multiple features thought to be pathogenetically related
caused by chromosomal abnromalities, single gene mutations, gestational/prenatal tratogenic effects
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common teratogens |
prenatal alcohol ACE inhibitors (lopril drugs) carbamazepine, cocaine, lithium, tetracyclines, valproate, others)
timing is important-- worse when admin during gastrulation stage-- third week of devleopment (day 17)
at this time, you get FAS facies can also get alcohol related neurodevelopmental disorders and alcohol related birth defects
(short palpebral fissures, long upper lip with deficient philtrum) |
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ARBD |
alcohol related birth defects heart/CV CNS: structural and functional poor linear growth and weight gain kidney, ears, eyes, face |
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what are nonsyndromic malformations |
isolated, only one primary malformation (orofacial clefts, NTDS, CV malformations, renal agenesis, etc)
most do NOT follow mendelian patterns recurence rates are requently in range of 1-5% usually complex-- combinatio nof single gene and multifactorial causation
complex human diseases: birth defects, intellectual disability, ADHD, autism, cancer, asthma
adults: HTN, stroke, diabetes, cancer, asthma, alcoholism, etc |
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what are discontinuous traits? |
medical conditions or abormal triats recognized significant deviations from the norm
signs and symptoms are either PRESENT or ABSENT: short stature, hypertension, microcephaly, intellectual disability can invoke a threshold |
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which neuroimaging is better?
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RI is better than CT for most patients-- higher resolution with no exposure to x rays CT better for craniosynostosis and calcifications |
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williams syndrome |
characteristic behavioral and developmental phenotype very friendly, ADD problems, anxiety, low average deletion 7 q11/23-- elastin gene distinctive facial features supravalvular aortic stenosis, pulm artery stenosis, hypercalcemia
most cases are de novo deletions, but can also involve incidences of inheritance from affected parents with balanced chromosome rearrangement involving WS critical region |
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which syndromes have cleft lips? |
trisomy 13--microcephaly, scalp defects, clefts, micropthalmia, polydactyly, cardiac defects, renal anomalies mean life expectancy 130 days
wolf-hirschhorn syndrome: 4p minus-- heart defects, dymorphic features, heart defects, intellectual disability, cleft lip/palate
22q deletio nsyndrome-- also have conotruncal heart defects, hypocalcemia, immune dysfunction, learning disabilities, psych disorders (digeorge)
van der woude syndrome-- lip ptis, cleft lip, cleft palate--AD with variable expression
native american myopathy-- AR-- cleft palate, club feet, risk of malignant hyperthermia with general anesthesia, due to mutation of STAC3 gene
teratogenic: can be seen in FAS
robin sequence: micrognathia (undersized jaw), glossoptosis (retracted tongue), cleft palate-- all due to undersized jaw)
cleft palate can also be due to disruption (amniotic bands)
prenatal testing can detect cleft lip but not cleft palate |
