This rare autosomal recessive condition is much more common in Ashkenazi Jews than in other ethnic groups. It is characterized by low birth weight, growth deficiency, and a sunlight-sensitive erythematous and telangiectatic rash, especially on the face from the first year of life. Sun exposure accentuates these changes and may induce bullae, with bleeding and crusting on the face (especially the lips and eyelids). The nose is prominent in a long thin face, and there is clinodactyly. Spotty hypopigmentation and hyperpigmentation may be seen on the skin, and also “twin spots,” which may be due to somatic recombination (Bloom 1966). Adult height is usually less than 150 cm. Intelligence is normal. There is a severe immune defect with reduced gammaglobulin (IgA and IgM) levels, leading to a high incidence of chronic severe infections of the respiratory and GI tract. About 20 % of patients with Bloom syndrome develop neoplasms, half of these before the age of 20 years, and Tumours may be multiple. Neoplasms are predominantly lymphatic and non-lymphatic leukemia, lymphoma, and carcinomas of the mouth, stomach, esophagus, colon, cervix, and larynx.
Early cervical screening should be offered to affected women. Screening for other cancers may be problematic, although regular oral examinations by a dental surgeon and colonoscopy are also probably worthwhile. Myeloid leukemia and myelodysplastic syndrome have been reported, often with monosomy for chromosome 7 (Ellis and German 1996; Aktas et al. 2000; Poppe et al. 2001). Wilms Tumours has been described in four children with Bloom syndrome, and one of these four children had a sib who developed a hepatocellular carcinoma at age of 15 years (Cairney et al. 1987; Jain et al. 2001).
Few patients survive into adulthood, but in those that do, colorectal cancer has been reported. In one case, this occurred in the context of ulcerative colitis (Wang et al. 1999), whereas in other cases, an attenuated familial adenomatous polyposis (FAP) phenotype was observed (Lowy et al. 2001). Interestingly, a mucinous (i.e., hereditary non-polyposis colorectal cancer-like) transverse colon cancer, with normal p53 expression, has been reported in a 16-year-old with Bloom syndrome. These observation led investigators to study the gene, BLM, identified by Ellis et al. (1995) in individuals from the population with colorectal cancer. One mutation, BLM: 2281del6ins7 is seen in approximately 1 in 110 Ashkenazi Jews, so this population was studied in detail. Overall, 1 in 54 Jews with colorectal cancer carried this allele, whereas the allele was seen in 1 in 118 controls (odds ratio, 2.76; 95 % CI, 1.4–5.5) (Gruber et al. 2002). This finding was supported by data showing that mice heterozygous for Blm developed twice the number of intestinal Tumours when crossed with mice carrying a mutation of the Apc Tumours suppressor gene (Goss et al. 2002). Somatic mutations in length repeats within BLM are also quite frequent in sporadic colorectal cancer (Calin et al. 1998) and, interestingly, tend to be associated with mucinous colorectal cancers (Calin et al. 2000). Knocking out BLM in karyotypically stable colorectal cancer cell lines results in increased sister chromatid exchange and homologous recombination (but without gross chromosomal rearrangements) (Traverso et al. 2003). Finally, in a murine model, chromosomal instability and Tumours predisposition seem to correlate inversely with BLM protein levels (McDaniel et al. 2003). Taken together, these findings suggest that homozygous individuals are at considerably increased risk for colorectal cancer and that heterozygosity for BLM can be added to the I1307K APC allele as a genetic risk factor for colorectal cancer in the Jewish population, I1307K, however, is at least 6 times as prevalent as BLM Ash , and thus the clinical significance of the latter allele is very limited. Another possible founder mutation has been reported in Japan: BLM: 631delCAA (Kaneko et al. 2004), and studies of this allele in colorectal cancer in Japan would be of interest.
At the nuclear level, an elevated frequency of chromosomal breaks is observed, with an increase in sister chromatid exchanges, and an abnormal profile of DNA replication intermediates is reported in this condition (Lonn et al. 1990). The exact mechanism by which BLM maintains replication fidelity is debated. In a mouse model of Bloom syndrome, viable mice were prone to cancers at many sites, and cell lines showed elevated levels of mitotic recombination (and therefore loss of heterozygosity) (Luo et al. 2000). These data were supported by results in human cancer cells, as discussed above (Traverso et al. 2003).
There is a registry for cases of Bloom syndrome to help affected individuals and their families and to assist in the assessment of the natural history of the disease. The registry can be contacted at http://med.cornell.edu/ bsr/. According to this website, as of 2009, there were 265 persons with Bloom syndrome registered.