Presentation on theme: "Medical Genetics in Pediatric Care: The Science of Medicine"— Presentation transcript:
1Medical Genetics in Pediatric Care: The Science of Medicine 2004 lecturesOver the last decade there have been continual predictions that the Human Genome Project was going to revolutionize primary care medicine. However, despite these predictions , genetic practice in primary care has undergone little change. I would like to analyze some of the reasons for this and begin to formulate a prescription for increased use of the tools of genetic medicine in primary care.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.Judith Miles, M.D., Ph.D.Children’s HospitalThe University of Missouri-Columbia
2The 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”
3History of Medical Genetics Early Genetics - Biblical, TalmudMendel sModern Experimental Genetics sMaize, drosophila, mouseMedical Genetics s to the present
4Medical Genetics: 1960s to the present Single Gene InheritanceVictor McKusick - Mendelian Inheritance in Man (1966)1,487 entries ---> >10,000 entries (2003)DysmorphologyDavid SmithCytogeneticsTrisomyMetabolic GeneticsPKU newborn screening – 1956Extended newborn screening/tandem mass spectroscopy
5Medical Genetics: 1960s to the present DNA GeneticsWatson and Crick’s Double Helix1992 –2003 Human Genome Project2003 -> the future of medical dx & txPrenatal Genetics1970s - Prenatal Ultrasound & AmniocentesisInheritance of Genetically Complex DisordersNon-Mendelian GeneticsGenomic ImprintingTriple Nucleotide RepeatsMitochondrial Inheritance1990s - Neuropsychiatric Disorders, Diabetes, CardiovascularInteraction of genes with environmental triggers
6Medical Genetics: An Organized Medical Specialty American Board of Medical GeneticsAmerican Board of Medical SpecialtiesMissouri Genetics:Newborn Screening legislationMissouri Genetic Disease ProgramGenetics Legislation Governor’s Advisory CommitteeGovernor’s Genetics Initiative
7Missouri Genetic Disease Legislation - 1985 House Bill No. 612 ( Reps Betty Hearnes and Judy O’Connor)Senate Bill No. 202 ( Senator Edwin Dirck)
8Why 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 StrokeDiabetesNeuropsychiatric - autism, manic depressive disease, alcoholism, ADHD etcNeurodegenerative: Alzheimers, ataxias
9Reasons Why Medical Genetics Hasn’t Lived Up to the Predictions Physicians are uncomfortable with basic geneticsPrimary care physicians don’t have time for geneticsGenetics of the “common disorders” hasn’t reached the stage where it is usefulsusceptibility genes have a low predictive valuePatients aren’t ready for genetic testingIssues of screening and presymptomatic testing are very complex
10We all look at the world through our own key holes We all look at the workd through our own key holeI counter that what the specialty of Medical Genetics has to bring to other physicians is not just DNA diagnosis but a different way of approaching diagnosis.
11Geneticists think about diagnosis differently We use different toolsFamily HistoryDysmorphology examDiagnostic DatabasesDNA diagnosesSyndrome diagnosesheterogeneityexpressivitypenetrance
12Genetic Approach To Diagnosis Recurrence risk drivenOrganized by etiologySymptoms the etiologic differential diagnosisIntra vs inter familial variability establishes the etiologic subgroups
13How Geneticists Think about Diseases Patterns of InheritanceSingle Gene MutationsChromosomeMultifactorialComplex/Non-Mendelian/EpigeneticThe geneticist adds the inheritance pattern into the diagnostic paradigmThe geneticist adds the inheritance pattern into the diagnostic paradigm
15Autosomal Dominant Inheritance Single gene which is dominant to its allele50% recurrence riskmales and females equally affectednew mutationsDefine allelesExamples: Marfans, neurofibromatosis, myotonic dystrophy
16The Marfan SyndromeChris Patton died playing pickup game. On scholarship for two years without diagnosis.“dead before he hit the ground.”
