1. AUTOSOMAL & SEX CHROMOSOMAL DISORDERS

2. Autosomal Disorders
Cytogenetics- study of chromosomes and their abnormalities
Abnormalities of autosomes:
Alteration in number (Aneuploidy)
Alteration in structure
Deletion
Translocation
Ring chromosome
Shift
Inversion

3. Autosomal Chromosomal Disorders
Approximately 1 of every 160 liveborn infants has a demontrable chromosomal abnormality
Associated with 50% – 60% of first trimester spontaneous abortions
5% of stillbirths

4. Chromosomal Syndromes
Diagnosis based solely on clinical characteristic possible but not reliable because:
1. No single anomaly is pathognomonic for a given syndrome
2. Patterns of anomalies for different chromosomal syndromes share common features
3. Phenotypic variation exists among people with apparently identical abnormal karyotypes
4. Malformations associated with chromosomal aberrations also can be associated with normal karyotypes (etiologic heterogenecity)

5. Chromosomal Syndromes
Characteristics
Multiple malformations (craniofacial, skeletal, cardiac and genitourinary)
Abnormal facies, low set or malform ears, and certain digital anomalies (eg. Clinodactyly, polydactyly, syndactyly and single palmar creases)
Mental retardation
Intrauterine and postnatal growth retardation

6. Autosomal Disorders A. Alteration in number (Aneuploidy)
1. Down’s syndrome (Trisomy 21)
2. Pataus syndrome (Trisomy 13)
3. Edwards syndrome (Trisomy 18)
B. Alteration in structure
1. Cri-du-chat syndrome (Deletion of chr.5)
2. Wolf’s syndrome (Deletion of chr.4)

7. Down syndrome (Trisomy 21)
Most frequent
Characteristics craniofacial features:
Brachycepaly, oblique palpebral fissures, epicathal folds, broad nasal bridge, a protruding tongue, and small low-set ears with overlapping helix and prominent antihelix
At birth infants are hypotonic
Other features:
Iridial Brushfield spots, broad short fingers, clinodactyly, wide space between first two toes
Simian Line-Present in only 30%

8. Down syndrome (Trisomy 21)
Common internal anomalies (cardiac lesions and duodenal atresia)
Mental retardation-mean IQ 50 (range 25-70) if IQ is mosaicism is suspected
Growth retardation and hypotonia persist and older patients opened become obese
Females are fertile male are not

9. Down syndrome (Trisomy 21)

10. Down Syndrome

11. Down syndrome (Trisomy 21)
Mechanism of chromosomal abnormalities:
Nondisjunction – 93% - 95%
Related to late maternal age; paternal effect does not occur until the 5th - 6th decade
Mosaicism (46/ ) – 2% - 3%
Translocations 3% - 5%
Translocations show no definite relationship to parental age and maybe either sporadic or familial:
Involves chromosome nos usually nos. 14
The recurrence risk is approximately 10% if mom is translocation carrier but only 2% - 3% if dad is carrier

12. Edwards syndrome (Trisomy 18)
Frequency of 1/8000 live births
Characteristics facial features:
Microcephaly prominent occiput; low-set abnormal, somewhat pointed (Fawn like) ears and micrognathia
Skeletal anomalies:
Overlapping fingers short sternum, shield chest, narrow pelvis, “rocker bottom” feet with protrusion of calceneum, great hallux is short and dorsiflexed (hammertoe)
Cardiac and renal anomalies
At birth fetal movement if feeble
Mean survival time few months only
Severe mental retardation for those who survives

13. Pataus syndrome Trisomy 13
1/20,000 live births
50% affected children died in the first month
Fewer than 5% survives past three years of age
Characteristic features: holoprosencephaly, eye anomalies (microphthalmia, anopthalmia or coloboma), cleaf lip and palate, polydactyly and cardiac defects
Other features: cutaneous scalp defects, hemangiomata on face and forehead, low-set ears with abnormal helix, and rocker botton feet (convex soles and protruding heels)

14. Pataus syndrome Trisomy 13
80% associated with nondisjunction (47,+13)
Translocation occurs in 20% and involves chromosomes nos
If either parent is carrier recurrence risk of an affected offspring increases but less than for Down syndrome

15. Cri-du-chat syndrome Deletion of short arm of chromosome 5 (5p)
Peculiar cry (meowing of a cat) due to softening of larynx
During infancy facies become rounded (“moonlike”) because of microcephaly hypertelorism broad nasal bridge downward slanting of palpebral fissures, micrognathia and low-set ears

16. As patients ages facies become elongated and philtrum shorter
Hypertonicity
Severe mental and growth retardation
Can reach adulthood

17. Deletion of chr.4 (Wolf’s Syndrome)
Results from absence of distal portion of 4p
Distinctive facial appearance: forehead high characterized by facial bossing (glabella is prominent), hypertelorism, bilateral epicantus, downward slanting palpebral fissures and protruding eyes, nose has a square apex and length of bridge is equal to each width-resemble helmets
Microcephaly and micrognathia common
Other malformations include: cardiac defects, hypospadias, umbilical hernias
Hypotonia and seizures are regular features in neonates
Severe mental retardation

18. Sex Chromosome Disorders
Turner’s Syndrome - XO
Klinefelter’s Syndrome - XXY
Triple X female - XXX
Double Y Male - XYY

19. Non-disjunction of Sex Chromosomes
Failure of sex chromosomes to separate during cell division

20. Turner’s Syndrome Monosomy X Somatic anomalies
Short stature – less than 4’10”
Webbing of neck
Shield chest
CVS (coarctation of aorta/VSD)
Renal (horseshoe kidneys)
Bilateral lymphedema of feet due to hypoplasia of superficial vessels
Skeletal – Cubitus valgus (54%)
At birth: decreased birth weight, birth length close to 50th percentile
Normal intelligence

21. Turner’s Syndrome

22. Turner’s Syndrome ( Monosomy X )
Chromatin negative
Absent Barr body
Streak gonads – normal gonads replaced by white fibrous streak, Oocytes are usually completely absent
Lack of normal ovarian development leads to deficient secretion of sex steroids; estrogen and androgen levels ; FSH and LH levels 
At puberty, pubic and axillary hair failed to develop in normal amount; breasts contain little parenchymal tissue; external genitalia, vagina and uterus small

23. Klinefelter’s Syndrome
1/1000 live born males
Testicular feminization syndrome
Androgen deficiency (lack of normal secondary sexual development)
increased gonadotropin levels (FSH LH)
gynecomastia
Hyalinization of seminiferous tubules
Infertility
External genitalia well differentiated although in neonates, may show micro-penis
Scrotum well developed, vas deferens normal, prostate small
Slightly taller than normal, legs are relatively long compared with their trunk and arms
More likely to be retarded (IQ 50-85) or socially maladjusted, often passive poorly motivated because of poor self-image

24. Klinefelter’s syndrome

25. Klinefelter’s Syndrome ( 47XXY )

26. Triple X syndrome 1/1000 live born females
Maybe associated with subnormal intelligence – IQ is 16 points below those of their sibs, IQ is (5%)
1/3 show some mental or behavioral problems
Suboptimal fertility
Delayed menarche or premature ovarian failure

27. Trisomy X

28. XYY syndrome Approximately 1/1000 liveborn males Tall stature
Increased tendency to psychiatric problems
Antisocial behavior and mental retardation
Usually have grossly normal testis and normal external genitalia; Spermatogenic arrest is seen in approximately half the cases

29. XYY syndrome

30. 46 XYY

31. Thank you very much!