Living with xeroderma pigmentosum: comprehensive photoprotection for highly photosensitive patients

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease of deoxyribonucleic acid (DNA) repair with ultraviolet (UV) radiation sensitivity and a 10 000‐fold increased risk of skin cancer. Symptoms include: freckle‐like pigmentation in sun‐exposed skin before age 2 years, severe burns after minimal sun exposure (50% of patients) and damage to exposed surfaces of the eyes with loss of vision and ocular cancer. About 25% of patients develop a progressive neurodegeneration. The combination of an inherited inability to repair UV‐induced DNA damage and environmental exposure to UV must occur for cutaneous and ocular symptoms to develop. There is no cure for XP, but many of its manifestations may be reduced or prevented through consistent UV protection; thus XP serves as a model for sun protection of patients with marked photosenstivity. Sun protective clothing including hats, sunglasses and face shields, sun screen lotions and avoidance of environmental sources of UV are cornerstones of prevention of skin and eye damage and cancer. Although XP is a serious disease with the potential for limitation of life expectancy, XP patients can live active lives while at the same time avoiding UV.     

Clinical and photobiological characteristics of xeroderma pigmentosum complementation group F: a review of cases from Japan

A 61-year-old female patient with xeroderma pigmentosum (XP), registered as XP46KO, was assigned to complementation group F by the cell fusion-complementation method. The XP46KO fibroblasts in culture exhibited a defective DNA repair capacity of 10-15% unscheduled DNA synthesis and a 3-fold sensitivity to the lethal effect of 254 nm ultraviolet light compared with normal cells. The patient had mild clinical symptoms consisting of numerous pigmented freckles and a small number of seborrheic keratosis-like papules. She had no skin cancers in the sun-exposed areas of the skin and so far no neurological abnormalities. A review of 11 Japanese group F patients revealed very mild skin symptoms with no ocular or neuro-psychiatric abnormalities. Single skin cancers occurred in only 3 of the 11 patients with an average age of 52 years for their first skin malignancy.     

Xeroderma pigmentosum and lentigo maligna in identical twins

Xeroderma pigmentosum (XP) is a rare autosomal recessive genodermatosis. Skin abnormalities result from an inability to repair UV-damaged DNA. Clinically, XP presents with early onset cutaneous changes (severe photosensitivity, actinic keratoses, and telangiectasias) and an increase of developing cutaneous malignancies beginning in early childhood, but lentigo maligna and melanomas are relatively rare. Here we report on homozygote twins in whom there was no positive family history. They showed subnormal physical growth. On ophthalmological examination, both had photophobia and decreased visual acuity. Since birth, several excisions had been performed for skin neoplasms. In one of them a pigmented patch developed over the frontal area which proved to be lentigo maligna and she was referred to a dermato-oncology center. They have been given isotretinoin and physical sunscreen since then. The follow-up period was extended to 2 years and no serious complications occurred from the above treatment. This is an interesting report about XP in twins with the presentation of the rare neoplasm lentigo maligna.     

Multiple facial basal cell carcinomas in xeroderma pigmentosum treated with topical imiquimod 5% cream

Xeroderma pigmentosum (XP) is an autosomal recessive disease characterized by solar sensitivity, photophobia, early onset of freckling, and solar‐induced cutaneous neoplastic changes. Management of patients with XP is a therapeutic challenge as they usually develop multiple cutaneous malignancies, making surgical therapy difficult, and continue to form skin malignancies at a high rate. We describe a 30‐year‐old Chinese man with XP who had been previously treated with excision and dermatoplasty. Upon recurrence of multiple superficial, ulcerative, and pigmented lesions, imiquimod 5% cream was recommended for 4 months. His multiple facial lesions demonstrated an excellent response to topical imiquimod 5% cream with minor side effects. This favorable response indicates that topical application of imiquimod 5% cream is an effective means of treating multiple basal cell carcinomas in XP.     

