Common genetic syndromes Flashcards
Deformation
An abnormal mechanical force which distorts an otherwise normal structure
Eg mild talipes (club foot), plagiocephaly in twins
Disruption
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
Malformation
Primary structural defect of an organ which results from an inherent abnormality in development
Eg cleft palate, neural tube defect
Dysplasia
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
Syndrome
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)
Sequence
Consequence of a cascade of events initiated by a single primary factor
Eg Potter sequence, Pierre Robin sequence
Potter sequence
Pathophysiology
Renal agenesis/leaking of amniotic fluid -> oligohydramnios -> deformation due to pressure effects -> lung hypoplasia -> death
Pierre Robin sequence
Causes
Pathophysiology
Causes include collagen syndrome (stickler), generalised undergrowth of mandible, neurogenic hypotonia, oligohydramnios
Mandibular hypoplasia -> micrognathia -> retroglossoptosis -> U shaped cleft palate
Association
Certain malformations tend to occur together but are not explained by sequence or syndrome
Eg VACTERL
VACTERL
Vertebral defects Anus imperforatum Cardiac defects Tracheo-Esophageal fistula Renal defect/retarded growth Limb defects
What is the cause of dysplasia?
Single gene disorder
What is the cause of malformation?
Single gene disorder
Chromosome abnormality
Multifactorial disorder
Teratogen
What is the cause of disruption?
Teratogen
Abnormal uterine environment
What is the cause of deformation?
Abnormal uterine environment
Preconceptual causes of birth defects
Chromosomal
Single gene
Multifactorial
Postconceptual causes of birth defects
Drugs and chemicals
Infections
Maternal illness
Physical agents
Single gene disorders
AD AR XD XR Other (mitochondrial)
Neurofibromatosis type 1
General
Autosomal dominant
1/3000
NF1 locus on chromosome 17 + gene cloned
Recurrence risk 50%
Neurofibromatosis type 1
Clinical features
Cafe au lait patches more than 5 of 0.5cm-1.5cm Neurofibroma Lisch nodules Intellectual disability Seizures Malignant changes Learning disorders
Common AD conditions
NF1
Achondroplasia
Marfan syndrome
Huntington’s disease
Oculocutaneous albinism
General
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%
Oculocutaneous albinism
Clinical features
Depigmented skin and hair Skin sensitivity Nystagmus Retina depigmented Visual problems Increased skin cancer susceptibility
Oculocutaneous albinism
Management
Limit skin sun exposure (protective clothing, sunscreen lotion, glasses)
Blind school
Suspicious skin lesions need attention
Dermatologist + ophthalmologist visits yearly
Genetic counselling
Common AR conditions
OCA Spinal muscular atrophy Thalassemia Sickle cell disease CF IEM
Duchenne muscular dystrophy
General
XR 1/3500 No ethnic variation DMD gene on X.p21 dystrophin product Carrier testing in females Becker's MD is a milder phenotype
Duchenne muscular dystrophy
Clinical features
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
Common XR conditions
Duchenne muscular dystrophy
Hemophilia A/B
Fragile X syndrome
X-linked dominant conditions
Rett syndrome
Goltz syndrome
Mitochondrial conditions
Myopathy
Blindness
Deafness
Imprinting disorders
Angelman syndrome
Prader-Willi syndrome
Chromosomal disorders
Numerical abnormalities
Down syndrome (46XY +21) Patau syndrome (T13) Edward syndrome (T18) Turner syndrome (45X) Klinefelter syndrome (47XXY)
Chromosomal disorders
Structural abnormalities
Balanced/unbalanced translocations Deletions Duplications Inversions Insertions Ring chromosomes
Down syndrome
General
Most common cause congenital mental disability in developed countries
1/600
Assoc with AMA >35yo
Down syndrome
Types
Non-dysjunction 92%-95%
Translocation (5%)
Mosaic (3%)
Down syndrome
Clinical features
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
Down syndrome
Management
Stimulation programs Special schooling Sheltered employment Surgery for cardiac defects Recurrent infections
Down syndrome
Recurrence risk
Non-dysjunction 1% and increases with AMA
Translocation 10% if mother 2% if father
Mosaic <1%
Down syndrome
Antenatal testing
Maternal serum screening Nuchal transparency on US Chorionic villi sampling Amniocentesis Fetal DNA in maternal circulation (non-invasive prenatal)
Edward syndrome
T18
>130 different noted abnormalities
Causes include non-dysunction, translocation, mosaicism, partial T18
Turner syndrome
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
Klinefelter syndrome
47XXY
1/500
Most common single cause for hypogonadism and infertility
Multifactorial inheritance
Examples
Neural tube defects
Cleft lip/palate
Congenital cardiac defects
Diabetes, HT, other common disorders
Neural tube defects
General
Multifactorial
Anencephaly/encephalocoele/spina bifida
Failure of neural tube to close by end of 4th week postconception
Genetic predisposition + folic acid deficiency (environment)
Neural tube defects
Recurrence risk
1 affected child 5%
2 affected children 10%
1 parent affected 4%
Folic acid preconceptually reduces risk 72%
Neural tube defects
Prenatal diagnosis
AFP on maternal and amniotic fluid
Maternal U/S
Teratogen
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
Susceptible stages of development for teratogenesis
0-17 days not susceptible 18-30 days highest susceptibility 31-60 days susceptibility continues 2nd trimester decreasing susceptibility 3rd trimester minimal susceptibility
Foetal alcohol syndrome
Clinical presentation
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)
Foetal alcohol syndrome
Etiology
Most common teratogen Heavy alcohol exposure Safe level unknown Bingeing more harmful Abstain!
Teratogen examples
Maternal disease Maternal infection Environmental chemicals Radiation Alcohol Drugs
Maternal diseases causing teratogenicity
DM Phenylketonuria Epilepsy Hyperthermia Hyperthyroidism Starvation
Maternal infections causing teratogenicity
Toxoplasmosis Rubella CMV HSV Syphilis HVZ Parvovirus HIV
Drugs causing teratogenicity
Anticoagulants (warfarin) Anticonvulsants (phenytoin) Anticancer drugs Antibiotics (tetracycline) Hormones (androgens, diethylstilbestrol) Psychiatric drugs (lithium) Vitamin A analogues (roaccutane) Salicylates (aspirin)
