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Board Review: Genetics

Board Review: Genetics. October 25, 2010. Major vs Minor Anomalies. Major: functional significance Polydactyly , colobomas , meningomyelocele , cleft lip Incidence 1% Minor: cosmetic significance Epicanthal folds, single transverse palmar crease, supernumerary nipples Incidence 14%

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Board Review: Genetics

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  1. Board Review: Genetics October 25, 2010

  2. Major vs Minor Anomalies • Major: functional significance • Polydactyly, colobomas, meningomyelocele, cleft lip • Incidence 1% • Minor: cosmetic significance • Epicanthal folds, single transverse palmar crease, supernumerary nipples • Incidence 14% • Both more common in premature babies

  3. Question 1 • Pierre Robin is best described as a • A. Deformation • B. Disruption • C. Dysplasia • D. Sequence • E. Association

  4. Malformation • Broad term • An abnormality of embryonic morphogenesis • Usually results from genetic, chromosomal, or teratogenic influences • May be multifactorial • Constitutes single primary defect • OR, component of multiple malformation syndrome • Often require surgical intervention

  5. Deformation • Alteration (often molding) of intrinsically normal tissue due to exposure of unusual extrinsic forces. • Uterine constraint from crowding • Potter facies • Most respond to medical therapy and have good prognosis

  6. Disruption Breakdown of normally formed tissue Vascular accidents Amniotic bands Earlier in embryogenesis: More severe

  7. Dysplasia • Abnormal organization of cells within tissue • Genetic basis • Achondroplasia • Most frequent cause of skeletal dysplasia

  8. Each of these can have an associated sequence Malformation: Embryonic morphogenesis Deformation: Alteration of intrinsically normal tissue by external force Disruption: Breakdown of normally formed tissue Dysplasia: Abnormal organization of cells within tissue

  9. Sequence • Single problem in morphogenesis • Cascade resulting in series of structural alterations • Recognizable pattern of multiple anomalies • Pierre Robin • Microretrognathia (single, primary malformation) • Glossoptosis: posterior placement of tongue • U-shaped cleft palate

  10. Association Pattern of malformations that occurs together too frequently to be due to random chance. No specific etiology is known.

  11. Autosomal Chromosome Abnormalities

  12. Down Syndrome Nonspecific

  13. Down Syndrome: Major Anomalies/Complications • Congenital heart disease (45%) • AV Canal Defects • GI anomalies (5%) • Duodenal atresia • Hirschsprung • Thyroid disorders • ! Regular Screening ! • Leukemia • 15 to 20 times more common • Neonates may have transient leukemoid reaction

  14. Down Syndrome • Cognitive impairment • IQ 20-80 • Mild to Moderate Developmental Delay • Early intervention, education, and sporting activities demonstrate improved outcomes. • Atlanto-axial instability

  15. Question 2 • A parent of a child with Down Syndrome is found to have a 21/21 translocation. What are the chances that her next child will have Down Syndrome? • A. 2% • B. 15% • C. 33% • D. 50% • E. 100%

  16. Down Syndrome • If either parent has 21/21 translocation • All children will have Down Syndrome • If parent has 21/centric translocation • 2% of father’s children • 15% of mother’s children

  17. Down Syndrome: Maternal Age • Remember!!!! • Most children with Down Syndrome are NOT born to older parents!!!!

  18. Other Trisomies • 13 (Patau) and 18 (Edwards) • May overlapping features! • Focus on characteristic features.

  19. Trisomy 13 P = Patau = Pits = Polydactyly 3 is a clefted 8 13= Midline defects

  20. 8 Trisomy 18 8

  21. Question 3 • A 15-year-old girl comes to your office because she never has had a menstrual period. She has no chronic illnesses and is active playing softball once a week. Her mother and sister both had menarche at age 13 years. On physical examination, she is at the 15th percentile for height and weight and has no hirsutism or acne, no breast development, and Sexual Maturity Rating 3 pubic hair development. • The MOST appropriate lab test is: • A. Karyotype • B. Progesterone and 17-hydroxyprogesterone • C. Microarray • D. FISH • E. Testosterone

  22. Sex Chromosome Abnormalities

  23. Turner Syndrome • 1/2000 liveborn females • Characteristics: • Primary amenorrhea • Sterility • Sparse pubic hair • Underdeveloped breasts • Short stature • Webbing of neck • Cubitusvalgus • Low hairline • Shield chest with wide spaced nipples • lymphedema

  24. Turner Syndrome • Other organ systems • Renal anomalies • Congenital heart disease • Bicuspid aortic valve (30%) • Aortic coarctation (10%) • Mental development usually normal • Findings may be subtle and missed until adolescence • Get karyotype on adolescent female with delayed puberty, especially if short stature

