common genetic syndromes
TRANSCRIPT
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Common Genetic syndromes
Dr. E.M. Honey
Department Genetics
Division Human Genetics
University of Pretoria
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Definitions
• Deformation
• Malformation
• Disruption
• Dysplasia
• Syndrome
• Associations
• Complex
• Sequences
• Major and minor anomalies
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Introduction
• Developing countries has a higher burden
• Genetic disorders not rare
• 2-3% of all births
• 12% of Paediatric admissions
• 50% of adult disorders have a genetic
component
• 11% of neonatal deaths
• More than 6000 syndromes described
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Classification(Causes) • Genetic:
Chromosomal 6%
Single gene 7,5%
Multifactorial 20-30%
Subtotal 30-40%
• Environmental: Drugs and chemicals 2%
Infections 2%
Maternal illness 2%
Physical agents 1%
Subtotal 5-10%
• Unknown: 50%
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Neurofibromatosis type 1
• Autosomal dominant
• 1 in 3000
• NF 1 locus on
chromosome 17 and
the gene has been
clones
• Recurrence risk 50%
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Clinical features:
• Café au lait patches
• Neurofibroma
• Lisch nodules
• Intellectual disability
• Seizures
• Malignant changes
(5-10%)
• Learning disorders
(40%)
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Oculocutaneous albinism
• Autosomal recessive
• Hereditary defect in the
metabolism of melanin
resulting in the
decrease or absence of
this pigment in the skin,
mucosa, hair or eyes
• 1 in 3900 (African
population)
• Recurrence risk 25%
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Clinical features:
• Depigmented skin
• Skinsensitivity
• Nystagmus
• Visual problems
• Increased
susceptibility to skin
cancer
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Management
• Limit skin exposure
• Protective clothing
• Protective sunscreen lotion
• Wear sunglasses
• School of the blind
• Attention to suspicious skin lesions
• Visit Dermatologist and Ophthalmologist on a yearly basis
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Duchenne muscular dystrophy
• X-linked recessive
• 1 in 3500 males with no
ethnic variation
• DMD gene on Xp21 -
dystrophin product
• Carrrier testing in affected
females possible
• Becker muscular
dystrophy: milder degree
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Clinical features
• Muscle weakness from 3-5
years
• Positive Gower’s sign
• Delay in walking
• Wheelchair bound by 11 years
• Death at a mean age of 18
years
• Pseudohypertrophy of calf
muscles and wasting of the
proximal muscles
• Mild to moderate intellectual
impairment
• Cardiac muscle involvement
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Down syndrome
• Commonest cause of
congenital mental
disability in developed
countries
• 1 in 700 pregnancies
• 3 types:
1. Non-dysjunction
(92-95%)
2. Translocation(5%)
3. Mosaic(3%)
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Clinical features
• Small brachicephalic
head, third fontanel
• Facial dysmorphism,
open mouth, protuberant
tongue, epicantic folds
and upslanting palpebral
features
• Short stature
• Prominent hypotonia
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Clinical features • Short stubby fingers,
single palmar crease and clinodactily
• Increased distance between first and second toes (“sandal gap”)
• Cardiac, skeletal and gastro-intestinal defects
• Mental retardation (IQ 20-50)
• Increased risk for haematological and endocrine diseases
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Management
• Mental retardation:
Stimulation
programmes,
special schooling(?)
and sheltered
employment
• Cardiac defects
• Recurrent infections
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Recurrence risk
• Non-disjunction - 1% and increase with AMA
• Translocation - 10% if from the mother and 2% if from
the father
• Mosaic - less than 1%
• Antenatal testing possible:
Maternal screening
Ultrasound: Nuchal translucency
Chorionic villi sampling or amniocentesis
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Trisomy 18 (Edward syndrome)
• Incidence of approximately 0,3 per 100
• More than 130 different abnormalities noted
• Non-disjunction(full), translocation, mosiac, partial trisomy 18
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Monosomy X/ 45X0 (Turner syndrome)
• Described in 1938
• Incidence of 1 in 2500 females
• Most 45X0 conceptuses die early
• Paternal X chromosome most likely missing
• No significant older maternal age and usually sporadic
• Approximately 6% of females with Turner syndrome have 45X/46XY mosaïcism
• If mentally deficient look for another chromosomal defect
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47XXY/ Klinefelter syndrome
• Most common single
cause for
hypogonadism and
infertility
• Affects approximately
1 in 500 males
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Neural tube defects
• Multifactorial
• Three conditions:
1. Anencephaly
2. Encephalocoele
3. Spina bifida
• Failure of the neural tube to
close by the end of the forth
postconceptual week
• Aethiology: Genetic
predisposition and
environmental factors e.a. folic
acid deficiency
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Neural tube defects
• Recurrence risk:
1 affected child 5%
2 affected children 10%
1 affected parent 4%
• Folic acid periconceptually reduces the risk by 72%
• Prenatal diagnosis: AFP(maternal and amniotic fluid) and maternal ultrasound
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Teratogenesis
• 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:
1st trimester: 0-17 days: not susceptible
18-30 days: highly susceptible
31-60 days: susceptibility continue
2nd trimester: decreasing susceptibility
3rd trimester: minimal susceptibility
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Fetal alcohol syndrome
• Most common teratogen
• Growth deficiency:
1. Small stature
2. Microcephaly
Mental deficiency
Poor fine motor
Hyperactivity
3. Facial dysmorphisms
Short nose
Inner epicantic folds
Smooth philtrum
Thin upper lip
Small midface
4. Other defects
Cardiac, skeletal
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Fetal alcohol syndrome(cont.)
• Etiology:
Heavy alcohol exposure
Unsure about “safe” level during pregnancy
Bingeing more harmful
All women should abstain from taking alcohol during pregnancy
Genetic predisposition
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Other Human teratogens
• Maternal disease: Diabetes mellitis, phenylketonuria,
epilepsy, hyperthermia, hypothyroidism, starvation
• Maternal infections: Toxoplamosis, Rubella, CMV,
Herpes simplex, syphilis, varicella zoster, parvovirus, HIV
• Environmental chemicals
• Radiation
• Drugs: Anticoagulants(Warfarin), anti-
convulsants(Phenytoin), anti-cancer drugs,
antibiotics(Tetracycline), hormones(androgens and
diethylstilbestrol), psychiatric drugs(Lithium), Vitamin A
congeners(Ruaccutane) and salicylates(Aspirin)
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Ambiguous genitalia
• Medical emergency!
• Differential diagnosis:
Chromosomal abnormalities
CAH
Testicular feminization
Hermaphrodite
Effect of androgens or estrogens in utero
Hypothalamic and pituitary defects
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