Multiple skin cancers in patients with mycosis fungoides after long‐term ultraviolet phototherapy

Phototherapy is a useful noninvasive therapy, but it can induce cutaneous malignant tumours, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). We report on a 79‐year‐old man who had long‐standing mycosis fungoides for 40 years, which had been treated with psoralen ultraviolet A therapy for 37 years at a dose of approximately 5000 J/cm². Approximately 6 years before presentation, numerous types of cutaneous malignancies, including actinic keratosis, BCC and SCC, had begun to develop all over the patient's body. We hypothesized that he was experiencing a pathogenesis similar to patients with xeroderma pigmentosum (XP), and we therefore assessed his DNA repair capacity. Based on these investigations, the patient was eventually diagnosed as non‐XP, even though we detected that his DNA repair capacity was slightly lower than that of normal controls, which may have led to the skin cancers. We speculate that multiple skin malignancies can be induced by long‐term phototherapy in patients with slightly impaired DNA repair capacity.     

Immunohistochemical prognostic criteria in xeroderma pigmentosum

Xeroderma pigmentosum (XP) is a rare inheritable disease characterized by severe sun sensitivity and early development of skin cancers. We compared the expression of cell proliferation markers and cell cycle checkpoint regulators in squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) from patients with and without XP. Immunostaining for p53, Ki-67, and proliferating cell nuclear antigen (PCNA) was determined in SCCs and BCCs from 18 XP patients and 30 controls. Nine of the 18 XP patients had SCC and BCC, and the other nine had only SCC. In the control group, 15 moderately differentiated SCCs and 15 BCCs were evaluated. Expressions of p53, Ki-67 and PCNA in XP and non-XP patients were assessed statistically by using the Chi-square method. Expression of Ki-67 and PCNA was found to be greater in SCC from XP patients than controls (P = 0.021 and P = 0.033, respectively). Expression of PCNA and p53 by BCCs was greater in XP patients (P < 0.001 and P = 0.027, respectively). There was a significant difference in Ki-67 (P < 0.001) and PCNA (P = 0.001) expression between the lesions of the XP patients who died during the follow up and XP patients who survived. In XP patients, SCCs with more than 10% Ki-67 expression and %50 PCNA expression have a poor prognosis. Our results suggest that increased Ki-67 and PCNA expression may be a predictor for recurrence of nonmelanocytic skin cancer and a poor prognosis.     

Risk factors for squamous cell carcinoma of the skin in Saskatchewan, Canada

Completed questionnaires regarding suspected risk factors for skin cancer were completed by 178 cases of SCC of the skin in Saskatchewan, Canada, and 284 age- sex- and location-matched controls. Significant risk factors identified using chi2 analyses were: farming, family history of skin cancer, light eye color, blond or red hair color, skin types I or II, obvious freckles in childhood, history of severe sunburn, and the use of the herbicide 2,4-Dichlorophenoxy acetic acid. The following relative risks were identified: (1) All cases of SCC of the skin and matched controls: agricultural occupation 1.49, history of severe sunburn 1.49. (2) All men with SCC of the skin and matched controls: history of severe sunburn 1.36 (3) All women with SCC of the skin and matched controls: agricultural occupation 1.83, and skin types I or II 1.48. No association was noted on our study between a history of psoriasis and development of SCC. Neither was an association between smoking and SCC found.     

着色性干皮病两例ERCC2和ERCC5基因突变分析

【摘要】 目的 分析2例着色性干皮病患儿基因突变。方法 收集2例着色性干皮病患儿临床资料,提取患儿及其父母外周血DNA,采用高通量全外显子组测序方法对患儿进行全外显子组测序,确定致病基因突变位点,再用Sanger测序法对患儿及其父母的DNA进行双向验证,重点关注着色性干皮病相关候选基因XPA、ERCC3、XPC、ERCC2、DDB2、ERCC4、ERCC5及POLH的变异。结果 例1为3岁男孩,面、耳、颈、双手背散发褐色斑点伴色素减退斑2年,步态不稳1年,皮疹夏季加重,以光暴露部位为主。例2为1岁5月龄男孩,面部散发褐色斑点伴少许色素减退斑1年。基因检测显示,例1 ERCC2基因发生复合杂合突变,即父源c.1805G>A（p.Gly602Asp）和母源c.586C>T（p.Arg196Ter）突变,为XPD型。例2 ERCC5基因发生复合杂合突变,即父源c.2533+2T>C和母源c.2453C>T（p.Ala818Val）突变,为XPG型。c.586C>T（p.Arg196Ter）和c.2533+2T>C既往未见报道。嘱防晒、避光,随访2年,患儿皮损较前有所增多,未出现恶性肿瘤。结论 ERCC2基因复合杂合突变可导致XPD型着色性干皮病,表现出皮肤和神经症状;ERCC5基因复合杂合突变可导致XPG型着色性干皮病,表现为轻症表型。早期临床特点结合基因检测有助于着色性干皮病患者的准确诊断及分型。     

