Analysis of clinical characteristics, prognosis and antibody pathogenicity of pemphigus patients positive for anti-desmoglein IgG autoantibodies in remission: a retrospective cohort study.

BACKGROUND: The detection of serum anti-desmoglein (Dsg) IgG autoantibodies has been reported to be useful for assessment of disease activity in pemphigus. However, previous studies have reported that anti-Dsg autoantibodies remain detectable in some patients without active pemphigus lesions. OBJECTIVES: To investigate the clinical characteristics and antibody pathogenicity of pemphigus patients positive for anti-Dsg IgG autoantibodies in remission. METHODS: We retrospectively investigated pemphigus patients with a history of clinical remission who visited the Department of Dermatology of Keio University during 2019 and 2020. The antibody pathogenicity was assessed by bead aggregation assay. RESULTS: When patients were recognized as having entered remission (PDAI = 0 and PSL ≦ 10 mg/day for 2 months), serum autoantibodies against Dsg were detected in 72 of 132 patients (54.5%, positive group; PG), but were not detected in 60 patients (45.5%, negative group; NG). Anti-Dsg antibody titres in remission declined from the active phase in 33 patients in the PG for whom data were available. There were no differences in the chance of reducing PSL to 5 mg/day (P = 0.885) and rate of relapse (P = 0.279) between PG and NG, but fewer patients in PG discontinued corticosteroids (P = 0.004). The ability of patients' sera to block aggregation of Dsg/desmocollin beads was significantly reduced in remission compared to the active phase. However, our results revealed that whole sera in remission still had pathogenic activity in seven of nine patients, and the approximately equal amounts of anti-Dsg antibodies in active phase and remission showed similar pathogenicity. CONCLUSIONS: This study will provide guidance in cases where autoantibodies are found to be positive in pemphigus patients during remission or steroid reduction.

Acquired dermal melanocytosis of the face and extremities.

Acquired dermal melanocytosis (ADM) is a relatively rare, but well-described disease among adolescent to middle-aged East Asian women, particularly those of Japanese and Chinese descent. Clinically, ADM manifests as multiple punctate and greyish-brown pigmented areas 1-3 mm in diameter occurring on both sides of the forehead and zygomatic region. The subtype of ADM affecting the face and extremities is extremely rare even in East Asian women. We describe three patients with ADM of the face and extremities (ADMFE) and their characteristic clinical features. All patients were Japanese women, and showed multiple greyish-brown pigmentations on both nasal wings and on the extensor surface of the extremities. We found that the clinical features were strikingly uniform, and that a pigmented lesion on the nasal wing can be an important clue to distinguish ADMFE from other hyperpigmented diseases of the hands and feet. One patient was treated with Q-switched ruby laser with excellent outcome. Increased awareness of ADMFE can lead to earlier diagnosis and potential treatment.

Quantification of allergic and irritant patch test reactions using ImageJ.

BACKGROUND/AIMS: It is often difficult to differentiate between allergic and irritant patch test reactions by visual inspection. The purpose of this study was to test an image analysis-based method that differentiates between the two reactions by quantifying the degree of erythema at the patch test site. METHODS: A total of 172 Japanese patients were patch-tested with sodium lauryl sulfate (SLS) and nickel sulfate, followed by digital photography and visual evaluation of the patch test areas by dermatologists at 48 and 72 h. The digital images were converted to erythema index (EI) images by image processing, and changes in ΔEI (the difference in the EI between the patch test site and the adjacent normal skin) values were analyzed. RESULTS: The ΔEI was significantly increased at 72 h relative to that at 48 h for positive nickel sulfate reactions (P < 0.0001), while no significant difference in the ΔEI was found for SLS reactions. CONCLUSION: Using image analysis, allergic patch test reactions may be distinguished from irritant reactions by evaluating the change in the degree of erythema at 48 and 72 h.

Immunoglobulin G deposition to nonhemidesmosomal lamina lucida and early neutrophil involvement are characteristic features in a case of anti-p200 pemphigoid.

The ultrastructural characteristics and immunolocalization of in vivo bound immunoglobulin G (IgG) in skin affected by anti-p200 pemphigoid have not been elucidated. To give insight into the mechanism of blister formation we report a new case of anti-p200 pemphigoid, studied with stage-oriented morphological analysis and immunoelectron microscopy. Skin biopsy specimens were evaluated ultrastructurally and histologically with immunohistochemistry. By observing the nonblister site, the blister edge and centre of the blister, we determined that neutrophil infiltration increases gradually at the dermoepidermal junction in association with the destruction of type IV collagen. Ultrastructurally, many neutrophils were observed under the lamina densa, with vacuole formation in the dermis. At the periphery of the blister, the lamina densa became fragmented and was observed either at the roof or the floor of the blister. At the centre of the blister, the lamina densa was mainly observed at the blister floor. Postembedding immunoelectron microscopy demonstrated that the IgG, bound in vivo, localized at the lamina lucida, while the area beneath the hemidesmosomes was spared. Together with the early involvement of neutrophils and the destruction of the basal lamina, we suggest that the binding of autoantibodies to the nonhemidesmosomal lamina lucida may induce inflammation with neutrophils, resulting in blister formation.

