Pathology

Genetic & Developmental

Diseases Introduction
• Genetic material contains code for development of fetus
• Genetic material is arranged into chromosomes
- 22 pairs of autosomes, 1 pair sex chromosomes [F 46xx, M 46xy]
• Genetic material in chromosomes is arranged into genes
• Problems in development of a fetus may be due to
- teratogen
• agent that causes a fetal abnormality
- problem with genetic code
• abnormal chromosomes
• defect in individual gene
- acquired neonatal syndromes
Developmental malformations
• A developmental malformation is a disturbance in the development of a fetus resulting in
abnormal features
• Causes of developmental malformations
- none identified (75%)
- genetic (20%)
- chromosomal (2%)
- infection (2%)
- chemical (1%)
Genetic factors
• Some genes control the development of the fetus
- defective growth control gene results in abnormal development
- majority spontaneously abort (lethal mutations)
- not all are fatal
- non-lethal examples
• cleft lip and palate
- multi-factorial inheritance
• achondroplastic dwarfism
- autosomal dominant inheritance
Teratogens
• Physical teratogens
- radiation (x-ray etc.)
- increased incidence of malformations (Hiroshima, Nagasaki)
• Chemical teratogens
- alcohol
• Fetal Alcohol Syndrome
- intra-uterine growth retardation
- reduced mental processes
- altered physical appearance
- thalidomide
- isotretinoin
Genetic & Developmental
Diseases
• Toxoplasmosis (parasite)
Infectious teratogens
- brain microcalcifications, (TORCH)
hydrocephaly, skin lesions
• Other (syphilis, listeria, )
• Rubella (German measles virus)
- microcephaly, congenital heart disease, micropthalmia
- 1st trimester exposure, unimmunized mother
• Cytomegalovirus
- brain microcalcifications, hydrocephaly
- skin lesions
• Herpes simplex virus
Numerical chromosomal abnormalities
• Aneuploidy
- general term for an abnormal number of chromosomes (loss/gain)
• Monosomy is the loss of a chromosome
- autosomal monosomies are fatal
- Y only sex chromosome (YO) is fatal
- X only sex chromosome (XO) is not fatal (Turner’s syndrome)
• Trisomy is the presence of an extra copy of a chromosome
- autosomal trisomies are not necessarily fatal
• trisomies of chromosomes 21,13, 18 may survive
- additional copies of sex chromosomes (Y,X) are not lethal

• Down’s syndrome (Trisomy 21)

- 1 in 800 neonates (most common chromosomal disorder)
- true Trisomy 21 in 95% of cases (translocation in 4%)
• usually maternal chromosome
• increased risk with increasing age
- typical features
- significant morbidity, increased mortality
- prenatal diagnosis possible
- different severities
- screen older mothers

• Turner’s Syndrome [Monosomy X (XO)]

- 1 in 3000 neonates
- abnormal segregation of X or Y
- typical features
- female phenotype
- infertile

• Klinefelter’s Syndrome [Trisomy X (XXX)]

- 1 in 700 neonates
- abnormal segregation of X or Y
- typical features
- male phenotype
- infertile (atrophic testes)
Genetic & Developmental Diseases
Structural chromosomal abnormalities
• Deletions
- loss of part of a chromosome
• p 11 WAGR [Wilms, Aniridia, Genital malformation, MR]
- loss in short arm of chromosome 11
• q 13 Retinoblastomas
- loss in long arm of chromosome 13
• Translocations
- transfer of part of one chromosome to another
- some Down’s [t21/14]
• extra copy of chromosome 21 due to translocation, not a complete extra chromosome

Single gene disorders

• Alleles
- genes present on autosomes (2 copies, one from each parent)
• Sex chromosome genes
- females (X X) have two copies of each gene
- males (XY) have some genes with only a single copy
• Dominant vs. recessive
- one gene copy (dominant allele) expressed in preference over other gene copy (recessive allele)
• Homozygote
- both copies of a gene are the same
• Heterozygote
- two copies of a gene are different

