Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
61 Cards in this Set
- Front
- Back
|
What is Screening?
|
The identification, among apparently healthy individuals, of those who are sufficiently at risk of a specific disorder to justify a subsequent diagnostic test or procedure,or in certain circumstances, direct preventive action.”
|
|
|
Odds of being affected given a positive result
|
Prevalence/(detection rate/false positive rate)
|
|
|
Types of Screening
|
Prenatal screening
-Maternal serum screening for NTD, DS, trisomy 18 Newborn screening Carrier screening for reproductive counseling -Tay-Sachs Disease -Cystic fibrosis Disease screening -Presymptomatic -Heart disease -Cancer -Pharmacogenetics or drug susceptibility -Infectious diseases |
|
|
OAPR
|
Odds of being affected given a positive result is dependent on prevalence of disorder in population being screened.
|
|
|
Maternal Serum Screening
|
Physician MUST offer screening for:
Neural tube defect Ventral wall defect Down Syndrome Trisomy 18 |
|
|
Neural Tube Defects
|
Failure of closure of neural tube
Among most common human congenital malformations Most conceptions with NTD spontaneously abort Varying etiologies Most occur without prior family history |
|
|
Anencephaly
|
Absence of skull vault & both hemispheres
Cerebellum usually absent Brain stem hypoplastic Always fatal -75% Stillborn -25% Live born, but die within hours or days. May have primitive reflexes |
|
|
Encephalocele
|
Herniation of brain tissue &/or meninges through bony defect in skull
80% closed defects Hydrocephalus in 50% Often associated with other syndromes 5-10% NTD cases |
|
|
Spina Bifida
|
Defective closure of vertebral column
Meningocele involves only meninges Myelomeningocele involves meninges and spinal cord tissue (most common) Closed lesion (20% cases) Open lesion (80% cases) |
|
|
Open Spina Bifida
|
Associated with higher morbidity and mortality
94% survivors moderately or severely disabled Extent of disability depends on open or closed lesion, location of lesion & presence or absence of hydrocephaly |
|
|
Closed Spina Bifida
|
20 % cases of spina bifida
Clinical sequelae variable More often less severely affected -70% walk unassisted -70% have bladder control & no urinary tract infections -60% have no hydrocephaly -70% have normal IQ |
|
|
Spina Bifida Occulta
|
Incomplete ossification of the posterior vertebral laminae
-L5 or S1 most common locations No clinical or genetic consequences Normal variant in kids < 2 years old Occurs in ~ 20% adults |
|
|
Ventral Wall Defects (VWD)
|
aka Abdominal Wall Defects
Omphalocele -1:4000 live births -Intestine protrudes into umbilical cord -Often associated with trisomy 13 or 18 Gastroschisis -1:10,000 live births -Opening to right of umbilical cord |
|
|
Down Syndrome (DS)
|
aka Trisomy 21
Symptoms: short stature, epicanthal folds, flat nasal bridge, transverse palmar crease, variable mental retardation, hypotonia, congenital heart defect in 40% Risk for DS pregnancy increases with increasing maternal age 55% DS births occur in women < 35 years old 23% DS fetuses lost before term |
|
|
Trisomy 18 (TRI18)
|
aka Edwards syndrome
70% miscarry before birth 5-10% survive to 1st birthday -Severe mental retardation -Multiple anomalies, including heart and kidney defects -See NTD and VWD Risk for Tri18 pregnancy increases with increasing maternal age (not as much as DS) |
|
|
Nuchal Translucency (NT)
|
Ultrasound marker of subcutaneous space between the skin and cervical spine
increased in fetuses with DS and other structural fetal anomalies |
|
|
PAPP-A (PA)
|
Pregnancy associated plasma protein A
Glycoprotein produced by trophoblasts and released into maternal circulation Not pregnancy specific Increases with increasing gestational age May function to cleave IGF BP4 |
|
|
alpha-Fetoprotein (AFP)
|
Produced by the fetal liver & yolk sac
Values increase during 2nd trimester (15%/week) Functional role undefined -Albumin analog |
|
|
Human Chorionic Gonadotropin (hCG)
|
Hormone synthesized & secreted by placenta
Levels increase rapidly in early pregnancy & decrease between 10-20 weeks gestation Contains alpha & beta subunits Beta subunit unique to hCG In late 1st & 2nd trimesters, most hCG is intact Results corrected for maternal weight & race |
|
|
Unconjugated Estriol (uE3)
|
Hormone synthesized by fetal adrenal glands, fetal liver & placenta
Appears in maternal circulation by 7-9 weeks gestation Levels increase throughout 2nd trimester Results corrected for maternal weight |
|
|
Dimeric Inhibin A (DIA)
|
Inhibin is a heterodimeric glycoprotein consisting of an B-subunit and either a Ba- or Bb-subunit.
