Medical Genetics in Pediatric Care: The Science of Medicine

1. 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

2. 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”

3. History of Medical Genetics Early Genetics - Biblical, Talmud Mendel - 1860s Modern Experimental Genetics - 1900s Maize, drosophila, mouse Medical Genetics - 1960s to the present

4. 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

5. 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

6. 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

7. Missouri Genetic Disease Legislation - 1985 House Bill No. 612 ( Reps Betty Hearnes and Judy O’Connor) Senate Bill No. 202 ( Senator Edwin Dirck)

8. 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

9. 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 Reasons Why Medical Genetics Hasn’t Lived Up to the Predictions

10. We all look at the world through our own key holes

11. We use different tools Family History Dysmorphology exam Diagnostic Databases DNA diagnoses Syndrome diagnoses heterogeneity expressivity penetrance Geneticists think about diagnosis differently

12. Genetic Approach To Diagnosis • Recurrence risk driven • Organized by etiology • Symptoms the etiologic differential diagnosis • Intra vs inter familial variability establishes the etiologic subgroups

13. 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

14. Dominant Inheritance Recessive Inheritance X-linked Inheritance Single Gene Disorders

15. Autosomal Dominant Inheritance

16. The Marfan Syndrome • Chris Patton - 1976 died playing pickup game. On scholarship for two years without diagnosis. • “dead before he hit the ground.”

17. 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)

18. Marfans Syndrome

19. Dominant Pedigree = Affected

20. Variable Expression The nature and severity of the disorder which varies among affected individuals

21. Penetrance Proportion of individuals who carry the gene and manifest the trait

22. Skeletal Ocular Cardiovascular Pulmonary Dural ectasia Skin and Integument Marfans Syndrome Diagnostic Criteria 2 major criteria + 3rd organ system or Family history of Marfans + 1 major criteria +2nd organ system American Journal of Medical Genetics, 1996

23. 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 - Major Criteria

24. 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. Skeletal - Minor Criteria

25. Major criteria: Ectopia lentis Minor criteria: abnormally flat cornea increased axial length of the globe hypoplastic iris or ciliary muscle  decreased miosis Ocular system

26. 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

27. 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

28. 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.

29. 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.

30. 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.

31. 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.

32. 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.

33. HeterogeneityThe finding that what had previously been thought to be one disorder, is actually made up of two or more etiologically distinct disorders

34. HomocystinuriaMarfanoid body habitus Tall stature Arachnodactyly Pectus excurvatum Scoliosis Ophthalmologic Myopia Lens dislocation Vascular Intimal hyperplasia Thrombosis

35. Homocystinuria • Mental retardation - 22% • Learning disabilities - high • Seizures - 10 to 15% • Schizophrenia - case reports • Psychiatric symptoms • Flat affect • Inappropriateness • Odd behavior • Concrete thinking

36. Recessive Pedigree = Affected

37. Homocystinuria • Mental retardation - 22% • Learning disabilities - high • Seizures - 10 to 15% • Schizophrenia - case reports • Psychiatric symptoms • Flat affect • Inappropriateness • Autistic behavior • Concrete thinking

38. X - Linked Recessive Inheritance

39. Child with Mental Retardation

40. Dysmorphology

41. Chromosome Disorders are Subtle

42. 47, XYY

43. 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

44. XYY Karyotype

45. Unbalanced Chromosome Translocation 46, XY, der(16)t(3;16) (p25;p13)mat

46. Pedigree 46,XX, T (3;16) TAB SAB SAB SAB = Unbalanced Translocation Carrier = Balanced Translocation Carrier

47. 22q- Syndrome - CATCH 22

48. Chromosome Deletions • DiGeorge Syndrome • Williams Syndrome • Prader Willi Syndrome • Angelman Syndrome • Cri de Chat Syndrome • Beckwith Weidemann Syndrome • etc.

49. DiGeorge Karyotype

50. Deletion by FISH Analysis