Prenatal Testing And Screening

Prenatal Testing And Screening
By:Adel D. Gilbert, MS, CGC
Genetic Medicine Education Coordinator
Institute of Genetic Medicine
Johns Hopkins University

Genetics Board Review Lecture
Lecture Outline
* Definitions
* Age related risks
* Etiology and phenotype of chromosome anomalies
* Risks, phenotype and testing options of ONTD
* 1st and 2nd Trimester Prenatal Testing Options
* 1st and 2nd Trimester MS Screening Options
* New approaches to combining these tools
* Ultrasound as a screening tool

Testing Defined
Screening Defined
* Identify those at increased risk who are not be perceived to be at risk
* Does not dx definitively
* Follow-up options available for definitive information
* Sensitivity=True positives/all affected
* Specificity=True negatives/all unaffected
Baseline Risk for Having a Child With a Serious Birth Defect
Phenotype
* Moderate mental retardation
* Characteristic facies
o upslanting palpebral fissures
o epicanthic folds,
o midface hypoplasia,
o macroglossia
* Congenital malformations
o heart (30-40%), atrioventricular canal
o gastrointestinal tract, such as duodenal stenosis or atresia, imperforate anus, and Hirschsprung disease
o Leukemia (both ALL and AML) 10-20x
o acute megakaryocytic leukemia occurs 200 to 400 times more frequently in the Down syndrome
o 90% have significant hearing loss, usually of the conductive type
Facial
* microcephaly with prominent occiput
* narrow bifrontal diameter
* short palpabral fissures
* low-set malformed ears
* cleft lip +/- palate
* narrow palatal arch
* micrognathia

Skeletal
* neck
* webbed
* chest
* short sternum
* widely spaced nipples
* hips:
* small pelvis, congenital dislocation of the hips, limited hip abduction
* extremities:
* phocomelia
* rockerbottom feet or equinovarus short dorsiflexed big toes fixed flexion deformity of the fingers (overlapping of the 2nd and 5th fingers over the 3rd and 4th fingers)simple arch pattern of the fingers and toes

hypoplasia of fingernails single crease of 5th finger or all fingers (absence of interphalangeal flexion creases)
Trisomy 18
Kleinfelter syndrome
Miscarriage
Turner syndrome
Neural Tube Defects
* Second most common major congenital defect (1-2/1000)
* Not a chromosome anomaly
* Routinely tested and screened for in pregnancy
* Failure neural tube to close at 28 days gestation
* 20% are closed lesions and difficult to detect prenatally

Open Neural Tube Defects
Closed lesions
Open lesions
INDICATIONS FOR PRENATAL DIAGNOSIS
PRENATAL DIAGNOSTIC PROCEDURES
* AMNIOCENTESIS
* CHORIONIC VILLUS SAMPLING
* PERCUTANEOUS UMBILICAL CORD SAMPLING

AMNIOCENTESIS
ULTRASOUND GUIDED
AMNIOCENTESIS
Amniocentesis Testing
* Chromosome analysis
* AF-AFP levels
* Acetylcholinesterase
* Risk of miscarriage associated with procedure 1/100-1/400
Advantages
* Highly reliable results 99+%
* Familiar
* Long standing reputation
* NTD detection
Disadvantages
* Late in gestation
o Decision making
o Privacy
o Mom feels movement
* Fear of needles
* Needle invades the sac

Fetus: 12 weeks gestation
Transcervical
Chorionic Villus Sampling
Transabdominal
Performed >10 wks-13 weeks
Chromosome analysis
Risk 1/100-1/200
* trophoblastic shell cells
* Syncitiotrophoblasts – poly-proliferate tissue type=directs
* cytotrophoblasts
* Mesodermal core=tissue culture
* frorm finger-like extensions

Disadvantages
* Placental mosaicism 1% of CVS is confirmed in the fetus ~ 10-40%
* Second trimester amniocentesis mosaicism ~ 0.1-0.3% & confirmed in a fetus up to 70% of the time.
* ?LRD risk prior to 70 days gestation (10 weeks)
* Higher loss rate
* Less access to procedure
* Higher chance of insufficient sample
* Early test=risk of sampling a fetus potentially destined to miscarry
* No ONTD testing
* More risk of vaginal bleeding
* Speculum

