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We examined the clinical, molecular and genetic features of a 16-year-old boy (XP2GO) with xeroderma pigmentosum (XP) and progressive neurological symptoms. The parents are not consanguineous. Increased sun sensitivity led to the diagnosis of XP at 2 years of age and a strict UV protection scheme was implemented. Besides recurrent conjunctivitis and bilateral pterygium, only mild freckling was present on his lips. He shows absent deep tendon reflexes, progressive sensorineural deafness and progressive mental retardation. MRI shows diffuse frontal cerebral atrophy and dilated ventricles. Symptoms of trichothiodystrophy (brittle hair with a tiger-tail banding pattern on polarized microscopy) or Cockayne syndrome (cachectic dwarfism, cataracts, pigmentary retinopathy and spasticity) were absent. XP2GO fibroblasts showed reduced post-UV cell survival (D(37) = 3.8 J/m(2)), reduced nucleotide excision repair, reduced expression of XPD mRNA and an undetectable level of XPD protein. Mutational analysis of the XPD gene in XP2GO revealed two different mutations: a common p.Arg683Trp amino acid change (c.2047C>T) known to be associated with XP and a novel frameshift mutation c.2009delG (p.Gly670Alafs*39). The latter mutation potentially behaves as a null allele. While not preventing neurological degeneration, early diagnosis and rigorous sun protection can result in minimal skin disease without cancer in XP patients.

Background: An association of Sweet syndrome with chronic myeloid leukemia (CML) has been recently observed in patients treated with tyrosine kinase inhibitors., Observations: We describe a 67-year-old patient with a 6-year history of Philadelphia chromosome translocation t(9;22)(q34;q11)-positive CML. The tyrosine kinase inhibitor AMN107 (nilotinib) kept the patient in chronic phase. After 10 months of taking nilotinib, he developed pneumonia with septic features. Seven days later, bullous skin infiltrations on the upper arms and a large, painful bullous swelling of the right neck occurred without any evidence of a viral, bacterial, or fungal blood infection. Findings from histologic examination showed massive infiltrations of the whole dermis with neutrophil granulocytes as well as with monocytoid histiocytic cells. Fluorescence in situ hybridization analysis of paraffin-embedded tissue revealed a BCR-ABL fusion, indicating the presence of t(9;22)(q34;q11). The addition of oral prednisolone to an adequate antibiotic treatment led to rapid resolution of the cutaneous infiltrations., Conclusions: Skin infiltrations consistent with Sweet syndrome can occur in patients with septic CML during the treatment with tyrosine kinase inhibitors, including nilotinib. Skin infiltrations can include specific CML cells.

Genomic instability is the driving force behind cancer development. Human syndromes with DNA repair deficiencies comprise unique opportunities to study the clinical consequences of faulty genome maintenance leading to premature aging and premature cancer development. These syndromes include chromosomal breakage syndromes with defects in DNA damage signal transduction and double-strand break repair, mismatch repair defective syndromes as well as nucleotide excision repair defective syndromes. The same genes that are severely affected in these model diseases may harbour more subtle variations in the 'healthy' normal population leading to genomic instability, cancer development, and accelerated aging at later stages of life. Thus, studying those syndromes and the molecular mechanisms behind can significantly contribute to our understanding of (skin) cancerogenesis as well as to the development of novel individualized preventive and therapeutic anticancer strategies. The establishment of centers of excellence for studying rare genetic model diseases may be helpful in this direction.

