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Common Chromosomal Abnormalities

Common Chromosomal Abnormalities. Anthony Liu, M.D. Overview- DNA. DNA By the Numbers: 3,000,000,000: Number of base pairs in the human genome 90%: Have no identifiable function 50,000: Total number of encoded genes 16,000: Base pairs in mitochondrial DNA. Overview.

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Common Chromosomal Abnormalities

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  1. CommonChromosomalAbnormalities Anthony Liu, M.D.

  2. Overview- DNA • DNA By the Numbers: • 3,000,000,000: Number of base pairs in the human genome • 90%: Have no identifiable function • 50,000: Total number of encoded genes • 16,000: Base pairs in mitochondrial DNA

  3. Overview • Chromosomal anomalies include abnormalities of chromosome number and structure • Occur in 0.4% of live births • Important cause of MR • Accounts for 12% of pediatric admissions • Genetic malformations: 25% of neonatal deaths in the US • Present in much higher frequencies among spontaneous abortions, still births • Phenotypic anomalies that result from chromosomal aberrations: due to imbalance of genetic information

  4. Basic Inheritance Patterns Autosomal Recessive

  5. Inheritance Patterns X- Linked Dominant

  6. Inheritance Patterns Autosomal Dominant

  7. Autosomal Dominant • TS • Achondroplasia • Retinoblastoma • Marfan’s Syndrome • Alport Syndrome • NF • Waardenburg, Huntington’s, vWF Disease

  8. Waardenburg

  9. Inheritance Patterns X- Linked Recessive

  10. X- Recessive • Hemophilia • G6PD • CGD • Duchenne MD

  11. Abnormalities of Chromosome Number • Euploidy- exact multiple of haploid number (46) • Polyploidy- euploidy with > 46 chromosomes • Conceptions- usually not viable unless mosaic • Triploidy- 3 sets of chromosomes • Result in abortion, occasionally viable • Aneuploidy- deviation from the multiples of haploid number; missing or extra chromosomes

  12. TRISOMIES • Most common abnormality of chromosome # • 3 representatives of a chromosome instead of 2 • Usually results from meiotic nondisjunction (failure of a chromosome pair to separate) • May be present in all cells or may occur in mosaic form • Pts exhibit a consistent phenotype depending on the chromosome

  13. Trisomy 21 • 1/600 births, 80% diagnosed as neonate • Varying MR and growth retardation • Pelvic dysplasia, cardiac malformations • Short, broad hands, transverse crease, hypoplasia of 5th finger, intestinal atresia, high arched/cleft palate • Hypotonia, flat face, slanted palpebral fissures, epicanthic folds • 5% of patients with phenotypic Down syndrome are the result of a translocation: t(14q21q), t(15q21q), t(13q21q)

  14. Speckled Iris:Brushfield Spots

  15. Trisomy 21 • More than half of conceptions spontaneously abort • ↑ Occurrence with advancing maternal age (also for other trisomies), and during teen years • Maternal serum testing (triple screen) can screen • NL values age dependent • ↓maternal serum AFP • ↓unconjugated estriol • ↑HCG

  16. Trisomy 21 Q Banding • Left: Two of a patient's chromosomes transmitted by the mother • Right: Two chromosomes paternal nondisjunction at second meiotic division

  17. Trisomy 18- Edwards syndrome • 1/5,000 births • Low BW, closed fists with index finger overlapping the 3rd digit and 5th overlapping the 4th • Narrow hips with limited abduction, short sternum, rocker–bottom feet, hypertonia • Head- microcephaly, prominent occiput, micrognathia, fine/small facial features • Cardiac, renal malformations, MR • 95% of cases are lethal in the 1st yr

  18. Trisomy 18 • Microcephaly prominent occiput micrognathia • Fine/small facial features • Hypertonia

  19. Trisomy 18 • Note finger position, hypoplasia of 5th fingernail • Simple arch pattern of the fingerpads • Toe dorsiflexion with hypoplasia of toenails • Often syndactyly

