A detectable mutation in the gene RECQL4 is present in 66% of clinically affected individuals. This gene is located at 8q24.3, and inheritance is believed to be autosomal recessive. RECQL4 encodes the ATP-dependent DNA helicase Q4, which promotes DNA unwinding to allow for cellular processes such as replication, transcription, and repair. A role for this protein in repair of DNA double-strand breaks has also been suggested. Mutations in similar DNA helicases lead to the inherited disorders of Bloom syndrome and Werner syndrome.
At least 19 different truncating mutations in this gene have been identified as deleterious. These mutations cause severe down-regulation of RECQL4 transcripts in this subset of individuals with Rothmund-Thomson syndrome. Cells deficient in RECQL4 have been found to be hypersensitive to oxidative stress, resulting in decreased DNA synthesis. Deficiencies in the RecQ helicases permit hyperrecombination, thereby leading to loss of heterozygosity. Loss of heterozygosity associated with deficiencies of this protein suggests that the helicases are caretaker-type tumor suppressor proteins.
Three of six families with Rothmund-Thomson syndrome were found to have homozygous mutations in the C16orf57 gene. Mutations in this gene have also been identified in individuals with dyskeratosis congenita, suggesting that these syndromes are related.
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.[158,159]
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%).[160,161] 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.