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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
-Heart disease
-Pharmacogenetics or drug susceptibility
-Infectious diseases
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
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
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

-1:4000 live births
-Intestine protrudes into umbilical cord
-Often associated with trisomy 13 or 18

-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
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

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%
Cystathionine B-Synthase Deficiency Homocystinuria
Clinical diagnosis in childhood
-Ectopia lentis- dislocation of lenses in & down
-Malar flush
-Vascular occlusive disease
increased HCYS and methionine
Cobalamin Deficiency
-10 defects affecting absorption/transport (n=3) or cellular utilization/coenzyme production (n=7).

-Maturity associated decline in intrisnsic factor levels (pernicous anemia)
Vitamin B12 Deficiency
Neurological symptoms:
Burning pain/loss of sensation in limbs
aka Subacute combined degeneration of the spinal cord
Vitamin B12 Deficiency
Hematological symptoms:
Hypersegmentation of neutrophils
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
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
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

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
test HPLC
Early symptoms of
Failure to thrive
E. coli sepsis
in galactosemia is due to
Gal-1-P Toxicity
Musty Odor & Liver Disease in PKU
Cataracts in Galactosemia due to
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
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
Supplemental NBS