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Chromosomal Disorders
Fahd AlshehriAli AlmaterAbdulrahman AlqahtaniAbdullah AlshehriAbdullah Alshahrani
Case scenario
• A 36-years old woman, G3P2 with one prenatal visit at 35 weeks but otherwise uneventful prenatal course delivers a 3900g female child.
• At birth the infant is noted to have decreased tone, upslanting palpebral fissures and epicanthal folds.
• The extremities show single transverse palmar crease
So,
• Advanced maternal age• Hypotonia• Dysmorphic features: palpebral fissures epicanthal folds simian crease
• What do you think?• Down Syndrome.
• What is your next step?• Karyotype
• What is the management?• Variable
• How to prevent?• Genetic counselling.
Screening?
• Should be offered ONLY when termination of pregnancy is acceptable.
What is “chromosomal disorders”?
• Any disorder that results in an abnormal chromsomal sets.
46, XYEUPLOIDY
Numerical chromosomal disorders
• Euploidy: = 2n = 46 chromosomes• Aneuploidy: ≠ 2n is the state of not having euploidy Examples: Down syndrome Turner syndrome
Risk factors
1- advanced maternal age: Increases the incidence of meiotic errors (non-disjunction). 2- history of unexplained 1st TM abortions. 3- exposure to irradiations. 4- previous baby with chromosomal disorder.
Aetiology
• Non-disjunction• Abnormal separation of
chromosomes during cell division. • The result:• Extra chromosome = trisomy• Missing a chromosome = monosomy
Trisomies
3 copies of a particular chromosome
Trisomy 21
• Down syndrome• 47,XX+21 • 47,XY+21
• The MC abnormality of chromosomal number.
Trisomy 21
• 96% non-disjunction • 4% translocation of the long
arm of chromosome 21 to chromosome 22
Trisomy 21
C|P:•Hypotonia: improves with age
•Characteristic facial features: Flattened occiput Upslanting palpebral fissures. Epicanthal folds. Large protruding tongue.
•Short broad hands.•Transverse palmar crease.•Wide gap between the first and second toes.
Trisomy 21
• Intellectual disability• 40% congenital heart
disease: The cause of early-life deaths• 10% GI anomalies: Duodenal atresia
Trisomy 21
•Increase risk of leukemia.•More susceptible to infection.•More risk of cataract.•Early-onset Alzheimer disease.
Trisomy 18
• Edwards syndrome.• 2nd MC.• 47,XX +18 • 47,XY +18• ˃ 95% aborted.• ˂ 10% survive the 1st
year.
Trisomy 18
C|P:•LBW•MR•Hypertonia•Prominent occiput•Low-set malformed ears•Short stature•Clenched fists.
Trisomy 18
• Microcephaly, micrognathia.
• Congenital heart disease.
• Rocker-bottom feet, hammer toe.
• Omphalocele.
Trisomy 13
• Patau syndrome.• 3rd MC.• 47,XX +13• 47,XY +13• ˂ 8% survive the 1st
year.
Trisomy 13
C|P:•LBW•Microcephaly•Midline facial defects•CNS anomalies & MR
Trisomy 13
•Male: Hypospadias & cryptorchidism•Female: Hypoplastic labia minora
Klinefelter syndrome
• 47,XXY• MC cause of
hypogonadism in males• Caused by non-
disjunction
Klinefelter syndrome
C|P:•With puberty: Presence of Pubic & axillar hair with testis of an infantile volume. Tall & long limbs. Slim. Osteopenia, osteoporosis. Gynecomastia
Klinefelter syndrome
↑ LH ↓ testesterone So, affected individuals are infertile
Monosomies
ONLY one copy of a particular chromosome
Monosomies
Turner syndrome
Turner syndrome
• The ONLY monosomic viable condition.
• 45, X0• 99% aborted, constituting 13%
of all 1st trimester abortions.• 25% mosaic.• Caused by mitotic non-
disjunction (post-conceptus mitotic non-disjunction event).
So, maternal age is not a risk factor.
Turner syndrome
C|P:•Facial characteristics: Low-set malformed ears. Triangular face. Flattened nasal bridge. Epicanthal folds.•Neck: webbed.•Chest: Shield-shaped. Widened inter-nipple distance.
