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 non-hematologic tumors, often prior to the third decade of life.[132,133] 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.[134,135,136,137,138,139,140]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.
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.[131,138,139,145,146] 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.