Congenital & Genetic Disease

Question 1

Congenital

Answer 1

Present at birth

Question 2

Genetic

Answer 2

Determined by genes

Question 3

CONGENITAL ABNORMALITIES

Answer 3

Malformations

Deformations

Disruptions

Syndrome

Question 4

Malformations

Answer 4

result from an intrinsically abnormal development process

Examples: Polydactyly, spina bifida, congenital heart disease

Question 5

Deformations

Answer 5

result from mechanical forces (small uterus, large fetus, oligohydramnios - Compression of fetus)

Examples: Positional abnormalities of the feet

Question 6

Disruptions

Answer 6

result from break down of a normal development process.

Example: Limb amputation due to an amniotic band

Question 7

Syndrome

Answer 7

A Syndrome is a characteristic association of several anomalies.

Potter Syndrome is an example of both malformations and deformations.
- The basic defect is absent or abnormal kidney development, resulting in decreased amniotic fluid (oligohydramnios) and compression of the fetus.
- These lead to abnormal development of the lung (pulmonary hypoplasia) and death due to respiratory insufficiency.
- The fetal compression also produces abnormal facies and abnormal positioning of hands and feet.

Question 8

TERATOGENS

Answer 8

Teratogens are agents that produce congenital malformations.

1. Congenital Infections
2. Drugs and Chemicals
3. Maternal Disorder
4. Ionizing Radiation

Question 9

Congenital Infections

Answer 9

Examples: Congenital Rubella (German Measles)

Maternal rubella occurring in the first trimester will cause fetal malformations.
- In a child or adult, rubella is a mild disease with fever and a transient skin rash.
- However, with a primary infection in a pregnant woman, there is hematogenous spread across the placenta to the fetus.
- The fetus is not capable of producing an immune response to the viral infection. The virus replicates in fetal cells, preventing their proper division resulting in growth retardation, cataracts, deafness and congenital heart disease.
- The risk is highest if fetal infection occurs during the first 8 weeks.

Other common congenital infections with teratogenic effects include cytomegalovirus, varicella zoster (chicken pox).

Question 10

Drugs and Chemicals

Answer 10

Examples: Thalidomide, Alcohol

Thalidomide was extensively used in some countries in the late 1950’s for symptomatic relief of nausea and vomiting of early pregnancy.
- In 1960, there was noted an increase in the number of infants born with limb defects.
- Astute observations by a German Physician suggested that this was due to thalidomide. Subsequent studies confirmed this relationship, including reproduction of similar effects in experimental animals.
- Thalidomide affects the embryo between the third and fifth weeks post-conception by interfering with proper limb growth, producing phocomelia (“seal limbs”).

Alcohol: Excessive alcohol consumption during pregnancy causes prenatal and post-natal growth retardation, mental retardation, joint anomalies, heart defects and abnormal facies called Fetal Alcohol Syndrome.
- This is the most common cause of mental retardation in the Western world, affecting 1/300 to 1/2000 live births.
- There is an obvious dose-response effect but no safety line.
- The harmful effects of maternal alcohol ingestion are not restricted to a sensitive period of early pregnancy but extend throughout gestation.

Question 11

Maternal Disorder

Answer 11

Example: Diabetes Mellitus

The overall risk for major congenital malformations in diabetic pregnancies is 6%.
- The risk can be over 20% if diabetes is not appropriately controlled during the first trimester.

Mothers with insulin-dependent diabetes have the highest risk.
- Malformations often involve kidneys, heart and brain.
- The severity of malformations is related to the degree of control of maternal diabetes during pregnancy.

Question 12

Ionizing Radiation

Answer 12

Offspring of pregnant women, exposed to the atomic bomb explosions in Hiroshima and Nagasaki, had an increased incidence of microcephaly and mental retardation.

