Chromosomal disease in human

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.

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
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”)

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. 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

16. Risk correlate with maternal age
• <25 y/o 1/1600
• 30 to 34 y/o 1/800
• 35 to 39 y/o 1/270
• > 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
Short, up slanting palpebral fissures
Small nose with flat nasal bridge;
Inner epicanthal folds
•Short, broad hands
• Stubby fingers

21. 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 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%

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

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

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

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
 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

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

46. 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. 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. 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

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.

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 10-15
points, when comparing these persons with their normal
siblings.
 The main effect is seen in language skills and social
domains.

56. ABNORMALITIES
 Low birth weight (less than 2.5
kg)-72%
 Slow growth-100%
 Cat-like cry-100%
 Mental deficiency-100%
 Hypotonia-78%
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.

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

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