  20. Trisomy 13- Patau syndrome • 1/7,000 births • Cleft lip/palate, flexed fingers with polydactyly, ocular hypotelorism, bulbous nose • Low-set malformed ears, small abnormal skull • Cerebral malformation, ie. holoprosencephaly • Microphthalmia; cardiac malformations; scalp defects; hypoplastic ribs; visceral and genital anomalies • Lethal in the 1st yr

  21. Trisomy 13 • Midline cleft lip/palate, microcephaly, hypotelorism, microphthalmos, bulbous nose, polydactyly, overlapping of fingers

  22. Trisomy 8, Mosaicism • 1/20,000 births • Long face, high prominent forehead, wide upturned nose, thick everted lower lip, microretrognathia, low-set ears, cleft palate • Osteoarticular anomalies common • Moderate MR

  23. MONOSOMIES • One representative of a chromosome is present • Nondisjunction: • One cell ends up with one copy (monosomic) and the other has 3 (trisomic) • Anaphase lag: • chromosome fails to move into the new daughter cell • All complete autosomal monosomies- lethal • Can survive in mosaic forms

  24. Sex Chromosome Anomalies: TURNER SYNDROME • 1/2,000 liveborn females • Loss of part or all of one sex chromosome • 45,X or may be mosaic. • Y material presence: gonads need removal (tumor) • Female, short stature, underdeveloped gonads • 10% have some Y chromosome material in cells • 1/3 dx at birth, other 2/3 dx with presentation of short stature or amenorrhea

  25. Sex Chromosome Anomalies: TURNER SYNDROME • Neonatal Exam • Neck webbing • Pedal/nuchal edema • Shield chest • Coarctation • Short stature

  26. Sex Chromosome Anomalies: KLINEFELTER SYNDROME • Extra X chromosome: 47,XXY • Male, relatively tall, gynecomastia, 2* sex development delayed • Dx after puberty • Have azoospermia and small testes- infertile • Others: 48,XXXY, and 49,XXXXY • Mosaic, having both normal and abnormal cell lines • Worsening MR with additional X • Abnormalities of Y also exist: XYY male • Have learning disabilities

  27. KLINEFELTER SYNDROME

  28. Sex Chromosome Anomalies:FRAGILE X SYNDROME • The fragile site located on the distal long arm of chromosome X (Xq27.3)- expanded segment • Most common form of MR in males • Other sites: FRAXE and FRAXF • Clinical: MR, macro-orchidism (puberty), long face, prominent jaw/ears • Females: Varying degrees of MR • Worsens with generation: Triple repeat sequence • Anticipation

  29. UNIPARENTAL DISOMY • Both chromosomes of a pair have been inherited from only one parent • Spinal muscular atrophy, CF, cartilage-hair hypoplasia, thalassemia, and Bloom syndrome • UPD for chromosome 15- some cases of Prader-Willi and Angelman syndrome

  30. Abnormalities of Chromosome Structure: DELETIONS • A piece of a chromosome is missing • Simple deletion or as a deletion with duplication of another chromosome segment • Usually associated with MR and malformations • Most commonly observed deletions: 4p-, 5p-, 9p-, 11p-, 13q-, 18p-, 18q- • May be observed in routine chromosome preparations • In submicroscopic deletions, can be detected only by using molecular probes

  31. Deletions • 4p–Wolf–Hirschhorn syndrome • “Greek helmet” facies with ocular hypertelorism, prominent glabella and frontal bossing; microcephaly, dolichocephaly, hypoplasia of the eye socket, ptosis, strabismus, nystagmus, epicanthic folds, cleft, beaked nose with prominent bridge, hypospadias, cardiac malformations, MR • 5p–Cri–du–chat syndrome • hypotonia, short stature, characteristic cry, microcephaly, protruding metopic suture, moonlike face, hypertelorism, bilateral epicanthic folds, high arched palate, wide nasal bridge, MR

  32. Wolf–Hirschhorn syndrome • Hypertelorism, frontal bossing; microcephaly, dolichocephaly, epicanthic folds, cleft lip and palate, beaked nose with prominent bridge

  33. Cri–du–Chat Syndrome • Small chin, flat nose • Protruding teeth • Thin Build • Moon facies • Hypertelorism • Bilateral epicanthic folds