Defects in the xeroderma pigmentosum type B (XPB) gene (ERCC3), a DNA helicase involved in nucleotide excision repair (NER) and an essential subunit of the basal transcription factor, TFIIH, have been described in only three families. We report three new XPB families: one has two sisters with relatively mild xeroderma pigmentosum (XP) symptoms not previously associated with XPB mutations and two have severe XP/Cockayne syndrome (CS) complex symptoms. All XP-B cells had reduced NER and post-ultraviolet (UV) cell viability. Surprisingly, cells from the milder XP sisters had the same missense mutation (c.296T>C, p.F99S) that was previously reported in two mild XP/CS complex brothers. These cells had higher levels of XPB protein than the severely affected XP/CS complex patients. An XPB expression vector with the p.F99S mutation partially complemented the NER defect in XP-B cells. The three severely affected XP/CS complex families all have the same splice acceptor site mutation (c.2218-6C>A, p.Q739insX42) in one allele. This resulted in alteration of 41 amino acids at the C terminus, producing partial NER complementation. This limited number of mutations probably reflects the very restricted range of alterations of this vital protein that are compatible with life. We found new mutations in the second allele yielding markedly truncated proteins in all five XP or XP/CS complex families: c.1273C>T, p.R425X; c.471+1G>A, p.K157insTSDSX; c.807-808delTT, p.F270X; c.1421-1422insA, p.D474EfsX475; and c.1633C>T, p.Q545X. The remarkable phenotypic heterogeneity of XPB is associated with partially active missense mutations in milder patients while severe XP/CS complex patients have nonsense mutations in both alleles with low levels of altered XPB proteins.

Tumorigenesis is a multi-step process in which exogenous and endogenous mutational events lead to accumulation of DNA mutations resulting in loss of cellular growth control. During the last decades knowledge about the molecular mechanisms of DNA mutations and the cellular systems that counteract the degeneration of the genome has increased rapidly. This expansion was driven in part by clinical and molecular investigations of syndromes with genetic in-stability. These syndromes are typically associated with an increased predisposition for tumor formation. They include nucleotide excision repair defective syndromes, mismatch repair defective syndromes, and the chromosome break-age syndromes. These diseases mirror vividly the phenotypic consequences of the failure of important cellular systems for the maintenance of the genomic integrity. They significantly contribute to our understanding of the molecular mechanisms of (skin) carcinogenesis and for the development of preventive and therapeutic anticancer strategies.

The variola virus was declared eradicated by the World Health Organization in 1980 but human infections by cowpox virus, another member of the genus Orthopoxvirus, are still observed, mainly in European countries. We report a woman who presented with two umbilicated vesicles surrounded by an indurated erythematous edema within cat scratch injuries on her thigh. The diagnosis of an Orthopoxvirus infection was based on the visualization of characteristic virus particles by electron microscopy and the detection of the A27L gene (14-kd fusion protein gene) of the genus Orthopoxvirus by polymerase chain reaction from a lesional skin biopsy specimen. Differential diagnoses of cat scratch disease, pustula maligna, and bullous impetigo were excluded by microbiologic investigation of the biopsy specimen. Both lesions scarred after 6 weeks of a continuous local antiseptic treatment.

Xeroderma pigmentosum group C (XP-C) is a rare autosomal recessive disorder. Patients with two mutant alleles of the XPC DNA repair gene have sun sensitivity and a 1000-fold increase in skin cancers. Clinically normal parents of XP-C patients have one mutant allele and one normal allele. As a step toward evaluating cancer risk in these XPC heterozygotes we characterized cells from 16 XP families. We identified 15 causative mutations (5 frameshift, 6 nonsense and 4 splicing) in the XPC gene in cells from 16 XP probands. All had premature termination codons (PTC) and absence of normal XPC protein on western blotting. The cell lines from 26 parents were heterozygous for the same mutations. We employed a real-time quantitative reverse transcriptase-PCR assay as a rapid and sensitive method to measure XPC mRNA levels. The mean XPC mRNA levels in the cell lines from the XP-C probands were 24% (P<10(-7)) of that in 10 normal controls. This reduced XPC mRNA level in cells from XP-C patients was caused by the PTC that induces nonsense-mediated mRNA decay. The mean XPC mRNA levels in cell lines from the heterozygous XP-C carriers were intermediate (59%, P=10(-4)) between the values for the XP patients and the normal controls. This study demonstrates reduced XPC mRNA levels in XP-C patients and heterozygotes. Thus, XPC mRNA levels may be evaluated as a marker of cancer susceptibility in carriers of mutations in the XPC gene.

