The diagnosis of XP is made on the basis of clinical findings and family history. Functional assays to assess DNA repair capabilities after exposure to radiation have been developed, but these tests are currently not clinically available in the United States. Sequence analysis testing may be done to confirm mutations in XPA and XPC previously identified in an affected family; however, molecular testing for mutations associated with other complementation groups is currently done only in research laboratories.
Multiple self-healing squamous epitheliomata (Ferguson-Smith syndrome)
Multiple self-healing squamous epitheliomata (MSSE), or Ferguson-Smith syndrome, first described in 1934, is characterized by invasive skin tumors that are histologically identical to sporadic cutaneous SCC, but they resolve spontaneously without intervention. Linkage analysis of affected families showed association with the long arm of chromosome 9, and haplotype analysis localized the gene to 9q22.3 between D9S197 and D9S1809. Transforming growth factor beta-receptor 1 (TGFBR1) was identified through next-generation sequencing as the gene responsible for MSSE. Loss-of-function mutations in TGFBR1 have been identified in 18 of 22 affected families. Gain-of-function mutations in TGFBR1 are associated with unrelated Marfan-like syndromes, such as Loeys-Dietz syndrome, which have no described increase in skin cancer risk.
Somatic loss of heterozygosity in Ferguson-Smith-related SCC has been demonstrated at this genomic location, suggesting that TGFBR1 can act as a tumor suppressor gene. The long arm of chromosome 9 has also been a site of interest in sporadic SCC. Up to 65% of sporadic SCCs have been found to have loss of heterozygosity at 9q22.3 between D9S162 and D9S165.
SCC occurring at extremely early ages is a hallmark of oculocutaneous albinism. One report describing a cohort of 350 albinos in Tanzania found 104 cutaneous cancers; of these, 100 were SCCs, three were BCCs, and one was melanoma. The median age for this population was 10 years.
Two types of oculocutaneous albinism are known to be associated with increased risk of SCC of the skin. Oculocutaneous albinism type 1, or tyrosinase-related albinism, is caused by mutations in the tyrosinase gene, TYR, located on the long arm of chromosome 11. The OCA2 gene, also known as the P gene, is mutated in oculocutaneous albinism type 2, or tyrosinase-positive albinism. Both disorders are autosomal recessive, with frequent compound heterozygosity.
Tyrosinase acts as the critical enzyme in the synthesis of melanin in melanocytes. Mutation in this gene in oculocutaneous albinism type 1 produces proteins with minimal to no activity, corresponding to the OCA1B and OCA1A phenotypes, respectively. Individuals with OCA1B have light skin, hair, and eye coloring at birth but develop some pigment during their lifetimes, while the coloring of those with OCA1A does not darken with age.
The gene product of OCA2 is a protein found in the membrane of melanosomes. Its function is unknown, but it may play a role in maintaining the structure or pH of this environment. Murine models with mutations in this gene had significantly decreased melanin production compared with normal controls.