Clinical and molecular epidemiological study of xeroderma pigmentosum in China: A case series of 19 patients.

Xeroderma pigmentosum (XP) is a rare genetic disorder which is divided into eight complementation groups: XP-A to XP-G and XP-V. Some XP patients demonstrate severe cutaneous and neurological manifestations, management of which requires timely diagnosis and intervention. We performed clinical evaluation and genetic analysis on 19 patients, the largest cohort of XP to date in China. Twenty-three mutations from six groups were identified, 16 of which were novel. All patients developed marked freckle-like pigmentation on sun-exposed sites while patients with XP-A, XP-D, XP-F and XP-G showed acute sunburn reactions. Only XP-A patients displayed progressive neurological degeneration. A relatively larger proportion of XP-A and XP-C were found in Chinese XP patients. One XP case and two carriers were prenatally determined. This study extended the mutation spectrum of XP in China and may aid in the diagnosis and treatment of Chinese XP patients.

High prevalence of vitamin D deficiency in patients with xeroderma pigmetosum-A under strict sun protection.

BACKGROUND/OBJECTIVES: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by defective repair of ultraviolet (UV) irradiation-induced DNA damage and high risk of skin cancer. Thus, these patients require strict photoprotection. Considering the importance of UV-mediated cutaneous vitamin D production, such rigorous photoprotection would cause vitamin D deficiency. Then, we have studied the vitamin D status in patients with XP-A, a group requiring the most strict photoprotection. SUBJECTS/METHODS: Twenty-one patients with XP-A (aged 6-25) were evaluated for their vitamin D intake, serum levels of 25-hydroxy-vitamin D (25OHD) and parathyroid hormone (PTH). Vitamin D intake was assessed by a 2-day food weighing method. RESULTS: Median dietary intake of vitamin D was 4.1 µg/day, and the median concentrations of serum 25OHD and PTH were 7.7 and 49.9 pg/ml, respectively. In 76% of the patients, serum 25OHD level was lower than 10 ng/ml, indicating vitamin D deficiency. Vitamin D intake and serum 25OHD level were significantly lower in patients under enteral nutrition (EN) than those with oral intake (OI). Multivariate analyses revealed that EN was a significant predictor of decreased serum 25OHD level (ß coefficient=-0.59, P=0.03). CONCLUSIONS: Vitamin D deficiency is highly prevalent in XP-A patients, and supplementation should be considered to avoid unfavorable skeletal consequences in these patients. In addition, determination of dietary vitamin D requirement has been a difficult work issue in the decision of dietary reference intakes (DRIs) because of its cutaneous production. Data from XP patients would yield useful information for the determination of DRIs for vitamin D.

[Association of Kaposi's disease-immunoglobulin monoclonal: a new case]. / Association maladie de Kaposi et immunoglobuline monoclonale: un nouveau cas.

Kaposi disease, a tumor virus-induced, is a cutaneomucosis disease, generated by the virus infection HHV 8 of the gamma-Herpesviridae family. This virus is involved in several lymphoid pathologies. Its role in the plasma cell proliferation genesis during monoclonal gammopathy is discussed, and results are contradictory. The occurrence of Kaposi disease during multiple myeloma was described in the literature. Through this observation, we report the first case associated with monoclonal gammopathy, evolved for 3 years by HIV negative patient, and we discuss the involvement of HHV8 virus in the development of monoclonal immunoglobulin.

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.

[Serum concentration of coenzyme Q in xeroderma pigmentosum].

Serum concentrations of CoQ were measured on 22 xeroderma pigmentosum (XP) patients. 10 severely handicapped patients and 32 healthy children and adults. CoQ levels in XP patients (0.5 +/- 0.16 microgram/ml) and handicapped patients (0.57 +/- 0.21 microgram/ml) were lower than those in healthy children and adults (0.73 +/- 0.2 microgram/ml). CoQ levels in XP patients tended to decrease with age and were extremely low in two bed-ridden patients (0.29 and 0.21 microgram/ml), suggesting that CoQ levels decreased with disease progression. We studied the clinical effects of CoQ therapy in 19 XP patients with low CoQ levels. Eight patients showed increased activity in daily life. It suggests that XP patients have the disturbance of energy metabolism due to mitochondrial dysfunction. We consider it is worthwhile to research the mitocondrial function and the trial of CoQ therapy on XP patients.