Dimeric inhibin A is the dimer of the a-subunit and the Ba-subunit. Hormone synthesized by the gonads and placenta. |
|
|
Dimeric Inhibin A
|
In early pregnancy, inhibin is secreted from both the corpus luteum and the placenta.
Inhibin A levels are increased with Down syndrome (@ 2 times non-Down Syndrome). Levels do not vary much with GA in 2nd trimester |
|
|
Factors Affecting Maternal Screening Markers
|
Gestational age dating (ultrasound)
Maternal weight # Fetuses Maternal race IDDM |
|
|
Multiples of the Median (MOM)
|
Patient result / Median for patient week of gestation
|
|
|
Multiples of the Median (MOM)
|
Medians determined between 10-13 weeks for 1st trimester and 15-21 weeks for 2nd trimester in each lab
Independent of gestational age Eliminates lab to lab variation |
|
|
Inborn Errors of Metabolism
|
Single gene disorders
1/100 Births 5% of all admissions to pediatric hospitals Congenital anomalies in top 10 causes of death in people < 24 y |
|
|
Inborn Errors of Metabolism
|
Abnormal proteins affecting metabolism of other molecules
-Altered flux through metabolic pathway due to increased substrate or secondary toxic analytes Abnormal proteins with relatively direct biologic effects Most autosomal recessive some x- linked |
|
|
Newborn Screening
|
Identification of a subgroup of neonates who are at increased risk for certain disorders, some of which are inborn errors of metabolism, in order to justify direct preventative action.
Identification of subgroups is independent of a family history for a specific disorder. |
|
|
Newborn Screening
|
Current NBS programs test for PKU, congenital hypothyroidism, sickle cell anemia, & galactosemia
Other disorders variably screened for include MSUD, homocystinuria, biotinidase deficiency, congenital adrenal hyperplasia, cystic fibrosis, tyrosinemia, G6PD deficiency, hearing defects. |
|
|
Carrier Screening
|
Adult populations.
Single gene disorders. |
|
|
Tay-Sachs disease
|
Autosomal recessive with incidence of 1:300,000 births
aka GM2-Gangliosidosis due to hexosaminidase-A deficiency Classic, infantile form is lethal by 5 years Increased prevalence in Ashkenazi Jews, French-Canadians, Louisiana Cajuns at @ 1:3600 births Population screening for carriers since mid-1970s -Started with enzymatic screening -Now also using DNA testing for common mutations |
|
|
Late onset Tay-Sachs disease
|
Adult onset
Progressive loss of functioning of the nervous system Low activity variant due to mutation in hexosaminidase A Compound heterozygotes of 2 different mutations |
|
|
Reasons for testing
|
Family history of Tay-Sachs disease child or adult-onset form of TSD
Carrier testing in healthy adults of appropriate ethnicity (preconceptual or premarital) Prenatal diagnosis |
|
|
Taye Sachs - Hex A 0-40%
|
-- carrier
|
|
|
Taye Sachs Hex A 40-55%
|
-- inconclusive
|
|
|
Taye Sachs Hex A 55 -75%
|
--noncarrier
|
|
|
Cystathionine B-Synthase Deficiency Homocystinuria
|
Clinical diagnosis in childhood
Symptoms: -Ectopia lentis- dislocation of lenses in & down -Malar flush -Osteoporosis -Vascular occlusive disease increased HCYS and methionine |
|
|
Cobalamin Deficiency
|
Congenital
-10 defects affecting absorption/transport (n=3) or cellular utilization/coenzyme production (n=7). Dietary -Vegans -Maturity associated decline in intrisnsic factor levels (pernicous anemia) |
|
|
Vitamin B12 Deficiency
Neurological symptoms: |
Burning pain/loss of sensation in limbs
Weakness Spasticity Paralysis Confusion Disorientation Demenia aka Subacute combined degeneration of the spinal cord |
|
|
Vitamin B12 Deficiency
Hematological symptoms: |
Hypersegmentation of neutrophils
Macrocytosis Anemia Leukopenia Thrombocytopenia Megaloblastic changes in bone marrow |
|
|
How would you screen for B12 deficiency?
