Table 3. Genes Associated with Fanconi Anemia (FA) continued...
The recommended approach for diagnosis begins with a six-cell panel assay for leukocyte telomere length testing. If telomere length is in the lowest 1% for three or more cell types, molecular genetic testing is indicated. Testing of DKC1 may be performed first in male probands, as mutations in this gene account for up to 36% of those identified in dyskeratosis congenita to date. Mutations in TINF2 and TERT are responsible for 11% to 24% and 6% to 10% of cases, respectively.[137,144,145,153,154] Clinical testing is available for all six genes.
Rothmund-Thomson syndrome, also known as poikiloderma congenitale, is a heritable disorder characterized by chromosomal instability. The cutaneous presentation of this condition is an erythematous, blistering rash appearing on the face, buttocks, and extremities in early infancy. Other characteristics of this syndrome include telangiectasias, skeletal abnormalities, short stature, cataracts, and increased risk of osteosarcoma. Areas of hyperpigmentation and hypopigmentation of the skin develop later in life, and nonmelanoma skin cancers can develop at an early age. Reports of multiple SCCs in situ have been reported in individuals as young as 16 years. The precise increased risk of skin cancer is not well characterized, but the point prevalence of nonmelanoma skin cancer, including both BCC and SCC, is 2% to 5% in young individuals affected by this syndrome. This prevalence is clearly greater than that found in individuals in the same age group in the general population. Although increased UV sensitivity has been described, SCCs are also found in areas of the skin that are not exposed to the sun.
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 hyper-recombination, 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 and poikiloderma with neutropenia, suggesting that these syndromes are related;[150,151] however, skin cancer risk in these conditions is not well characterized. (Refer to the Dyskeratosis congenita (Zinsser-Cole-Engman syndrome) section of this summary for more information.)