Table 3. Genes Associated with Fanconi Anemia (FA)
|Gene||Locus||Approximate Incidence Among FA Patients (%)||Pattern of Disease Transmission|
|AR = autosomal recessive; XLR =X-linked recessive.|
The proteins involved with DNA crosslink repairs have been termed the FANC pathway because of their involvement with Fanconi anemia. They interact with several other proteins associated with hereditary cancer risk, including those for Bloom syndrome and ataxia-telangiectasia. Further investigation has revealed that FANCD1 is the same gene as BRCA2, a gene that causes predisposition to breast and ovarian cancer. Other Fanconi anemia genes, FANCJ (BRIP1) and FANCN (PALB2), have also been identified as rare breast cancer susceptibility genes. (Refer to the PDQ summary on Genetics of Breast and Ovarian Cancer for more information about BRCA2, BRIP1, and PALB2.) Individuals who are heterozygous carriers of other Fanconi anemia–associated mutations do not appear to have an increased risk of cancer, with the possible exception of a twofold increase in breast cancer incidence in FANCC mutation carriers.
Dyskeratosis congenita (Zinsser-Cole-Engman syndrome)
Dyskeratosis congenita, like Werner syndrome, results in premature aging and is considered a progeroid disease. The classic clinical triad for diagnosis includes dysplastic nails, reticular pigmentation of the chest and neck, and oral leukoplakia. In addition, individuals with this disorder are at markedly increased risk of myelodysplastic syndrome, acute leukemia, and bone marrow failure. Ocular, dental, neurologic, gastrointestinal, pulmonary, and skeletal abnormalities have also been described in conjunction with this disease, but clinical expressivity is variable. Developmental delay may also be present in variants of dyskeratosis congenita, such as Hoyeraal Hreidarsson syndrome and Revesz syndrome.
Approximately 10% of individuals with dyskeratosis congenita will develop nonhematologic tumors, often prior to the third decade of life.[138,139] Solid tumors may be the first manifestation of this disorder. Head and neck cancers were the most commonly reported, accounting for nearly half of the cancers observed. Cutaneous SCC occurred in about 1.5% of the subjects, and the median age at diagnosis was 21 years. These cancers are generally managed as any other SCC of the skin.
Several genes associated with telomere function (DKC1, TERC, TINF2, NHP2, NOP10, and TERT) have been implicated in dyskeratosis congenita; approximately half of the individuals with a clinical diagnosis of this disease have an identified mutation in one of these six genes.[140,141,142,143,144,145,146]TERC and TINF2 are inherited in an autosomal dominant manner, whereas NHP2 (NOLA2) and NOP10 (NOLA3) show autosomal recessive inheritance and TERT can be either autosomal dominant or autosomal recessive. DKC1 shows an X-linked recessive pattern. Alterations in these genes result in shortening of telomeres, which in turn leads to defects in proliferation and spontaneous chromosomal rearrangements. Levels of TERC, the RNA component of the telomerase complex, are reduced in all dyskeratosis congenita patients. Missense mutations in WRAP53, a gene with a protein product that facilitates trafficking of telomerase, have also been associated with an autosomal recessive form of dyskeratosis congenita. Mutations in C16orf57 were identified in 6 of 132 families who did not have a mutation detected in other known genes.C16orf57 mutations are also associated with poikiloderma with neutropenia. (Refer to the Rothmund-Thomson syndrome section of this summary for more information about poikiloderma congenitale.)