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dental developmental pathology /certified fixed orthodontic courses by Indian dental academy

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The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.

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dental developmental pathology /certified fixed orthodontic courses by Indian dental academy

  1. 1. Developmental Pathology INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com www.indiandentalacademy.com
  2. 2. Cytogenetics • Examination of chromosomes under the microscope • Necessary to induce cells to undergo mitosis in order to see individual chromosomes • Molecular cytogenetic techniques (e.g., FISH) can be performed on interphase cells (cells that are not actively dividing) www.indiandentalacademy.com
  3. 3. Reasons to do a cytogenetic study • Diagnose constitutional disorders – I.e., disorders present at birth -- classic example is trisomy 21 (Down syndrome) – Typically involve more than one cell line • Add further diagnostic or prognostic information to a diagnosis of an acquired disorder – I.e., diseases that are NOT constitutional -- these are most commonly malignancies – Typically involve only the cell line or tissue involved by the malignancy www.indiandentalacademy.com
  4. 4. www.indiandentalacademy.com 48-hour culture; overnight exposure to colcemid
  5. 5. 72-hour culture; several hours’ colcemid; ethidium bromide added www.indiandentalacademy.com
  6. 6. www.indiandentalacademy.com
  7. 7. www.indiandentalacademy.com
  8. 8. Basic Terminology • Constitutional Chromosomal Abnormalities • Acquired Chromosomal Abnormalities • Numerical abnormalities • Structural abnormalities – Balanced – Unbalanced www.indiandentalacademy.com
  9. 9. www.indiandentalacademy.com
  10. 10. Karyotype -- Blood www.indiandentalacademy.com
  11. 11. Karyotype -- Marrow www.indiandentalacademy.com
  12. 12. FISH diagram (scanned) www.indiandentalacademy.com
  13. 13. Fluorescence in s itu hybridization (FISH) • Specimen is collected as previously described for each tissue type • Indications for FISH include: – Microdeletions (e.g., Prader-Willi, Angelman and DiGeorge syndromes) – Cryptic translocations (e.g., t(12;21)) – Cancer translocations (e.g., BCR-abl, PML-RARA) and rearrangements (e.g., MLL) – Enumeration of chromosomes or detection of translocations or rearrangements in interphase nuclei www.indiandentalacademy.com
  14. 14. Clinical History • Approximately 32 weeks’ gestation • Abnormalities detected on ultrasound: – Abnormal head shape – Frontal bossing – Clenched fists www.indiandentalacademy.com
  15. 15. www.indiandentalacademy.com
  16. 16. www.indiandentalacademy.com
  17. 17. www.indiandentalacademy.com
  18. 18. www.indiandentalacademy.com
  19. 19. Newest method -- array-based Comparative Genomic Hybridization • DNA is extracted from patient • DNA from patient and sex-matched control are labeled in different colors • Labeled DNA is hybridized to a chip (microarray) on which are oligonucleotides spaced across the genome (density or spacing of oligos depends on platform) • Results in ratio of patient to control at www.indiandentalacademy.com these loci
  20. 20. Array CGH • Used to detect abnormalities too small to be seen under the microscope (each G-band can contain hundreds of genes) • Can detect only unbalanced rearrangements (e.g., deletions, duplications) • Balanced rearrangements (e.g., inversions, insertions) will NOT be detected by array-CGH www.indiandentalacademy.com
  21. 21. www.indiandentalacademy.com
  22. 22. www.indiandentalacademy.com
  23. 23. Specimen to draw for a cytogenetic study? • SODIUM heparin tube • Recommend at least 1 ml (3 if poss) www.indiandentalacademy.com
  24. 24. Trisomy (one extra chromosome) • Typically arises from a nondisjunction error in either meiosis I, meiosis II or mitosis (if due to amitotic error, the trisomy is mosaic) • Most autosomal trisomies arise from maternal nondisjunction errors – Strong correlation between increasing maternal age and risk for nondisjunction – Advanced Maternal Age (AMA) is the most common reason for referral for a prenatal chromosome study – 95% of trisomy 21 is due to maternal nondisjunction errors www.indiandentalacademy.com
  25. 25. www.indiandentalacademy.com
  26. 26. www.indiandentalacademy.com
  27. 27. Major “viable” trisomies • Chromosome 13 (obsolete name, Patau synd) • Chromosome 18 (obsolete name, Edward synd) • Chromosome 21 (Down synd) • All other chromosomes have been reported in trisomic state; unless mosaic, virtually uniformly fatal in utero or shortly after birth www.indiandentalacademy.com
