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Background: The vacuoles, E1-enzyme, X linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease (AID) due to postzygotic UBA1 variants., Objectives: To investigate the presence of VEXAS syndrome among patients with adult-onset undiagnosed AID. Additional studies evaluated the mosaicism distribution and the circulating cytokines., Methods: Gene analyses were performed by both Sanger and amplicon-based deep sequencing. Patients' data were collected from their medical charts. Cytokines were quantified by Luminex., Results: Genetic analyses of enrolled patients (n=42) identified 30 patients carrying UBA1 pathogenic variants, with frequencies compatible for postzygotic variants. All patients were male individuals who presented with a late-onset disease (mean 67.5 years; median 67.0 years) characterised by cutaneous lesions (90%), fever (66.7%), pulmonary manifestations (66.7%) and arthritis (53.3%). Macrocytic anaemia and increased erythrocyte sedimentation rate and ferritin were the most relevant analytical abnormalities. Glucocorticoids ameliorated the inflammatory manifestations, but most patients became glucocorticoid-dependent. Positive responses were obtained when targeting the haematopoietic component of the disease with either decitabine or allogeneic haematopoietic stem cell transplantation. Additional analyses detected the UBA1 variants in both haematopoietic and non-haematopoietic tissues. Finally, analysis of circulating cytokines did not identify inflammatory mediators of the disease., Conclusion: Thirty patients with adult-onset AID were definitively diagnosed with VEXAS syndrome through genetic analyses. Despite minor interindividual differences, their main characteristics were in concordance with previous reports. We detected for the first time the UBA1 mosaicism in non-haematopoietic tissue, which questions the previous concept of myeloid-restricted mosaicism and may have conceptual consequences for the disease mechanisms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Key Clinical Message: The presence of more than one genetic/genomic disorder is not uncommon. It is therefore essential to continuously consider new signs and symptoms over time. Administration of gene therapy could be extremely difficult in particular situations., Abstract: A 9-month-old boy presented to our department for evaluation of developmental delay. We found that he was affected by intermediate junctional epidermolysis bullosa (COL17A1, c.3766 + 1G > A, homozygous), Angelman syndrome (5,5 Mb deletion of 15q11.2-q13.1), and autosomal recessive deafness type 57 (PDZD7, c.883C > T, homozygous)., Competing Interests: The authors have no conflict of interest to declare., (© 2023 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or, most frequently, generalized bullous lesions. A subset of patients only develops excoriations, prurigo-like lesions, and eczematous and/or urticarial erythematous lesions. The disease, which is significantly associated with neurological disorders, has high morbidity and severely impacts the quality of life., Objectives and Methodology: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology sought to update the guidelines for the management of BP based on new clinical information, and new evidence on diagnostic tools and interventions. The recommendations are either evidence-based or rely on expert opinion. The degree of consent among all task force members was included., Results: Treatment depends on the severity of BP and patients' comorbidities. High-potency topical corticosteroids are recommended as the mainstay of treatment whenever possible. Oral prednisone at a dose of 0.5 mg/kg/day is a recommended alternative. In case of contraindications or resistance to corticosteroids, immunosuppressive therapies, such as methotrexate, azathioprine, mycophenolate mofetil or mycophenolate acid, may be recommended. The use of doxycycline and dapsone is controversial. They may be recommended, in particular, in patients with contraindications to oral corticosteroids. B-cell-depleting therapy and intravenous immunoglobulins may be considered in treatment-resistant cases. Omalizumab and dupilumab have recently shown promising results. The final version of the guideline was consented to by several patient organizations., Conclusions: The guidelines for the management of BP were updated. They summarize evidence- and expert-based recommendations useful in clinical practice., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: The BIOCHIP (Dermatology Mosaic 7; EUROIMMUN, Lubeck, Germany) is a novel multiplex indirect immunofluorescence (IIF) technique used in the serological diagnosis of bullous pemphigoid (BP) and pemphigus., Objective: To validate the accuracy and inter-rater reliability (IRR) of the BIOCHIP in the diagnosis of BP, pemphigus foliaceus (PF) and pemphigus vulgaris (PV)., Methods: Sera from patients with BP (n = 38), PF (n = 8), PV (n = 23), control patients (n = 64) and healthy control volunteers (n = 39) were tested. Sera were collected and analysed during the course of the disease at 1-5 different time points. The BIOCHIP was performed for all patients, digital images were captured of each incubated field, and the images were shared with 10 dermatologists experienced in reading IF from around the world to report. There were 312 BIOCHIP slides consisting of 1872 photos in total. All patients were de-identified. Fleiss Kappa was used to estimate the IRR., Results: Fleiss Kappa was computed for each category (Oesophagus, Oesophagus immunofluorescence pattern, Salt-Split Skin (SSS), SSS immunofluorescence location, BP180, BP230, Dsg 1 and Ds3). The inter-rater agreement between the 10 raters varied between fair and moderate for all categories. Those that demonstrated fair concordance included monkey oesophagus (k = 0.257, P < 0.0001), oesophagus pattern (k = 0.357, P < 0.0001), Dsg1 (k = 0.390, P < 0.0001) and BP230 (k = 0.281, P < 0.0001). Moderate agreement was demonstrated for SSS (k = 0.416, P < 0.0001), SSS immunofluorescence location (k = 0.505, P < 0.0001), Dsg3 (k = 0.437, P < 0.0001) and BP180 (k = 0.559, P < 0.0001)., Conclusion: The BIOCHIP mosaic-based immunofluorescence test is a simple, time and effort saving test that can aid in the diagnosis and screening of BP, PV and PF. However, the level of agreement was relatively low. The authors found the most common causes to be variable levels of training, indicating the presence of a learning curve in the interpretation of the results and ambiguous staining patterns leading to incongruent results., (© 2019 European Academy of Dermatology and Venereology.)