Turner syndrome
• Heart:MC: coarctation of aorta• Kidneys:Horse-shoe kidneys.• Stature: short• Hypothyroidism.
Turner syndrome
• Streak gonads.• Amenorrhea.• Lack of 2ry sexual
characteristics.
Loss of a portion of chromosome
Syndromes involving chromosomal deletions
• 1. Cri du Chat syndrome• 2. Williams syndrome• 3. WAGR syndrome• 4. Prader-Willi syndrome• 5. Angelman syndrome
Syndromes involving chromosomal deletions
• 1. Cri du Chat syndrome• 2. Williams syndrome• 3. WAGR syndrome• 4. Prader-Willi syndrome• 5. Angelman syndrome
Cri du Chat syndrome
• Deletion of the short arm of ch.5
• Most cases: de-novo.
Cri du Chat syndrome
C|P:•LBW•Hypotonia•FTT•Develpmental delay•Microcephaly
Cri du Chat syndrome
• Dysmorphism: Hypertelorism. Epicanthal folds. Downward obliquity of the
papebral fissures. Low-set malformed ears. Cleft lip & palate.
• Congenital heart diseases.
Syndromes involving chromosomal deletions
• 1. Cri du Chat syndrome• 2. Williams syndrome• 3. WAGR syndrome• 4. Prader-Willi syndrome• 5. Angelman syndrome
Williams syndrome
• Deletion of ch. 7q11Most cases: de-novo.
Williams syndrome
C|P:•Congenital heart diseases 80%•Stature: short•Elfin facies•Moderate MR (IQ= 50-60)•Autism 10%•hypercalcemia•Coktail party personality
Syndromes involving chromosomal deletions
• 1. Cri du Chat syndrome• 2. Williams syndrome• 3. WAGR syndrome• 4. Prader-Willi syndrome• 5. Angelman syndrome
WAGR syndrome
• Deletion of 11p13
WAGR =• Wilms tumor• Aniridia• Genito-urinary
anomalies:• Mental Retardation
Syndromes involving chromosomal deletions
• 1. Cri du Chat syndrome• 2. Williams syndrome• 3. WAGR syndrome• 4. Prader-Willi syndrome• 5. Angelman syndrome
Prader Willi & Angelman syndromes
• Both are due to deletion of ch. 15q11
• Both are caused by “genomic imprenting”.
NON-HERITABLE change in DNA.
Prader Willi & Angelman syndromes
If Paternal ch. 15 is missing, either due to: 1- Deletion of paternal ch. 15 2- Uni-parental disomy: Duplication of maternal ch. 15 in absence of the paternal chromosome
The result is : Prader-Willi syndrome
Prader Willi & Angelman syndromes
If Maternal ch. 15 is missing, either due to: 1- Deletion of maternal ch. 15 2- Uni-parental disomy: Duplication of paternal ch. 15 in absence of the maternal chromosome
The result is : Angelman syndrome
Prader-Willi syndrome
C|P:•MR•Hypotonia:Improved during the 1st year
•Almond-shaped eyes•Small hands & feet•Hypogonadotropic hypogonadism•obesity
Angelman syndrome = Happy Puppet syndrome
C|P:•MR•Ataxic movements:Resembling a puppet gait•Seizures:Characterized by inappropriate laughter
Duplicated part of a chromosome, within a chromosome
Syndromes involving chromosome duplication
• 1. Inverted duplication chromosome 15
• 2. Cat-Eye syndrome
Syndromes involving chromosome duplication
• 1. Inverted duplication chromosome 15
• 2. Cat-Eye syndrome
Inverted duplication chromosome 15
• 40% of syndromes involving chromosome duplication.
• 47,XX +inv dup (15q)• 47,XY +inv dup (15q)
• The larger the lesion, the worse the prognosis
Syndromes involving chromosome duplication
• 1. Inverted duplication chromosome 15
• 2. Cat-Eye syndrome
Cat-Eye syndrome
• Duplication of 22q11
• Iris coloboma = cat-eye appearance
Cat-Eye syndrome
C|P:•Iris coloboma•Mild MR•Behavioral disturbances•Ocular hyper-telorism•Downward slanting palpebral fissures•Micrognathia•Anal atresia with recto-vestibular fistual & renal agenesis