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  • Clinically, Bloom syndrome (BS) features (a) proportional dwarfism, usually accompanied by (b) a sun-sensitive erythematous skin lesion limited to the face and dorsa of the hands and forearms, (c) a characteristic facies and head configuration, and (d) immunodeficiency, often associated with otitis media and pneumonia. (e) Affected males fail to produce spermatozoa, and females although sometimes fertile experience an unusually early cessation of menstrual cycles. (f) Excessive numbers of well-circumscribed areas of dermal hypo- and hyperpigmentation are present. (g) The three major complications are chronic lung disease, diabetes mellitus, and—by far the most important and most frequent—cancer.

  • BS is a genetically determined trait that is transmitted in a straightforward autosomal recessive fashion, with mutations at a single locus, BLM, being responsible. Various mutations at BLM are segregating in human populations, but the same phenotype (BS) is produced by either homozygosity or compound heterozygosity of those so far identified. The mutations are predominantly null alleles, but missense mutations also have been detected. BS is rare in all populations, but in the Ashkenazi Jewish population, one particular mutant allele, a 6-bp deletion and 7-bp insertion that results in premature translation termination, has, through founder effect, reached a relatively high carrier frequency of approximately 1 percent; in 31 percent of all persons with BS, one or both parents are Ashkenazi Jews.

  • The genome is abnormally unstable in the somatic cells of persons with BS. Mutations arise spontaneously and accumulate in numbers manyfold greater than normal, including both microscopically visible chromatid gaps, breaks, and rearrangements and mutations at specific loci. Exchanges take place excessively between chromatids, usually at what appear to be homologous sites. One consequence of this hyperrecombinability is the reduction to homozygosity of constitutionally heterozygous loci distal to the points of crossing-over. The hyperrecombinability in persons with BS who are genetic compounds can lead to reversion at BLM itself: Crossing-over between two different mutated sites within BLM can result in the generation of a functionally normal gene, and thereby correction of the cellular phenotype of the somatic cells that comprise the progeny of the cell in which the recombinational event had occurred.

  • Many of the clinical characteristics of BS may be viewed as direct or indirect consequences of the hypermutability. It is postulated to be a major causative factor in BS's small size by way of the induction of factors which either inhibit further cell division or promote cell death. Another major consequence of the hypermutability is proneness to neoplasia; BS more than any other known human state predisposes to the development of cancer of the types and sites that affect the general population, and at unusually early ages. BS thus is the prototype of a class of disease that may be called the somatic mutational disorders.

  • Diagnosis of BS is based on clinical observation; the phenotype is striking. Laboratory confirmation ordinarily is by cytogenetic demonstration of the characteristically increased tendency of chromatid exchange to take place. BS is the only condition known ...

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