Background: Phaeoacremonium parasiticum is considered a rare infectious agent that is part of a heterogeneous group of fungi causing phaeohyphomycosis. This organism is capable of producing subcutaneous infections, eumycetomas, osteomyelitis, arthritis, myositis and also disseminated diseases, such as fungemia and endocarditis., Case Report: We describe a case of cutaneous infection by P. parasiticum in a kidney transplant patient. The identification of this microorganism was performed by microbiological and histopathological studies and confirmed with the sequence of the gene encoding β-tubulin and a real time panfungal PCR targeting 18S ribosomal RNA gene. The microorganism was correctly identified by phenotypic and molecular methods. The patient was treated with oral antifungal therapy and a debulking surgery and evolved without any complication., Conclusions: The diagnosis of this infection is difficult and usually affects kidney transplant patients, but the reasons of this association are still unknown., (Copyright © 2019 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.)

First described in 1961, photoonycholysis (PO) is a rare nail alteration that may result from drug intake, from topical aminolevulinate photodynamic therapy or from photosensitive conditions such as porphyria or pseudoporphyria. Spontaneous PO is rare. This review updates the numerous causes of PO and highlights some new ways producing this condition. Four different types of PO are clearly recognized without relationship with the responsible drug. An updated list of potential inducing drug is provided. Some practical points on PO have been raised. The inability to reproduce photoonycholysis experimentally should be emphasized, and the pathogenesis of PO still needs to be clarified., (© 2018 European Academy of Dermatology and Venereology.)

Medullary carcinoma of the thyroid gland accounts for only 5-10% of thyroid carcinomas. Also, metastases to the skin of malignant tumors are infrequently (2-9% of patients). In the case herein reported in a 64-year old woman, a metastatic nodule on the scalp was the presenting clinical manifestation of a medullary thyroid carcinoma. A comprehensive review of the literature was conducted for similar cases using PubMed. Only 18 cases of cutaneous metastases of medullary thyroid carcinoma have been previously reported in the literature, but skin lesions were the presenting complaint of the thyroid neoplasm in only three.