Benefits
* Earlier in gestation
* rapidly growing cell cultures practically free of maternal cell contamination
* an efficient direct method to obtain high quality metaphases from the of the syncitiotrophoblasts tissue which the fetal karyotype is defined within a few hours of chorionic villi sampling (specialty cyto techinque)
* is suitable for a rapid, direct diagnosis of the related metabolic diseases.
* placental mosaicism (trisomic rescue in fetus) can increase the risks of genetic abnormalities such as uniparental disomy

Fetal Blood Sampling
Percutaneous Umbilical Cord Sampling
(PUBS) or Cordocentesis
* ~2% risk of loss
* Technically difficult prior to 20 weeks
* Blood disorders such as hemophilia and anemia
o Useful for detection of Rh isoimmunization of the fetus (blood cell count and oxygen level)→erythroblastosis fetalis (HDN)
* Chromosomal abnormalities Fetal karyotype in 48 hours
* Infections such as toxoplasmosis and rubella.
* The procedure is also used to perform blood transfusions to the fetus and to administer medication directly into the fetal blood supply.

Reproductive Decision Making
RISK Fetal Aneuploidy
Procedure Related RISK
TO TEST OR NOT TO TEST
* I want to know
* The benefits outweigh the risks
* Options are desirable
* Because my doctor says so…..
* Not sure I want to know
* Risks are a big worry
* Options stink
* Because my doctor says so….

SECOND TRIMESTER
MATERNAL ANALYTES FOR ANEUPLOID
SCREENING
FETAL
Alpha-fetoprotein- AFP
Estriol- uE3
PLACENTAL
Estriol- uE3
Human chorionic gonadotrophin- hCG
Inhibin-A

2nd Trimester MSS Overview
Used for detection of:
+ ONTD
+ Down syndrome
+ trisomy 18
+ Smith-Lemli-Opitz syndrome
Serum Marker
Smith Lemli Opitz Syndrome
* Defect enzyme in the conversion of 7-dehydrocholesterol to cholesterol.
* Affects 1 in 20,000 to 40,000 births
* Autosomal Recessive
* Mental Retardation
* Slow growth
* Heart defects
* Facial cleft
* Screen positive women have uE3 < 0.4 MoM
* ~2% baby affected
* Testing AF for 7-8- dehydrocholesterol (7/8-DHC) levels

Turner T13 Triploidy Pregnancy complications
ONTD screening
Detection Rates
MSAFP
Add Ultrasound
Screening for DS
2nd Trimester 1/270 Cut-off
First Trimester Integrated Screening For Trisomies =FIRST
Nuchal Translucency (NT)
First Trimester Screening
Down syndrome DR ~1:270 Cut-off
Nasal bone
Recommendations 1st Trimester Nuchal >3.5
* CVS
* Targeted ultrasound evaluation 18-20
* Echocardiogram
* Residual 5-6% risk neonate may have a yet undefined genetic syndrome…
Fetal Nasal Bone
* 65% DS have absent nasal bone
* General population 1%
o African Americans 8%-10%
* Secondary screen
* Difficult to obtain
* Higher false positive in 1st

Integrated Screening
PAPP-A and Nuchal
Quad Screen
Screen Positive
Screen Negative
Timeline weeks
Decision Making
Advantages
* Increases detection rate
* Decreases false positive rate (fewer tests and fewer procedure related losses)
Disadvantages
* Long wait time for result
* Unable to utilize CVS and early detection
* Late GA by the time amnio results final
Contingent

First Trimester Screening
High risk
Low Risk
Intermediate
Triple Screening Integration
Offer CVS
High risk
Low Risk
US and Amnio
Stop
Advantages
* Increase detection rate 90%
* Decrease FPR 2%
* Reduce the number of amnios performed in low risk pregnancies
Disadvantages
* New (limited data)
* Hard to determine uptake
* Offered at few institutions
RISK OF ANEUPLOIDY BASED ON GA AND ANOMALY

3D Ultrasound
Fetal Face
24 weeks Gestation
Fetal MRI
FETOSCOPY
Amnion (stuck twin)
Umbilical cord

