Common genetic syndromes

Question 1

Deformation

Answer 1

An abnormal mechanical force which distorts an otherwise normal structure

Eg mild talipes (club foot), plagiocephaly in twins

Question 2

Disruption

Answer 2

An abnormal structure of an organ or tissue as a result of external factors disturbing the normal developmental process (ischemia, infection, trauma)

Eg amniotic band syndrome

Question 3

Malformation

Answer 3

Primary structural defect of an organ which results from an inherent abnormality in development

Eg cleft palate, neural tube defect

Question 4

Dysplasia

Answer 4

An abnormal organisation of cells into tissue in all parts of the body in which that particular tissue is present

Eg ectodermal dysplasia, skeletal dysplasia

Question 5

Syndrome

Answer 5

Consistent patterns of abnormalities for which there is often a known underlying cause

Eg Down (chromosomal), Van Der Woude (single gene), Amniotic Band Syndrome (disruption)

Question 6

Sequence

Answer 6

Consequence of a cascade of events initiated by a single primary factor

Eg Potter sequence, Pierre Robin sequence

Question 7

Potter sequence

Pathophysiology

Answer 7

Renal agenesis/leaking of amniotic fluid -> oligohydramnios -> deformation due to pressure effects -> lung hypoplasia -> death

Question 8

Pierre Robin sequence
Causes
Pathophysiology

Answer 8

Causes include collagen syndrome (stickler), generalised undergrowth of mandible, neurogenic hypotonia, oligohydramnios

Mandibular hypoplasia -> micrognathia -> retroglossoptosis -> U shaped cleft palate

Question 9

Association

Answer 9

Certain malformations tend to occur together but are not explained by sequence or syndrome

Eg VACTERL

Question 10

VACTERL

Answer 10

Vertebral defects
Anus imperforatum
Cardiac defects
Tracheo-Esophageal fistula
Renal defect/retarded growth
Limb defects

Question 11

What is the cause of dysplasia?

Answer 11

Single gene disorder

Question 12

What is the cause of malformation?

Answer 12

Single gene disorder
Chromosome abnormality
Multifactorial disorder
Teratogen

Question 13

What is the cause of disruption?

Answer 13

Teratogen

Abnormal uterine environment

Question 14

What is the cause of deformation?

Answer 14

Abnormal uterine environment

Question 15

Preconceptual causes of birth defects

Answer 15

Chromosomal
Single gene
Multifactorial

Question 16

Postconceptual causes of birth defects

Answer 16

Drugs and chemicals
Infections
Maternal illness
Physical agents

Question 17

Single gene disorders

Answer 17

AD
AR
XD
XR
Other (mitochondrial)

Question 18

Neurofibromatosis type 1

General

Answer 18

Autosomal dominant
1/3000
NF1 locus on chromosome 17 + gene cloned
Recurrence risk 50%

Question 19

Neurofibromatosis type 1

Clinical features

Answer 19

Cafe au lait patches more than 5 of 0.5cm-1.5cm
Neurofibroma
Lisch nodules
Intellectual disability
Seizures
Malignant changes
Learning disorders

Question 20

Common AD conditions

Answer 20

NF1
Achondroplasia
Marfan syndrome
Huntington’s disease

Question 21

Oculocutaneous albinism

General

Answer 21

Autosomal recessive
Hereditary defect in metabolism of melanin -> decrease/abscence of pigment in the skin, mucosa, hair +/- eyes
P gene chromosome 15
OCA2 1/4000
Recurrence risk 25%

Question 22

Oculocutaneous albinism

Clinical features

Answer 22

Depigmented skin and hair
Skin sensitivity
Nystagmus
Retina depigmented
Visual problems
Increased skin cancer susceptibility

Question 23

Oculocutaneous albinism

Management

Answer 23

Limit skin sun exposure (protective clothing, sunscreen lotion, glasses)
Blind school
Suspicious skin lesions need attention
Dermatologist + ophthalmologist visits yearly
Genetic counselling

Question 24

Common AR conditions

Answer 24

OCA
Spinal muscular atrophy
Thalassemia
Sickle cell disease
CF
IEM

Question 25

Duchenne muscular dystrophy | General

Answer 25

``` XR 1/3500 No ethnic variation DMD gene on X.p21 dystrophin product Carrier testing in females Becker's MD is a milder phenotype ```

Question 26

Duchenne muscular dystrophy | Clinical features

Answer 26

``` Muscle weakness 3/5yo Positive Gower's sign Delay in walking Wheelchair bound by 11yo Death at +/- 18yo Pseudohypertrophy of calf muscles + wasting of proximal muscles Mild to moderate intellectual impairment Cardiac muscle involvement ```