|
Measure serum/plasma homocysteine and MMA
Sensitive, functional measurement of B12 deficiency Often elevated before B12 levels decline |
|
|
Galactosemia
|
Autosomal recessive
-Mutations in galactose-1-phosphate uridyltransferase (GALT) -Chromosome 9p13 > 150 mutations characterized Neonatal onset |
|
|
Of the 4 classical disorders screened for by state of CA (PKU, congenital hypothyroidism, hemaglobinopathies, galactosemias) the one that presents at birth
|
galactosemia
|
|
|
Hemoglobinopathies
|
3 overlapping groups:
-Structural defects (> 750 defined) -Thalassemias (>170 B) -Hereditary persistence of fetal hemoglobin Most common single gene disorders in world (5% carriers;370k affecteds/year) Compound heterozygotes common Complex clinical phenotypes |
|
|
Sickle Cell Anemia
|
Autosomal recessive
Hemoglobin beta chain mutation Common in Africans & Mediterraneans Clinical diagnosis after 1 year old Onset: FTT, overwhelming sepsis, splenomegaly, aseptic necrosis of bones |
|
|
Sickle cell anemia
|
ß chain mutation
(ß6: A to T or Glu to Val) Results in polymerization of ß-globin chains & decreased deformability of RBC; shortened RBC survival Homozygotes: hemolytic anemia, painful vasoocclusive episodes, leg ulcers, jaundice, stroke, decreased resistance to infections, delayed growth & sexual maturation Heterozygotes normal |
|
|
Time of Screening
|
Critical
Full term baby: >12 hours & < 6 days Best: as close to discharge as possible Before any RBC transfusions Heel stick Filter paper sample |
|
|
screening for PKU
|
test Phe & Tyr levels
|
|
|
screening for Hypothyroidism
|
test TSH level
|
|
|
screening for Galactosemia
|
test GALT assay
|
|
|
Hemoglobinopathies
|
test HPLC
|
|
|
Early symptoms of
Vomiting Failure to thrive Hepatomegaly E. coli sepsis in galactosemia is due to |
Gal-1-P Toxicity
|
|
|
Musty Odor & Liver Disease in PKU
|
Phenylacetate
|
|
|
Cataracts in Galactosemia due to
|
Galactitol
|
|
|
in PKU, enzyme block at PHENYLALANINE HYDROXYLASE results in decrease of:
|
Tyrosine DOPA Melanin
|
|
|
Late symptoms of UDP Gal Deficiency
|
Neurologic problems
Ovarian dysfunction |
|
|
PKU symptoms can also be seen when there is a absense of this cofactor
|
Biopterin-H4
|
|
|
Human Chorionic Gonadotropin (hCG)
|
Hormone synthesized & secreted by placenta
Levels increase rapidly in early pregnancy & decrease between 10-20 weeks gestation Contains alpha & beta subunits Beta subunit unique to hCG In late 1st & 2nd trimesters, most hCG is intact Results corrected for maternal weight & race |
|
|
Unconjugated Estriol (uE3)
|
Hormone synthesized by fetal adrenal glands, fetal liver & placenta
Appears in maternal circulation by 7-9 weeks gestation Levels increase throughout 2nd trimester Results corrected for maternal weight |
|
|
Congenital Hypothyroidism
|
Usually sporadic
Most infants normal at birth Onset of symptoms after several months of age: large posterior fontanel, prolonged jaundice, macroglossia, hoarse cry, distended abdomen, umbilical hernia, hypotonia. Long term: developmental disabilities, poor growth, goiter, constipation, poor peripheral circulation, bradycardia, myxedema |
|
|
Which Diseases in California?
|
Phenylketonuria (PKU)
Congenital hypothyroidism Galactosemia Hemoglobinopathies Supplemental NBS |