Prenatal Testing And Screening.ppt

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Neurobiology of autism

Neurobiology of autism
By:Christopher Gillberg, MD, PhD
Professor of Child and Adolescent Psychiatry
University of Göteborg (Queen Silvia´s Hospital)
University of London (St George´s Hospital Medical School)


Autism spectrum disorders: neurobiology

* Overview
* Acquired brain lesions
* Genetics
* Where in the brain is autism?
* Psychosocial interactions
* Intervention implications
* Outcome implications
* The future

Overview
* At least four clinical presentations of autism (autism/autistic spectrum disorder)
* Autistic disorder (Kanner syndrome)
* Asperger’s disorder (Asperger syndrome)
* Childhood disintegrative disorder (Heller syndrome)
* PDD NOS (atypical autism, other autistic-like condition, other autism spectrum disorder)
* Prevalence much higher than believed in the past: ASD in 1% of population, AD in 0.2%
* Associated with learning disability 15% (80% in autistic disorder/AD)
* Associated with epilepsy 5-10% (35% in AD)
* Medical disorder in 5% (25% in AD)
* Skewed male:female ratio 2-4:1
* High rate of visual, hearing and motor impairments (including at birth)
* Sibling rate raised; identical twin conocordance rate much raised in classic autism

”Acquired” brain lesions
* Tuberous sclerosis, Fragile X syndrome, Partial tetrasomy 15, Down syndrome, XYY, XO, Hypomelanosis of Ito, Rett complex variants, Angelman syndrome, Williams syndrome, CHARGE association, Smith-Magenis syndrome, Smith-Lemli-Opitz syndrome, 22q11 deletion, Silver-Russell syndrome, Fetal alcohol syndrome, Retinopathy of prematurity, Thalidomide embryopathy, Moebius syndrome, Herpes and rubella infection
* Known medical disorders 25% in autistic disorder ”proper” (unselected samples) and 2-5% in Asperger syndrome
* These are either genetic in their own right, affect autism susceptibility gene areas, or cause brain lesions through direct/indirect insults
* High rate of pre- and perinatal risk factors
* Tuberous sclerosis
o 3-9% of all autism cases, more common in those with epilepsy
o chromosome 16p involved in one variant (autism susceptibility genetic area? ADHD susceptibility genetic area)
o dopamine genes on chromosome 9 affected in other TS variant
o autism likely if TS lesions in temporofrontal regions and if there are many lesions

* Herpes encephalitis
o affects temporofrontal areas more often than other brain structures
o can lead to classic symptoms of autism even in previously unaffected individuals who are 14 and 31 years of age
* Thalidomide embryopathy
o 5% of all have (classic) autism
o Brainstem lesions
o Day 20-24 postconceptionally

Genetics
* Sibs affected in 3%: core syndrome
* Sibs affected in 10-20%: spectrum disorder
* Identical twins affected in 60-90%
* Non-identical twins affected in 0-3%
* All of these findings refer to probands with autism proper, not spectrum disorders
* First-degree relatives increased rates of affective disorders (depression, bipolar), social phobia, obsessive-compulsive phenomena, and ”broader phenotype symptoms”, ADHD?, Tourette syndrome?
* First-degree relatives also show possibly increased rates of learning disorders including MR, dyslexia and SLI
* Genes on certain chromosomes (e.g. 2, 6, 7, 16, 18, 22, and X) may be important (genome scan studies of sib-pairs)
* Clinical findings in particular syndromes such as partial tetrasomy 15 (15q), Angelman (15q), tuberous sclerosis (9q, 16p), fragile X (X), Rett syndrome (X), Turner syndrome (X)

* Neuroligin genes on X-chromosome mutated in some cases
o (Jamain, Bourgeron, Gillberg et al 2003. Laumonnier et al 2004)
* Neuroligin genes on other chromosomes, including chromosome 17
o (Jamain et al 2003)
* Other neurodevelopmental genes according to microarray study
o (Larsson, Dahl, Gillberg et al 2003)

Where in the brain is autism?