Background and Objectives: Ocular/periocular involvement in pemphigus vulgaris (OPV) has rarely been reported. The objective of the present study was to investigate the pattern of OPV and define the prognostic value of its manifestation., Patients and Methods: From 1985 to 2014, a total of 167 patients with pemphigus vulgaris (PV) were treated at four tertiary Spanish hospitals. In this retrospective study, we included all patients with OPV. Clinical data and information on associated symptoms were obtained from patients' medical records., Results: Only 24 (14.3 %) of all PV patients had ocular lesions. In most cases, -ocular involvement was preceded by PV lesions at various other sites (mean duration: 33.7 months). Ocular PV lesions occurred during flares of mucocutaneous pemphigus, and was never the only mucosal manifestation. The most common clinical signs were conjunctival hyperemia (87.5 %), erosions on the eyelids (41.6 %) as well as of the palpebral/bulbar conjunctiva (33.3 %) and at the medial epicanthus (20.8 %). The most relevant associated symptoms included local pain/stinging (71.4 %), irritation (47.6 %), photophobia (38.1 %), and epiphora (23.9 %). Ocular PV improved with systemic and adjuvant topical therapies. Only two patients experienced sequelae., Conclusions: In patients with PV, ocular involvement is an exception. Ocular PV is associated with greater disease activity, and usually follows a benign course. Sites affected are the conjunctiva, the eyelids, or both., (© 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Hintergrund Und Ziele: Es gibt nur wenige Berichte zur Beteiligung der okulären/periokulären Region beim Pemphigus vulgaris (PV). Ziel der vorliegenden Studie war es, das Krankheitsbild des okulären PV (OPV) zu untersuchen und seinen prognostischen Wert zu definieren., Patienten Und Methodik: Zwischen 1985 und 2014 wurden insgesamt 167 Patienten mit Pemphigus vulgaris an vier tertiären spanischen Krankenhäusern behandelt. Wir haben alle Patienten mit OPV in diese retrospektive Studie aufgenommen. Klinische Daten sowie Informationen zu Begleitsymptomen wurden den Krankenakten der -Patienten entnommen., Ergebnisse: Lediglich 24 (14.3 %) PV-Patienten hatten okuläre Läsionen. Meist gingen dem okulären Befall PV-Läsionen an verschiedenen anderen Stellen voraus (durchschnittliche Dauer: 33,7 Monate). Okuläre PV-Läsionen traten während der Schübe eines mukokutanen Pemphigus auf und waren niemals die einzige Mukosa-Manifestation. Die häufigsten klinischen Symptome waren konjunktivale Hyperämie (87,5 %) und Erosionen an den Augenlidern (41,6 %), sowohl an der palpebralen/bulbären Konjunktiva (33,3 %) als auch am medialen Epikanthus (20,8 %). Zu den wichtigsten Begleitsymptomen gehörten lokale Schmerzen/Brennen (71,4 %), Reizung (47,6 %), Photophobie (38,1 %) und Epiphora (23,9 %). Der OPV besserte sich unter systemischer und unterstützender topischer Behandlung. Lediglich bei zwei Patienten traten Spätfolgen auf., Schlussfolgerungen: Bei Patienten mit PV sind die Augen nur in Ausnahmefällen betroffen. Ein okulärer PV ist mit größerer Krankheitsaktivität assoziiert und hat in der Regel einen gutartigen Verlauf. Betroffen sind die Konjunktiva und/oder die Augenlider., (© 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies., (Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Background: Radiotherapy as a first-choice treatment for in situ extramammary Paget disease has been successfully used., Objectives: To review the most relevant aspects of radiotherapy as first-choice treatment in selected cases of in situ extramammary Paget disease of the vulva., Patients and Methods: Two Caucasian females aged 76 and 92 years with in situ extramammary Paget disease localized in the genital region were treated by means of ortovoltage X-rays: 100 kV, 8 mA, 1.7 mm Al filter, field size of 12-cm cone, and source skin distance of 30 cm. Both patients received 40 Gy, 200 cGy per fraction, five fractions per week., Results: Complete regression of in situ extramammary Paget disease was observed in both patients after radical radiation therapy and neither local recurrences nor internal malignancies were detected., Conclusions: Radiotherapy is a curative treatment in selected cases of in situ extramammary Paget disease affecting the vulva.

Background: Paraneoplastic pemphigus (PNP) is an autoimmune mucocutaneous disease associated with specific B-cell lymphoproliferative neoplasms. There has been an increasing number of individual reports in the childhood and adolescent population., Objectives: To examine the clinical and immunopathological features of PNP occurring in children and adolescents., Patients and Methods: We analysed the clinical and immunopathological findings of 14 patients under the age of 18 years with a confirmed diagnosis of PNP. Sera from all patients were analysed by indirect immunofluorescence (IF) and immunoprecipitation for plakin autoantibodies, immunoblotting for detection of plectin autoantibodies, and enzyme-linked immunosorbent assay (ELISA) for the detection of desmoglein (Dsg) 1 and Dsg3 autoantibodies., Results: Severe oral mucositis was observed in all patients, and lichenoid cutaneous lesions in eight of 14 patients. The average age at presentation was 13 years. Striking findings included: pulmonary destruction leading to bronchiolitis obliterans in 10 patients, association with Castleman's disease in 12 patients, and a fatal outcome in 10 patients. The underlying neoplasm was occult in 10 patients. Histological findings include lichenoid and interface dermatitis with variable intraepithelial acantholysis. Deposition of IgG and C3 in the mouth and skin by direct IF was not found in some cases, but indirect IF detected IgG autoantibodies in all cases. Immunoprecipitation revealed IgG autoantibodies against desmoplakin I, envoplakin and periplakin in all cases, and against desmoplakin II and the 170-kDa antigen in 13 and 10 patients, respectively. Dsg3 and Dsg1 autoantibodies were present in 10 and three patients, respectively, and plectin autoantibodies in 13 patients., Conclusions: PNP in children and adolescents is most often a presenting sign of occult Castleman's disease. It presents with severe oral mucositis and cutaneous lichenoid lesions. Serum autoantibodies against plakin proteins were the most constant diagnostic markers. Pulmonary injury appears to account for the very high mortality rates observed.

