1. Chromosomal abnormalities Lecturer: prof. Pavlyshyn H.A., MD

2. Chromosomal abnormalities  Generally 5-6/1000 the incidence of chromosomal abnormalities.  These abnormalities are caused by errors in the number or structure of chromosomes.  Many children with a chromosomal abnormality have mental and/or physical birth defects.  Some chromosomal abnormalities result in miscarriage or stillbirth.  50% of spontanous abortion are chromosomal abnormal.

3. Chromosomal Disorders  The defects are classified as abnormalities of number or structure and content (autosomes, sex chromosomes)  Numerical defects - are abnormalities of the euploid number of chromosomes (46),  Examples: trisomy 21 (Down syndrom),  trisomy 18, trisomy 13,  Klinefelter syndrome (47,XXY)  Turner syndrome (45, X)

4. Chromosomal Disorders  The defects are classified as abnormalities of number or structure and content (autosomes, sex chromosomes)  Structural defects - result from chromosome breakage and rearrangement.  Possibilities include unbalanced translocation, deletion, duplication, inversion, isochromosome and centric fragment.  Examples: cri du chat syndrome (5q deletion), Wilms tumor with aniridia (11 q deletion), Prader-Willi syndrome

5. Single Chromosome Disorders 1.Deletion - portions of the chromosome are lost (genetic material is missing); 2. Duplication - genetic material is present twice; 3. Inversion - parts of the chromosome are flipped (genetic material is “flipped”)

6. Two Chromosome Disorders ( Both types are called “translocation”) Insertion Genetic material is added from another chromosome when cells go through meiosis, parts of the chromosomes stick together and switch Translocation Material is swapped with another chromosome

7. Chromosomal Disorders  M osaicism – refer to the presence of two or more cell lines with different chromosome compositions in an individual.  Mosaicism occurs as a result of chromosomal non-disjunction after fertilization ( when cells go through meiosis the chromosomes don’t separate correctly and either too many or not enough are passed on).  The genetic changes is not carried by parents, so the risk for recurrence of a child with mosaicism is usually negligible.

8. Types of defects  Trisomy 21 (95 %);  Some cases result from translocation  More rarely, mosacism (about 2%) Down Syndrome (Trisomy 21) is the most common autosomal trisomy compatible with life  Karyotype = 47,XX+21 or 47,XY+21

9. DOWN SYNDROME Clinical features  Characteristic appearance with dysmorphic features;  General. Hypotonia with tendency to keep mouth open and protrude the tongue;  Excessive mobility, flexibility of joints.  Relatively small, short stature with awkward gait.

10. DOWN SYNDROME Clinical features  Central Nervous System  Mental retardation (mean IQ< 50)  Developmental delay  Hypotonia  Alzheimer-like dementia  Signs of hypothyroidism  Leukemia

11. DOWN SYNDROME Craniofacial  Microcephaly, brachycephaly with relatively flat occiput  Flat facial profile  Short, up slanting palpebral fissures  Small nose with flat nasal bridge;  Brushfield, speckled spots of the iris  Inner epicanthal folds Small mandible, small mouth with protruding tongue Small ears with abnormal shape Late closure of fontanels ;

12. DOWN DISEASE Flat facial profile Short, up slanting palpebral fissures Small nose with flat nasal bridge; Inner epicanthal folds Short, broad hands Stubby fingers

13. Down Syndrome Rough skin Mentally retarded Small round face Protruding tongue Impotency in males Short lifespan “Happy children”

14. The palm of patient with Down syndrome crease simian

15. DOWN SYNDROME PRINCIPAL FEATURES IN NEONATE  Hypotonia 80%  Poor Moro reflex 85%  Hyperflexibiliry of joints 80%  Excess skin on back of neck 80%  Flat facial profile 90%  Slanted palpebral fissures 80%  Anomalous auricles 60%  Dysplasia of pelvis 70%  Dysplasia of mid phalanx fifth finger 60%  Simian crease 45%

16. Down syndrome With early intervention and special education, many learn to read and write and participate in various childhood activities.