* Clinical finding: macrocephalus common
o (Bayley et al 1997, Gillberg & deSouza 2002)
* Acquired brain lesions implicate temporal, frontal, fronto-temporal and bilateral dysfunction in core syndrome; right or left dysfunction in spectrum disorder
o (Gillberg & Coleman 2000)
* Autopsy data suggest: amygdala, pons and cerebellum
o (Bauman 1988)
* Brainstem damage suggested by
o Thalidomide
+ (Strömland, Gillberg et al 1994)
o Moebius syndrome association
+ (Gillberg & Steffenburg 1997)
o CHARGE association
+ Johansson et al 2004
o Auditory brainstem responses
+ (Rosenhall, Gillberg et al 2003)
o Decrease in/lack of postrotatory nystagmus
+ (Ornitz, Ritvo 1967)
o Aberrant muscle tone and concomitant squint
+ (Gillberg & Coleman 2000)
* Cerebellar dysfunction suggested by
o Autopsy studies
+ (Bauman et al 1992, Bayley et al 1999, Oldfors, Gillberg et al 2000, Weidenheim, Rapin, Gillberg et al 2001)
o Imaging studies
+ (Courchesne 1988)
o Relationship to ataxia
+ (Åhsgren, Gillberg et al 2003)
* Frontotemporal brain dysfunction suggested by
o Autopsy studies
o Functional imaging studies
o Neuropsychological studies
o Combined neuropsychological-neuroimaging studies
o Clinical picture
* Neuropsychological studies show
o Metarepresentation problems
o Central coherence problems
o Non-verbal learning disability in AS
o Verbal learning disability in AD
o Executive function deficits
o Procedural (complex) learning deficits
o Superior fact learning
o Aberrant reading of facial expression

* At least four biological variants of autism?
o Early brainstem/cerebellar associated with severe secondary problems
o Midtrimester bitemporal lobe damage
o Uni- or bilateral frontotemporal dysfunction in high-functioning cases
o Multi-damage autism

* Likely that several functional neural loops are implicated and that all impinge on neurocognitive/social cognitive functions that are crucially (but possibly not specifically) impaired in autism

Where in the brain is autism?
* Dopamine
o (Gillberg et al 1987)
* Serotonin (in LD also)
o (Coleman 1976)
* Noradrenaline dysfunction
o (Gillberg et al 1987)
* Neuroligins
o (Jamain et al 2003)
* GFA-protein
o (Ahlsén et al 1993)
* Gangliosides
o (Nordin et al 1998)
* Endorphines
o (Gillberg et al 1985)
* Immune system
o (Plioplys 1989)
* Glycine, GABA, Ach, glutamate?

Psychopharmacology of autism
* Only dopamine antagonists (neuroleptics) have been convincingly shown to affect core symptoms of autism
o (van Buitelaar 2000)
* SRIs?
* Antiepileptics??
* Peptides?? And peptide-targeted drugs

The pathogenetic chain
* Genetic or environmental insult
* Damage or neurochemical dysfunction
* Neurocognitive and social cognitive functions restricted (metarepresentations, central coherence, executive functions, procedural learning, )
* The ”syndrome” (or, sometimes, the ”arbitrary” symptom constellation) of autism
* The dyad of social impairment plus the monad of restricted behaviour pattern as a common comorbidity? (rather than the triad?)

Psychosocial interactions
* Not associated with social class
* Not associated with psychosocial disadvantage; however, “pseudoautism” described in children exposed to extreme psychosocial deprivation
* Temporally restricted major improvement in good psychoeducational setting
* Immigration links? Indirect link with genetic factors?
* Abnormal child triggers unusual interactions
* Some parents have autism spectrum disorders themselves
* Anxiety, violent behaviours, self-injury and hyperactivity reduced in autism-know-how-millieu

Implications for treatment
* All people are individuals first and foremost; at least as true in autism as in “neurotypicality”
* People WITH autism; not autistic people!
* Change attitudes
* Respect for people in the autism spectrum
* Focus on changing environment and
* Foster adaptive skills
* If known underlying disorder: treat this (and be aware of syndrome-specific symptoms such as gaze avoidance in fragile X)
* If epilepsy: treat this (however, there are major caveats here)
* If hearing, vision, or motor impaired: treat this
* Psychoeducational measures
* Symptomatic biological treatments
* No medication for majority
* Atypical neuroleptics, antiepileptics, SSRIs, stimulants, lithium (and other drugs) for some
* Diets??
* Physical exercise!!
* “Sensory awareness” environment (reduce noise, certain sounds, smell etc.)
* Concrete, visual (not always), straight-forward
* Minimize ambiguities and symbolic interpretation

