Chromosomal Disorders Fahd Alshehri Almater Abdulrahman Alqahtani Abdullah

Chromosomal Disorders Fahd Alshehri Almater Abdulrahman Alqahtani Abdullah Alshehri Abdullah Alshahrani

Case scenario • A 36 -years old woman, G 3 P 2 with one prenatal visit at 35 weeks but otherwise uneventful prenatal course delivers a 3900 g 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.

Chromosomal disorders Number structure

Chromosomal disorders Y X EUPLOIDY , 6 4 Number structure

Numerical chromosomal disorders • Euploidy: = 2 n = 46 chromosomes • Aneuploidy: ≠ 2 n 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 1 st 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 Monosomies

Trisomies 3 copies of a particular chromosome

Trisomy 21 Klinefelter Trisomies Trisomy 18 Trisomy 13

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.

Down syndrome Klinefelter Trisomies Trisomy 18 Trisomy 13

Trisomy 18 • • • Edwards syndrome. 2 nd MC. 47, XX +18 47, XY +18 ˃ 95% aborted. ˂ 10% survive the 1 st 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.

Down syndrome Klinefelter Trisomies Edwards syndrome Trisomy 13

Trisomy 13 • • • Patau syndrome. 3 rd MC. 47, XX +13 47, XY +13 ˂ 8% survive the 1 st year.

Trisomy 13 C|P: • LBW • Microcephaly • Midline facial defects • CNS anomalies & MR

Trisomy 13 • Male: Hypospadias & cryptorchidism • Female: Hypoplastic labia minora

Down syndrome Klinefelter Trisomies Edwards syndrome Patau syndrome

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

Trisomies Monosomies

Monosomies ONLY one copy of a particular chromosome

Monosomies Turner syndrome

Turner syndrome • The ONLY monosomic viable condition. • 45, X 0 • 99% aborted, constituting 13% of all 1 st trimester abortions. • 25% mosaic. • Caused by mitotic non-disjunction (post-conceptus mitotic nondisjunction 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 2 ry sexual characteristics.

Chromosomal disorders Number structure

Deletion Duplication

Loss of a portion of chromosome Deletion Duplication

Deletion Duplication

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. 7 q 11 Most 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 11 p 13 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. 15 q 11 • 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 1 st 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

Deletion Duplication

Duplication Duplicated part of a chromosome, within a chromosome Deletion

Deletion Duplication

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 (15 q) • 47, XY +inv dup (15 q) • 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 22 q 11 • 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