Table 3. Genes Associated with Fanconi Anemia (FA) continued...
Loss of genomic stability is also the major cause of Bloom syndrome. This disorder shows increased chromosomal breakage and is diagnosed by increased sister chromatid exchanges on chromosomal analysis. Clinical manifestations of Bloom syndrome include severe growth retardation, recurrent infections, diabetes, chronic pulmonary disease, and an increased susceptibility to cancers of many types. The typical skin lesion seen in this disorder is a photosensitive erythematous telangiectatic rash that occurs in the first or second year of life. Although it is most commonly found on the face, it can also be present on the dorsa of hands or forearms. SCC of the skin is the third most common malignancy associated with this disorder. Skin cancer accounts for approximately 14% of tumors in the Bloom Syndrome Registry. Skin cancers occur at an earlier age in this population, with a mean age of 31.8 years at the time of diagnosis.
The BLM gene, located on the short arm of chromosome 15, is the only gene known to be mutated in Bloom syndrome. This gene encodes a 1,417-amino acid protein that is regulated by the cell cycle and demonstrates DNA-dependent ATPase and DNA duplex-unwinding activities. Its helicase domain shows considerable similarity to the RecQ subfamily of DNA helicases. Absence of this gene product is thought to destabilize other enzymes that participate in DNA replication and repair.[166,167]
This rare chromosomal breakage syndrome is inherited in an autosomal recessive manner and is characterized by loss of genomic stability. Sixty-four deleterious mutations described in the BLM gene include nucleotide insertions and deletions (41%), nonsense mutations (30%), mutations resulting in mis-splicing (14%), and missense mutations (16%).[168,169] A specific mutation identified in the Ashkenazi Jewish population is a 6-bp deletion/7-bp insertion at nucleotide 2,281, designated as BLMASH. Many of these mutations result in truncation of the C-terminus, which prevents normal localization of this protein to the nucleus. Absence of functional BLM protein can cause increased rates of mutation and recombination. This somatic hypermutability can thereby lead to an increased risk of cancer at an early age in virtually every organ, including the skin.
Cells from people with Bloom syndrome have been found to have abnormal responses to UV radiation. Normal nuclear accumulation of TP53 after UV radiation was absent in 2 of 11 primary cultures from individuals with Bloom syndrome; in contrast, responses in cultures from people who have XP and ataxia-telangiectasia were normal. The gene product of the BLM gene has also been found to complex with Fanconi proteins, raising the possibility of connections between the BLM and Fanconi anemia pathways for DNA stability.
Like Bloom syndrome, Werner syndrome is characterized by spontaneous chromosomal instability, resulting in increased susceptibility to cancer and premature aging. Diagnostic criteria, often in the setting of consanguinity, include cataracts, short stature, premature graying or thinning of hair, and a positive 24-hour urinary hyaluronic acid test. Cardinal cutaneous manifestations of this disorder consist of sclerodermatous skin changes, ulcerations, atrophy, and pigmentation changes. Individuals with this syndrome have an average life expectancy of fewer than 50 years. Cancers have an early onset and occur in up to 43% of these patients. The spectrum of tumors associated with this disorder has primarily been described in the Japanese population and includes an increased incidence of sarcoma, thyroid cancers, and skin cancers. Approximately 20% of the cancers reported in this syndrome are cutaneous, with melanoma and SCC of the skin accounting for 14% and 5%, respectively. Acral lentiginous melanomas are overrepresented, and SCCs may exhibit more aggressive behavior, with metastasis to lymph nodes and internal organs.[175,177]