Porth's Essentials of Pathophysiology, 4e

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Genetic and Congenital Disorders

C h a p t e r 6

Occasionally, mitotic errors during cleavage of the fertilized ovum or in somatic cells give rise to two or more cell lines characterized by distinctive karyotypes, a condition referred to as mosaicism . Sometimes mosa- icism consists of an abnormal karyotype and a normal one, in which case the physical deformities caused by the abnormal cell line usually are less severe. Chromosomal abnormalities are commonly identified according to the shorthand description of the karyotype. In this system, the total number of chromosomes is given first, followed by the sex chromosome complement, and then the description of any abnormality. For example, a male with trisomy 21 is designated 47,XY,+21. Aberrations in chromosome structure occur when there is a break in one or more of the chromosomes followed by rearrangement or deletion of the chromosome parts. 1–4 Among the factors believed to cause chromosome break- age are exposure to radiation sources, such as x-rays; influence of certain chemicals; extreme changes in the cellular environment; and viral infections. Several pat- terns of chromosome breakage and rearrangement can occur (Fig. 6-8). There can be a deletion of the broken portion of the chromosome. One of the most common deletion disorders is 22q11.2 deletion syndrome (to be discussed). When one chromosome is involved, the bro- ken parts may be inverted. Isochromosome formation occurs when the centromere, or central portion, of the chromosome separates horizontally instead of vertically. Ring formation results from a break involving both ends of a chromosome, deletion of the outermost fragments, and joining of the remaining centric portion of the chro- matids to form a ring. Translocation occurs when there are simultaneous breaks in two chromosomes from dif- ferent pairs, with exchange of chromosome parts. With a balanced reciprocal translocation, no genetic informa- tion is lost; therefore, persons with translocations usually are normal. However, these persons are translocation carriers and may have normal and abnormal children. A special form of translocation called a centric fusion or Robertsonian translocation involves two chromosomes in which the centromere is near the end, most commonly chromosomes 13 and 14 or 14 and 21. Typically, the break occurs near the centromere, affecting the short arm in one chromosome and the long arm in the other. Transfer of the chromosome fragments leads to one unusually long and one extremely short fragment. The short fragment is usually lost during subsequent divisions. In this case, the person has only 45 chromosomes, but the amount of genetic material that is lost is so small that it often goes unnoticed. The chief clinical importance of this type of translocation is that carriers of a robertsonian transloca- tion involving chromosome 21 are at risk for producing a child with Down syndrome (to be discussed). The manifestations of aberrations in chromosome structure depend to a great extent on the amount of genetic material that is lost. Many cells sustaining Structural Chromosomal Abnormalities

Chromosomal Disorders Chromosomal disorders form a major category of genetic disease, accounting for a large proportion of reproductive wastage (early gestational abortions), congenital malfor- mations, and intellectual disabillity. Specific chromosomal abnormalities can be linked to more than 60 identifiable syndromes that are present in 0.7% of all live births, 2% of all pregnancies in women older than 35 years of age, and 50% of all first-term abortions. 2 During cell division (i.e., mitosis) in nongerm cells, the chromosomes replicate so that each cell receives a full diploid number. In germ cells, a different form of divi- sion (i.e., meiosis) takes place (see Chapter 5). During meiosis, the double sets of 22 autosomes and the two sex chromosomes (normal diploid number) are reduced to single sets (haploid number) in each gamete. At the time of conception, the haploid number in the ovum and that in the sperm join and restore the diploid number of chromosomes. ■■ Sex-linked disorders, which are associated with the X chromosome, are those in which an unaffected mother carries one normal and one mutant allele on the X chromosome. She has a 50% chance of transmitting the defective gene to her sons, who are affected, and her daughters, who are carriers. Because of a normal paired gene, female heterozygotes rarely experience the effects of a defective gene. ■■ Several genetic disorders do not follow the mendelian pattern of inheritance.These include diseases caused by genomic imprinting, triplet repeat mutations, and mutations in mitochondrial genes.The fragile X syndrome is an inherited form of mental retardation that results from a repeating sequence of three (CGG) nucleotides on a fragile site on the long arm of the X chromosome. Disorders of mitochondrial DNA, which are inherited from the mother, interfere with production of cellular energy.The nervous system, and heart and skeletal muscles, which have a high need for cellular energy, tend to be the most seriously affected. ■■ Multifactorial inheritance disorders are caused by multiple genes and, in many cases, environmental factors. Although they cannot be predicted with the same accuracy as single-gene disorders, they tend to involve a single organ or tissue derived from the same embryonic developmental field. Cleft lip and cleft palate are common examples.