Table 3. Genes Associated with Fanconi Anemia (FA) continued...
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.)
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.