17The Marfan Syndrome Flo Hyman - 1986 Ruptured her aorta during professional volleyball matchMember of U.S. national team for 12 years - Olympic silver medalist (‘84)
20among affected individuals Variable ExpressionThe nature and severity of the disorder which variesamong affected individuals
21Proportion of individuals who carry the gene PenetranceProportion of individuals who carry the geneandmanifest the trait
22Marfans Syndrome Diagnostic Criteria SkeletalOcularCardiovascularPulmonaryDural ectasiaSkin and Integument2 major criteria + 3rd organ systemorFamily history of Marfans+ 1 major criteria+2nd organ systemAmerican Journal of Medical Genetics, 1996
23Skeletal - Major Criteria Pectus carinatumPectus excavatum requiring surgery U/L ratio or span/height 1.05scoliosis > 20° or spondylolisthesis+ wrist and thumb signs elbow extension (< 170°)medial displacement of medial malleolus pes planusprotrusio acetabulae
24Skeletal - Minor Criteria Pectus excavatum of moderate severityjoint hypermobilityhigh arched palate with crowding of teethcharacteristic faciesFor skeletal system to be considered involved, at least 2 major criteria or one major plus 2 minor criteria must be present.
25Ocular system Major criteria: Minor criteria: Ectopia lentis abnormally flat corneaincreased axial length of the globehypoplastic iris or ciliary muscle decreased miosis
26Cardiovascular - Major Criteria Dilatation of the ascending aorta with or without aortic regurgitation and involving at least the sinuses of ValsalvaDissection of the ascending aorta
27Cardiovascular - Minor Criteria Mitral valve prolapse +/- mitral valve regurgitationDilatation 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
28Cardiovascular - Minor Criteria Calcification of the mitral annulus below the age of 40 yearsDilatation or dissection of the descending thoracic or abdominal aorta below the age of 50 years.
29CardiovascularFor 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.
30Pulmonary System Major criteria: none Minor criteria: spontaneous pneumothoraxapical blebs on CXRFor the pulmonary system to be involved one of the minor criteria must be present.
31Skin and Integument Major criteria: none Minor criteria: striae atriophicae not associated with marked weight changes, pregnancy or repetitive stressrecurrent or incisional herniaeFor the skin and integument to be involved one of the minor criteria must be present.
32Dura Major criteria: Minor criteria: none lumbosacral dural ectasia by CT or MRIMinor criteria: noneFor the dura to be involved the major criterion must be present.
33Heterogeneity The finding that what had previously been thought to be one disorder, is actually made up of two or more etiologically distinct disorders
43XYY Male Alan Varrin Behavior Impulsive Low normal IQ Poor social interactions and self esteemNon-violentnever smoked, drank, used drugsRecurrent Car Theft and check cashing x 160 year sentence as a recurrent offenderEligible for disability and vocational rehabilitation under MRDD
51Multifactorial Disorders Caused by a combination of genetic and environmental factorsRecurrence Risk is about 3% for 1o relativesStructural Birth Defects:Spina Bifida,Cleft lip and palate, Congenital HeartsAdult Aging Disorders:Hypertension, Diabetes, AlzheimersNeuropsychiatric DisordersAutism, Depression, Alcoholism, Schizophrenia
53Clinical Genetic Data Bases Online Mendelian Inheritance in Man – OMIMwww. Omim.orgGene ClinicsNational Newborn Screening and Genetics Resource Center web site: NNSGRC –Alliance of Genetic Support Groups
54Future of Medical Genetics Better DiagnosesBetter TreatmentsBetter PreventionCuresBetter informed consumers, health care providers, lawyers, public policy makers
56Questions 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?
57Predictive/Presymptomatic Genetic Testing Family history of the disorderHuntington diseaseFamilial adenomatous polposis - FAPBreast cancerPopulation ScreeningHemochomatosis
58The Huntington Disease Collaborative Research Group THE GENE IS CLONEDMarch 23, 1993The Huntington Disease Collaborative Research Group
60Genetics of Huntingtons Chromosome 4Autosomal Dominant - 50% risk for offspringTriple Nucleotide Repeat DisorderCAG repeat size classification< 30 = Normal30-38 = Indeterminate>39 = considered to be in the HD range
61Presymptomatic Dx Advantages Ability to have unaffected childrenInformed family planningCareer decisionsRelief from fearRelieve children from fearResearch
62Presymptomatic Dx Disadvantages Loss of hopeSuicideMarital problemsPressure to take the testInsurance problemsKnowledge of risk to childrenEvery ache and pain --- this is it!
67GENETests www.genetests.org Gene Tests: whose doing what tests?Directory of Medical Genetics LaboratoriesGene 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-reviewedGene Clinics: Find appropriate referrals anywhere.
80GENEClinics 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