Xeroderma pigmentosum complementation group G—report of two cases

Genetic complementation studies allowed assignment of a brother (XP124LO) and sister (XP 125LO), aged 14 and 12 years respectively, to the rare complementation group of classical xeroderma pigmentosum (XP), XP-G. Both patients manifested only mild cutaneous changes, with no UV-induced skin tumours, although abnormal sensitivity to UVB wavelengths was demonstrated by irradiation monochromator skin testing. Physical and neurological development was normal. Measurement of UV-induced unscheduled DNA synthesis in cultured fibroblasts showed reduction of repair synthesis to 14% and 16% of normal in XP124LO and XP125LO, respectively. This contrasts with a reduction to 5% of normal in previously described group G patients, XP2BI and XP3BR, who had correspondingly severe cutaneous and neurological manifestations.     

Radiation therapy for high-risk squamous cell carcinomas in patients with xeroderma pigmentosum: report of two cases and review of the literature

Radiation therapy (RT) represents an important adjuvant treatment modality for high-risk squamous cell carcinomas (SCCs). Despite the frequency of aggressive cutaneous and extracutaneous malignancies, there have been relatively few reports of RT in individuals with xeroderma pigmentosum (XP). We describe 2 adolescent boys with XP and high-risk SCCs of the skin that were treated with standard RT regimens without acute or chronic complications. After follow-up periods of 2 and 7 years, both of these patients had developed fewer skin cancers on the treated side of the face. A review of reported cases revealed that XP patients generally have normal cellular and clinical responses to ionizing radiation, which reflects the specificity of their nucleotide excision repair defect for ultraviolet radiation-induced DNA damage.     

Unexpected extradermatological findings in 31 patients with xeroderma pigmentosum type C

Background Xeroderma pigmentosum type C (XP‐C) is a rare, autosomal, recessive condition characterized by the association of various clinical manifestations mostly involving the skin and eyes. Objectives To evaluate the clinical manifestations in a homogeneous, genetically characterized cohort of patients with XP‐C. Methods All patients with XP‐C, which was confirmed genetically or by unscheduled DNA synthesis, from the registry of our department and from the French association of patients ‘Les Enfants de la Lune’ were contacted. During a planned consultation, clinical information was collected using a standardized case‐record form. Results In total, 31 patients were seen. The mean age at diagnosis was 2·95 years; skin symptoms started at a mean age of 1·49 years. Among the patients, 52% had relatively short stature, with a height‐for‐weight z‐score below ?1 SD; 62% showed pyramidal syndrome and 45% had photophobia and/or conjunctivitis. Four patients had several pyogenic granulomas. Twenty‐four patients (77%) had skin cancer. The mean age of onset of the first skin cancer was 4·76 years (range 2–14·5 years). Basal‐cell carcinoma was the most frequent cancer. Melanomas were rare and mostly desmoplastic. Multinodular thyroid was the most frequent internal tumour. Conclusions Our data highlight several new aspects of XP‐C. Patients with XP‐C are at risk of developing pyogenic granulomas, desmoplastic melanomas and multinodular thyroid. Involvement of the central nervous system is frequent, but its mechanism remains unclear. The relatively short stature of the patients needs further investigation in order to be explained. XP‐C is not only a cancer‐prone disorder but is also a polysystemic disorder.     