  34. Deletions • 9p– • Craniofacial dysmorphology with trigonocephaly, slanted palpebral fissures, discrete exophthalmos, arched eyebrows, flat and wide nasal bridge, short neck with pterygium colli, genital anomalies, long fingers and toes, cardiac malformations, MR • 13q– • Low birthweight, FTT, MR. Facial features include microcephaly, flat wide nasal bridge, hypertelorism, ptosis, micrognathia. Ocular malformations are common. The hands have hypoplastic or absent thumbs and syndactyly

  35. Deletions • 18p– cephalic and ocular malformations, cleft lip and palate, MR. Most (80%) have only minor malformations • 18q– hypotonia with “froglike” position with the legs flexed, externally rotated, depressed midface and apparent protrusion of the mandible, deep–set eyes, short upper lip, everted lower lip (“carplike” mouth); antihelix of the ears is very prominent, MR, belligerent personality • 21q– hypertonia, microcephaly, downward–slanting palpebral fissures, high palate, prominent nasal bridge, large low–set ears, micrognathia, MR, may have skeletal malformations

  36. Microdeletions • 7q23–Williams • Round face with full cheeks, stellate pattern in iris, strabismus, supravalvular aortic stenosis, varying MR, and a very friendly personality • 8q24.1–Langer-Giedion • Sparse hair, multiple cone-shaped epiphyses, multiple cartilaginous exostoses, bulbous nasal tip, thickened alar cartilage, upturned nares, prominent philtrum, large protruding ears, MR

  37. Williams Syndrome • Round face with full cheeks and lips • MR • Very friendly personality

  38. Microdeletions • 11p13–Hypernephroma (Wilms tumor) • Aniridia, male genital hypoplasia of varying degrees, gonadoblastoma, long face, upward slanting palpebral fissures, ptosis, beaked nose, low–set poorly formed auricles, and MR • 16p13–Rubinstein-Taybi • microcephaly, ptosis, beaked nose with low-lying philtrum, broad thumbs and large toes, and MR

  39. Imprinting • Genomic imprinting: Phenotypic expression depends on the parent of origin for certain genes and chromosome segments • 15q11–13 (paternal) Prader-Willi • 15q11–13 (maternal) Angelman

  40. Prader-Willi • 1/15,000 live births • Hypotonia at birth, obesity, short stature, small hands and feet, hypogonadism, MR • Compulsive eaters • 15q11–13 deletion

  41. Prader-Willi

  42. Angelman Hypotonia, fair hair, midface hypoplasia, prognathism, seizures, jerky ataxic movements, uncontrollable bouts of laughter, severe MR

  43. Microdeletions • 20p12–Alagille syndrome • Bile duct paucity with cholestasis, heart defects, particularly pulmonary artery stenosis, ocular abnormalities (posterior embryotoxin), butterfly vertebrae, long nose with broad midnose • 22q11–DiGeorge-VCF • Hypoplasia or agenesis of the thymus and parathyroid glands, hypoplasia of auricle, abnormal facies, cardiac anomalies (truncus, TOF), cleft palate, short stature, behavioral problems

  44. TRANSLOCATIONS • 1/500 liveborn human infants • Involve the transfer of chromosomal material from one chromosome to another • Inherited or appear de novo, with no affected family members

  45. TRANSLOCATIONS • Robertsonian translocations • involve two acrocentric chromosomes that fuse near the centromeric region with subsequent loss of the nonfunctional short arms • Carriers phenotypically normal, but are at increased risk for miscarriages and abnormal offspring • Reciprocal translocations • Breaks in nonhomologous chromosomes with reciprocal exchange of the broken segments. • Carriers phenotypically normal but also at increased risk for miscarriages and abnormal offspring

  46. Other • INVERSIONS- chromosome breaks at two points, broken piece is then inverted and joined into the same chromosome • RING CHROMOSOMES- deletion at each end of the chromosome. The “sticky” ends then join to form the ring.

  47. Other • DUPLICATIONS- presence of extra genetic material from the same chromosome • Result from the abnormal segregation in carriers of translocations or inversions • INSERTIONS- piece of chromosome breaks at two points and is incorporated into a break in another part of a chromosome, requires 3 breakpoints

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