[Light protection for xeroderma pigmentosum]. / Lichtschutz bei Xeroderma pigmentosum.

Xeroderma pigmentosum is a rare autosomal recessive disorder which is caused by germinal mutations responsible for the repair of ultraviolet (UV) radiation-induced DNA lesions. It is characterized by hypersensitivity to UV radiation, poikiloderma, ocular surface disease, and in some patients pronounced sunburn and neurological disease. Patients have a very high risk of developing ocular and skin cancer on exposed body sites. No cure is available for these patients except complete protection from all types of UV radiation.

Ocular manifestations of xeroderma pigmentosum: long-term follow-up highlights the role of DNA repair in protection from sun damage.

OBJECTIVE: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations in DNA repair genes. Clinical manifestations of XP include mild to extreme sensitivity to ultraviolet radiation resulting in inflammation and neoplasia in sun-exposed areas of the skin, mucous membranes, and ocular surfaces. This report describes the ocular manifestations of XP in patients systematically evaluated in the Clinical Center at the National Institutes of Health. DESIGN: Retrospective observational case series. PARTICIPANTS: Eighty-seven participants, aged 1.3 to 63.4 years, referred to the National Eye Institute (NEI) for examination from 1964 to 2011. Eighty-three patients had XP, 3 patients had XP/Cockayne syndrome complex, and 1 patient had XP/trichothiodystrophy complex. METHODS: Complete age- and developmental stage-appropriate ophthalmic examination. MAIN OUTCOME MEASURES: Visual acuity; eyelid, ocular surface, and lens pathology; tear film and tear production measures; and cytologic analysis of conjunctival surface swabs. RESULTS: Of the 87 patients, 91% had at least 1 ocular abnormality. The most common abnormalities were conjunctivitis (51%), corneal neovascularization (44%), dry eye (38%), corneal scarring (26%), ectropion (25%), blepharitis (23%), conjunctival melanosis (20%), and cataracts (14%). Thirteen percent of patients had some degree of visual axis impingement, and 5% of patients had no light perception in 1 or both eyes. Ocular surface cancer or a history of ocular surface cancer was present in 10% of patients. Patients with an acute sunburning skin phenotype were less likely to develop conjunctival melanosis and ectropion but more likely to develop neoplastic ocular surface lesions than nonburning patients. Some patients also showed signs of limbal stem cell deficiency. CONCLUSIONS: Our longitudinal study reports the ocular status of the largest group of patients with XP systematically examined at 1 facility over an extended period of time. Structural eyelid abnormalities, neoplasms of the ocular surface and eyelids, tear film and tear production abnormalities, ocular surface disease and inflammation, and corneal abnormalities were present in this population. Burning and nonburning patients with XP exhibit different rates of important ophthalmologic findings, including neoplasia. In addition, ophthalmic characteristics can help refine diagnoses in the case of XP complex phenotypes. DNA repair plays a major role in protection of the eye from sunlight-induced damage.

Retinoids in the chemoprevention of non-melanoma skin cancers: why, when and how.

INTRODUCTION: The chemoprevention refers to the use of various types of chemical agents for preventing carcinogenic progression. Systemic retinoids are the most studied chemopreventive agents due to their capacity to regulate cell proliferation and their demonstrated efficacy in several clinical studies. OBJECTIVES: The aim of the authors was to give precise indications regarding the use of the systemic retinoid in the chemoprevention of non-melanoma skin cancer (NMSC). METHODS: The authors reviewed the literature found through a search to MEDLINE (from 2001 to December 2011). RESULTS: Both acitretin and isotretinoin are effective for the prevention of NMSC. Isotretinoin is preferred in xeroderma pigmentosum and nevoid basal cell carcinoma syndrome, whereas acitretin is more used in transplant recipients, psoriasis and severe sun damage. CONCLUSION: Despite numerous studies of the literature concerning retinoids in chemoprevention of NMSC, precise details of the type of retinoid to use, dosage and the duration of this preventive treatment and how to manage side effects in the case of long-lasting treatment are still not uniform and comparable. Moreover, neither guidelines nor approval by Food and Drug Administration exist to regulate the use of retinoids in chemoprevention.

Xeroderma pigmentosum family support group: Helping families and promoting clinical initiatives.

The past two decades of research into Xeroderma pigmentosum (XP), an autosomal recessive disease, has been marked by significant progress in understanding the molecular basis of this rare disease. More importantly, especially from the perspective of the affected families, is that this knowledge has been applied to diagnose the condition both in utero as well as in the very early days of life. The eight known XP genes and their different phenotypes present a number of challenges that the XP Workshop sponsored by the NIH in 2010 has highlighted. There is little current treatment specifically designed for any of the XP types other than standard dermatological and neurological evaluations and care. The Xeroderma Pigmentosum Family Support Group (XPFSG) is dedicated to serving families with children and adults with all forms of XP and to help them better understand the condition, to identify practical measures which can be taken by the XP patients and their families to mitigate the effects of the disease, and to serve as patient advocates to help families discuss issues with their physicians. We summarize our efforts in terms of outreach within the US and abroad to affected families and discuss XPFSG-sponsored clinical initiatives that include molecular diagnoses, treatment, and initial proof-of-concept studies that can, if successful, improve the lives of XP patients in the near term.