Xeroderma pigmentosum in Libya

BACKGROUND: A preliminary study of 24 cases of xeroderma pigmentosum (XP) was presented in 1990 and later published in 1992. Since then we have seen 18 further cases. OBJECTIVE: To study the clinical profile of Libyan cases of XP. METHODS: With the help of a special protocol, all 42 cases (23 girls and 19 boys from 29 families) treated and followed between 1981 and 1994 were subjected to detailed analysis. RESULTS: A history of consanguinity was present in the parents of 39 patients. XP in Libya is characterized by a relatively high incidence (approximately 15-20 per million of the population), early onset of initial manifestations (median age, 12 months) and malignant tumors (median age, 8 years), severe ocular and oral lesions in a high percentage of patients, and early death (median age, 15.5 years). The malignant skin tumors seen were squamous cell carcinoma (SCC) in 23 patients, basal cell carcinoma (BCC) in 17 patients, and basosquamous carcinoma in two patients. Malignant melanoma was not seen, but lentigo maligna was found in one case. SCC of the tongue, carcinoma of the thyroid, and lymphatic leukemia affected individual patients. Subnormal physical growth was observed in six patients, but none of the patients had significant neurologic abnormalities. The results of etretinate therapy in nine patients revealed that it is an effective preventive agent against carcinogenesis, but not a curative one. CONCLUSIONS: Severe ophthalmic manifestations affected a higher percentage of patients at an early age. Malignant melanoma did not develop in any case, except for lentigo maligna in one patient.     

Xeroderma pigmentosum complementation group F: Report of a case and review of Japanese patients

Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder characterized by extraordinary sensitivity to sunlight, resulting in cutaneous malignant tumors. Among XP, XP‐F presents relatively uniquely in Japanese. To clarify the characteristics of this group, we describe a case of XP‐F and review Japanese cases previously reported. A 50‐year‐old Japanese woman was referred to us with multiple, variously sized, light‐ or dark‐brown macules on the face and sunlight‐exposed extremities. She had experienced bulla formation with approximately 10 min of sunlight exposure during her elementary school years. Her parents had been first cousins, and her mother and sister had photosensitivity. She showed no neurological or developmental abnormalities. Ultraviolet (UV) irradiation testing revealed normal levels for minimal erythema dose with UV‐A and UV‐B. Sensitivity to UV‐C and DNA repair ability in the patient's fibroblasts were indicated between that in normal individuals and that in an XP‐A patient. Complementation assay revealed that transfection of the XPF gene led most efficient DNA repair compared with the other XP genes. Therefore, the patient was diagnosed with XP‐F. Twenty‐three cases of Japanese patients (six males, 17 females) with XP‐F have been reported, including the present case. Our review suggested a relatively high prevalence of 50% (11/22) for cutaneous malignant tumors. A significant difference was evident in the mean age at first medical consultation between patients with cutaneous malignant tumors (53.6 years) and patients without such tumors (30.8 years). This suggests that cutaneous malignant tumors could occur in the age range of 30–50 years in XP‐F patients.     

Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome treated with acitretin

We describe a 3-year-old male patient with the ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome, who developed cutaneous and ocular involvement in infancy. In addition, he had growth retardation and borderline intelligence; no other systemic involvement was found on detailed investigation. A moderate response to acitretin therapy (1 mg/kg) administered for 6 months was observed, with improvement in cutaneous features and corneal erosions and no change in alopecia or photophobia.     

Excellent response of basal cell carcinomas and pigmentary changes in xeroderma pigmentosum to imiquimod 5% cream

Xeroderma pigmentosum (XP) is an autosomal recessive disease in which patients have a 1000-fold increased risk of developing cutaneous neoplasms. Management of patients with XP is a difficult therapeutic challenge as they usually present with many cutaneous malignancies and continue to form skin tumours at a high rate. We describe a 19-year-old woman with XP who had been previously treated with many different therapeutic approaches. She had an excellent clinical response of her multiple small pigmented basal cell carcinomas and pigmentary changes using imiquimod 5% cream with only minor side-effects.     

Xeroderma pigmentosum group D patient bearing lentigo maligna without neurological symptoms

A 35-year-old Japanese female patient with xeroderma pigmentosum (XP), registered as XP114TO, was assigned to complementation group D by the cell fusion complementation test. The patient had manifested moderate solar sensitivity and freckles by the age of 6 years. The skin phototest using 290- and 300-nm monochromatic ultraviolet (UV) light revealed slightly lowered minimal erythema doses at 24 h after irradiation. The XP114TO skin fibroblasts exhibited about the 6-fold higher sensitivity to the lethal effect of 254-nm UV as did normal cells. Unscheduled DNA synthesis (UDS) induced in XP114TO cells by 254-nm UV (10 J/m2) was 33% of normal, falling into the group D range of 25-50% UDS. The patient developed lentigo maligna on the right side of the nose. Unlike the typical XP group D cases in the West, she showed no neurological abnormalities.     

