NU570

Digital Library: Lectures: Developmental and Genetic Diseases

 Embryonic and fetal development depends on the sequential activation and repression of thousands of genes. This fascinating biological phenomenon works remarkably well; however, birth defects can occur. In fact, one of every fifty babies is born with a major congenital defect worldwide.

Developmental and genetic disorders are classified as either: i) errors of morphogenesis, ii) chromosomal abnormalities, iii) single-gene defects, or iv) polygenic inherited diseases. Chromosomal abnormalities may be structural or numerical. Single-gene defects may be either autosomal dominant, autosomal recessive, or sex-linked.

Major congenital diseases for you to focus on this week include: Neural tube defects, fetal alcohol syndrome, TORCH complex, Down syndrome, Klinefelter syndrome, Turner syndrome, neurofibromatosis, familial hypercholesterolemia, cystic fibrosis, muscular dystrophy, and fragile X syndrome. Major diseases of infancy and childhood include respiratory distress syndrome and sudden infant death syndrome.

Here are the Key Points:

  1. Teratogens are chemical, physical, and biological agents that cause developmental anomalies.

  2. The formation of primordial organ systems in the first trimester of pregnancy is the stage of embryonic development most susceptible to teratogenesis.

  3. Spina bifida refers to incomplete closure of the vertebral column and spinal cord.

  4. Maternal consumption of alcohol can cause growth and mental retardation, as well as facial dysmorphology.

  5. Chromosomal abnormalities include both structural changes (eg, translocation or deletion) and numerical changes (eg, nondisjunction). Nondisjunction represents failure of paired chromosomes to separate during either mitosis or meiosis.

  6. Down syndrome (trisomy 21) is the most common cause of inherited mental retardation.

  7. Klinefelter (47 XXY) and Turner (45 XO) syndromes are caused by changes in the number of sex chromosomes.

  8. Familial hypercholesterolemia is one of the most common autosomal dominant disorders, and is characterized by accelerated atherosclerosis and coronary artery disease.

  9. Cystic fibrosis is the most common lethal autosomal recessive disorder, with an incidence of 1 in 2500 newborns.

The following images illustrate Key Morphological Concepts:
1. This birth defect is an example of an ERROR OF MORPHOGENESIS, which most likely occurred during the second week of development. This defect is also referred to as Janiceps. It reflects partial duplication of the primitive streak during gastrulation.
2. This is an example of a SPINA BIFIDA in an aborted fetus. This dysraphic anomaly represents failure of the posterior neural tube to close during the first trimester of pregnancy. Note the herniated menigocele.
3. This is an example of CONGENITAL HEART DISEASE in an infant who was exposed to German measles (rubella) in utero. Note the prominent ventricular septal defect.
4. This is an example of POLYDACTYLY, a reduplication of the fifth digit of the hand. This is a single gene defect, with an autosomal dominant pattern of inheritance.
5. This is an example of FAMILIAL HYPERCHOLESTEROLEMIA. It is one of the most common autosomal dominant genetic diseases in the US, affecting nearly 1 in 500 adults. Note the deposits of cholesterol and lipid-laden macrophages around the eyes of this patient. This disease is caused by a defect in the low-density lipoprotein (LDL) receptor
6. This angiogram shows evidence of CORONARY ARTERY ATHEROSCLEROSIS and occlusion (white patches) in a young man with familial hypercholesterolemia. This patient is at significant risk for development of ischemic heart disease.
7. This is an example of OSTEOGENESIS IMPERFECTA, an autosomal dominant genetic disease linked to the production of an abnormal collagen. As a result of this molecular/genetic defect, the patients' bones are brittle and undergo repeated fractures at sites of minor trauma.
8. This is an example of a CLEFT LIP and CLEFT PALLET, one of many polygenic (multi-gene) disorders. Other examples of polygenic inheritance include diabetes, hypertension, congenital heart disease and schizophrenia.