Transcript No Slide Title

Medical Genetics in Pediatric Care:
The Science of Medicine
2004 lectures
Judith Miles, M.D., Ph.D.
Children’s Hospital
The University of MissouriColumbia
The Genetic Invasion of Primary Care:
Fact or fancy?
• Michael McGinnis, director of the U.S. Office of
Disease Prevention and Health Promotion
predicted in 1988 …”most people will be getting
genetic profiles by the year 2000”
• Art Beaudet, in his 1998 Presidential Address to
the American Society of Human Genetics
predicted …”it is likely that primary-care
medicine will soon incorporate age-related
panels for genetic screening focused on those
disorders for which there is compelling
therapeutic intervention”
History of Medical Genetics
• Early Genetics - Biblical, Talmud
• Mendel - 1860s
• Modern Experimental Genetics - 1900s
– Maize, drosophila, mouse
• Medical Genetics - 1960s to the present
Medical Genetics: 1960s to the present
– Single Gene Inheritance
• Victor McKusick - Mendelian Inheritance in Man (1966)
– 1,487 entries ---> >10,000 entries (2003)
– Dysmorphology
• David Smith - 1964
– Cytogenetics
• Trisomy 21 - 1959
– Metabolic Genetics
• PKU newborn screening – 1956
• Extended newborn screening/tandem mass spectroscopy - 2003
Medical Genetics: 1960s to
the present
–DNA Genetics
•1953 - Watson and Crick’s Double Helix
•1992 –2003 Human Genome Project
•2003 -> the future of medical dx & tx
– Prenatal Genetics
• 1970s - Prenatal Ultrasound & Amniocentesis
– Inheritance of Genetically Complex Disorders
• Non-Mendelian Genetics
– Genomic Imprinting
– Triple Nucleotide Repeats
– Mitochondrial Inheritance
• 1990s - Neuropsychiatric Disorders, Diabetes, Cardiovascular
– Interaction of genes with environmental triggers
Medical Genetics:
An Organized Medical Specialty
– American Board of Medical Genetics - 1980
– American Board of Medical Specialties - 1993
– Missouri Genetics:
• Newborn Screening legislation - 1965
• Missouri Genetic Disease Program - 1980
• Genetics Legislation  Governor’s Advisory Committee - 1986
• Governor’s Genetics Initiative - 1990
Missouri Genetic Disease
Legislation - 1985
House Bill No. 612 ( Reps Betty Hearnes and Judy O’Connor)
Senate Bill No. 202 ( Senator Edwin Dirck)
Why Genetics Should be Part of
Primary Care
• Spontaneous abortions - 60%
• Neonatal deaths - 50%
• Birth defects - 70%
• Mental Retardation/ Learning disabilities - 70%
• Cancers: Breast (BRAC 1 and 2), Colon (FAP)
• Cardiovascular and Stroke
• Diabetes
• Neuropsychiatric - autism, manic depressive
disease, alcoholism, ADHD etc
• Neurodegenerative: Alzheimers, ataxias
Reasons Why Medical Genetics
Hasn’t Lived Up to the Predictions
 Physicians are uncomfortable with basic genetics
 Primary care physicians don’t have time for
genetics
 Genetics of the “common disorders” hasn’t
reached the stage where it is useful
susceptibility genes have a low predictive value
 Patients aren’t ready for genetic testing
 Issues of screening and presymptomatic testing
are very complex
We all look
at the
world
through our
own key
holes
Geneticists think about diagnosis differently
 We use different tools
 Family History
 Dysmorphology exam
 Diagnostic Databases
 DNA diagnoses
 Syndrome diagnoses
 heterogeneity
 expressivity
 penetrance
Genetic Approach To Diagnosis