Widespread cutaneous carcinomas associated with human papillomaviruses 5, 14 and 20 after introduction of methotrexate in two long-term PUVA-treated patients

BACKGROUND: PUVA treatment for patients with severe psoriasis has been demonstrated to be highly effective. However, an increased risk of nonmelanoma and melanoma skin cancers has been reported. It is generally accepted that the risk of squamous-cell carcinoma (SCC) is significantly increased in patients with long-term PUVA therapy. The role of methotrexate (MTX) and infection with oncogenic human papillomaviruses which may act as cocarcinogens is poorly documented. CASE REPORTS: Two cases of multiple SCCs associated with numerous PUVA keratoses and PUVA freckles after long-term PUVA therapy and subsequent treatment with MTX are presented. In 1 case, the tumor progressed to metastatic SCC. Tumors and scrapings of psoriatic skin lesions were analyzed for the presence of oncogenic human papillomavirus (HPV) genotypes. The genotype of HPV-5, -14 and -20 was detected in scrapings and skin tumors using PCR amplification. CONCLUSION: These observations support the concept that long-term PUVA treatment is carcinogenic and rise questions concerning an additional influence of MTX in the development and progression of skin cancer. The risk of metastatic SCC seems to be underestimated in high-dose PUVA-treated patients due to longer latency for developing metastases and the small number of studies with long-term follow-up. Treatment with MTX should be considered cautiously in patients previously exposed to high doses of PUVA. The presence of oncogenic HPVs in carcinomas and psoriatic skin lesions detected only with the highly sensitive nested PCR method is not necessarily a proof of their implication in skin carcinogenesis.     

X-Linked ocular albinism; Nettleship-Falls ocular albinism

A 39-year-old man with foveal hypoplasia, nystagmus, and decreased visual acuity was found to have multiple, cutaneous, hypopigmented macules. Macromelanosomes were demonstrated in normal skin on histopathologic examination. The patient's constellation of findings along with a strong X-linked inheritance pattern in family members led to the diagnosis of X-linked ocular albinism, which is an uncommon condition that is characterized by congenital nystagmus, iris translucency, hypopigmentation of the ocular fundus, strabismus, foveal hypoplasia, photophobia, and impaired vision.     

Sensitivity to UV radiation of fibroblasts from a Japanese group A xeroderma pigmentosum patient with mild neurological abnormalities

A 12-year-old girl, suffering from xeroderma pigmentosum (XP), had mild cutaneous and neurological abnormalities. She showed no neurological abnormalities at the age of seven, but areflexia of the patellar tendons at II. She had no malignant tumours. The skin fibroblasts from the patient were about twice as sensitive to the lethal effects of 254 nm ultraviolet (UV) radiation as those of Group C XP patients, and about twice as resistant as those of typical Group A XP patients. The ability of these fibroblasts to reactivate UV-damage adenovirus 5 was intermediate between those of Group C and typical Group A patients. The patient's cells were assigned to genetic complementation Group A by use of the cell-fusion technique. This is the first case in Japan of a Group A XP patient with mild neurological abnormalities. The mild cutaneous manifestations of this patient may be explained by the residual ability of the cells to repair UV-damaged DNA.     

The rapid onset of multiple squamous cell carcinomas in two patients commenced on ustekinumab as treatment of psoriasis

We report the cases of two patients who developed eruptive cutaneous squamous cell carcinomas (SCC) soon after commencement of ustekinumab, as treatment of moderate to severe plaque type psoriasis. Ustekinumab is a human monoclonal antibody with a novel mechanism, selectively targeting the shared p40 subunit of interleukin-12 (IL-12) and IL-23. Its efficacy has been well documented in three large phase-III trials (PHOENIX I, PHEONIX 2, ACCEPT). Safety data on this new biological agent continue to grow. To date, no link between ustekinumab and cutaneous carcinogenesis has been demonstrated and, to our knowledge, these cases are the first of their kind. Importantly, both these patients had independent risk factors for developing non-melanoma skin cancers; however, the specific time correlation with the administration of ustekinumab is of note. Our report suggests that ustekinumab may allow the development of cutaneous carcinomata in predisposed individuals.