Simplified method for the determination of 25-hydroxy and 1alpha,25-dihydroxy metabolites of vitamins D2 and D3 in human plasma. Application to nutritional studies.

A simplified method for the determination of 25-hydroxy and 1alpha,25-dihydroxy metabolites of vitamins D2 and D3 in human plasma was developed. Plasma samples were deproteinizated and applied to a Bond Elut C18OH cartridge to separate 25-hydroxyvitamin D (25-OH-D) and 1alpha,25-dihydroxyvitamin D [1,25(OH)2D] fractions. The 25-OH-D fraction was purified by a Bond Elut C18 cartridge and 25-OH-D2 and 25-OH-D3 were assayed by HPLC using a Zorbax SIL column. The 1,25(OH)2D fraction obtained above was subsequently applied to HPLC using a Zorbax SIL column to separate 1,25(OH)2D2 and 1,25(OH)2D3 fractions which were determined by a radioreceptor assay (RRA) using calf thymus receptor. The method was applied to nutritional studies.

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.

Chromosomal fragility in the cancer-prone disease xeroderma pigmentosum preferentially involves bands relevant for cutaneous carcinogenesis.

Spontaneous and folate-induced chromosomal fragility was analyzed in peripheral blood lymphocytes from 6 patients affected by the cancer-prone disease xeroderma pigmentosum (XP), from the parents of 4 of the patients, and from 12 normal subjects. All XP patients were defective in nucleotide-excision repair; 4 belonged to group C and 1 each to groups A and D. A tendency toward increased spontaneous chromosomal fragility was observed in the XP family members, and lesions indicating substantial chromosomal damage, which were not observed in any healthy donors, were frequently found. The spontaneous lesion sites in lymphocytes from homozygous and heterozygous carriers of XP defects appeared to be significantly associated with those observed in normal skin fibroblasts from the same subjects. These XP spontaneous fragility sites showed a statistically significant association with the rearrangement breakpoints reported in skin pre-tumoral and tumoral lesions from normal and unrelated XP donors. Under conditions of folate deprivation, the chromosomal fragility level, the pattern and the frequency of expression of fragile sites in XP patients and in their parents were similar to normal. However, XP patients generally showed a higher susceptibility to breakage at sites described as mutagen and carcinogen targets.

Effects of topoisomerase II inhibition in lymphoblasts from patients with progeroid and "chromosome instability" syndromes.

DNA topoisomerase II is involved in DNA topologic changes through the formation of a cleavable complex. This is stabilized by the antitumor drug VP16, which results in DNA breakage, aberrant recombination, and cell death. In this work, we compare the chromosomal damage induced by VP16 with that induced by bleomycin (BLM) in lymphoblasts from patients affected by the chromosome breakage syndromes ataxia telangiectasia (AT), xeroderma pigmentosum (XP), and Bloom syndrome (BS), and by the progeroid syndromes Werner (WS) and Cockayne (CS). Patients affected by AT, XP, BS, and WS have a greatly enhanced risk of developing cancer. The results show that AF and WS cells are hypersensitive to VP16, as revealed in the higher proportion of metaphases showing exchange figures and more than two breaks. All lines except AT and one CS line showed normal sensitivity to BLM. Our data on the sensitivity to VP16 of all these mutant cells underline the fact that VP16 damage is amplified only in cells that have abnormal illegitimate recombination (i.e., AT and WS).

[The effect of the environment on the repair of DNA damage in human lymphocytes]. / Vliianie okruzhaiushchei sredy na reparatsiiu povrezhdenii DNK limfotsitov cheloveka.

The dependence of UV-induced unscheduled DNA synthesis (UDS) in the unstimulated lymphocytes of human peripheral blood on the ionic strength (mu) of the culture medium has been shown. In the level of mu lower or higher than the physiological (mu ph) one, UDS significantly decreases. The effect of modification of mu due to the changes of ionic strength is absent in the lymphocytes of the classic form of xeroderma pigmentosum. The phenomenon may become useful in the development of a new test for revealing cells with a genetically or physiologically changed system of UV-induced DNA repair. The mechanisms of investigated phenomenon, particularly their dependence on the structure of chromatin, as well as the influence of ionic strength on binding of the repair enzymes with DNA are discussed.

