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

• Heart defects may not be apparent at birth– 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 Facts

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 Trisomy 18

Growth Small tonormal

Small to IUGR IUGR,premature

Head Brachycephaly Forehead, Holo-prosencephaly

Occiput

Hands Creases, V Polydactyly Clenched

Heart 40% VSD,CCAVC

80% VSD,PDA,ASD, dextrocard.

VSD,ASD,PDA, CoA

Skin Neck 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– Scanty axillary or pubic hair– Lack of breast development– Amenorrhea– Streak gonads/rudimentary ovaries– Infertility

• Mosaicism

Clinical Features of Turner Syndrome 2

• 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

• 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

500-1000mg/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; F508 is the most common

Lesch-Nyhan syndrome• 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

• 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