A Japanese-specific recurrent mutation and a novel splice site mutation in the LAMC2 gene identified in two Japanese families with Herlitz junctional epidermolysis bullosa.

BACKGROUND: Herlitz junctional epidermolysis bullosa (H-JEB) is an extremely rare genodermatosis characterized by lethality owing to severe blister formation. We report two unrelated Japanese patients with H-JEB. Genetic analyses detected a single nonsense mutation on the LAMC2 gene in these two patients. AIM: To identify the mutation involved and describe the first reported Japanese recurrent mutation in the LAMC2 gene. METHODS: Direct sequencing was performed of DNA from either peripheral blood or fetal cells in amniotic fluid. Reverse transcriptase PCR was used to confirm that an aberrant transcript resulted from the splice site mutation. A haplotype analysis was performed to define the origin of the recurrent mutation. RESULTS: Both patients had blisters and erosions on the trunk and limbs at birth, with nail dystrophy. Patient 1 died as a result of sepsis at 30 weeks of age, and patient 2 died as a result of disseminated intravascular coagulation at 20 weeks of age. Mutation analysis of the LAMC2 gene revealed that patient 1 was compound heterozygous for a nonsense mutation (p.Cys553X) and a novel splice site mutation (c.2868+1delG), and patient 2 was a homozygous for p.Cys553X. Prenatal diagnosis performed during a subsequent pregnancy in family 2 revealed that this second child was heterozygous for p.Cys553X, and was thus not affected. Haplotype analysis suggested that a p.Cys553X allele derived from the same origin had been independently inherited by these two unrelated families. CONCLUSIONS: p.Cys553X in the LAMC2 gene may be a Japanese-specific recurrent mutation as a result of a founder effect, and it may therefore be useful for initial screening in the mutation analysis of H-JEB.

Malignant eccrine spiradenoma: case report and review of the literature, including 15 Japanese cases.

Malignant eccrine spiradenoma (MES) is an extremely rare cutaneous malignant tumour. An 86-year-old man presented at our hospital with an enlarging tumour on the dorsum of the left hand. An excisional biopsy was taken and histological examination showed a solid island of cells of two distinct types: cells with abundant cytoplasm and oval vesicular nuclei, and small round cells with less cytoplasm and hyperchromatic nuclei with a high frequency of mitosis. We diagnosed this tumour as MES. Although we did not perform further treatment because of the patient's age, there was no sign of recurrence or metastasis in the 2 years of follow-up after excisional biopsy. We reviewed cases of malignant eccrine spiradenoma in the English and Japanese literature and found that 'sarcomatous' or 'squamous' change in histopathology was significantly correlated with a poorer prognosis. It is therefore important for treatment planning to evaluate the entire specimen histologically.

A novel de novo splice-site mutation in the COL7A1 gene in dominant dystrophic epidermolysis bullosa (DDEB): specific exon skipping could be a prognostic factor for DDEB pruriginosa.

We report a Japanese infant who had a novel de novo splice-site mutation in the COL7A1 gene, which resulted in in-frame exon 87 skipping. Very interestingly, most of the previously reported cases with the same exon skipping presented as dystrophic epidermolysis bullosa (DEB) pruriginosa. The proband in this study showed an extremely mild clinical phenotype, with no nail dystrophy, pruritus or prurigo-like lesions. However, dominant (DDEB) pruriginosa often shows a typical mild DEB phenotype until the onset of pruritus, making it likely that as she gets older the proband will present with features consistent with DDEB pruriginosa. By knowing in advance the anticipated clinical course, it might be possible to reduce or even prevent development of nodular prurigo-like lesions by sufficient control of pruritus. Our study should contribute to further refinement of the genotype-phenotype correlations in DEB, emphasizing the significance of mutation analysis for correct diagnosis and possibly for prediction of prognosis.

Novel mutation p.Gly59Arg in GJB6 encoding connexin 30 underlies palmoplantar keratoderma with pseudoainhum, knuckle pads and hearing loss.