Vitamin D levels of XP-patients under stringent sun-protection.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by an increased skin cancer risk due to defective repair of ultraviolet (UV)-radiation induced DNA damage. Therefore patients with XP are required to apply stringent sun-protection. Since the skin needs UV-B irradiation for de novo vitamin D synthesis, it has been postulated that sun-protection may lead to a clinically relevant reduction of vitamin D levels. To investigate whether reduced vitamin D levels in XP-patients are caused by the stringent sun-protection measures employed, in this study we examined 15 patients with XP. The 25-hydroxyvitamin (25-OHD) and 1,25-dihydroxyvitamin D (1,25-(OH)2D) serum levels were measured. Additionally, patients received a questionnaire about their sun-protection-behaviour. Serum levels for 25-OHD were decreased in 10 of 15 (67%) patients, however there was no statistically significant association between decreased 25-OHD serum levels and duration of sun-protection (p = 0.84). Results for 1,25-(OH)2D levels showed a probability of < 0.16 and between 0.16 and 0.77 for sun-protection duration of < 20 and 20 to 40 years, respectively (p = 0.0058). There was no statistically significant association between the duration of sun-protection with drometrizole trisiloxane and the probability of reduced 25-OHD and 1,25-(OH)2D levels. In conclusion, this investigation indicates that vitamin D serum levels in patients with XP may be normal, increased or decreased but this is not causally linked to the stringent photoprotective measures carried out in our group of investigated XP-patients.

Gene transduction in skin cells: preventing cancer in xeroderma pigmentosum mice.

UV radiation is the most common risk factor for skin cancer. Patients with the autosomal recessive DNA repair disorder xeroderma pigmentosum (XP) suffer high incidence of skin cancer after sunlight exposure. XP-mutant mice are attractive models to study this syndrome, as they, too, develop UV radiation-induced skin tumors, mimicking the human phenotype. Recombinant adenovirus carrying the human XPA gene was used for in vivo gene therapy in UVB-irradiated skin of such mice. Virus s.c. injection led to the expression of the XPA protein in basal keratinocytes and prevented deleterious effects in the skin, including late development of squamous cell carcinoma. Thus, efficient adenovirus gene delivery to the skin is a promising tool for reconstitution of specific DNA repair defects in XP patients.

Recapitulation of the cellular xeroderma pigmentosum-variant phenotypes using short interfering RNA for DNA polymerase H.

The lesion-specific DNA polymerase POLH gene is mutated in xeroderma pigmentosum variant (XP-V) patients who exhibit an increased skin cancer incidence from UV exposure. Normal cells in which POLH expression was reduced using short interfering RNAs (siRNAs) were compared with the XP-V cellular phenotype that results from naturally occurring inactivating mutations. Stable clones expressing siRNA had partially reduced POLH protein levels, and intermediate levels of UV sensitivity and S phase checkpoint activation, but similar levels of Mre11 foci as in XP-V cells. Therefore, suppression of POLH expression levels by siRNA recapitulates most of the phenotypes seen in cells from XP-V patients with inactivating mutations in POLH.

Normal vitamin D levels can be maintained despite rigorous photoprotection: six years' experience with xeroderma pigmentosum.

BACKGROUND: Although sun protection is advocated for skin cancer prevention, sunlight is also important in generation of vitamin D in the skin. There is concern that sun protection may result in an abnormally low level of vitamin D. OBJECTIVE: To assess the risk of vitamin D deficiency in a sunlight-deprived population, we studied eight ambulatory patients with xeroderma pigmentosum (XP) who practiced intensive sun protection during a chemoprevention study of oral isotretinoin. METHODS: We surveyed the patients to determine the extent of sun protection and vitamin D intake and measured the serum levels of two vitamin D metabolites (25-hydroxyvitamin D [25-OHD] and 1,25-dihydroxyvitamin D [1,25-(OH)2D]), calcium, and parathyroid hormone during 6 years. RESULTS: The patients all wore protective clothing and sunscreens when outdoors. Estimated mean vitamin D intake was normal. The mean values of serum 25-OHD were low normal, but 1,25-(OH)2D, calcium, ionized calcium and parathyroid hormone levels were normal. Lack of seasonal variation in serum 25-OHD indicated rigorous photoprotection. CONCLUSION: Despite rigorous sun protection normal vitamin D levels can be maintained in ambulatory patients with XP.

[Environmental and occupational factors in skin carcinogenesis. Indications for therapy and prevention]. / Fattori ambientali e professionali nella cancerogenesi cutanea. Indicazioni di terapia e prevenzione.

The authors review the environmental and occupational factors in cutaneous cancerogenesis, group them according to their characteristics, and in particular distinguish between factors of physical and chemical nature. The authors also discuss the influence of predisposing factors related to the somatic makeup (xeroderma pigmentosus) and to work environment. Particular emphasis is given to skin precancerous and therefore to the importance of a mass screening and an effective health education. The authors illustrate the disorder with their clinical pictures.

[Xeroderma pigmentosum. Therapeutic indications on the basis of 3 cases seen recently (author's transl)]. / Xéroderma pigmentosum. Les orientations thérapeutiques à propos de 3 cas récemment observés.

This condition is a genodermatosis, seen chiefly around the shores of the Mediterranean, characterised by early pigment disturbances which progress virtually inexorably towards a diffuse epitheliomatosis which usually results in death before the age of 20 years. Progression of the lesions is precipitated by exposure to UV rays. These lesions are seen essentially in exposed areas, in particular oculopalpebral. Treatment is first preventive (decrease in exposure to sun and protection). Otherwise, surgery remains the most effective method: either excision as required, or extensive cervicofacial prophylactic excision followed by grafting.