Outcome
* Very variable
* Better with early diagnosis
* Majority probably live to be old, but increased mortality in subgroup
* Basic problems remain, albeit modified
* High rate of secondary psychiatric problems (personality disorder, affective, social, catatonia)

Outcome
* Better but also very restricted in Asperger syndrome
+ Cederlund et al 2004
* If autism and no language at age 7, classic autism in adulthood
* If autism and no language at age 3, some classic, some Asperger in adulthood
* If autism and some language at age 3, most will be Asperger in adulthood


The future
* Specific knowledge (including genetic) and treatment for subgroups (new diagnostic criteria)
* Symptomatic treatments
* Psychoeducation
* Acceptance and attitude change!
* People with autism, not autists or autistic people! Cannot be stressed enough
* Respect!

Neurobiology of autism .ppt

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SGA and IUGR

SGA and IUGR
By Tina Burleson Stewart, MD

What is the difference between SGA and IUGR?
Can these terms be used interchangeably?
SGA - small for gestational age infants
* an infant whose weight is lower than the population norms
* defined as weight below 10th percentile for gestational age or greater than 2 standard deviations below the mean
* cause may be pathologic or nonpathologic

IUGR - intrauterine growth retardation
* defined as failure of normal fetal growth
* caused by multiple adverse effects on fetus
* due to process that inhibits normal growth potential of fetus


So what is the difference between SGA and IUGR?
* These terms are related but not synonomous.
* Not all IUGR infants are small enough to fit the qualifications for SGA.
* Not all SGA infants are small because of a growth-restrictive process, and therefore, do not meet criteria for IUGR.

Incidence
* 3-10% of all pregnancies
* 20% of stillborn infants
* perinatal mortality 4-8 times higher
* half have serious or long-term morbidity

Epidemiology
* more common in low socioeconomic class
* more common in those of African-American race
* leading cause in third world countries is inadequate nutrition of mother
* leading cause in US is uteroplacental insufficieny

Causes of IUGR
* maternal factors
* fetal factors
* placental factors
* environmental factors

Maternal causes of IUGR
* inadequate nutrition of mother
* multiple gestation
* uteroplacental insufficiency
* hypoxia
* drugs

Mother’s Malnutrition
* lack of adequate food supply
* poor weight gain
* chronic illness
* malabsorption

Multiple Gestation
* difficult to provide optimal nutrition for greater than one fetus
* uterine capacity limitations

Uteroplacental Insufficiency
* preeclampsia
* chronic HTN
* renovascular disease
* vasculopathy from diabetes
* drugs

Hypoxia
* maternal hemoglobinopathies - sickle cell
* maternal anemia
* maternal cyanotic heart disease
* mom living at high altitudes

Maternal Drug Use and Toxin Exposure
* cigarettes
* cocaine
* amphetamines
* antimetabolites - MTX
* bromides
* heroin
* hydantoin
* isoretinoin (Accutane)
* methadone
* alcohol
* methyl mercury
* phencyclidine
* phenytoin (Dilantin)
* polychlorinated biphenyls
* propanolol
* steroids - prednisone
* toluene
* trimethadione
* warfarin (Coumadin)

Fetal Causes of IUGR
* genetics
* congenital infection
* inborn errors of metabolism

Chromosome Disorders associated with IUGR

* trisomies 8, 13, 18, 21
* 4p- syndrome
* 5p syndrome
* 13q, 18p, 18q syndromes
* triploidy
* XO - Turner’s syndrome
* XXY, XXXY, XXXXY
* XXXXX

Syndromes associated with low birth weight
* Aarskog-Scott syndrome
* anencephaly
* Bloom syndrome
* Cornelia de Lange syndrome
* Dubowitz syndrome
* Dwarfism (achondrogenesis, achondroplasia)
* Ellis-van Creveld syndrome
* Familial dysautonomia
* Fanconi pancytopenia
* Hallerman-Streiff syndrome
* Meckel-Gruber syndrome
* Microcephaly
* Mobius syndrome
* Multiple congenital anomalads
* Osteogenesis imperfecta
* Potter syndrome
* Prader-Willi syndrome
* Progeria
* Prune-belly syndrome
* Radial aplasia; thrombocytopenia
* Robert syndrome
* Robinow syndrome
* Rubinstein-Taybi syndrome
* Silver syndrome
* Seckel syndrome
* Smith-Lemli-Opitz syndrome
* VATER and VACTERL
* Williams syndrome