• Overview of single gene disorders

- disorder due to defect in a particular gene
- demonstrate particular patterns of inheritance (Mendelian Patterns)
• autosomal dominant, autosomal recessive
• sex linked dominant, sex linked recessive
- different patterns are based on the number of copies of defective gene required for expression of a
disorder
• autosomal dominant disorders require only one abnormal copy of a gene be present in order for disorder to be
expressed
• autosomal recessive disorders require both copies of a gene be abnormal in order for disorder to be expressed
• carrier has only one defective copy of a gene
- important because provides information on likelihood of another child having the disorder
Autosomal dominant disorders
• General rules of inheritance
- trait apparent in heterozygotes
- heterozygote has 50 % chance of transmitting to offspring
- trait expressed in every generation
- unaffected offspring don’t transmit trait
• Examples
- Marfan’s syndrome
- Familial Hypercholesterolemia
• Exceptions to rules
- variable penetrance (% of individuals with gene who express it)
 - variable expressivity (degree of expression in individual with gene)
Genetic & Developmental
Diseases
Infectious teratogens (TORCH)
Genetic & Developmental Diseases
Autosomal dominant disorders
• Marfan’s Syndrome
- 1/10,000
- defect in the fibrillin gene, a structural protein
- characteristic phenotype (Abraham Lincoln)
• skeletal abnormalities
- tall, thin; loose joints
• cardiovascular abnormalities
- aortic aneurysms, dissections, valves
• occular abnormalities
- dislocation of lenses, retinal detachments
- life expectancy shortened
• death usually due to rupture of a dissecting aneurysm
• Familial hypercholesterolemia
- 1/800
- defect in LDL Receptor gene
• LDL carries cholesterol destined for removal by liver
• removal by liver requires liver receptor to take-up LDL
• no receptor ^ inefficient cholesterol removal
- cholesterol deposits in tissue
• premature atherosclerosis
• xanthomas in soft tissues and skin
- homozygotes have higher LDL than heterozygotes
• develop ischemic heart disease before age of 20

Autosomal recessive disorders

• General rules of inheritance
- only homozygotes affected
- parents are asymptomatic carriers
- offspring are carriers
[1/4 affected, 1/2 carriers, 1/4 normal]
• Examples
- cystic fibrosis
- lysosomal storage disorders
• Cystic fibrosis
- 1/2500, carrier rate is 1/25
- defect in chloride transport gene
- thick exocrine secretions (pancreas, lung, intestines)
• obstruction of ducts and infections
- neonate
• meconium ileus, failure to thrive
• respiratory complications
- mucus plugs, infections
- chloride sweat test to help diagnose
- decreased life expectancy
 Genetic & Developmental
Diseases
• Lysosomal storage diseases
X -linked
group of recessive disorders
diseases due to defects in different enzymes
- different diseases depending on which enzyme gene is defective
- accumulation of materials, storage in lysosomes
- lipidoses, mucopolysaccharidoses, glycogenoses
• Examples
- Tay-Sachs (defective hexosaminidase)
• brain changes, eye changes, 3-5 yr life expectancy
- Gaucher Disease (defective glucocerebrosidase)
• enlarged spleen, anemia, normal life expectancy (type I)

• Phenylketonuria (PKU)
- Ashkanazi jews
- defective phenylalanine hydroxylase gene
- phenylalanine hydroxylase conversts PheA ^ Tyr
- in PKU, accumulation of PheA and other metabolites, and decreased Tyr, result in psychoneural
changes
- prevention
• heel prick to identify, routine screen
• Phe A deficient diet for normal psychoneural development
• PKU expectant mother also must adhere to diet

X linked recessive disorders

• General rules of inheritance
- usually only males affected
- transmission by unaffected (carrier) mother
- 1/2 of female offspring are carriers
- 1/2 male offspring are affected
- female offspring of affected males are carriers
• Examples
- Hemophilia
- Muscular dystrophy
- Fragile X syndrome

• Hemophilia
- defect in genes coding for coagulation proteins (called “factors”)
• hemophilia type A [Factor VIII gene (1/5000)]
• hemophilia type B [Factor IX gene (1/30000)]
- defective Factor VIII results in defective clotting (bleed)
- features (Romanovs- Russian royal family)
• variable (related to genetic alteration)
• bleeding
- joint spaces, minor trauma
• secondary complications
- treatment
• factor replacement
Genetic & Developmental
Diseases
• Duchenne and Becker’s Muscular Dystrophy
Autosomal
- disorders duerecessive disorders
to defective dystrophin protein
• dystrophin protein
- attachment of cytoskeleton
- weakened cell structure, esp. skeletal muscles
- Duchenne type
• 1/3300
• severe disease (severe muscle wasting, starts early)
- Becker’s type
• 1/20,000
• less severe disease, later onset