Background: Hepatoerythropoietic porphyria (HEP) is usually a severe form of cutaneous porphyria, characterized biochemically by an increased urinary excretion of polycarboxylated porphyrins. The disease is the result of a profound deficiency (<10% of normal activity) of uroporphyrinogen decarboxylase (UROD) activity. Hepatoerythropoietic porphyria is inherited as an autosomal recessive trait, whereas familial porphyria cutanea tarda is dominant. At least 30 different mutations of the UROD gene have been identified in patients with HEP and familial porphyria cutanea tarda, with 1 predominant missense mutation (glycine-to-glutamic acid substitution at codon 281) in Spanish patients with HEP., Observation: A 5-year-old patient with first-degree-related parents presented with HEP and mild symptomatology. We found low levels of UROD enzymatic activity and a new homozygous mutation of the UROD gene, a phenylanine-to-leucine substitution at codon 46 (F46L). Both parents were healthy carriers of the mutation. The mother had reduced UROD activity (50% of normal), whereas the father had normal UROD activity. Prokaryotic expression of the F46L mutation using a pGEX vector has been used to confirm the deleterious effect of the mutation. When the mother started a new pregnancy, a prenatal study showed the absence of F46L mutation in the fetus and no accumulation of porphyrins in the amniotic fluid., Conclusions: A new mutation in the UROD gene causes a mild HEP phenotype. A normal UROD enzymatic activity was observed in the father, despite the presence of the heterozygous mutation. To our knowledge, this observation is the first description of a prenatal exclusion of HEP.

Purpose: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca Pharmaceuticals, Alderley Park, United Kingdom) is under development as an anticancer agent. We studied the pharmacodynamic effects of ZD1839 on EGFR in the skin, an EGFR-dependent tissue, in cancer patients participating in ZD1839 phase I clinical trials., Patients and Methods: We studied 104 pre- and/or on-ZD1839 therapy ( approximately at day 28 of therapy) skin biopsies from 65 patients receiving escalating doses of daily oral ZD1839. We measured ZD1839 effects on EGFR activation by immunohistochemistry using an antibody specific for the activated (phosphorylated) EGFR. Effects on receptor signaling (activated mitogen-activated protein kinase [MAPK]), proliferation, p27(KIP1), and maturation were also assessed., Results: Histopathologically, the stratum corneum of the epidermis was thinner during therapy (P <.001). In hair follicles, prominent keratin plugs and microorganisms were found in dilated infundibula. ZD1839 suppressed EGFR phosphorylation in all EGFR-expressing cells (P <.001). In addition, ZD1839 inhibited MAPK activation (P <.001) and reduced keratinocyte proliferation index (P <.001). Concomitantly, ZD1839 increased the expression of p27(KIP1) (P <.001) and maturation markers (P <.001) and increased apoptosis (P <.001). These effects were observed at all dose levels, before reaching dose-limiting toxicities., Conclusion: ZD1839 inhibits EGFR activation and affects downstream receptor-dependent processes in vivo. These effects were profound at doses well below the one producing unacceptable toxicity, a finding that strongly supports pharmacodynamic assessments to select optimal doses instead of a maximum-tolerated dose for definitive efficacy and safety trials.