BACKGROUND: Connexins, components of the gap junction, are expressed in several organs including the skin and the cochlea. Mutations in connexin genes including GJB2 (Cx26), GJB3 (Cx31), GJB4 (Cx30.3), GJB6 (Cx30) and GJA1 (Cx43) are responsible for various dermatological syndromes and/or inherited hearing loss, frequently showing overlapping phenotypes. OBJECTIVES: To clarify the spectrum of clinical phenotypes caused by connexin mutations. METHODS: We report a 32-year-old Japanese woman with mild palmoplantar keratoderma (PPK) with severe sensorineural hearing loss, knuckle pads and pseudoainhum of her toes. RESULTS: Direct sequencing revealed no mutation in GJB2, but a novel heterozygous missense mutation p.Gly59Arg in GJB6. Electron microscopy revealed no apparent morphological abnormality of gap junctions in the patient's lesional epidermis. CONCLUSIONS: The patient harboured the novel GJB6 missense mutation p.Gly59Arg in the first extracellular loop of Cx30. Mutations in glycine 59 of Cx26 are associated with PPK-deafness syndrome, and the similar phenotype here supports the observed heteromeric channel formation; the dominant nature of the mutation suggests an effect on gap junctions similar to that of the comparable mutation in Cx26.

Indeterminate cell histiocytosis successfully treated with ultraviolet B phototherapy.

Indeterminate cell histiocytosis (ICH) is a rare disorder, characterized by infiltration of the skin by neoplastic cells that are characteristically positive for S-100 and CD1a, but lack Birbeck's granules. A 75-year-old man presented with a 4-year history of multiple papules on the trunk, limbs, face and neck. Skin biopsy revealed dense infiltration of histiocytic cells that were CD1a+/S100+, but lacked Birbeck's granules. No other abnormality was seen during a general examination including a computed tomography scan of the body, gallium scintigraphy, and an abdominal sonography. Broadband ultraviolet B (UVB) treatment was used for the skin lesions, and partial but almost complete remission was obtained. The case suggests that UVB phototherapy is an option for treatment of ICH.

Novel mutation of the Notch3 gene in a Japanese patient with CADASIL.

We report a novel missense mutation of the Notch3 gene in a Japanese family with CADASIL. The Cys49Gly mutation in this family is located in exon 2 of the Notch3 gene. Most of the documented Notch3 gene mutations occur in exons 3 or 4. On the other hand, there are few reports around the world of mutations in exon 2 of the Notch3 gene, and this is the first report of a mutation in exon 2 of the gene in a Japanese family. In general, CADASIL mutations involve a cysteine residue. Such mutations may influence the tertiary structure of the Notch3 protein, resulting in protein dysfunction. Thus, the CADASIL in the present case may be a consequence of the mutation in exon 2 causing a structural change in the Notch3 protein.

Prenatal exclusion of harlequin ichthyosis; potential pitfalls in the timing of the fetal skin biopsy.

BACKGROUND: Harlequin ichthyosis (HI) is a severe and usually fatal congenital skin disorder with autosomal recessive inheritance. Several cases of HI prenatal diagnosis have been performed using fetal skin biopsy, mainly at around 23 weeks estimated gestational age (EGA), and reported in the literature. However, prenatal testing must be done earlier than 21 weeks EGA in several countries including Japan where the present HI families live, because termination is legally allowed only until 22 weeks EGA. OBJECTIVES: We report the successful prenatal exclusion of HI in two fetuses from two independent families and discuss the technical difficulties and potential pitfalls in the prenatal exclusion of HI at early gestation stages. METHODS: Fetal skin biopsy specimens and amniotic fluid samples at 19 and 20 weeks EGA from two fetuses at risk of HI were examined by light and electron microscopy. RESULTS: For the prenatal diagnosis in case 1, the fetal skin biopsy samples were obtained at 20 weeks EGA and showed normal keratinization in the hair canals; no abnormalities were observed in the keratinized cells. In case 2, the interfollicular epidermis and the hair follicles in the samples obtained at 19 weeks EGA had not differentiated enough to show proper keratinization. However, lamellar granules were normally formed in the inner root sheath cells of the late bulbous hair pegs. From these ultrastructural findings, the case 1 fetus was diagnosed as unaffected with HI, and the case 2 fetus was diagnosed as unlikely to be affected. Subsequently, both were born as healthy, unaffected babies. CONCLUSIONS: The timing of biopsies at 19 weeks EGA is not ideal for fetal skin biopsy because the samples are not always sufficiently differentiated for the prenatal diagnosis of HI. However, morphological observations of lamellar granules gives us important additional information useful for HI prenatal diagnosis.