Transcript Examples of Chromosomal or Mendelian Disorders • Trisomies – 16 most common in spontaneous lost pregnancies, does not survive to birth – 21,18,13 • Sex Chromosomes –

Examples of Chromosomal or
Mendelian Disorders
• Trisomies
– 16 most common in spontaneous lost
pregnancies, does not survive to birth
– 21,18,13
• Sex Chromosomes
– Turner
• Vs Noonan
– Klinefelter
• Dominant Structural Protein Disorders
• X-linked disorder
Clinical features of DS 1
• Physical
– Characteristic flat facies, oblique palpebral
fissures, epicanthal folds,
– Dysplastic ear, narrow palate, abnormal teeth,
protruding tongue
– Cardiac malformations (40%)
– Gastrointestinal obstruction, duodenal atresia,
Hirschsprung disease
– Premature aging, Alzheimer-like symptoms in 40s
– Hypotonia, palmar/digital anomalies
– Male sterility
Clinical features of DS 2
• Mental retardation
– IQ 75 if mother has >16 years of schooling
– IQ 30 if both parents have <12 years of
schooling
– Some selective deficits in rule-based
systems such as numbers and grammar
– May be able to function with minimal
assistance
Clinical features of DS 3
• Hearing
40%
• Thyroid dysfunction 25-30x general
population
• Increased risk of Diabetes mellitus
• Leukemoid response or congenital leukemia
– Increased risk of ALL, AML and ANLL
– 10-100 x general population
• Immunodeficiency
Trisomy 21 Facts
• Heart defects may not be apparent at birth
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sensitivity of PE: 61-74%
ECG improves sensitivity by 15%
Echo is needed
19/52 have normal PE and significant intracardiac
defect at birth
• Survival in DS without heart disease is 99%
at one year
Trisomy 21
• About 70% of conceptions are lost
– 20% between 16 weeks and term
– 20% between 10 and 16 weeks
• Maternal non-disjunction in 86%
– 75% are meiosis I errors
• Paternal origin 9% almost equal MI and
MII
• Somatic mutations 5%
Clinical Features Trisomy 18
• Prenatal onset Growth Retardation
• Single umbilical artery
• Prominent occiput, lowset, malformed
auricles, short palpebral fissures,small mouth
• Clenched hand, overlap of 2nd on 3rd and 5th
on 4th finger
• Cardiac (VSD, ASD, ductus), Renal, GU
(cryptorchidism, hypoplastic labia), Skeletal,
Abdominal anomalies
• Early demise: 60% first 2 months, 90% by
one year.
Clinical features Trisomy 13
• Holoprosencephaly, defects of optic and
olfactory nerves
• Microcephaly with sloping forehead
• Defects of eyes
• Cleft lip and/or palate
• Scalp defect: aplasia cutis at vertex
• Cardiac defects (80%) VSD, PDS,ASD
• Polydactyly, prominent heel, flexion
deformities, abnormal creases
• 5% survive the first 6 months, median survival
2.5 days
Common Trisomies
Trisomy 21
Trisomy 13
Growth Small to
Small to IUGR
normal
Head Brachycephaly Forehead, Holoprosencephaly
Hands Creases, V
Polydactyly
Heart
Trisomy 18
IUGR,
premature
Occiput
Clenched
Skin
40% VSD,
CCAVC
Neck
80% VSD,PDA, VSD,ASD,
ASD, dextrocard. PDA, CoA
Scalp defects
Redundancy
Face
Eyes
Clefts
Proportions
Clinical Features of Turner
Syndrome 1
• Congenital lymphedema
– Puffy feet and hands
– Leads to the ‘webbed neck’
• Low posterior hair line
• Absence of secondary sex characteristics
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Scanty axillary or pubic hair
Lack of breast development
Amenorrhea
Streak gonads/rudimentary ovaries
Infertility
• Mosaicism
Clinical Features of Turner
Syndrome 2
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Short stature
Coarctation of the aorta
Renal anomalies (40%)
Normal intelligence
Short metacarpal IV
Multiple pigmented nevi
Facial features: downturned mouth, narrow
palate, small mandible
• 99% fetal losses of X fetuses