  25. Turner Syndrome Karyotype 45X Recurrence risk for parents is 1-2% unless a parent has abnormal X 15% are Mosaics If mosaic has an XY cell line, gonads should be removed

  26. Question 4 • Does the risk of having a child with Turner Syndrome or Klinefelter Syndrome increase with advanced maternal age? • A. Yes for both • B. No for Turner, Yes for Klinefelter • C. Yes for Turner, No for Klinefelter • D. No for both

  27. Klinefelter Syndrome 1/500 newborn boys Physical stigmata may not be obvious until puberty Testosterone levels usually low (variable) IQ is normal (or mildly decreased) Behavioral problems may be more common

  28. Klinefelter Syndrome • Karyotype • XXY 80% • XY/XXY in 20% • IF additional X present (XXXY) • More cognitive and skeletal abnormalities • Congenital Heart Disease may be seen • PDA most common • Parents’ recurrence risk 1-2% • Risk increases with maternal age

  29. Klinefelter

  30. Question 5 • A new 13 year old male patient has a long, narrow face and enlarged, protruding ears, and joint laxity. He is very active, has difficulty making eye contact, and engages in some hand flapping. His most recent testing showed an IQ of 45. Family history reveals that the maternal uncle has intellectual disability. • The MOST appropriate test to confirm the diagnosis is • A. Karyotype • B. Skin biopsy for staining • C. Molecular DNA analysis • D. MRI of Brain • E. Clinical Diagnosis Only

  31. Molecular Cytogenetic Syndromes

  32. NEWSFLASH!! There is an excess of males in the mentally retarded population This is largely due to Fragile-X

  33. Fragile-X • Most common chromosomal cause of MR • May be expressed (less severe) in females • Expression may be amplified over generations (anticipation) • Physical • Long face • Long, protruding ears • MR • Prominent jaw • Macroorchidism • May have hyper-extensible joints

  34. Fragile-X • Trinucleotide repeat disorder • Inheritance X-linked Dominant • Variable expressivity • Expression amplified over generations • Look for Hx of affected male family members (uncles) • Choose molecular DNA analysis • Methylation study • Otherwise PCR or Southern Blot

  35. Disorders of Imprinting Angelman Prader-Willi

  36. Imprinting • Function of certain genes is dependent on their parental origin • Maternal vs Paternal • Particularly for 15q11-13 • Prader-Willi • Deletion of paternally derived Chromosome 15 • Angelman • Deletion of maternally derived Chromosome 15 • Diagnosis: Methylation, High-resolution cytogenetics, or FISH

  37. Prader-Willi Infant Prader-Willi Toddler • Hypotonia resolves • Insatiable appetite • Obesity • Extreme tantrums • Markedly Hypotonic baby • May have decreased DTR • May be SGA • Poor feeding and FTT • Developmental Delay

  38. Prader-Willi Child/Adult • Diabetes Mellitus • Slipped Capital Femoral Epiphysis • Limited life expectancy • Cardiorespiratory complications • Pickwickian syndrome • AKA (Obesity hypoventilation) • Skin picking

  39. Angelman Severe cognitive deficits Speech impaired or absent Inappropriate paroxysms of laughter May have ataxia and seizures

  40. Question 6 You evaluate a 16-year-old varsity volleyball player. The girl's height is 71 inches, weight is 125 lb, and blood pressure is 115/74 mm Hg. You note scoliosis and a 3/6 holosystolic murmur heard at the cardiac apex with radiation to the left axillaChoose the MOST likely diagnosis A. Ehlers-Danlos B. Infective endocarditis C. Marfan syndrome D. Rheumatic heart disease E. Williams syndrome

  41. Genetic Connective Tissue Disorders

  42. Connective Tissue Disorders • Avoid contact sports • Connective tissue (joint) injury • Marfan: Also avoid any strenuous exercise • Aortic dissection

  43. Marfan Syndrome AD- Fibrillin Gene Normal intelligence = upward lens Findings more obvious with aging

  44. Ehlers-Danlos • Mostly AD • Defect of collagen • Fragil “velvety” skin • “Cigar Paper” • Scar formation • Impaired wound healing • Use glue or tape

  45. Ddx • Beals Syndrome • Abnormal fibrillin 2 • Tall, arachnodactyly • Broad forehead and hypertelorismare distinct features

  46. Ddx • Homocystinuria • Error of methionine metabolism • Tall, thin habitus, scoliosis, pectus • Distinctive features: • Inferiorly displaced lens • Hypercoaguability • Mental retardation • Treatment • May respond to B6 (pyridoxine)

  47. Inborn errors of metabolism

  48. Inborn Errors of Metabolism • Altered or abnormal gene that codes for the production of an abnormal product • Enzyme or cofactor needed for metabolic process • Cannot make end-product • Abnormal structure and function • Increased precursors

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