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An adolescent case of xeroderma pigmentosum variant confirmed by the onset of sun exposure‐related skin cancer during Crohn's disease treatment

The patient was a 16‐year‐old boy who was diagnosed with Crohn's disease at 13 years of age, who was treated with mesalazine, azathioprine, and infliximab. Concurrently, the patient developed small freckle‐like pigmented spots on sun‐exposed areas, which gradually increased in number. At 14 and 16 years of age, a blue‐gray macule and a nodule appeared on his face, respectively. A histopathological examination revealed that the macule had only postinflammatory pigmentation, while the nodule was basal cell carcinoma. The sensitivity to UV‐killing by colony formation of the patient's cells was normal but was enhanced by caffeine treatment. In addition, a pathologic mutation in the POLH gene was identified and a diagnosis of xeroderma pigmentosum variant (XP‐V) was established. XP‐V is a cutaneous type of XP that is commonly diagnosed from middle age after the induction of skin cancer on sun‐exposed areas. Our patient had a genetically sensitive background (XP‐V), and we considered that immunosuppressive agents for Crohn's disease may have enhanced the photocarcinogenesis at a young age. This finding implies that we should be careful about a skin cancer production and that protection from UV may be essential when pediatric patients with a genetic background of UV sensitivity take immunosuppressive agents.

agents. Crohn's disease is more common in adults than in children, but frequency of Crohn's disease among children has been reported to be increasing and pediatric patients with Crohn's disease should start taking medications earlier and should continue taking them for longer in comparison with adult patients with Crohn's disease. 4,5 We herein report an interesting case of a Japanese adolescent patient of XP-V, in which the diagnosis of XP-V was confirmed by the onset of a sun exposure-related skin cancer during Crohn's disease treatment. In the present case, immunosuppressive agents, which were administered for Crohn's disease over a few years, were thought to have increased the risk of UV-induced skin cancer in a patient whose genetic background of XP-V made him photosensitive and more cancer-prone than a patient without XP.

| CASE REPORT
A 16-year-old Japanese boy, born from nonconsanguineous parents, has developed diarrhea, remittent fever, and stomatitis at age of 13.
A local physician found a longitudinal ulcer in the terminal ileum via endoscopy. Consequently, this patient was diagnosed with Crohn's disease and treatment was initiated with mesalazine (Pentasa â ), azathioprine (Imuran â ), and infliximab (Remicade â ). Concurrently, the patient developed small freckle-like pigmented spots on the sunexposed skin, including the face, the dorsal aspect of both hands and the lateral sides of both forearms: The number of these spots gradually increased. At 14 years of age, a black macule appeared in the right preauricular region. At 16 years of age, the patient newly noticed a nodule at the root of his nose and was referred to our department for the evaluation and treatment of these skin problems.
At his first visit to our clinic, he had multiple small freckle-like pigmented spots on sun-exposed skin areas, a black nodule at the right root of his nose and a blue-gray macule in the right buccal region ( Figure 1A,B). A physical examination revealed no neurological symptoms. We performed incisional biopsies of the nodule and macule.
The histopathological examination of the specimens revealed that the nodule at the nose root was basal cell carcinoma ( Figure 2A,B), while the macule in the right buccal region was postinflammatory pigmentation ( Figure 2C,D). Further evaluation was performed because XP was suspected as a background factor, based on the fact that he had developed basal cell carcinoma on the face in his teens and had multiple small freckle-like pigmented spots on his sunexposed skin. A host cell reactivation assay using an ultraviolet irradiation (UV)-irradiated reporter gene in the cultured primary fibroblasts derived from the patient suggested that he had normal NER capacity. The evaluation of UV sensitivity by colony formation was also normal; however, this sensitivity was enhanced by caffeine treatment. Finally, a compound heterozygous mutation (c.c907t groups. According to a report by Tanioka et al, the mean age at the initial presentation of BCC was 41.5 years in patients with Japanese XP-V, which is much earlier than that in healthy Japanese subjects. 2,3 However, our patient developed BCC at the age of 16, which indicates that he developed skin cancer at a considerably younger age in comparison with most XP-V patients. The patient's genetic background (XP-V) and the effects of immunosuppressive therapy for Crohn's disease are thought to have influenced the development of BCC during adolescence in the present case. In addition, the patient had been a member of a soccer club until 13 years of age; thus, he had a history of a high degree of sun exposure. Nishigori et al 6 reported on 2 patients with XP-V who developed BCC at 12 and 27 years of age, and who had a habit of swimming and windsurfing, respectively, and who thus had a high degree of sun exposure before the diagnosis of XP-V. In our patient, treatment for Crohn's disease was initiated at 13 years of age with the oral administration of azathioprine and mesalazine. The intravenous infusion of infliximab was added 2 years later, and only the administration of azathioprine was discontinued at 15 years of age.
There has been no evidence to support that mesalazine increases the carcinogenic risk until now. On the other hand, there are several reports indicating that the incidence of skin cancer was increased by azathioprine through interaction with ultraviolet radiation. 7,8 Azathioprine is metabolized in vivo into 6-thioguanine nucleotides (6-TGNs), which corresponds with chromophores and absorb UVA, leading to the generation of reactive oxygen species. The generation of reactive oxygen species induces oxidative DNA damage, such as 8-oxoguanine, which may relate to the mutagenesis. 9 On the other hand, our patient showed defective translesion synthesis because of his genetic disease (XP-V). Thus, photoproducts such as cyclobutane pyrimidine dimer and 6-4-photoproduct, due to UVB, form easily and also promote mutation. 1 In addition, if TNF-a is inhibited by infliximab, adverse effects may occur with regard to the immune function against the tumor. In our patient, azathioprine was administered for only 2 years. However, it was thought that these multiple, complicated effects led to BCC in childhood.
It is still unclear how the long-term use of biological drugs affects the risk of development malignant tumors. 10 In patients who received immunosuppressive agents for underlying diseases from childhood, the risk of skin cancers may be high. When for children receive immunosuppressive therapy for inflammatory bowel disease or after renal transplantation, it is important to provide thorough education on the prevention of skin cancer from a young age as they are likely to receive such therapy for longer periods of time than adult patients. When children receiving immunosuppressive therapy develop freckle-like pigmented spots, dermatologists should immediately examine the patient to determine whether they have developed XP and provide the patient with appropriate education on protection from UV light, and to regularly screen the patient for skin cancer in the clinic.

CONFLI CT OF INTEREST
The authors declare no conflict of interest.