Structural Chromosome Abnormalities

Structural rearrangements involve breakage and reunion of chromosomes. Although less common than numerical abnormalities, they present additional challenges from a genetic counseling standpoint. This is because structural abnormalities, unlike numerical abnormalities, can be present in "balanced" form in clinically normal individuals but transmitted in "unbalanced" form to progeny, thereby resulting in a hereditary form of chromosome abnormality.

Rearrangements may involve exchanges of material between different chromosomes (translocations) or loss, gain, or rearrangements of individual chromosomes (e.g., deletions, duplications, inversions, rings, or isochromosomes). Of particular clinical importance are translocations, which involve two basic types: Robertsonian and reciprocal. Robertsonian rearrangements are a special class of translocation, in which the long arms of two acrocentric chromosomes (chromosomes 13, 14, 15, 21, and 22) join together, generating a fusion chromosome that contains virtually all of the genetic material of the original two chromosomes. If the Robertsonian translocation is present in unbalanced form, a monosomic or trisomic conception ensues. For example, ~3% of Down syndrome cases are attributable to unbalanced Robertsonian translocations, most often involving chromosomes 14 and 21. In this instance, the affected individual has 46 chromosomes, including one structurally normal chromosome 14, two structurally normal chromosomes 21, and one fusion 14/21 chromosome. This effect leads to a normal diploid dosage for chromosome 14 and to a triplication of chromosome 21, thus resulting in Down syndrome. Similarly, a small proportion of individuals with trisomy 13 syndrome are clinically affected because of an unbalanced Robertsonian translocation.

Reciprocal translocations involve mutual exchanges between any two chromosomes. In this circumstance, the phenotypic consequences associated with unbalanced translocations depend on the location of the breakpoints, which dictate the amount of material that has been "exchanged" between the two chromosomes. Because most reciprocal translocations involve unique sets of breakpoints, it is difficult to predict the phenotypic consequences in any one situation. In general, severity is determined by the amount of excess or missing chromosome material in individuals with unbalanced translocations.

In addition to rearrangements between chromosomes, there are several examples of intrachromosome structural abnormalities. The most common and deleterious of these involve loss of chromosome material due to deletions. The two best-characterized deletion syndromes, Wolf-Hirschhorn syndrome and cri-du-chat syndrome, result from loss of relatively small chromosomal segments on chromosomes 4p and 5p, respectively. Nonetheless, each is associated with multiple congenital anomalies, developmental delays, profound retardation, and reduced lifespan.

Reff:

Harrison's Internal Medicine > Chapter 63. Chromosome Disorders >