– 2-4% all concepti but 1/5000 live births
Noonan syndrome
• Short Stature 50%
• Turner-like features: sternum, neck, cubitus valgus
• Hypertelorism, ptosis, down-slanting palpebral
fissures
• Pulmonary stenosis, cardiomyopathy
• Normal chromosomes
• Either sex; AD, mutations in PTPN11, a gene
encoding the non-receptor protein tyrosine
phosphatase SHP2 in 50% , 12q24.1
• Variable fertility (cryptorchidism)
• Bleeding diathesis in 1/3
• Mental retardation 25%
XXY: Klinefelter Syndrome
• May have mental retardation
• Growth
– Tendency for long limbs
• Height mean 75th centile
• Hypogonadism
– Childhood
– Adolescence/adult
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Small testicular volume
Inadequate testosterone production
Infertility
Fibrosis/hyalinization of seminiferous tubules
Gynecomastia in 25-50%
Normal sexual functioning
Dominant disorders of
Structural Proteins
• Marfan
– ocular, skeletal, cardiac disease
– chromosome 15q21.1
– defect in fibrillin-1
• effect on elastic fibers as disruption of
microfibrillar component
• elastin unaffected
• Osteogenesis imperfecta
– collagen defect
– skeletal system; sclera
– AD and AR forms; type II lethal as neonate
Dominant disorders of
Structural Proteins 2
• Ehlers-Danlos
– defect in collagen synthesis or assembly
• synthesized as precursor; hydroxylated;
glycosylated; assembled; secreted; cleaved;
aggregation; cross-linked
– Hyperextensibility of joints and of skin,
altered wound healing and scar formation
– Premature rupture of membranes/premature
birth
– Skin, cardiac, vascular, joint, ocular, hollow
viscera
– multiple types
Defects in Receptor Proteins
• Familial Hypercholesterolemia
– Autosomal dominant
• heterozygotes manifest disease signs milder and
later than homozygotes
– LDL receptor defects
• type 1 no receptors; type 2 dysfunctional binding
at receptors; type 3 internalization defect
• decreased transport of LDL cholesterol into cells;
upregulation of hepatic cholesterol synthesis
• early onset atherosclerosis
• hypercholesterolemia 12-25mMol 5001000mg/dl
• xanthomas, corneal arcus
• early death
• Gene Therapy
Single Gene, Multiple
Mutations
• Cystic Fibrosis
– Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR)
– Acts as chloride channel
– Reduced chloride transport (and water)
• increased sweat electrolytes
• viscous secretions
– Chronic lung disease, pancreatic insufficiency,
hepatic disease
– Autosomal recessive gene at 7q31
– Many mutations; D F508 is the most common
Lesch-Nyhan syndrome
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Spasticity after 4-6 months of age
Choreoathetosis
Self-mutilation despite pain sensation intact
Mental retardation usually mild
Articulation defects / autistic features
Growth deficiency
Uric acid stones which leads to renal failure
Hypoxanthine-Guanine
PhosphoRibosylTransferase deficiency
mutations range from point to deletions
One Gene Many Diseases
• Chromosome 17, PMP22 gene; peripheral
myelin protein
• Duplication of PMP22 1.5 Mb (3 copies) gives
AD Charcot-Marie-Tooth disease Type 1
• Deletion (1 copy) is Hereditary Neuropathy
with Liability to Pressure Palsies
• Point mutations are Dejerine-Sottas
syndrome characterized by distal muscle
weakness, sensory alterations, muscle
atrophy and enlarged spinal nerve roots
‘Common’ Single Gene Defects
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Cystic Fibrosis
Sickle Cell Disease
Thalassemias
Hemophilias
Huntington Chorea
– Gain of function
• Post-axial
Polydactyly
• Retinoblastoma
• Alpha-1 Antitrypsin
Disease
• Familial Isolated Growth
Hormone Deficiency
– Dominant negative
• Thyroid Binding Globulin
deficiency
– X-linked
• Neurofibromatosis type 1
– 50% new mutations