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 21C|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 18C|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 13C|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 syndromeC|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 syndromeC|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 syndromeC|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 syndromeC|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 syndromeC|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 syndromeC|P:•Iris coloboma•Mild MR•Behavioral disturbances•Ocular hyper-telorism•Downward slanting palpebral fissures•Micrognathia•Anal atresia with recto-vestibular fistual & renal agenesis