Background: Compared with intraoperative sentinel lymph node identification using blue dye only, the introduction of a hand-held gamma probe has improved the identification rates. In this retrospective study, further aspects related to the introduction of gamma-guided preparation are analysed in detail., Patients and Methods: 81 patients who underwent sentinel biopsy using the blue dye technique were compared to 247 patients whose operations were guided by blue dye and gamma probe., Results: After the introduction of radio-guided surgery, the sentinel node identification rate increased from 87.7 % to 99.2 % (P < 0.00001). The number of harvested sentinel lymph nodes increased from 1.4 +/- 0.9 to 1.8 +/- 0.09 (P < 0.00001). The "clinical false-negative rate" decreased from 15.8 % to 9.6 %. The percentage of positive completion lymphadenectomy decreased from 50 % to 24.6 %. The risk of postoperative seroma decreased as a consequence of gamma guided preparation (5.1 % versus 15 %, P = 0.01). Regarding overall survival and recurrence-free survival, there were no significant differences between both groups. The 5-year-probability of nodal basin failure was 7.9 % after negative sentinel biopsy and 25.3 % after positive sentinel lymphonodectomy plus consecutive completion lymphadenectomy., Conclusions: Combined application of blue dye and gamma-probe improved sensitivity and decreased the risk of postoperative seroma. The probability of recurrence and survival was not influenced by the technique of intraoperative sentinel node identification.

Individuals with the rare DNA repair deficiency syndrome xeroderma pigmentosum (XP) are sensitive to the sun and exhibit a 1000-fold increased risk for developing skin cancers, including cutaneous melanoma. Inherited polymorphisms of XP genes may contribute to subtle variations in DNA repair capacity and genetic susceptibility to melanoma. We investigated the role of three polymorphic alleles of the DNA repair gene XPC in a hospital-based case-control study of 294 Caucasian patients from Germany who had cutaneous melanoma and 375 healthy cancer-free sex-matched Caucasian control subjects from the same area. We confirmed that the XPC intron 9 PAT+, intron 11 -6A, and the exon 15 2920C polymorphisms are in a linkage disequilibrium. Only 1.6% of the 669 donors genotyped were discordant for these three polymorphisms. The allele frequencies (cases: controls) were for intron 9 PAT+ 41.7%:36.9%, for intron 11 -6A 41.8%:37.0% and for exon 15 2920C 41.3%:37.3%. Using multivariate logistic regression analyses to control for age, skin type and number of nevi, the three polymorphisms were significantly associated with increased risks of melanoma: OR 1.87 (95% CI: 1.10-3.19; P = 0.022), OR 1.83 (95% CI: 1.07-3.11; P = 0.026), and OR 1.82 (95% CI: 1.07-3.08; P = 0.026), respectively. Exploratory multivariate analyses of distinct subgroups revealed that these polymorphisms were associated with increased risks for the development of multiple primary melanomas (n = 28). The results of our case-control study support the hypothesis that the intron 9 PAT+, intron 11 -6A and exon 15 2920C haplotype may contribute to the risk of developing cutaneous melanoma by increasing the rate of an alternatively spliced XPC mRNA isoform that skips exon 12 and leads to reduced DNA repair. Our results should be validated in independent samples in order to guard against false positive findings.

We describe a new family with the rare genodermatosis keratosis punctata palmo-plantaris Buschke-Fischer-Brauer (keratoma disseminatum). In all, 3 family members in 3 generations were affected, a pattern consistent with autosomal dominant inheritance. Clinical symptoms started in the third decade with disseminated, small, round, hyperkeratotic papules on the palms and soles. Punctate keratoses coalesced into hyperkeratotic plaques on pressure points. Identification of additional families is necessary to permit definitive genetic classification of this genodermatosis.

