Bloom Syndrome

BS is a rare, autosomal recessive disorder characterized by growth deficiency, unusual facies, sun-sensitive telangiectatic erythema, immunodeficiency, and predisposition to a variety of different cancers.⁸,⁸⁷ It is most frequent among

Ashkenazi Jews. Approximately 250 patients have been recognized.

CLINICAL FEATURES

Facial erythema and telangiectasia superficially resembling lupus erythematosus are often present within the first few weeks after birth in the malar area, on the nose, and around the ears.⁸⁷ Sun exposure accentuates these abnormalities and may induce bullae, bleeding, and crusting of the lips and eyelids. Café-au-lait spots are common, at times accompanied by adjacent depigmented areas. Patients are well proportioned but small. Adult height is usually under 150 cm. Patients have a long, narrow head with a characteristic facies consisting of a narrow, prominent nose, relatively hypoplastic malar areas, and a receding chin.

Patients with BS are predisposed to multiple infections, as there is immune dysfunction. Fertility is decreased and diabetes mellitus is common.

Approximately 20 percent of patients with BS develop malignancies, comprising a normal spectrum of cancer types, of which one-half occur before age 20 years.⁸⁷ Patients usually die before the age of 30 years from either cancer or infection.

GENE DEFECT, PATHOGENESIS, AND

 LABORATORY ABNORMALITIES

BS is caused by mutations in BLM, which encodes a RecQ helicase.^8,10,89 BS cells are characterized by an increase in the frequency of spontaneous sister chromatid exchanges  and in exchanges between homologous chromosomes. The latter is often visualized by quadriradial chromosomes. These are four-armed chromosomes most likely formed by recombination between two chromosomes (and almost never found in unaffected individuals). These observations demonstrate that BS cells are characterized by hyper-recombination.

Although the exact mechanisms of how mutations in the BLM helicase lead to hyper-recombination are still not completely understood, it has been suggested that they are related to defective DNA replication or defective resolution of stalled replication forks. Hyperrecombination may result in an increased frequency of loss of heterozygosity and through that mechanism, in conjunction with increased spontaneous mutation frequency, an increased frequency of malignant transformation. The immune deficiency, characterized by diminished immunoglobulin levels, reduced cellular proliferative response to mitogens, and decreased proliferation in the mixed leukocyte reaction, probably further contributes to the increased cancer risk.

TESTING

The observation of quadriradial chromosomes (observed in 0.5 percent to 14 percent of lymphocytes of BS patients) and the approximately 10-fold increased frequency of spontaneous sister chromatid exchanges are used to diagnose BS. A founder deletion/insertion mutation in the BLM gene was identified in Ashkenazi Jews at a frequency of approximately 1 percent (BLM^Ash) and can be used for DNA diagnosis of BS patients and carriers among Ashkenazi Jews.