Question 27

Common XR conditions

Answer 27

Duchenne muscular dystrophy Hemophilia A/B Fragile X syndrome

Question 28

X-linked dominant conditions

Answer 28

Rett syndrome | Goltz syndrome

Question 29

Mitochondrial conditions

Answer 29

Myopathy Blindness Deafness

Question 30

Imprinting disorders

Answer 30

Angelman syndrome | Prader-Willi syndrome

Question 31

Chromosomal disorders | Numerical abnormalities

Answer 31

``` Down syndrome (46XY +21) Patau syndrome (T13) Edward syndrome (T18) Turner syndrome (45X) Klinefelter syndrome (47XXY) ```

Question 32

Chromosomal disorders | Structural abnormalities

Answer 32

``` Balanced/unbalanced translocations Deletions Duplications Inversions Insertions Ring chromosomes ```

Question 33

Down syndrome | General

Answer 33

Most common cause congenital mental disability in developed countries 1/600 Assoc with AMA >35yo

Question 34

Down syndrome | Types

Answer 34

Non-dysjunction 92%-95% Translocation (5%) Mosaic (3%)

Question 35

Down syndrome | Clinical features

Answer 35

``` Small brachycephalic head Third fontanelle Increased nuchal skin Facial dysmorphism Open mouth Protuberant tongue Epicanthic folds Upslanting palpebral features Short stature Prominent hypotonia Short stubby fingers Single palmar crease Clinodactyly Sandal gap Cardiac defects Skeletal defects GIT defects Mental retardation Increased haemotological + endocrine risk eg thyroid ```

Question 36

Down syndrome | Management

Answer 36

``` Stimulation programs Special schooling Sheltered employment Surgery for cardiac defects Recurrent infections ```

Question 37

Down syndrome | Recurrence risk

Answer 37

Non-dysjunction 1% and increases with AMA Translocation 10% if mother 2% if father Mosaic <1%

Question 38

Down syndrome | Antenatal testing

Answer 38

``` Maternal serum screening Nuchal transparency on US Chorionic villi sampling Amniocentesis Fetal DNA in maternal circulation (non-invasive prenatal) ```

Question 39

Edward syndrome

Answer 39

T18 >130 different noted abnormalities Causes include non-dysunction, translocation, mosaicism, partial T18

Question 40

Turner syndrome

Answer 40

45X 1/2500 females Most conceptuses die early Most likely paternal X chromosome missing Usually sporadic and AMA not significant Does not cause mental deficiency - look for another defect

Question 41

Klinefelter syndrome

Answer 41

47XXY 1/500 Most common single cause for hypogonadism and infertility

Question 42

Multifactorial inheritance | Examples

Answer 42

Neural tube defects Cleft lip/palate Congenital cardiac defects Diabetes, HT, other common disorders

Question 43

Neural tube defects | General

Answer 43

Multifactorial Anencephaly/encephalocoele/spina bifida Failure of neural tube to close by end of 4th week postconception Genetic predisposition + folic acid deficiency (environment)

Question 44

Neural tube defects | Recurrence risk

Answer 44

1 affected child 5% 2 affected children 10% 1 parent affected 4% Folic acid preconceptually reduces risk 72%

Question 45

Neural tube defects | Prenatal diagnosis

Answer 45

AFP on maternal and amniotic fluid | Maternal U/S

Question 46

Teratogen

Answer 46

A drug, chemical infectious or physical agent, maternal disease or metabolic agent that by acting on the developing fetus causes a structural or functional abnormality (congenital malformation or birth defect) present at birth

Question 47

Susceptible stages of development for teratogenesis

Answer 47

``` 0-17 days not susceptible 18-30 days highest susceptibility 31-60 days susceptibility continues 2nd trimester decreasing susceptibility 3rd trimester minimal susceptibility ```

Question 48

Foetal alcohol syndrome | Clinical presentation

Answer 48

``` Growth deficiency: Small stature Microcephaly (mental deficiency, poor fine motor, hyperactivity) Facial dysmorphism (short nose, micropthalmia, inner epicanthic folds, smooth philtrum, thin vermillion border, small midface) Other (cardiac, skeletal defects) ```

Question 49

Foetal alcohol syndrome | Etiology

Answer 49

``` Most common teratogen Heavy alcohol exposure Safe level unknown Bingeing more harmful Abstain! ```

Question 50

Teratogen examples

Answer 50

``` Maternal disease Maternal infection Environmental chemicals Radiation Alcohol Drugs ```

Question 51

Maternal diseases causing teratogenicity

Answer 51

``` DM Phenylketonuria Epilepsy Hyperthermia Hyperthyroidism Starvation ```

Question 52

Maternal infections causing teratogenicity

Answer 52

``` Toxoplasmosis Rubella CMV HSV Syphilis HVZ Parvovirus HIV ```

Question 53

Drugs causing teratogenicity

Answer 53

``` Anticoagulants (warfarin) Anticonvulsants (phenytoin) Anticancer drugs Antibiotics (tetracycline) Hormones (androgens, diethylstilbestrol) Psychiatric drugs (lithium) Vitamin A analogues (roaccutane) Salicylates (aspirin) ```