Serum carcinoembryonic antigen (CEA) as a clinical marker in acquired idiopathic generalized anhidrosis: a close correlation between serum CEA level and disease activity.

BACKGROUND: Hypohidrosis/anhidrosis are congenital or acquired sweating impairments. Among them, acquired idiopathic generalized anhidrosis/hypohidrosis (AIGA) is the most common, and characterized by favourable response to systemic corticosteroid, however, no clinical markers for disease severity or activity have been developed. OBJECTIVE: Our aim was to verify the usefulness of serum carcinoembryonic antigen (CEA) level monitoring as a clinical marker for disease activity of AIGA. METHODS: Ten cases of AIGA diagnosed at Asahikawa Medical University, from 1980 to 2014 were included in the study. CEA and/or CEACAM1 expression level was analysed using immunohistochemistry and enzyme-linked immunosorbent assay. RESULT: CEA expression was restricted to the apical membrane of glandular cells in eccrine sweat glands in most of the three types of cases we examined [healthy control, patients with atopic dermatitis (AD) or urticaria]. However, CEA expression was detected diffusely and much more intensively in eight of the 10 AIGA cases included in this study. CEACAM1-expression was much more restricted on the apical membrane of glandular cells of both the AIGA cases and the other control subjects. While serum CEA levels increased in all five AIGA cases examined (5.8-43.2 ng/mL), it remained within normal limits in all control subjects: nine healthy individuals; 10 cases of AD; 10 cases of idiopathic urticaria; four cases of normohidrotic cholinergic urticaria (Mann-Whitney's U-test, P < 0.05). The increased serum CEA levels in AIGA decreased in conjunction with improved sweating during methyl prednisolone pulse therapy or repeated bathing. CONCLUSION: Serum CEA level may serve as a clinical marker for AIGA activity.

Expression profile of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins during skin barrier repair.

BACKGROUND: Recent studies have emphasized the importance of heritable and acquired skin barrier abnormalities in common inflammatory diseases such as psoriasis and atopic dermatitis (AD). To date, no comprehensive studies on the effect of experimental barrier disruption on cornified envelope protein expression have been performed. OBJECTIVES: To analyse the effect of experimental skin barrier disruption on the expression of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins. METHODS: We examined mRNA (day 1, 3 and 7) and protein (day 1, 2, 4 and 9) expression levels of structural proteins and regulatory molecules after sodium dodecyl sulphate (SDS) application on normal skin, and tape stripping of uninvolved epidermis of patients with psoriasis and AD and healthy controls. RESULTS: Upon tape stripping, several structural molecules were significantly downregulated (at the mRNA level as well as the protein level), including LCE5A, LCE2B, FLG, FLG2 and LOR, whereas others were upregulated: IVL, SPRR1, SPRR2, HRNR and most notably LCE3A. The epidermal crosslinking enzymes TGM1, TGM3 and TGM5 were all upregulated, whereas proteases involved in the desquamation process (CTSV, KLK5 and KLK7) were downregulated or unaffected. Most results were similar in SDS-instigated irritant contact dermatitis. There was no significant difference in response between normal epidermis and nonlesional skin of patients with psoriasis and AD. CONCLUSIONS: Skin barrier disruption induces a temporary barrier repair response composed of increased expression of several cornification-related proteins, and decreased expression of some structural and desquamation-related proteins.

The nuclear factor kappa B p50 subunit and cortactin as markers to distinguish between keratoacanthoma and well-differentiated squamous cell carcinoma.

BACKGROUND: Distinguishing keratoacanthoma (KA) from well-differentiated squamous cell carcinoma (SCC) is sometimes difficult. Recent evidence indicates that the nuclear factor kappa B p50 subunit (p50) and cortactin might be useful to distinguish between these two conditions. AIM: To verify whether p50 and cortactin are useful differentiation markers to distinguish between subungual KA and well-differentiated SCC. METHODS: Immunohistochemistry using p50, cortactin and Ki-67 was performed on 20 patients with KA and 20 patients with facial well-differentiated SC. Ki-67 staining was also evaluated and scored. RESULTS: Both p50 and cortactin had higher levels of expression in KA than in SCC. Both were localized to the basal-cell layer of KA, whereas they were scattered without polarity throughout the SCC lesions. Although the Ki-67 index was not significantly different between KA and SCC, the staining pattern also showed loss of polarity in SCC. CONCLUSION: p50 and cortactin might be useful makers to distinguish between KA and well-differentiated SCC.

