Surgical correction of microstomia in a patient with antilaminin 332 mucous membrane pemphigoid.

Microstomia is a term used to describe a small oral aperture. Most of the reported cases are caused by scar contracture after facial trauma, burn injury, and tumor excision. We experienced a rare case of microstomia in a patient with antilaminin 332 mucous membrane pemphigoid, which was an acquired autoimmune disease and showed blisters and erosive lesions mainly on the mucous membranes. The patient had recurrent aphthous stomatitis and presented microstomia caused by scar contracture of oral mucosa. We surgically corrected microstomia by 5-flap Z-plasty for commissuroplasty and 2 Z-plasty of both upper and lower lips for an enlargement of oral aperture. The patient could achieve an enough oral aperture and was satisfied with the result. There was no recurrence of microstomia for 2 years.

Involvement of hypoxia-inducible factor activity in inevitable air-exposure treatment upon differentiation in a three-dimensional keratinocyte culture.

Formation of the human skin epidermis can be reproduced by a three-dimensional (3D) keratinocyte culture system, in which air-exposure is inevitable upon initiation of differentiation. In the continuous submerged culture without air-exposure, even with a differentiation-compatible medium, several keratinocyte-specific proteins were not induced resulting in the formation of aberrant epidermal layers. To clarify the mechanism by which air-exposure promotes keratinocyte differentiation, we performed a comparative analysis on biological properties between submerged and air-liquid interphase culture systems. By transcriptomic analysis, hypoxia-inducible factor (HIF)-related genes appeared to significantly change in these cultured cells. In submerged culture, the transcriptional activity of HIF on its canonical response element was enhanced, while air-exposure treatment drastically reduced the transcriptional activity despite the high HIF protein level. Regulating HIF activity through reagents and genetic manipulation revealed that the reduced but retained HIF-transcriptional activity was essentially involved in differentiation. Furthermore, we showed, for the first time, that artificial supplementation of oxygen in the submerged culture system could restore keratinocyte differentiation as observed in the air-exposed culture. Thus, we mechanistically evaluated how HIF regulates the air-exposure-dependent differentiation of keratinocytes in a 3D culture system.

Immediate response to apremilast in patients with palmoplantar pustulosis: a retrospective pilot study.

BACKGROUND: Recent case reports have shown the efficacy of apremilast for the treatment of palmoplantar pustulosis (PPP). However, no study has statistically analyzed the clinical efficacy of oral apremilast in patients with PPP. OBJECTIVES: To evaluate the effectiveness of apremilast, a phosphodiesterase 4 inhibitor, for PPP. MATERIALS AND METHODS: Among 13 patients who were diagnosed with PPP, 10 patients with PPP with either palmoplantar pustules (>1 mm diameter) or sternoclavicular joint pain were retrospectively analyzed. RESULTS: Palmoplantar Pustulosis Area and Severity Index (mean ± SD: baseline, 13.4 ± 9.5 vs. after treatment, 5.1 ± 5.6; P = 0.013) and the number of pustules measuring > 1 mm in diameter (3.9 ± 3.9 vs. 1.3 ± 1.9; P = 0.029) significantly improved in 2 (±1) weeks. Moreover, the Dermatology Life Quality Index (9.7 ± 7.0 vs. 3.3 ± 3.6; P = 0.009) and palmoplantar itching (visual analog scale [VAS] score) (5.6 ± 3.5 vs. 2.1 ± 2.2; P = 0.026) significantly improved in 2 weeks, whereas VAS scores of palmoplantar pain (4.8 ± 4.4 vs. 1.1 ± 2.4; P = 0.081) and sternoclavicular joint pain (3.2 ± 3.8 vs. 2.0 ± 2.6; P = 0.194) did not significantly improve. Diarrhea was observed in 60.0% of our patients. CONCLUSION: Our study demonstrated that apremilast can effectively treat cutaneous manifestations and arthralgia in Japanese patients with PPP who had apparent pustules and/or clavicular-sternocostal arthralgia. Owing to the retrospective design of the study and a small sample size, placebo-controlled clinical trials with a larger number of patients are warranted to confirm the efficacy of apremilast for treatment of PPP.