Background: Dermabrasion is one approach to the treatment of treating giant melanocytic congenital nevi. Treatment is recommended to reduce the risk of spontaneous malignant transformation of giant nevi into malignant melanomas that usually occur in childhood., Objective: To describe the development of a multicentric malignant melanoma in a giant melanocytic congenital nevus after dermabrasion., Methods: We report about a 46-year-old male patient who developed a multicentric malignant melanoma in a giant melanocytic congenital nevus. The nevus was located on his left shoulder extending to his neck and chest. Previously, dermabrasion of the nevus was performed twice at the ages of 26 and 28., Results: To our knowledge, this is the first report of malignant transformation of a giant nevus into a multicentric malignant melanoma diagnosed 20 years after the procedure of dermabrasion., Conclusion: We conclude that a close follow-up of such patients is mandatory.

We summarize the clinical data of 47 patients with the rare genodermatosis keratosis punctata palmoplantaris Buschke-Fischer-Brauer. The pedigrees of 14 German families were studied. In three families there was only one member affected, two or more affected members were found in the other families. These family pedigrees were consistent with autosomal dominant inheritance. Variable expression of the disease was noted in members within one family. Over pressure points punctate keratoses coalesced into hyperkeratotic plaques. There was palmoplantar hyperhidrosis in 3 families associated with keratosis. Continuous systemic retinoid treatment can clear symptoms. Future genetic classification on a molecular basis may reveal the existence of more than one entity of this clinically heterogeneous genodermatosis.

XPC DNA repair gene mutations result in the cancer-prone disorder xeroderma pigmentosum. The XPC gene spans 33 kb and has 16 exons (82-882 bp) and 15 introns (0.08-5.4 kb). A 1.6 kb intron was found within exon 5. Sensitive real- time quantitative reverse transcription-polymerase chain reaction methods were developed to measure full-length XPC mRNA (the predominant form) and isoforms that skipped exons 4, 7 or 12. Exon 7 was skipped in approximately 0.07% of XPC mRNAs, consistent with the high information content of the exon 7 splice acceptor and donor sites (12.3 and 10.4 bits). In contrast, exon 4 was skipped in approximately 0.7% of the XPC mRNAs, consistent with the low information content of the exon 4 splice acceptor (-0.1 bits). A new common C/A single nucleotide polymorphism in the XPC intron 11 splice acceptor site (58% C in 97 normals) decreased its information content from 7.5 to 5.1 bits. Fibroblasts homozygous for A/A had significantly higher levels (approximately 2.6-fold) of the XPC mRNA isoform that skipped exon 12 than those homozygous for C/C. This abnormally spliced XPC mRNA isoform has diminished DNA repair function and may contribute to cancer susceptibility.

We studied three newly diagnosed xeroderma pigmentosum complementation group G patients with markedly different clinical features. An Israeli-Palestinian girl (XP96TA) had severe abnormalities suggestive of the xeroderma pigmentosum/Cockayne syndrome complex including sun sensitivity, neurologic and developmental impairment, and death by age 6 y. A Caucasian girl (XP82DC) also had severe sun sensitivity with neurologic and developmental impairment and died at 5.8 y. In contrast, a mildly affected 14-y-old Caucasian female (XP65BE) had sun sensitivity but no neurologic abnormalities. XP96TA, XP82DC, and XP65BE fibroblasts showed marked reductions in post-ultraviolet cell survival and DNA repair but these were higher in XP65BE than in XP82DC. XP96TA fibroblasts had very low XPG mRNA expression levels whereas XP65BE fibroblasts had nearly normal levels. Host cell reactivation of an ultraviolet-treated reporter assigned all three fibroblast strains to the rare xeroderma pigmentosum complementation group G (only 10 other patients previously reported). XP96TA and XP82DC cells had mutations in both XPG alleles that are predicted to result in severely truncated proteins including stop codons and two base frameshifts. The mild XP65BE patient had an early stop codon mutation in the paternal allele. The XP65BE maternal allele had a single base missense mutation (G2817A, Ala874Thr) that showed residual ability to complement xeroderma pigmentosum complementation group G cells. These observations agree with earlier studies demonstrating that XPG mutations, which are predicted to lead to severely truncated proteins in both alleles, were associated with severe xeroderma pigmentosum/Cockayne syndrome neurologic symptoms. Retaining residual functional activity in one allele was associated with mild clinical features without neurologic abnormalities.