  28. 28. Trisomy 21 (1 in 800 live births; incidence greater if mat. age >35) • • • • • • Hypotonia Short neck with loose skin at nape Flat nasal bridge Brushfield spots around edge of iris Epicanthal folds Short, broad hands with single transverse palmar crease • Congenital heart disease • Mental retardation • Increased riskwww.indiandentalacademy.com for leukemia
  29. 29. www.indiandentalacademy.com Thompson & Thompson, Genetics in Medicine, 7th ed, p. 91
  30. 30. Trisomy 13 (1 in 15-25000 live births) • Growth retardation • Severe central CNS malformations (e.g., holoprosencephaly) • Microcephaly • Cleft lip, cleft palate • Polydactyly • Congenital heart, renal and genitourinary malfomations www.indiandentalacademy.com
  31. 31. www.indiandentalacademy.com Thompson & Thompson, Genetics in Medicine, 7th ed, p. 95
  32. 32. Trisomy 18 (1 in 7500 live births) • Severe cardiac malformations • Low-set, malformed ears • Characteristic clenched fist (2nd and 5th digits overlap) • Rocker-bottom feet • Mental retardation • Increased maternal age is a risk factor www.indiandentalacademy.com
  33. 33. Thompson & Thompson, Genetics in Medicine, 7th ed, p. 94 www.indiandentalacademy.com
  34. 34. Sex chromosome numerical abnormalities • Male – Klinefelter (47,XXY): 1/1000 males – 47,XYY: 1/1000 males – 46,XX males: 1/20,000 males • Female – – – – Turner (45,X): 1/5000 females Trisomy X (47,XXX): 1/1000 females 46,XY females: 1/20,000 females Androgen insensitivity (testicular feminization): 1/20,000 females www.indiandentalacademy.com
  35. 35. Klinefelter syndrome • Tall, thin body habitus; long legs • Signs of hypogonadism at puberty – Small testes, underdeveloped secondary sex characteristics • May have gynecomastia • Almost always infertile • May be mosaic for a normal (or other abnormal) cell line www.indiandentalacademy.com
  36. 36. www.indiandentalacademy.com Thompson & Thompson, Genetics in Medicine, 7th ed, p. 106
  37. 37. Turner syndrome • Approx. 99% of 45,X conceptions die in utero; livebirth approx 1/4000 females • Approx. 50% cases 45,X; remainder are mosaic for another cell line, either 46,XX or with a structurally abnormal X (e.g., isochromosome Xq) www.indiandentalacademy.com
  38. 38. Turner syndrome • • • • Short stature Broad chest with widely spaced nipples Gonadal dysgenesis (e.g., streak gonads) Webbed neck (from lymphedema during fetal life) • Lymphedema of dorsum of feet • Low posterior hairline • Renal and cardiovascular abnls, incl. coarctation of aorta www.indiandentalacademy.com
  39. 39. www.indiandentalacademy.com Thompson & Thompson, Genetics in Medicine, 7th ed, p. 108
  40. 40. Microdeletion/microduplication syndromes • Very small (sometimes visible by Gbanding, sometimes not) deletions • Result from unequal crossing over between homologous regions on chromosomes during meiosis • Typically confirmed by FISH www.indiandentalacademy.com
  41. 41. www.indiandentalacademy.com Thompson & Thompson, Genetics in Medicine, 7th ed, p. 97
  42. 42. www.indiandentalacademy.com
  43. 43. Microdeletion syndromes Thompson & Thompson, Genetics in Medicine, 7th ed, p. 96 www.indiandentalacademy.com
  44. 44. DiGeorge/velocardiofacial syndromes • Characteristic craniofacial features • Varying degrees of mental retardation may be a feature • Conotruncal heart defects (e.g., tetralogy of Fallot, pulmonary atresia, absent pulmonary valve) • Over 30 different genes in this region, so phenotype dependent on size of deletion www.indiandentalacademy.com
  45. 45. Prader-Willi/Angelman syndromes • Both due to a deletion within the proximal long arm of a chromosome 15 • Manifestations depend on which chromosome 15 is deleted: the 15 that came from the patient’s mother or the 15 that came from the patient’s father: – IMPRINTING – Need specialized molecular studies to determine which homolog is deleted www.indiandentalacademy.com
  46. 46. www.indiandentalacademy.com
  47. 47. www.indiandentalacademy.com
  48. 48. www.indiandentalacademy.com Cassidy SB et al, 2000, Am J Med Genet 97:136
  49. 49. Prader-Willi • • • • Severe hypotonia in infancy Hypogonadism Feeding difficulties in infancy Over time, feeding difficulties resolve and hyperphagia ensues --> extreme foodseeking behavior • Obesity • Mild mental retardation, learning difficulties, behavioral issues www.indiandentalacademy.com
  50. 50. Angelman • Severe mental retardation and developmental delay • Jerky, ataxic gait (“puppet”-like) together with characteristic arm position • Paroxysms of inappropriate laughter • Virtually absent speech www.indiandentalacademy.com