Adult orbital xanthogranulomatous disease: adult-onset xanthogranuloma of periorbital location.

Adult orbital xanthogranulomatous disease (AOXGD) is a rare granulomatous disorder, which has four subtypes: adult-onset xanthogranuloma (AOX), adult-onset asthma with periocular xanthogranuloma, necrobiotic xanthogranuloma and Erdheim-Chester disease. We report a 42-year-old woman who presented with yellowish nonulcerative nodules on her eyelids. On histopathological examination of a nodule, mild degeneration of collagen fibres was seen, with surrounding infiltration of numerous foam cells and Touton giant cells in the deep dermis. Lymphoid follicles were seen in the reticular dermis. There was no apparent necrobiosis of collagen fibres. There were no clinical symptoms of asthma and no laboratory signs of paraproteinaemia during a follow-up of more than 5 years. We diagnosed this case as AOX, but further long-term follow-up would be required for the differentiation from the other AOXGDs. Dermatologists should be aware of these rare granulomatous disease conditions with ocular/orbital location, because they may cause ophthalmological complications.

Recalcitrant facial pemphigus vulgaris: correlation of skin lesions with the ratio of antidesmoglein antibodies 1 and 3.

Pemphigus vulgaris (PV) is an autoimmune bullous disease characterized by autoantibodies against desmogleins. We report a case of recalcitrant PV, which progressed from the mucosal to the mucocutaneous type, with a corresponding increase in anti-desmoglein (Dsg)1 and decrease in anti-Dsg3 antibody titres. Thus, the clinical features seemed to correlate with the ratio of anti-Dsg1 and 3. The patient also had anti-Dsg4 antibodies, which might be related to the nonscarring diffuse hair loss and marked facial involvement she also had. The patient did not respond to treatment with systemic steroid, ciclosporin, azathioprine, cyclophosphamide or double filtration plasmapheresis, and eventually died from fulminant thrombotic thrombocytopenic purpura of unknown cause.

Subungual keratoacanthoma: analysis of cell proliferation and copy number variation of oncogenes compared with periungual squamous cell carcinoma.

BACKGROUND: Subungual keratoacanthoma (SUKA) is a rare cutaneous tumour with several features distinct from ordinary KA. SUKA may not show spontaneous regression and sometimes grows progressively, resulting in phalangeal bone destruction. This makes its distinction from digital squamous cell carcinoma (SCC) difficult. Aim. To investigate differences in molecular expression between SUKA and digital SCC. METHODS: In addition to immunohistochemical analysis of Ki-67, one of the markers differentiating KA from SCC, we investigated the copy numbers of various oncogenes by multiplex ligation-dependent probe amplification (MLPA) using two cases of SUKA and three cases of periungual SCC. RESULTS: Ki-67 was moderately or strongly positive in SCC but negative in SUKA. The MLPA analysis showed that the nuclear factor (NF)κB1 and cortactin (CTTN; formerly known as EMS1) genes are amplified in SUKA but not in digital SCC. This increase in NFκB1 was confirmed by immunohistochemical analysis. CONCLUSION: NFκB1 could be a novel marker to differentiate between SUKA and SCC. Although this study was performed on limited numbers of patients with SUKA, MLPA analysis could be applied to differentiate other benign tumours from their malignant counterparts.

CEDNIK syndrome results from loss-of-function mutations in SNAP29.

BACKGROUND: CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis and keratoderma) syndrome is a rare genodermatosis which was shown 5 years ago in one family to be associated with a loss-of-function mutation in SNAP29, encoding a member of the SNARE family of proteins. Decrease in SNAP29 expression was found to result in abnormal lamellar granule maturation leading to aberrant epidermal differentiation and ichthyosis. OBJECTIVES: To delineate the molecular consequences of disease-causing mutations in SNAP29. METHODS: We used direct sequencing, in vitro mutagenesis and three-dimensional organotypic cell cultures. RESULTS: We identified a novel homozygous insertion in SNAP29 (c.486insA) in two sibs presenting with ichthyosis and dysgenesis of the corpus callosum. In vitro transfection experiments indicated that this mutation results in SNAP29 loss-of-function. Further substantiating this notion, we could replicate histological features typical for CEDNIK syndrome in three-dimensional primary human keratinocyte organotypic cell cultures downregulated for SNAP29. CONCLUSIONS: The identification of a second mutation in SNAP29 in the present study definitely establishes a causal relationship between defective function of SNAP29 and the pleiotropic manifestations of CEDNIK syndrome. Our present and previous data position SNAP29 as an essential component of the epidermal differentiation machinery.

