Incomplete erythropoietic protoporphyria caused by a splice site modulator homozygous IVS3-48C polymorphism in the ferrochelatase gene.

Erythropoietic protoporphyria (EPP) is an inherited cutaneous porphyria caused by both the partial deficiency of ferrochelatase (FECH) and the existence of cytosine at IVS3-48 in trans to a mutated FECH allele. However, physicians occasionally encounter patients with EPP with a mild phenotype associated with a slight increase in the erythrocyte-free protoporphyrin concentration and no FECH gene mutations. In this study, genetic analyses were performed on three patients with a mild phenotype of EPP, with photosensitivity, slightly increased erythrocyte-free protoporphyrin concentrations and only a few fluorocytes in the peripheral blood. After obtaining the patients' and their parents' informed consent, a direct sequence analysis of the FECH gene and a restriction fragment length polymorphism analysis were performed on samples from the patients. The FECH gene mutation was not detected in the direct sequence analyses in any of the patients. However, all three patients had the homozygous IVS3-48C polymorphism. These findings suggest that homozygous IVS3-48C polymorphism of the FECH gene is associated with a slight elevation of the protoporphyrin level in erythrocytes, resulting in a mild EPP phenotype.

Usefulness of ultrasonography in the diagnosis of ischaemic fasciitis.

We present the case of a 68-year-old woman who developed a painful subcutaneous tumour in the sacral region. Histological examinations revealed a characteristic zonal pattern with a central zone of liquefactive necrosis, surrounded by proliferated atypical fibroblasts and prominent vessels, indicating ischaemic fasciitis. We demonstrate that the characteristic features of ischaemic fasciitis revealed by ultrasonography are strongly associated with those revealed by pathological findings. We thus believe that ultrasonography is a valid tool for making an accurate diagnosis of ischaemic fasciitis.

Diffuse and focal palmoplantar keratoderma can be caused by a keratin 6c mutation.

The palmoplantar keratodermas (PPKs) are a large group of genodermatoses comprising nearly 60 genetically distinct diseases. They are characterized by hyperkeratosis on the palms and soles with or without extrapalmoplantar hyperkeratotic lesions. Focal PPK is one of the hallmarks of pachyonychia congenita, a rare autosomal dominant disorder resulting from mutations in the keratin genes KRT6A, KRT6B, KRT16 or KRT17. Recently, in-frame deletion mutations of KRT6C have been identified in three families with focal PPK with slight or no nail changes. We report here a novel KRT6C mutation identified in a Japanese family with PPK with phenotypic heterogeneity, presenting with not only focal but also diffuse hyperkeratosis. The proband had diffuse hyperkeratosis on the soles and small focal hyperkeratoses on the palms, while the two other affected individuals showed focal hyperkeratoses on the soles. All three patients were heterozygotes for c.1414G>A in KRT6C, predicted to result in p.Glu472Lys. These findings strongly suggest that screening of patients with nonepidermolytic diffuse PPK, in whom the pathogenic mutations are yet to be determined, might identify mutations in KRT6C.

A severe and refractory case of anti-p200 pemphigoid resulting in multiple skin ulcers and scar formation.

Anti-p200 pemphigoid is a recently described autoimmune blistering skin disease that is characterized by the presence of autoantibodies against an unidentified 200-kDa dermal autoantigen. Most of the previous cases have been successfully treated using mild-to-moderate immunosuppressive therapies, which resulted in a good prognosis. We report here a severe and refractory case of anti-p200 pemphigoid that developed in a 53-year-old woman, in which blisters led to multiple skin ulcers, followed by severe scar formation. In the present case, methylprednisolone pulse therapy was effective enough to reduce the disease activity.

Usefulness of thermography techniques for evaluating the disease activity in Kimura's disease.

Kimura's disease (KD) is a rare, chronic inflammatory disorder predominantly affecting the head and neck. A case of KD in a 30-year-old man is reported. Thermography was useful for evaluating the activity of the condition.

Cutaneous pemphigus vulgaris with skin features similar to the classic mucocutaneous type: a case report and review of the literature.

Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering skin disease that specifically involves oral mucosa. It was recently shown that a very small number of patients with PV show no mucous membrane involvement although they have circulating autoantibodies directed against both desmoglein (Dsg)1 and Dsg3 that are associated with histopathological suprabasal acantholysis. These cases are classed as cutaneous-type PV. We report here a case of cutaneous-type PV that occurred in a 50-year-old man. Clinical examination revealed numerous tense and spreading blisters and erosions over the patient's entire body, similar to the classic mucocutaneous-type PV. Interestingly, none of the previously reported patients with cutaneous PV had shown skin features like those of mucocutaneous PV, whereas the present case clearly demonstrated very typical clinical features similar to those in mucocutaneous PV.

The human 230-kD bullous pemphigoid antigen gene (BPAG1). Exon-intron organization and identification of regulatory tissue specific elements in the promoter region.

The 230-kD bullous pemphigoid antigen (BPAG1), a hemidesmosomal protein, is encoded by a gene at the human chromosomal locus 6p11-12. We have elucidated the exon-intron organization of the entire human BPAG1 gene, including approximately 2.6 kb of 5'-flanking DNA. Seven overlapping genomic clones, spanning approximately 20 kb, contained the entire approximately 9 kb coding sequence of BPAG1 and consisted of 22 separate exons, which varied from 78 to 2,810 bp in size. The 5' flanking region of DNA, upstream from the ATG initiation codon for translation, was found to contain several putative transcriptional response elements. Most interestingly, two motifs potentially conferring keratinocyte specific expression to the gene were detected. The presence of such elements was suggested by approximately 20-fold higher expression of a promoter/chloramphenicol acetyl transferase (CAT) construct in normal human epidermal keratinocytes that express the endogenous gene, as compared to several non-expressing cell types. Transient transfections with 5'-deletion clones of the promoter/reporter gene (CAT) constructs identified a region containing a putative tissue specific element, KRE2, which also conferred tissue specificity to the expression of the truncated promoter downstream from this element, however, a mutated derivative of KRE2 was not functional. Detailed knowledge of the structure and regulation of the BPAG1 gene will aid in further elucidation of diseases affecting the cutaneous basement membrane zone.

Keratinocyte gene therapy for systemic diseases. Circulating interleukin 10 released from gene-transferred keratinocytes inhibits contact hypersensitivity at distant areas of the skin.

This study has examined the systemic effects of a circulating gene product, human interleukin 10 (IL-10), released from transduced keratinocytes. IL-10 is an anti-inflammatory cytokine which has an inhibitory effect on contact hypersensitivity (CHS). An expression vector (phIL-10) was constructed for human IL-10 and was injected into the dorsal skin of hairless rats. Local expression of IL-10 mRNA and protein was detected by reverse-transcriptase polymerase chain reaction and immunohistochemical staining, respectively. Enzyme-linked immunosorbent assay showed that the amount of IL-10 in the local keratinocytes and in the circulation increased with the dose of phIL-10 transferred. To determine whether circulating IL-10 could inhibit the effector phase of CHS at a distant area of the skin, various doses of phIL-10 were injected into the dorsal skin of sensitized rats before challenge on the ears. Our results showed that the degree of swelling of the ears of phIL-10- treated rats was significantly lower than that in the negative control animals. These results suggest that IL-10 released from transduced keratinocytes can enter the bloodstream and cause biological effects at distant areas of the skin. This study demonstrates that it may be possible to treat systemic disease using keratinocyte gene therapy.