  51. 51. Marfan syndrome • Autosomal dominant connective tissue disorder due to mutations in fibrillin 1 (FBN1) gene • FBN1 encodes an extracellular matrix glycoprotein • Wide-ranging systemic effects: – Skeletal, ocular, pulmonary, skin • Clinical diagnosis; heterogeneity of gene makes identification of causative gene extremely difficult www.indiandentalacademy.com
  52. 52. Marfan • • • • • • • • • Tall stature, arachnodactyly Pectus excavatum Joint laxity Narrow palate Ectopia lentis Mitral valve prolapse Aortic dilatation, dissection Pulmonary blebs, pneumothorax Striae www.indiandentalacademy.com
  53. 53. www.indiandentalacademy.com
  54. 54. www.indiandentalacademy.com
  55. 55. www.indiandentalacademy.com
  56. 56. www.indiandentalacademy.com
  57. 57. Cystic Fibrosis • Autosomal recessive: patients have mutations in both CFTR (CF transmembrane conductance regulator gene) alleles • Predominantly dz of northern Europeans, with carrier rate approx 1 in 29 (incidence of dz approx 1/2500) • Lungs and exocrine pancreas primarily affected • Increased sweat chloride concentrations www.indiandentalacademy.com
  58. 58. CF Clinical Features • Pulmonary findings – Very thick secretions, recurrent infections, COPD and bronchiectasis • Pancreatic findings – Decreased secretion of pancreatic enzymes such as trypsin and lipase (pts can take supplements) • Other features: meconium ileus in 10-20% newborns with CF • CBAVD: Congenital bilat absence of vas deferens (some pts with absent to very mild features of CF may present with infertility) www.indiandentalacademy.com
  59. 59. Fragile X syndrome • X-linked mental retardation syndrome due to unstable CGG repeats in promoter region of FMR1 gene on very distal long arm of X chromosome • Prevalence 16-25/100,000 in gen pop; most common cause of inherited mental retardation www.indiandentalacademy.com
  60. 60. www.indiandentalacademy.com
  61. 61. Fragile X • Due to expansion of repetitive sequences (similar disorders: Huntington, myotonic dystrophy, various ataxias) • CGG repeat in 3’ untranslated region of FMR1 gene: – – – – 5-40 repeats: normal 41-58 repeats: gray zone 59-200 repeats: premutation >200 repeats: full mutation • This expansion occurs during maternal meiosis (so mothers of Fragile X pts have premutations); risk of expansion to full mutation increases with size of www.indiandentalacademy.com premutation
  62. 62. Fragile X clinical features • Both males and females can manifest features (usually more pronounced in males as no other copy of normal X) • Moderate mental retardation (usu. milder in females) • Hyperactivity, hand flapping or biting, temper tantrums • Post-pubertal males: long face, prominent jaw and forehead, large ears, large testes (FMR1 is normally expressed in testes) www.indiandentalacademy.com
  63. 63. www.indiandentalacademy.com From: geneticsmodules.duhs.duke.edu
  64. 64. Duchenne Muscular Dystrophy • X-linked progressive myopathy due to mutations or deletions within the DMD gene • Incidence: approx 1/3500 male births • DMD encodes dystrophin, expressed in muscle (smooth, cardiac and skeletal) • Mutations lead to partially functional or nonexpressed dystrophin (severity of disease based in part on expression status of dystrophin) www.indiandentalacademy.com
  65. 65. DMD clinical features • Progressive muscle degeneration and weakness • Begins with hip girdle and neck flexors, begins to spread distally • Usually manifests by age 5 (Gowers maneuver) and have calf pseudo-hypertrophy • Cardiac findings present in approx 95% pts; chronic heart failure in 50% • Confined to wheelchair by age 12 or so • Median age at death is 18 years www.indiandentalacademy.com
  66. 66. From: medgen.genetics.utah.edu www.indiandentalacademy.com
  67. 67. References • Nussbaum RL, McInnes RR, Willard HF. Tho m p s o n & Tho m p s o n G e ne tic s in M d ic ine e (7 th e d ). Elsevier Saunders, 2007. – Excellent in-depth introduction to clinical genetics. • Jones KL. Sm ith’s Re c o g niz a ble Pa tte rns o f Hum a n M lfo rm a tio n. Elsevier Saunders, a 2006. – Outstanding guide, with many pictures and differential diagnoses, of many genetic syndromes and abnormalities. Lists of syndromes associated with various clinical findings (e.g., dental and maxillofacial abnormalities). • www.genetests.org – Very well-written and updated reviews under the www.indiandentalacademy.com section, GeneReviews.
  68. 68. Thank you For more details please visit www.indiandentalacademy.com www.indiandentalacademy.com

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