Syndrome

Characteristic association of several abnormalities

Caused by single etiologic agent affect several tissues
May or may not be sequential
Potters syndrome
o Absent or abnormal kidney development
o Decreased amniotic fluid
o Abnormal development of lings
o Abnormal feces and abnormal positioning of hands and feet
o Example of malformation and deformation

50% of the time, etiology is unknown

Genetic (12-25)
Environment (8-13)
Multifactorial (20-25)

Environmental causes

Mother was exposed to specific agents

Teratogens
Includes
o Infectious organisms
Mother is infected while pregnant
Usually viruses
Can include: Rubella, CMV, Herpes
Rubella causes mild disease in children and adults
In fetus: virus replicates in fetal cells, prevents proper cell
division, causes growth retardation, cataracts deafness,
and congenital heart disease
o Drugs and chemicals
Include: Thalidamide, alcohol, folate antagonists, anticonvulsants, 13-cis-retinoic acid
o Maternal disorders
Maternal biabetes
6% risk of abnormalities in diabetic pregnancies
Maternal hyperglycemia fetal hyperinuslemia
o Large babies
o Cardiac anomalies
o Central nervous system malformations
o Ionizing radiation
Radiotherapy for treatment of cancer
Atomic bomb explosions

Causes of genetic disease

Complex
Poorly understood
What we do know:
o Timing of the insult is important (susceptibility between 3 rd and 9th
week of gestation, less susceptible in the 2 nd and 3rd trimesters)
o Teratogen may act at several steps (cell migration, proliferation,
interaction)

Congenital Abnormalities Summary

Present atbirth
Types (malformation, deformation, disruption, syndrome)
Cause teratogen
Pathogenesis complex, timing of the insult is important

Genetic Diseases

Environmentally determined
Genetically determined
o Classic genetic diseases
o Cancer
o Cardiovascular disease
o Three categories
Chromosomal
46 chromosomes (22 pairs of autosomes, 1 pair of sex)
7.5% of all pregnancies most are not compatible with
survival, 50% of all early spontaneous abortions
0.5 1% of all live born infants (DO NOT REMEMBER
THESE NUMBERS!!!)
Can be classified into
o Numerical
Autosomes (Down syndrome trisomy 21)
DownsSyndrome most common
chromosomal disorder (1:800 live born
infants)
Major cause of mental handicap
Parents have a normal karyotype
Significant increased risk with
maternal age
Features include: flat facial profile and
epicanthic folds, palpebral fissure,
mental handicap, abundant neck skin,

congenital heart disease, increased

risk of acute leukemia
The pathogenesis is unknown
Sex chromosomes (Turner XO, Klinefelter
XXY)
More common than the autosomes
Abnormalities less severe than the
autosomes
Problems related to sexual
development and fertility
Difficult to diagnose at birth, first
recognized at puberty
Turners syndrome most common sex
chromosomes abnormality in females,
phenotically female, features include:
o Failure to develop secondary
sex characteristics
o Normal mental health
o Infertility
Klinefelters most common Xchromosomes abnormality in males
o Elongated body
o Small atrophic testes
o Lack of secondary sex
characteristics
Structural
Results of chromosome breakage followed by
loss or rearrangement of material
Include
Deletion (e.g. Cri-du-chat, Prader Willi)
Balanced translocations

Single gene
Monogenic or Mendelian disorders
Involvea single gene but with large effect (partial to full
expression)
80 85% are familial (remainder are new mutations)
Patterns of inheritance
o Autosomal dominant
One parent has the disease
50% risk to the children
Both sexes equally affected
o Autosomal recessive
Two parents usually normal, but are carriers
25% chance of inheriting disease
Both sexes equally affected
o X- linked

o
o
o

Mother is often a carrier

50% for sons to be affected
50% chance for daughters to be carriers
Usually affect a protein (enzyme, cell receptor, or
non-enzyme protein)
Identifying the protein may aid in treatment
Marfan syndrome
Autosomal dominant
Defect in non-enzyme protein (fibrillin)
Chromosome 15
Fibrillin is affected (ECM glycoproteins, forms
matrix, found in aorta, ligaments, and lens of
eyes)
Features include strucutal abnormalities (tall,
long extremities), ocular changes (lens can
dislocate), cardiovascular lesion (aortic
dilatation)
Cannot be treated
Familial hypercholesterolemia
Autosomal dominant
Defect in a receptor protein (LDL receptor)
Most frequent mendelian disorder
Chromosome19
LDL receptor binds LDL and increases uptake
Receptor for LDL not functioning
Increase plasma levels of LDL
Loss of feedback control increased
synthesis
Incorporated into vessel wall
Increased risk of coronary heart
disease and heart attacks
Cystic Fibrosis
Autosomal recessive
Chromosome 7
Most common in Caucasians
Involve epithelial transport protein (CFTR)
Affects fluid secretion
Produce an abnormal viscous secretion
Affects the pancreas (intestinal
malabsorption) and lung
PKU
Autosomal recessive
Enzyme defect phenylalanine hydroxylase
Phenylalanine usuallyderivedfrom food,
required for protein synthesis, excess
phenylalanine is converted to tyrosine by
phenylalanine hydroxylase

Deficiency of enzyme
Increase levels of phenyalanine
Mental retardation, seizures and inability to
walk due to deposition in the CNS
Treatment via restricting phenylalanine
intake
Phenylalanine is also a teratogen (mothers
need to decrease intake)
Hemophilia A
X-linked
Affects gene coding for Vactor VIII
Involved in coagulation cascade
Decreased or abnormal factor VIII, causes
prolonged bleeding, easy bruising,
spontaneous hemorrhages

Multifactorial
Combined actions of: environemental and two or more
mutant genes
Fatures
o Run in families
o Cannot be attributed to a specific inheritance
pattern
o Involve common human ailments
Cleft lip
Congenital heart disease
Gout
Hypertension
Diabetes mellitus
Both environmental and genetic