Question 13

GENETIC DISEASES

Answer 13

1. CHROMOSOMAL DISORDERS
   - Numerical Abnormalities
   - Structural Abnormalities
2. SINGLE GENE DISORDERS (Monogenic Disorders)
   - Autosomal Dominant
   - Autosomal Recessive
   - X-Linked Recessive
3. MULTIFACTORIAL (POLYGENIC) DISORDERS

Question 14

Numerical Abnormalities - CHROMOSOMAL DISORDERS

Answer 14

1. Autosome
   - Example: Down Syndrome, Trisomy 21
   - The chromosomal disorder affects approximately 1/800 live born infants. Malformations include abnormal facies, palmar creases, congenital heart disease, duodenal stenosis or atresia and mental retardation.
   - There is a significant increased risk with advanced maternal age. With the maternal age 30 years, the incidence is about 1/900 whereas by 45 years the risk is 1/25
2. Sex Chromosome
   - Examples: Turner Syndrome (XO), Klinefelter Syndrome (XXY)
   - Abnormal numbers of sex chromosomes produce abnormalities less severe than with abnormal numbers of autosomes.
   - However, these individuals fail to develop normal secondary sexual characteristics, are infertile and have skeletal abnormalities.

Question 15

Structural Abnormalities - CHROMOSOMAL DISORDERS

Answer 15

Example: Cri-du-chat Syndrome (partial deletion in the short arm of chromosome 5).
- Manifestations of this syndrome include cat-like cry in infancy, small head and facial abnormalities.

Question 16

Autosomal Dominant

Answer 16

One parent has the disease
50% risk to children
Both sexes are equally affected

Marfan Syndrome
- This is a disorder of connective tissue.
- Manifestations include long limbs, dislocation of lens of eye and abnormal dilation of aorta.
- The gene is on chromosome 15.

Familial Hypercholesterolemia
- This is one of the most common genetic diseases and a leading cause of coronary heart disease.
- The basic defect is mutations in the gene encoding the low-density lipoprotein (LDL) receptor, resulting in an elevated cholesterol level in plasma and deposition of cholesterol in arteries.
- One of 500 persons carries the abnormal gene and may have coronary heart disease in early middle age.
- In homozygotes (1/1,000,000), the coronary heart disease is usually fatal in childhood.
- The gene is located in chromosome 19.

Question 17

Autosomal Recessive

Answer 17

both parents are normal, but carriers
25% risk to children
both sexes are equally affected

Cystic Fibrosis
- This is the most common autosomal recessive disease in Caucasian children with an incidence of 1/1600.
- Carrier frequency is about 1/20.
- The respiratory tree mucus is abnormal, causing repeated lung infection with the destruction of the lung tissue.
- The patients also have pancreatic insufficiency resulting in intestinal malabsorption.
- The gene (cystic fibrosis transmembrane regulator CFTR) is on chromosome 7

Phenylketonuria (PKU)
- This is an example of metabolic disease resulting from a mutation in phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine.
- Accumulation of phenylalanine in body fluids damages the developing brain in early childhood and causes severe mental retardation.
- This disease can be diagnosed by newborn screening and treated by a low-phenylalanine diet.
- Almost all the offspring of female PKU patients not on a low-phenylalanine diet are abnormal with mental retardation, microcephaly, growth retardation, and congenital heart disease.
- This is due not to their own genetic defect but to the highly teratogenic effect of elevated levels of phenylalanine in the mother’s circulation.

Question 18

X-Linked Recessive

Answer 18

mother carrier
50% chance for sons to be affected
50% chance for daughters to be carriers

Example:

Hemophilia A Absent normal blood clotting with prolonged bleeding time, and bleeding into joints and muscles. This is due to deficiency of coagulation factor VIII which is encoded by a gene on the chromosome X.

Question 19

MULTIFACTORIAL (POLYGENIC) DISORDERS

Answer 19

These disorders are due to the effect of multiple genes and the interaction between the genetic factors and environmental factors.

appear to run in families

do not fit any inheritance pattern of single gene disorders.

Examples: Cleft palate, congenital heart disease, spina bifida.