Congenital Infections associated with IUGR
* rubella
* cytomegalovirus
* toxoplasmosis
* herpes
* syphilis
* varicella
* hepatitis B
* coxsackie
* Epstein-Barr
* parvovirus
* Chagas disease
* malaria

Metabolic disorders associated with low birth weight
* agenesis of pancreas
* congenital absence of islets of Langerhans
* congenital lipodystrophy
* galactosemia
* generalized gangliosidosis type I
* hypophosphatasia
* I cell disease
* leprechaunism
* maternal and fetal phenylketonuria
* maternal renal insufficiency
* maternal Gaucher disease
* Menke syndrome
* transient neonatal diabetes mellitus

Placental Causes of IUGR
* placental insufficency
o very important in the 3rd trimester
* anatomic problems
o infarcts
o aberrant cord insertions
o umbilical vascular thrombosis
o hemangiomas
o premature placental separation
o double vessel cord
* microscopic changes
o villous necrosis
o fibrinosis

Environmental Causes of IUGR
* high altitude - lower environmental oxygen saturation
* toxins

IUGR classification
* SYMMETRIC
* height, weight, head circ proportional
* early pregnancy insult: commonly due to congenital infection, genetic disorder, or extrinsic factors
* normal ponderal index
* low risk of perinatal asphyxia
* low risk of hypoglycemia
* ASYMMETRIC
* head=height, both > weight
* brain growth spared
* later in pregnancy: commonly due to uteroplacental insufficiency, maternal malnutrition, hypoxia, or extrinsic factors
* low ponderal index
* increased risk of asphyxia
* increased risk of hypoglycemia

Ponderal Index
* The ponderal index is used determine those infants whose soft tissue mass is below normal for their stage of skeletal development. Those who have a ponderal index below the 10th % can be classified as SGA.
* Ponderal Index = birth weight x 100 crown-heel length

Diagnosis
Prior to delivery, it is necessary to determine the correct gestational age.
* last menstrual period - most precise
* size of uterus
* time of quickening (detection of fetal movements)
* early ultrasound - the earlier the better accuracy
o biparietal diameter
o abdominal circumference - best sensitivity
o ratio of head to abdominal circumference
o femur length
o placental morphology and amniotic fluid

Diagnosis after delivery (OUR JOB!)
* low birth weight - this parameter alone misses big IUGR infants and overdiagnoses constitutionally small infants
* appearance - thin with loose, peeling skin; scaphoid abdomen; disproportionately large head; may be dysmorphic
* ponderal index
* Ballard/Dubowitz - accurate within 2 weeks of gestation if birth weight >999g, most accurate within 30-42 hrs of age
* birth/weight curves

Complications
* hypoxia
o perinatal asphyxia
o PPHN
* hematologic - polycythemia
* meconium aspiration
* metabolic
o hypoglycemia
o hypocalcemia
o acidosis
* hypothermia
* neurological
o more tremulous
o more easily startled
o less visual fixation
o less activity
o less oriented to visual and auditory stimuli

Management in utero
* serologic testing if desired by parents
* decrease mother’s activity
* stop or decrease risk factors if possible
* closely monitor with biophysical profile or nonstress testing or amniotic fluid measurements
* ultrasound every 10-21 days
* teach mom fetal kick counting
* deliver if reaches 36 weeks

Management after birth
* obtain history of risk factors
* appropriate resuscitation
* prevent heat loss
* watch for hypoglycemia
o check glucoses
o early feeding
o parenteral dextrose
* check hematocrit
* screen for congenital infections
* screen for genetic abnormalities
* check calcium

Outcome

* depends on cause of IUGR/SGA and neonatal course
* symmetric IUGR - poor outcome because early insult
* asymmetric IUGR - better outcome because brain spared
* very bad if brain growth failure starts at < 26 weeks
* school performance influenced by social class
* 25-50% likelihood of neurodevelopmental problems


SGA and IUGR.ppt

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