Serum cytokines and growth factor levels in Japanese patients with psoriasis.

BACKGROUND: Although the precise pathomechanism of psoriasis is still unknown, various cytokines and growth factors derived from T cells, dendritic cells or keratinocytes, are critically involved in this disease. There have been several studies determining the serum levels of cytokines in patients with psoriasis, but with conflicting results. The levels of various cytokines and growth factors were measured in the sera of patients with psoriasis and compared with those of healthy controls. The correlation with disease severity was also determined. METHODS: Sera were collected from 122 patients with psoriasis and 78 healthy controls for ELISA analysis to evaluate the levels of cytokines and growth factors. The severity of psoriasis was determined by the Psoriasis Area and Severity Index (PASI). RESULTS: Serum levels of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-2, IL-6, IL-7, IL-8, IL-12, IL-17, IL-18 and vascular endothelial growth factor (VEGF) were significantly increased in patients with psoriasis compared with those of healthy controls. The serum levels of IL-2, soluble intercellular adhesion molecule-1, epidermal growth factor, hepatocyte growth factor and amphiregulin were not significantly different from those of healthy controls. Increased serum levels of TNF-alpha, IFN-gamma, IL-12, IL-17, IL-18 and VEGF correlated with PASI. Furthermore, these cytokine levels were decreased after psoriasis treatment. In contrast, serum levels of IL-10 were decreased in psoriasis and negatively correlated with PASI. DISCUSSION: Serum levels of TNF-alpha, IFN-gamma, IL2, IL-6, IL-7, IL-8, IL-12, IL-17, IL-18 and VEGF were positively correlated and that of IL-10 was negatively correlated with PASI in Japanese patients with psoriasis. These parameters might be useful for determining the disease activity of psoriasis.

Some epidermolysis bullosa acquisita sera react with epitopes within the triple-helical collagenous domain as indicated by immunoelectron microscopy.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) autoantibodies recognize epitopes predominantly within the N-terminal noncollagenous (NC)-1 domain of type VII collagen. Recently, some EBA cases with reactivity to other domains, i.e. the triple-helical (T-H) collagenous domain and the NC-2 domain, have been reported. OBJECTIVES: To investigate the ultrastructural localization of epitopes for sera from five patients with EBA that were unreactive by immunoblotting with the NC-1, NC-2 and collagenous domains of type VII collagen. METHODS: Immunogold postembedding indirect immunoelectron microscopy was performed using normal human skin and type VII collagen-deficient skin as substrates. RESULTS: Postembedding indirect immunoelectron microscopy revealed that the five EBA sera showed immunoreactivity in the dermis, mainly located 0-400 nm below the lamina densa. IgG labelling was not observed in type VII collagen-deficient skin from a patient with recessive dystrophic epidermolysis bullosa. The distribution histogram found in this study was different from those of sera that reacted with the NC-1 and/or NC-2 domains, and was similar to those of sera reacting with the T-H collagenous domain. CONCLUSIONS: Our results suggest that epitopes within the T-H collagenous domain of type VII collagen are recognized by IgG antibodies from some EBA sera. These antibodies appear to be found in patients with inflammatory-type EBA.

Hutchinson-Gilford progeria syndrome with severe skin calcinosis.

We describe a case of Hutchinson-Gilford progeria syndrome (HGPS) with long-term follow-up. A 1-month-old girl with marked sclerodermatous skin changes developed various symptoms of HGPS during follow-up. These included sclerotic skin, pigmentation, skin atrophy with translucent veins, wispy hair and alopecia, nail dystrophy and decreased sweating. Marked skin calcinosis was observed over almost the entire body, a symptom that has apparently been ignored in the literature. At 16 years old, the girl underwent surgery for a skull fracture and subdural haematoma, which was followed by chronic ulceration. Wet dressing with insulin-like growth factor was used with considerable effect. Mutation of the lamin A/C (LMNA) gene mutation, which encodes nuclear lamin A and C, has been reported to be the cause of HGPS. Our case showed the mutation G608G (GGC-->GGT), which resulted in a cryptic splice site and consequently in a truncated lamin A/C protein.