A case of drug-induced Stevens-Johnson syndrome-like eruption predominating in mucosa: A case report.

Atypical Stevens-Johnson syndrome (SJS) is a variant of SJS with complete absence of or only few cutaneous manifestations. It usually affects children with Mycoplasma-induced respiratory infection. It was unique because our case was induced by drug and occurred in an adult.

Reduced stratum corneum acylceramides in autosomal recessive congenital ichthyosis with a NIPAL4 mutation.

BACKGROUND: NIPAL4, encoding the NIPA-like domain containing 4 protein (NIPAL4), is one of the causative genes of autosomal recessive congenital ichthyosis (ARCI). The physiological role of NIPAL4 and the pathogenetic mechanisms of ARCI caused by NIPAL4 mutations remain unclear. OBJECTIVE: To clarify the changes of ceramide components in the lesional stratum corneum (SC) and the gene expression profile in the lesional skin of an ARCI patient with a novel frameshift mutation in NIPAL4. METHODS: We performed ultrastructural and immunohistochemical analyses of the skin. We used RNA sequencing to determine the mRNA expression in the skin of the patient and healthy individuals. We investigated ceramide components using tape stripped SC samples from the patient. RESULTS: mRNA expression profiling in the patient's skin showed significant upregulation of IL-17/TNFα-related genes (IL17C, IL36A, IL36G, S100A7A, S100A9) and psoriasis hallmark genes (VNN3, LCE3D, PLA2G4D), and significant downregulation of lipid-associated genes (GAL, HAO2, FABP7). Ceramide analysis in the patient's SC revealed amounts of CER[NS] with carbon chain-length (C) 32-52 were increased, while amounts of most acylceramide with C66:2 - C72:2 were reduced relatively to those in healthy individuals. After the retinoid treatment, CER[NS] with carbon chains C46-54, CER[EOH] and CER[EOP] increased. CONCLUSION: IL-17C and IL-36 family cytokines might be involved in the pathogenetic process of ARCI with NIPAL4 mutations. Reduced amounts of the acylceramides in the SC are associated with the skin phenotype due to NIPAL4 mutations. Efficacy of the oral retinoid treatment might be due to restored amounts of CER[EOH] and CER[EOP] in the SC.

SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation.

The corneocyte lipid envelope, composed of covalently bound ceramides and fatty acids, is important to the integrity of the permeability barrier in the stratum corneum, and its absence is a prime structural defect in various skin diseases associated with defective skin barrier function. SDR9C7 encodes a short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7) recently found mutated in ichthyosis. In a patient with SDR9C7 mutation and a mouse Sdr9c7-KO model, we show loss of covalent binding of epidermal ceramides to protein, a structural fault in the barrier. For reasons unresolved, protein binding requires lipoxygenase-catalyzed transformations of linoleic acid (18:2) esterified in ω-O-acylceramides. In Sdr9c7-/- epidermis, quantitative liquid chromatography-mass spectometry (LC-MS) assays revealed almost complete loss of a species of ω-O-acylceramide esterified with linoleate-9,10-trans-epoxy-11E-13-ketone; other acylceramides related to the lipoxygenase pathway were in higher abundance. Recombinant SDR9C7 catalyzed NAD+-dependent dehydrogenation of linoleate 9,10-trans-epoxy-11E-13-alcohol to the corresponding 13-ketone, while ichthyosis mutants were inactive. We propose, therefore, that the critical requirement for lipoxygenases and SDR9C7 is in producing acylceramide containing the 9,10-epoxy-11E-13-ketone, a reactive moiety known for its nonenzymatic coupling to protein. This suggests a mechanism for coupling of ceramide to protein and provides important insights into skin barrier formation and pathogenesis.

Studies on differentiation-dependent expression and activity of distinct transglutaminases by specific substrate peptides using three-dimensional reconstituted epidermis.