Recurrence risk driven

Organized by etiology

Symptoms
the etiologic
differential diagnosis

Intra vs inter familial variability
establishes the etiologic subgroups
How Geneticists Think about Diseases
• Patterns of Inheritance
– Single Gene Mutations
– Chromosome
– Multifactorial
– Complex/Non-Mendelian/Epigenetic
The geneticist adds the inheritance pattern into the
diagnostic paradigm
Single Gene Disorders
• Dominant Inheritance
• Recessive Inheritance
• X-linked Inheritance
Autosomal Dominant Inheritance
The Marfan Syndrome
• Chris Patton - 1976
died playing pickup
game. On
scholarship for two
years without
diagnosis.
• “dead before he hit
the ground.”
The Marfan Syndrome
• Flo Hyman - 1986
• Ruptured her aorta
during professional
volleyball match
• Member of U.S.
national team for
12 years - Olympic
silver medalist
(‘84)
Marfans Syndrome
Dominant Pedigree
= Affected
Variable Expression
The nature and severity of the
disorder which varies
among affected individuals
Penetrance
Proportion of individuals who
carry the gene
and
manifest the trait
Marfans Syndrome Diagnostic
Criteria
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Skeletal
Ocular
Cardiovascular
Pulmonary
Dural ectasia
Skin and
Integument
2 major criteria + 3rd organ
system
or
Family history of Marfans
+ 1 major criteria
+2nd organ system
American Journal of Medical Genetics, 1996
Skeletal - Major Criteria
• Pectus carinatum
• Pectus excavatum
requiring surgery
•  U/L ratio or
span/height  1.05
• scoliosis > 20° or
spondylolisthesis
• + wrist and thumb
signs
•  elbow extension
(< 170°)
• medial displacement
of medial malleolus 
pes planus
• protrusio acetabulae
Skeletal - Minor Criteria
• Pectus excavatum of
moderate severity
• joint hypermobility
• high arched palate
with crowding of teeth
• characteristic facies
• For skeletal system to
be considered
involved, at least 2
major criteria or one
major plus 2 minor
criteria must be
present.
Ocular system
• Major criteria:
– Ectopia lentis
• Minor criteria:
– abnormally flat
cornea
– increased axial
length of the globe
– hypoplastic iris or
ciliary muscle 
decreased miosis
Cardiovascular - Major Criteria
• Dilatation of the ascending aorta with or
without aortic regurgitation and involving at
least the sinuses of Valsalva
• Dissection of the ascending aorta
Cardiovascular - Minor
Criteria
• Mitral valve prolapse +/- mitral valve
regurgitation
• Dilatation of the main pulmonary artery, in
the absence of valvular or peripheral
pulmonic stenosis or any other obvious
cause, below the age of 40 years
Cardiovascular - Minor
Criteria
• Calcification of the mitral annulus below
the age of 40 years
• Dilatation or dissection of the descending
thoracic or abdominal aorta below the age
of 50 years.
Cardiovascular
• For the cardiovascular system to be involved
a major criteria or only one of the minor
criteria must be present.
• Dilatation of the aortic root is diagnosed
when the maximum diameter at the sinuses of
Valsalva, measured by echocardiography, CT
or MRI, exceeds the upper normal limits for
age and body size.
Pulmonary System
• Major criteria: none
• Minor criteria:
– spontaneous pneumothorax
– apical blebs on CXR
• For the pulmonary system to be involved
one of the minor criteria must be present.
Skin and Integument
• Major criteria: none
• Minor criteria:
– striae atriophicae not associated with marked
weight changes, pregnancy or repetitive stress
– recurrent or incisional herniae
• For the skin and integument to be involved
one of the minor criteria must be present.
Dura
• Major criteria:
– lumbosacral dural ectasia by CT or MRI
• Minor criteria: none
• For the dura to be involved the major
criterion must be present.
Heterogeneity
The finding that what had
previously been thought to be one
disorder, is actually made up of
two or more etiologically distinct
disorders
Homocystinuria
Marfanoid body habitus
Tall stature
Arachnodactyly
Pectus excurvatum
Scoliosis
Ophthalmologic
Myopia
Lens dislocation
Vascular
Intimal hyperplasia
Thrombosis
Homocystinuria
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Mental retardation - 22%
Learning disabilities - high
Seizures - 10 to 15%
Schizophrenia - case reports
Psychiatric symptoms
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Flat affect
Inappropriateness
Odd behavior
Concrete thinking
Recessive Pedigree
= Affected
Homocystinuria
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Mental retardation - 22%
Learning disabilities - high
Seizures - 10 to 15%
Schizophrenia - case reports
Psychiatric symptoms
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Flat affect
Inappropriateness
Autistic behavior
Concrete thinking
X - Linked Recessive Inheritance
Child with Mental Retardation
Dysmorphology
Chromosome Disorders are Subtle
47, XYY
XYY Male
Alan Varrin
Behavior
Impulsive
Low normal IQ
Poor social interactions and self esteem
Non-violent
