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

2. Chromosomes Normal cells of humans contain 46chromosomes;
occurring in pairs and numbered from
1 (the largest) to 22 (the smallest);
The chromosomes may be divided into two major types: the 44 autosomes and the 2 sex chromosomes.
Autosomes are indistinguishable in males and females, who are genetically distinguished on the basis of their complement of sex chromosomes.
Males have an X and a Y chromosome, and females have two X chromosomes.

3. What are chromosomes?
Chromosomes are tiny, string-like structures in cells of the body that contain the genes.
Each person normally has 23 pairs of chromosomes,
or 46 in all.
This is a normal karyotype of human chromosomes. A karyotype is a picture of chromosomes lined up to look at and compare.

5. 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.

6. 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)

7. 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

8. Single Chromosome Disorders
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”)

9. 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

10. Chromosomal Disorders
Chromosomal non-disjunction: when cells go through meiosis the chromosomes don’t separate correctly and either too many or not enough are passed on.

11. Chromosomal Disorders
Mosaicism – 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.

12. When to suspect it Unexplained infertility Multiple abortion >2
Prior case of defective baby
Presence of congenital anomalies (mental retardation, multiple congenital abnormalities, dysmorphic features)
45% have minor single anomalies
9% 3 minor anomalies
1.5% HAVE major anomaly
2 or more major anomalies may represent genetic syndrome or chromosomal abnormalities

13. Classification of chromosomes diseases
Sex linked (Klinefelter syndrome, Turner syndrome, Trisomy X);
Autosomal inheritance

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

16. Risk correlate with maternal age
<25 y/o 1/1600
35 to 39 y/o 1/270
30 to 34 y/o 1/800
> 40 y/o 1/80

17. 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.

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

19. 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;

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

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

22. The palm of patient with Down syndrome
crease simian

23. Cardiac – CHD: PDA, VSD, ASD,
Atrioventricular Septal Defect
(AV-Canal) ;

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

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

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

28. Trisomy 18
severe birth defects + mental retardation

29. 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

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

31. 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

32. Small sternum, small nipples

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

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

35. 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

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

37. Polydactyly of feet

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

40. 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)

41. 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

42. Sex chromosome disorders involve abnormalities in the number or structure of the X or Y chromosome
Turner syndrome
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;

43. Prenatal diagnostics of Turner syndrome
Blister hyhrome of neck area and edema of fetus

44. 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

45. Webbing Neck Lymphedema
Криловидна складка на шиї
Webbing Neck Lymphedema

46. Functional and structural abnormalities
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.

47. Congenital anomaly of uterus and testis

48. 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;

49. Tendency to become obese
Turner syndrome
Short stature
Tendency to become obese

50. PROGNOSIS Depends on the type and severity of malformations
Life span probably
normal in most cases

51. Klinefelter syndrome
Hypogenitalism and Hypogonadism. Long Legs, Dull Mentality, and/or Behaviorals
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

52. XXY SYNDROME, KLINEFELTER SYNDROME

53. 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.

54. 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.

55. 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 points, when comparing these persons with their normal siblings.
The main effect is seen in language skills and social domains.

56. Deletion 5p syndrome (cri-du-chat , cat’s cry syndrome)
The cause of this syndrome is a deletion of part of the short arm of chromosome 5.
ABNORMALITIES
Low birth weight (less than 2.5 kg)-72%
Slow growth-100%
Cat-like cry-100%
Mental deficiency-100%
Hypotonia-78%

57. Deletion 5p syndrome (cri-du-chat , cat’s cry syndrome)
Cat-like cry in infancy, microcephaly, downward slant of the palpebral fissures

58. Deletion 5p syndrome (cri-du-chat , cat’s cry syndrome) Clinical features
Beginning in the newborn period and continuing through the first few months of life
Children affected with this disorder have a striking cat-like cry that is caused by laryngeal hypoplasia.

59. Prenatal diagnostic of chromosomal diseases