X-linked, non-classic inheritance

• Fragile X syndrome
- a portion of the X chromosome is “fragile”
• due to CGG triplet repeats
• with each generation, get increased number of “repeats”
• once reach certain number of repeats, get expression of disorder
- features
• mental retardation, enlarged testes
- may not appear to follow Mendelian patterns
• pre-mutation in individual who does not have critical number of repeats to cause expression of disorder
• increased expression of trait in subsequent generations

Multifactorial inheritance
• Disorders arising from complex interaction of multiple gene products and external factors
• Risk of developing disorder is approximately 5-10%
• Features
- trait is product of multiple genes, no Mendelian pattern
- exogenous and endogenous factors contribute to expression
- dose effect
- to determine risk of transmission look at family data, severity, sex
• Example
- Dysraphia
- Diabetes mellitus type 2
• Dysraphias (“neural tube defect”)
- incomplete fusion of midline structures, spectrum of abnormalities
- anencephaly
• complete absence of brain
- spina bifida
• defect in vertebral bones
- meningocele
• defect in vertebra, meninges
- risk of transmission
• if one child affected, increased risk etc.
- folate if pregnant helps to decrease risk
• Diabetes Mellitus Type 2
- diabetes is a group of diseases due to a relative lack of insulin and characterized by
increased blood glucose
- type 2 diabetes is a multifactorial disease
- genetic component
• familial incidence
• twin studies
- environmental factors
- transmission from affected parent to child in approx. 10 %

Prenatal diagnosis
• Many genetic disorders are incurable
• Prevention of developmental diseases
- immunization
- avoidance of toxins (EtOH)
- folate
- Prenatal diagnosis
• diagnose genetic disease early in pregnancy
• therapeutic abortion
• cytogenetic or molecular analysis
• Ultrasound
- malformation identification
• Chorionic villus sampling
- biopsy of placental villus
- fetal cells for analysis
• chromosomal
• molecular techniques
• Amniotic fluid
- biochemical analysis, fetal cells
• Maternal blood
- triple screen (B-HCG, estradiol, AFP)

Prematurity
• Normal pregnancy lasts 40 wks, ave. baby weighs 3500 g
• Premature baby
- delivered before 37 weeks
• IUGR
- birth weight less than 3200 g
• Immature baby
- delivered before 37 wks and weight less than 1500 g
• Causes
- Maternal (malnutrition, smoking, substance abuse)
- Fetal (genetics)
- Placental (insufficiency)
Genetic
Genetic & & Developmental
Developmental Diseases
Acquired
Diseasesneonatal syndromes
• Neonatal Respiratory Distress Syndrome
Multifactorial inheritance
- syndrome of increasing shortness of breath, usually preterm baby
- pathophysiology
• surfactant (lecithin) in lungs decreases surface tension of alveoli
• premature infant has inadequate surfactant
• atelectasis (alveoli collapse)
• hyaline membranes form (hyaline membrane disease)
- periventricular brain hemorrhage
- long term respiratory difficulties
- surfactant released into amniotic fluid before birth, therefore able to assess levels of surfactant
- give corticosteroids prior to delivery to increase surfactant
• Birth Injury
- Mechanical trauma during delivery
- malposition, large baby
- skull fracture
- intracranial hemorrhage (subdural)
- peripheral nerve injury
- long bone fractures
• Sudden Infant Death Syndrome
- sudden, unexpected death of an otherwise healthy infant that remains unexplained even after autopsy and
examination of scene
- 1 in 500, 90% occur before 6 months
- death usually occurs during sleep (crib death, cot death)
- pathogenesis not understood
• prone to apnea, possibly immature development of hypothalamus
- Maternal factors
• young, low socioeconomic status, smoking, drug use
- Infant factors
• low birth weight, male, not first sib, prone position