never smoked, drank, used drugs
Recurrent Car Theft and check cashing x 1
60 year sentence as a recurrent offender
Eligible for disability and vocational
rehabilitation under MRDD
XYY Karyotype
Unbalanced Chromosome
Translocation
46, XY, der(16)t(3;16) (p25;p13)mat
Pedigree
46,XX, T (3;16)
TAB
= Unbalanced Translocation Carrier
= Balanced Translocation Carrier
SAB
SAB
SAB
22q
Syndrome - CATCH 22
Chromosome Deletions
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DiGeorge Syndrome
Williams Syndrome
Prader Willi Syndrome
Angelman Syndrome
Cri de Chat Syndrome
Beckwith Weidemann Syndrome
etc.
DiGeorge Karyotype
Deletion by FISH Analysis
Multifactorial Disorders
• Caused by a combination of genetic and
environmental factors
• Recurrence Risk is about 3% for 1o relatives
• Structural Birth Defects:
– Spina Bifida,Cleft lip and palate, Congenital Hearts
• Adult Aging Disorders:
– Hypertension, Diabetes, Alzheimers
• Neuropsychiatric Disorders
– Autism, Depression, Alcoholism, Schizophrenia
Spina Bifida & Anencephaly
Clinical Genetic Data Bases
• Online Mendelian Inheritance in Man – OMIM
• www. Omim.org
• Gene Clinics
• www.geneclinics.org
• National Newborn Screening and Genetics
Resource Center web site: NNSGRC –
• www.genes-r-us.uthscsa.edu/
• Alliance of Genetic Support Groups
• www.medhlp.netusa.net/www/agsg.htm
Future of Medical Genetics
Better Diagnoses
Better Treatments
Better Prevention
Cures
Better informed consumers, health care
providers, lawyers, public policy makers
Genetic Testing
USES
• Diagnostic
• Predictive
• Carrier
• Prenatal
• Newborn
Screening
TOOLS
• Cytogenetic
• Metabolic
• DNA
Questions about genetic testing?
• What kind of genetic test is it?
• How would the genetic test be used?
• Would the genetic test help or hurt my
patient?
• How is the genetic test applied in this
situation?
• Where can I find a lab that does the test?
• Who will interpret the results?
Predictive/Presymptomatic
Genetic Testing
• Family history of the disorder
• Huntington disease
• Familial adenomatous polposis FAP
• Breast cancer
• Population Screening
• Hemochomatosis
HUNTINGTON DISEASE
THE GENE IS CLONED
March 23, 1993
The Huntington Disease Collaborative Research Group
Huntingtons - Clinical Features
Classical Triad
Choreiform Movements
Dementia
(95%)
(Subcortical/basal ganglion dysfunction)
Personality Changes
Genetics of Huntingtons
• Chromosome 4
• Autosomal Dominant - 50% risk for offspring
• Triple Nucleotide Repeat Disorder
– CAG repeat size classification
– < 30 = Normal
– 30-38 = Indeterminate
– >39 = considered to be in the HD range
Presymptomatic Dx
Advantages
Ability to have unaffected children
Informed family planning
Career decisions
Relief from fear
Relieve children from fear
Research
Presymptomatic Dx
Disadvantages
Loss of hope
Suicide
Marital problems
Pressure to take the test
Insurance problems
Knowledge of risk to children
Every ache and pain --- this is it!
63 y
33 y
d. 35 y
28 y
39 y
14 y
= FAP
10 y
6y
GENETests
www.genetests.org
• Gene Tests: whose doing what tests?
– Directory of Medical Genetics Laboratories
• Gene Reviews: A medical knowledge base relating
genetic testing to the diagnosis, management, and
genetic counseling of individuals and families with
specific inherited disorders.
– Expert-authored and Peer-reviewed
• Gene Clinics: Find appropriate referrals anywhere.
Prenatal Screening
vs
Definitive Testing
• Population Screening
– MSAFP + testing
– Ultrasound
– Most other “routing prenatal tests”
• Definitive Testing
– amniocentesis
– chorionic villus sampling
Prenatal Testing
• Routine: Chromosome abnormalities
– One test
– Sporadic
– Usually indicated by maternal age or abnormal
serum screen or ultrasound findings
– Relatively frequent
Spectral
Karyotype
Prenatal Testing
• Non-routine: Single-gene disorders
– Thousands of individual tests
– Heritable
– Usually indicated by family history
– Rare
Osteogeneis Imperfecta Type 2
Osteogenesis Imperfecta Type 2
Carrier Testing
• Carrier of a recessive gene:
ex. Cystic Fibrosis, Duchenne Muscular
Dystrophy, Tay Sachs, Sickle Cell Anemia
• Carrier of a chromosome translocation
Genetic Testing: Newborn Screening
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Phenylketonuria
Sickle Cell Disease
Galactosemia
Hypothyroidism
Congenital Adrenal Hyperplasia
Expanded Newborn Screening
Maple Syrup Urine Disease
Homocystinuria
Biotinidase Deficiency
Population Screening
• Cystic Fibrosis Screening
– NIH consensus panel - April 1997
recommended offering testing to:
• family members
• partners of carriers
• couples planning a pregnancy
• couples seeking prenatal testing
• Adult Screening
– Hemochomatosis Screening
Child’s
Double
Helix
GENEClinics
• www.geneclinics.org
• A medical knowledge base relating genetic
testing to the diagnosis, management, and
genetic counseling of individuals and
families with specific inherited disorders.
• Expert-authored and Peer-reviewed