Corneoscleral locally aggressive fibrous histiocytoma in Xeroderma Pigmentosum patient: A case report

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder that has been found in all continents and racial groups in relation to faulty repair of DNA with sun exposure. Several cutaneous and ocular tumors have been described in relation to XP including fibrous histiocytoma (FH). The diagnosis of conjunctival FH is challenging owing to the rarity of this tumor and the diversity of its classification into benign, locally aggressive and malignant. We are describing a recurrent FH exhibiting a locally aggressive behavior in a child with history of XP. Detailed histopathological features are presented with literature review.     

New areas of focus at workshop on human diseases involving DNA repair deficiency and premature aging

Researchers and clinicians interested in human diseases of DNA repair deficiency and premature aging gathered at the National Conference Center in Lansdowne, Virginia on 5-8 September 2006 to attend a workshop co-organized by Vilhelm Bohr (National Institute of Aging) and Kenneth Kraemer (National Cancer Institute). An important feature of this workshop was the participation of representatives from xeroderma pigmentosum (XP), Cockayne Syndrome (CS) and trichothiodystrophy (TTD) family support groups. Studies presented at the workshop described important new insights into the phenotypic complexity of XP, CS and TTD, renewed focus on the neurological manifestations of each of these diseases, as well as keen interest in the role of oxidative stress and mitochondrial dysfunction in neurodegenerative processes and normal and/or premature aging. This workshop report summarizes some of the presentations and outcomes of the workshop.     

ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes

Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5′ incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.     

A型着色性干皮病1例XPAC基因的复合无义突变

目的检测1例A型着色性干皮病患者及其父母的XPAC基因的突变情况。方法收集患者及其父母资料,提取外周血DNA,采用PCR扩增XPAC基因编码区的全部外显子,DNA直接测序,明确突变位点,并以50个无关正常人作对照。结果患者XPAC基因分别于第631及第682位发生C→T突变,使第211位及第228位氨基酸均由精氨酸变成终止密码子(R211X,R228X)突变,两突变分别来自其父母。50例健康对照者不存在此两种突变。结论R211X及R228X复合无义突变为引起该患者的A型着色性干皮病的病因。     

DNA-based prenatal diagnosis in a Chinese family with xeroderma pigmentosum group A

BACKGROUND: Xeroderma pigmentosum (XP) is a group of autosomal recessive diseases characterized by hypersensitivity to ultraviolet rays. Among its eight complementation groups, XP group A (XPA) is the most severe type. The XPAC gene has been identified as the defective gene in XPA patients. OBJECTIVES: To examine genomic DNA from a Chinese family with XPA, to determine the XPAC mutation and, after genetic counselling, to undertake DNA-based prenatal diagnosis in a subsequent pregnancy. METHODS: Fetal DNA was extracted from amniotic fluid and used to amplify exon 5 of XPAC containing the potential mutation. Direct sequencing and restriction endonuclease digestion were used for prenatal diagnosis. RESULTS: We identified a homozygous nonsense XPAC mutation of 631C-->T, which results in an R211X mutation in XPA protein, in the proband. Both her parents are heterozygous. Prenatal diagnosis demonstrated a heterozygous sequence predicting an unaffected child, and a healthy girl was born. CONCLUSIONS: These data provide the first example of a DNA-based prenatal test for genodermatosis in China.     

Investigation of the sister chromatid exchange (SCE) frequency in one patient with xeroderma pigmentosum

Summary The frequency of SCE was investigated in peripheral lymphocytes of one patient with XP. Although lymphocytes did not show high levels of spontaneous chromosome damage, 10^-8 M Mitomycin C greatly increased the frequency of SCE. The results are interpreted as an expression of mutagen induced chromosomal instability due to impaired DNA repair, which is a significant anomaly of the disease.     

<Emphasis Type="Italic">XPC</Emphasis> intron11 C/A polymorphism as a risk factor for prostate cancer

Objectives

DNA repair genes play an important role in protection against environmental and endogenous DNA damage, and constitute the first line of defense against cancer. Xeroderma pigmentosum complementation group C (XPC) is involved in the damage recognition step during nucleotide excision repair. The relationship between XPC intron11 C/A polymorphism and cancer risk has not been widely studied. Hence, this study evaluated the relationship between the XPC intron11 C/A polymorphism and prostate cancer risk.

Materials and methods

This hospital-based cohort consisted of 152 patients with prostate cancer and 142 male controls. The XPC intron11 C/A genotype was determined using the PCR–RFLP method. Medical, occupational, and cigarette-smoking history was obtained from each participant using questionnaires.

Results

Logistic regression analysis revealed that compared to controls, the frequencies of the A/A and C/A genotypes were significantly higher than those of the C/C genotype in cancer patients (OR = 2.03, 95 % confidence interval (CI) 1.03–3.98 and OR = 1.91, 95 % CI 1.13–3.24, respectively). We also found that the frequency of the A/A genotype was significantly higher in cancer cases than in controls among non-smokers (OR = 7.7, 95 % CI 1.38–42.88, compared to the C/C genotype).

Conclusion

We found that the XPC intron11 C/A polymorphism was associated with an increased risk of prostate cancer. Among non-smokers, the A/A genotype was significantly more prevalent in prostate cancer patients than in controls.