17.  Incidence 1/8000  Sever Mental retardation and many physical birth defects  >90% dead in 1 st year Trisomy 18 Edwards syndrome

18. Trisomy 18 chromosome Edwards syndrome Polyhydramnios, Small placenta Intrauterine growth retardation; Craniofacial dysmorphism (strawberry-shaped head) Microcephaly; Micrognathia (small mandible); Small face with prominent occiput

19. Edwards syndrome (18+) Overlap of second finger on third, fourth finger on fifth Fixed finger contractures

20. Trisomy 18 Edwards syndrome  Weak cry  Small sternum, small nipples and pelvis  Hypoplasia of skeletal muscle, subcutaneous and adipose tissue.  CHD, VSD, PDA and horseshoe kidney, omphalocele

21. Edwards syndrome (18+) Rocker-bottom feet Hypogonadism - small penis, cryptorchidism

22. Trisomy 13 Patau syndrome (13+)  severe birth defects  mental retardation

23. Trisomy 13 Patau syndrome (13+)  IUGR – intrauterine growth retardation  Open scalp lesion, scalp defect (cutis aplasia)  Cleft palate (may be bilateral)  Microcephaly  Malformed ears  Microphthalmos, coloboma of the eyes

24. Patau syndrome (13+) variable defect in facial development Microcephaly Cleft palate

25. Trisomy 13 Patau syndrome (13+)  CNS malformations, midline brain defect, holoprosencephaly  CHD - variety of cardiac defect (VSD, ASD, TGV

26. Newborn boy with diagnosed Patau syndrome (cleft lip and palate, polydactyly of left hand, atrial septal defect) Boy 5 yrs old with Patau syndrome (congenital deafness and blindness)

27. Patau syndrome (13+) PROGNOSIS  50% of patients die before 1 month of age  70 % - die before age 6 month,  90 % - die before age 1 year

28. Sex chromosome disorders involve abnormalities in the number or structure of the X or Y chromosome  Affects 1 in 2500 newborn girls;  One X chromosome is either missing or abnormal;  In 55% of girls who have Turner-syndrom there is a 45, X karyotype;  In 25 % of patients – the structure of one of the X chromosomes is altered (deletion, duplication).  in 15 % of patients – mosacism; Turner syndrome

29. XO SYNDROME (Turner Syndrome) Short Female, Broad Chest with Wide Space of Nipples, Congenital Lymph edema  Dysmorphic features – lymphedema of hands and feet at birth,  shield-shaped chest,  webbing of the neck,  appearance of short neck  low posterior hairline,  Cubitus valgus (increased carrying angle)  Short stature (height adult – 135 cm)  Multiple pigmented nevi

30. Webbing Neck Lymphedema

31. Turner syndrome Functional and structural abnormalities  GONADAL dysgenesis is present in 100% of patients, is associated with primary amenorrhea and lack of pubertal development due to absence of ovarian hormones.  Females are unable to become pregnant  GONADOBLASTOMA (tumor of abdominally located gonads with Y-containing cells) in patients who have a cells line with Y chromosome.

32. continue  RENAL anomalies (40 %) include duplication of the collecting system and horseshoe kidney.  CHD (20 %) – AS, CA, bicuspid aortic valve. Dissecting aortic aneurysm in young adulthood may be a serious complication.  Thorax. Broad chest with widely spaced nipples that may be hypoplastic; often mild pectus excavatum;

33. Turner syndrome Short stature Tendency to become obese

34. Hypogenitalism and Hypogonadism. Long Legs, Dull Mentality, and/or Behaviorals Klinefelter syndrome  80 % - children with Klinefelter syndrome have a male karyotype with an extra chromosome X-47,XXY  20% - have multiple sex chromosome aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY), mosaicism (46,XY/47,XXY);  20% of aspermic adult male (blocked spermatogenesis

35. Klinefelter syndrome  Puberty occurs at the normal age, but the testes remain small.  Patients develop secondary sex characters late;  50% develop gynecomastia.  They have taller stature.  Because many patients with Klinefelter syndrome are phenotypically normal until puberty, the syndrome often goes undiagnosed until they reach adulthood, when their infertility aids in their clinical identification.  Patients with 46,XY/47,XXY have a better prognosis for testicular function.

36. XXY syndrome. A, 9 year XXY child: note is small penis, long legs. B, 16 year untreated XXY adolescent; note the gynecomaslia and scoliosis. C, 21 year untreated XXY adult; note the obesity and hypovirilization.

37. Klinefelter syndrome  Their intelligence shows variability and ranges from above to below average.  Persons with KS can show behavioral problems, learning disabilities, and deficits in language. Problems with self- esteem are often the case with adolescents and adults. Substance abuse, depression, and anxiety have been reported in adolescents with Klinefelter syndrome.  Those who have higher X chromosome counts show impaired cognition. It has been estimated that each additional X chromosome reduces the IQ by 10-15 points, when comparing these persons with their normal siblings.  The main effect is seen in language skills and social domains.