Chromosomal Disorders Fahd Alshehri Ali Almater Abdulrahman Alqahtani Abdullah Alshehri Abdullah Alshahrani Chromosomal Disorders

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.

Chromosomal disorders Number structure

Chromosomal disorders Number structure EUPLOIDY 46, XY

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 Monosomies

Trisomies Monosomies

Trisomies 3 copies of a particular chromosome

Trisomies Trisomy 21 Klinefelter Trisomy 18 Trisomy 13

Trisomies Trisomy 21 Klinefelter 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.

Trisomies Down syndrome Klinefelter Trisomy 18 Trisomy 13

Trisomies Down syndrome Klinefelter Trisomy 18 Trisomy 13

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.

Trisomies Down syndrome Klinefelter Edwards syndrome Trisomy 13

Trisomies Down syndrome Klinefelter Edwards syndrome Trisomy 13

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

Trisomies Down syndrome Klinefelter Edwards syndrome Patau syndrome

Trisomies Down syndrome Klinefelter 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

Trisomies Monosomies

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: Neck: webbed. Chest: 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.

Chromosomal disorders Number structure

Chromosomal disorders Number structure

Deletion Duplication

Loss of a portion of chromosome Deletion Duplication Loss of a portion of chromosome

Deletion Duplication

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: Congenital heart diseases. 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. 7q11 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 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

Deletion Duplication

Duplicated part of a chromosome, within a chromosome Deletion Duplication Duplicated part of a chromosome, within a chromosome

Deletion Duplication

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