The Papillon-Lefèvre syndrome, inherited in an autosomal recessive pattern, manifests with palmoplantar keratoderma and early, destructive periodontitis. Recently, mutations in the gene encoding cathepsin C have been disclosed in a limited number of families with Papillon-Lefèvre syndrome. We have examined two multiplex families with Papillon-Lefèvre syndrome, and evaluated the gene encoding cathepsin C for mutations. The mutation detection strategy consisted of polymerase chain reaction amplification of all seven exons and flanking intronic sequences, followed by direct nucleotide sequencing. This strategy identified two missense mutations, W39S and G301S, affecting highly conserved amino acid residues within the cathepsin C polypeptide. The affected individuals were homozygotes whereas heterozygous carriers of the mutations were clinically unaffected, confirming the recessive nature of the mutations. Addition of these cathepsin C gene mutations into the expanding Papillon-Lefèvre syndrome mutation database allows further development of genotype/phenotype correlations towards understanding this severe genodermatosis.

Background: Metastatic skin cancer is a rare complication of internal malignancies. Patients who do develop skin metastases seldom present with a zosteriform distribution. Objective: To elucidate the characteristics of zosteriform metastatic skin cancer, 15 cases from the medical literature and 3 cases seen in our clinic were reviewed clinically and histopathologically. Methods: The age and sex of each patient, site of the primary tumor, pathology of primary and metastatic lesions, location of the skin cancer and presence of pain were determined for the 18 cases of zosteriform skin cancer. Results: The most frequent site of the primary tumor was the breast (4 cases), ovary or lung (3 cases each), prostate, bladder or stomach (2 cases each) and uterus or colon (1 case each). The most common site of the skin metastases was the chest wall (8 cases) and abdominal wall (7 cases). The histology of the primary lesion was compatible with adenocarcinoma (10 cases), transitional cell carcinoma or serous papillary cystadenocarcinoma (2 cases each) and ductal carcinoma (1 case). Eleven cases developed on the nearest covering skin and/or on the same side as the primary tumor. Eleven patients complained of pain. Seven cases were treated as herpes zoster with antiviral agents. Conclusion: Approximately 50% of cases of metastatic skin cancer developed on the nearest skin covering and on the same side as the primary tumor. This evidence may be useful when trying to pinpoint the location of the primary tumor. One third of patients with skin metastases were misdiagnosed and their lesions were treated initially as herpes zoster. When a band-like eruption is seen in patients with internal malignancies, the possibility of metastatic skin lesions should be considered. A skin biopsy is necessary to confirm the diagnosis.

Acrodermatitis enteropathica is an autosomal recessive disease characterized by skin involvement due to defective intestinal zinc absorption. Usually, the skin lesions include erythema, erosions, and small blisters in perioral, perianal regions, and hands and feet, which develop soon after weaning from the breast. The acrodermatitis enteropathica gene has been localized to chromosomal region 8q24.3 and subsequently the SLC39A4 gene has been disclosed as the acrodermatitis enteropathica gene. SLC39A4 mutations have been demonstrated in several acrodermatitis enteropathica families, and in this study we have examined two Japanese acrodermatitis enteropathica families for SLC39A4 mutations. The mutation detection strategy consisted of polymerase chain reaction amplification of all 12 exons and flanking intronic sequences, followed by direct nucleotide sequencing. It revealed three novel mutations, 1017ins53, which creates a premature termination codon, and two mis-sense mutations, R95C and Q303H.

Epidermolysis bullosa (EB) is a group of heritable mechanobullous disorders characterized by fragility of the skin and mucous membranes (Fine et al, 1991;Christiano and Uitto, 1996a). A special subset, the dystrophic forms of EB (DEB), is inherited either in an autosomal dominant (DDEB) or in an autosomal recessive (RDEB) fashion. Ultrastructurally, DEB is characterized by abnormalities in the anchoring fibrils, attachment structures extending from the lower portion of the dermal-epidermal basement membrane to the underlying dermis (McGrath et al, 1993). These structures can be morphologically altered, reduced in number, or entirely absent in patients with DEB.Biochemical evidence has indicated that type VII collagen is the major, if not the exclusive, component of anchoring fibrils (Sakai et al, 1986; McGrath et al, 1993). This observation suggested that type VII collagen and the corresponding gene, COL7A1, are the candidate gene/protein systems for mutations in DEB (Uitto and Christiano, 1992). Subsequently, a number of distinct genetic lesions in COL7A1 have been demonstrated (Christiano and Uitto, 1996a, b; Hovnanian et al, 1997; Uitto et al, 1999).Examination of the mutation database in DEB has suggested that, in general, the mutations are family specific, with relatively little evidence of recurrent mutations due to a founder effect or ''hotspot'' mutations (Uitto et al, 1999); however, careful examination of the database revealed that three mutations, 5818delC, 6573 ϩ 1G→C, and E2857X occur in more than one unrelated family and that these mutations are present only in individuals of Japanese ethnic origin (Uitto et al, 1999). These observations suggested therefore that these three mutations may be restricted to the Japanese gene pool. In this study, we examined a cohort of 50 Japanese patients for the presence of these three mutations. All patients had clinical and genetic features consistent with DEB, including increased fragility of the skin and mucous membranes, and characteristic extracutaneous manifestations, including esophagus strictures and/or nail dystrophy, and the diagnosis was confirmed by immunohistochemistry and/or electron microscopy.Total genomic DNA was isolated from the patients' peripheral blood leukocytes by standard techniques. The three recurrent mutations described in this study reside in exon 70, intron 81, and exon 116, and the conditions for amplification of the corresponding regions of the genomic DNA and for the heteroduplex analysis have been described elsewhere (Shimizu et al, 1996;Christiano et al, 1997;Tamai et al, 1997). All three mutations changed a restriction endonuclease site that could be used for verification of the mutations, as well as for screening for the presence of such mutations in patients with DEB (Fig 1).Screening of 50 unrelated Japanese patients with RDEB revealed the presence of any of the three mutations in multiple individuals (Table I). Specifically, mutations 5818delC and E2857X were Manuscript

The hemagglutinating virus of Japan (HVJ)-liposome method involves the entrapment of DNA and nuclear protein within liposomes and the use of HVJ to enhance liposome fusion with cell membranes. This method has been used successfully for in vivo gene transfer to various types of tissue. In this study, we investigated whether this method transfers genes effectively to normal and malignantly transformed keratinocytes in vivo. We applied HVJ-liposome complex (HLC) containing the beta-galactosidase gene to the tape-stripped skin of hairless rats and detected the enzyme activity in the keratinocytes of the treated skin. Comparison of this method with the naked DNA injection method, which was shown recently to be useful for in vivo gene transfer to keratinocytes, demonstrated that the transfer efficiency of the latter was about 5 times higher than that of the former. We assessed the efficacy of the HVJ-liposome method for gene transfer to transformed keratinocytes by examining the effect of HLC containing the herpes simplex virus thymidine kinase gene on the growth of mouse squamous cell carcinomas. Local injection of HLC into the tumors followed by administration of ganciclovir to mice resulted in tumor growth inhibition. These results indicate that the HVJ-liposome method is suitable for in vivo gene transfer to keratinocytes; also that this method may prove a good tool for basic research into keratinocyte biology and future keratinocyte gene therapy.