During skin formation, particularly during differentiation of keratinocytes, unique post-translational modifications play a role in forming a proteinaceous supermolecule called the cornified envelope (CE), which is necessary for barrier function. Transglutaminases (TGs) are essential enzymes involved in the cross-linking of various keratinocyte structural proteins to complete CE formation. The TG family consists of eight isozymes, with two members, TG1 and TG3, located mainly in the epidermis. In an in vitro three-dimensional (3D) culture system, reconstruction of the epidermis allows cornification of the terminally differentiated keratinocytes. In this study, using isozyme-specific substrate peptides that enable detection of TG activity, we investigated the expression and the activation pattern of each isozyme during differentiation in this culture system. In the differentiating cells, the protein levels, enzymatic activities, as well as localization of TG1 and TG3 exhibited distinct patterns. Specific knockdown of these enzymes by siRNA revealed less cornification, suggesting that each TG contributes to the epidermal formation. In conclusion, we demonstrate the efficiency of the 3D system for studying differentiation-dependent expression and activity of distinct TGs by specific substrate peptides. ENZYME: Transglutaminase, EC2.3.2.13.

Indeterminate dendritic cell neoplasm accompanied by eosinophilic pneumonia successfully treated by systemic steroid therapy: Report of the first case with muscular and parotid involvement and review of published work.

A 34-year-old Japanese man presented with an indolent nodule on the right flank. Computed tomography of the chest and abdomen demonstrated a large nodule measuring 55 mm × 50 mm in the abdominal oblique muscle layer of the right flank, and several small nodules were seen in the muscle layer throughout the body and subcutaneous tissue of the lower abdomen. 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography revealed nodular lesions in the bilateral parotid glands, bilateral cervical lymph nodes and lower lobe of the right lung. Intermittently, ground-glass shadows developed in the bilateral lungs. Histologically, sheet-like nodules in the abdominal oblique muscle layer and parotid gland were composed of large polygonal cells with convoluted nuclei and ample eosinophilic cytoplasm. Several lymphocytes and considerable eosinophils were intermingled. Lung biopsy demonstrated an inflammatory infiltrate of lymphocytes and considerable eosinophils in the alveoli. Immunohistochemically, polygonal cells were positive for S100 protein and CD1a, but negative for langerin and BRAFV600E . Some cells were positive for CD68. Electron microscopy demonstrated histiocytic cells with phagosomes and interdigitating processes. However, no Birbeck granules were observed. Eosinophilia was seen in the peripheral blood. Multifocal nodules and ground-glass shadows gradually diminished following systemic administration of oral prednisolone. We describe a case of indeterminate dendritic cell neoplasm with multifocal involvement of the muscle, subcutis, lymph node and parotid gland accompanied by chronic eosinophilic pneumonia that was successfully treated by systemic steroid therapy. Neither muscular nor parotid indeterminate dendritic cell neoplasms accompanied by eosinophilic pneumonia have been previously reported.

PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis.

Mutations in patatin-like phospholipase domain-containing 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. Here we show that PNPLA1, an enzyme expressed in differentiated keratinocytes, plays a crucial role in the biosynthesis of ω-O-acylceramide, a lipid component essential for skin barrier. Global or keratinocyte-specific Pnpla1-deficient neonates die due to epidermal permeability barrier defects with severe transepidermal water loss, decreased intercellular lipid lamellae in the stratum corneum, and aberrant keratinocyte differentiation. In Pnpla1-/- epidermis, unique linoleate-containing lipids including acylceramides, acylglucosylceramides and (O-acyl)-ω-hydroxy fatty acids are almost absent with reciprocal increases in their putative precursors, indicating that PNPLA1 catalyses the ω-O-esterification with linoleic acid to form acylceramides. Moreover, acylceramide supplementation partially rescues the altered differentiation of Pnpla1-/- keratinocytes. Our findings provide valuable insight into the skin barrier formation and ichthyosis development, and may contribute to novel therapeutic strategies for treatment of epidermal barrier defects.