medical genetics in pediatric care: the science of medicine judith miles, m.d., ph.d. children’s...
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Medical Genetics in Pediatric Care: The Science of Medicine
Judith Miles, M.D., Ph.D. Children’s Hospital
The University of Missouri-Columbia
2004 lectures
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
– 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: 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
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)
• 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
Why Genetics Should be Part of Primary Care
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
• Patterns of Inheritance
– Single Gene Mutations
– Chromosome
– Multifactorial
– Complex/Non-Mendelian/Epigenetic
How Geneticists Think about Diseases
The geneticist adds the inheritance pattern into the diagnostic paradigm
• Dominant Inheritance
• Recessive Inheritance
• X-linked Inheritance
Single Gene Disorders
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
• Skeletal
• Ocular
• Cardiovascular
• Pulmonary
• Dural ectasia
• Skin and Integument
American Journal of Medical Genetics, 1996
2 major criteria + 3rd organ system
Family history of Marfans + 1 major criteria
+2nd organ system
or
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 - MinorCriteria
• 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 - MinorCriteria
• 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
MyopiaLens dislocation
Vascular Intimal hyperplasia Thrombosis
Homocystinuria
Mental retardation - 22% Learning disabilities - high Seizures - 10 to 15% Schizophrenia - case reports Psychiatric symptoms
Flat affect Inappropriateness Odd behavior Concrete thinking
Recessive Pedigree
= Affected
Homocystinuria
Mental retardation - 22% Learning disabilities - high Seizures - 10 to 15% Schizophrenia - case reports Psychiatric symptoms
Flat affect Inappropriateness Autistic behavior Concrete thinking
X - Linked Recessive Inheritance
Child with Mental Retardation
Dysmorphology
Chromosome Disorders are Subtle
47, XYY
XYY MaleAlan Varrin
Behavior ImpulsiveLow normal IQPoor social interactions and self esteemNon-violent never smoked, drank, used drugs
Recurrent Car Theft and check cashing x 160 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
TAB SAB SAB SAB
= Unbalanced Translocation Carrier
= Balanced Translocation Carrier
46,XX, T (3;16)
22q- Syndrome - CATCH 22
Chromosome Deletions
• 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
Better Diagnoses
Better Treatments
Better Prevention
Cures
Better informed consumers, health care
providers, lawyers, public policy makers
Future of Medical Genetics
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 (95%)
Dementia (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!
= FAP
10 y10 y
d. 35 yd. 35 y63 y63 y
39 y39 y 33 y33 y 28 y28 y
6 y6 y14 y14 y
GENETestswww.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
• Phenylketonuria• Sickle Cell Disease • Galactosemia• Hypothyroidism• Congenital Adrenal Hyperplasia• Expanded Newborn Screening• Maple Syrup Urine Disease• Homocystinuria• Biotinidase Deficiency
• 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
Population 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