[The dependence of DNA repair induced by genetically hazardous exposures on the ionic strength of the medium containing the cells]. / Zavisimost' reparatsii DNK, indutsirovannoi geneticheski opasnymi vozdeistviiami, ot ionnoi sily sredy, v kotoroi nakhodiatsia kletki.

The dependence of UV-induced unscheduled DNA synthesis (UDS) in non-stimulated lymphocytes of human peripheral blood on the ionic strength (mu) of the culture medium has been shown. With the level of mu lower or higher than physiological (mu ph) the UDS significantly decreases. The effect of modification of mu due to changes in ionic strength is absent in the lymphocytes of patients with the classic form of xeroderma pigmentosum. This phenomenon may become useful for development of a new test revealing cells with genetically or physiologically changed system of UV-induced DNA repair. Mechanisms of investigated phenomenon, particularly their dependence on the chromatin structure, as well as the influence of ionic strength on binding the repair enzymes with DNA are discussed.

Differences in the kinetics of DNA repair in cancer patients and healthy controls.

The time course of DNA repair, using (3H)thymidine uptake as parameter, was measured during 8 h after a single exposure to 2, 8, and 16 UV-C J/m2 in lymphocytes of 8 cancer patients, 1 xeroderma pigmentosum patient and 10 controls. All patients had reduced repair, and all controls normal repair, as calculated 2 h after a single exposure. Six patients reached normal levels with a delay of 2-6 h, whereas 2 patients and the xeroderma pigmentosum patient did not. Although the kinetic curves in controls and patients had a similar form, those for 8 and 16 J/m2 in patients were shifted so that they corresponded to that of 2 J/m2 in controls. Additionally the ability to repair repeated damage (cells irradiated twice or three times at 2-hour intervals with doses of 2 or 8 J/m2) was investigated in 6 patients and in 7 controls. The incorporation values showed significant differences between patients and controls at each dose and time point. Cancer patients tend to repair repeated damage less efficiently than controls. Using these parameters subtle differences between the repair ability of individuals might be identified. Because of the known connection between reduced DNA repair and carcinogenesis, this might help to distinguish cancer-prone individuals.

Porphyrins and nucleic acid in some photosensitive skin diseases.

This study was suggested to evaluate the possible role of porphyrins and DNA, and their interaction, in some photosensitive premalignant and malignant dermatoses. Twenty-five patients with photosensitive skin diseases viz. xeroderma pigmentosum and basal cell carcinoma, were randomly selected at the outpatient clinic of Dermatology in Mansoura University Hospital. Twenty-five matched normal individuals were used as a control group. In basal cell carcinoma patients, a high increase in skin DNA and decrease in skin total porphyrin, haemoglobin and haem concentrations were observed. In xeroderma pigmentosum, a significant decrease in both skin DNA and skin total porphyrin were found, at the same time, there were elevations in urinary total porphyrin, PBG and ALA concentrations, and a high decrease in haemoglobin and haem levels.

Search for consanguinity within and among families of patients with trichothiodystrophy associated with xeroderma pigmentosum.

The association of two rare hereditary disorders, trichothiodystrophy (TTD) and xeroderma pigmentosum (XP), was found in four patients from three families, apparently unrelated but living in the same geographical area. In order to test the hypothesis of a common ancestor, consanguinity within and among the families was checked using three different approaches: reconstruction of genealogical trees, typing of blood markers, and surname analysis. The results of the three types of analyses strengthen the hypothesis that, in at least two out of the three families, the genetic defect determining the TTD/XP phenotype is identical by descent, as a consequence of remote inbreeding. This implies that if two mutations are responsible for the two diseases they are at linked loci or affect the same gene.

Chromosome and blood marker studies in families of patients affected by xeroderma pigmentosum and trichothiodystrophy.

Chromosome and blood marker studies were performed in the families of 4 patients in which the association of 2 rare recessive Mendelian disorders, xeroderma pigmentosum (XP-D) and trichothiodystrophy (TTD), was present. Blood genotypes did not indicate any linkage with the pathologic condition, nor any segregation anomaly. Cytogenetic analysis using high-resolution banding techniques showed a normal karyotype both in the heterozygous and in the homozygous individuals. These findings lead us to exclude a cytologically detectable chromosome rearrangement, such as a microdeletion, as a possible cause of the association of XP-D and TTD in our patients.