Background: Topical corticosteroids and calcipotriol have been used separately for many years to treat psoriasis. A new combination ointment has been formulated, which contains both calcipotriol and the corticosteroid betamethasone dipropionate., Objective: To compare the combination ointment with betamethasone dipropionate ointment, calcipotriol ointment and ointment vehicle in patients with psoriasis vulgaris., Methods: 1,603 patients were randomised to one of the 4 double-blind treatments used once daily for 4 weeks., Results: The mean percentage change in the PASI at the end of treatment was -71.3 (combination), -57.2 (betamethasone), -46.1 (calcipotriol) and -22.7 (vehicle). The mean difference of combination minus betamethasone was -14.2 (95% CI: -17.6 to -10.8, p < 0.001), of combination minus calcipotriol -25.3 (95% CI: -28.7 to -21.9, p < 0.001) and of combination minus vehicle -48.3 (95% CI: -53.2 to -43.4, p < 0.001). 6.0% of patients (combination) reported local adverse reactions compared to 4.9% (betamethasone), 11.4% (calcipotriol) and 13.6% (vehicle)., Conclusion: Calcipotriol/betamethasone dipropionate combination ointment used once daily is well tolerated and more effective than either active constituent used alone., (Copyright 2002 S. Karger AG, Basel)

Linear IgA disease is an autoimmune subepidermal blistering disease characterized by IgA deposits at the cutaneous basement membrane zone. IgA antibodies from linear IgA disease sera react with antigens of 97 kDa (LABD97) and 120 kDa (LAD-1), both of which appear to be fragments of the extracellular domain of bullous pemphigoid 180 (type XVII collagen). The aim of this study was to determine whether linear IgA disease sera react with the immunodominant region of BP180 (NC16A domain), which is a major target of IgG autoantibodies produced by patients with bullous pemphigoid. Indeed, 11 of 50 linear IgA disease sera were found to contain IgA autoantibodies that recognized a recombinant form of NC16A by immunoblotting. The same sera also reacted with NC16A by enzyme-linked immunosorbent assay. An epitope mapping analysis uncovered four linear IgA disease-associated epitopes located within the 45 amino acid N-terminal stretch of NC16A, all of which were previously identified as antigenic sites targeted by bullous pemphigoid autoantibodies. Eight of the linear IgA disease sera that were reactive with NC16A also recognized LAD-1 secreted by the SCC-25 cell line, and five sera recognized BP180 extracted from keratinocytes. Linear IgA disease sera depleted of reactivity to NC16A by immunoadsorption continued to react with both the LAD-1 antigen and BP180 by immunoblotting and with the basement membrane zone by indirect immunofluorescence microscopy. Our results demonstrate that IgA autoantibodies from a subset of linear IgA disease patients react with the same sites on BP180 that are targeted by IgG autoantibodies in bullous pemphigoid.

The objective of this study was to establish normal reference ranges for porphyrins in healthy neonates. There is little information about urinary porphyrin excretion in this age group. This knowledge may provide an early diagnostic tool for detecting subtle alterations or latent forms in disorders of heme biosynthesis. Fifty healthy neonates were selected from the Department of Obstetrics. Total urinary porphyrins in random specimens were analysed by a spectrofluorometry method. The measurement of porphyrin fractions was made by fluorometric high-performance liquid chromatography (HPLC). The results were adjusted to urinary creatinine excretion to correct any imprecision and interindividual variation in body mass. The urinary total porphyrin had a median value of 331.50 (nmol/L). A statistically significant relationship between total porphyrin (nmol/L) and creatinine (mmol/L) was found (p < 0.01). The porphyrin/creatinine ratio showed a median value of 56.30 nmol/mmol creatinine. The study of individual porphyrins revealed that coproporphyrin and uroporphyrin were the major porphyrins excreted in neonates (coproporphyrin represents 81.98% and uroporphyrin 16.64% of total porphyrin); in both cases, isomer I was predominant with median values of 22.36 and 6.25 nmol/mmol creatinine, respectively. No significant relationships were found between porphyrin excretion and sex, gestational age, weight, or height. Our data provide the reference limits for porphyrins in neonates as a diagnostic guideline for evaluation of subtle alterations in heme biosynthesis.

Lichen planus pemphigoides is an autoimmune subepidermal blistering disease. The finding of immunoglobulin G antibodies directed against the basement membrane zone differentiates it from bullous lichen planus. The aim of this study was to identify the target antigen of lichen planus pemphigoides autoantibodies. Sera from lichen planus pemphigoides patients (n = 4) stained the epidermal side of NaCl-split human skin in a pattern indistinguishable from that produced by bullous pemphigoid sera. In bullous pemphigoid, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. We previously demonstrated that bullous pemphigoid sera predominantly react with a set of four epitopes (MCW-0 through MCW-3) clustered within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, lichen planus pemphigoides sera were also strongly reactive with recombinant bullous pemphigoid 180 NC16A. The lichen planus pemphigoides epitopes were further mapped using a series of overlapping recombinant segments of the NC16A domain. All lichen planus pemphigoides sera reacted with amino acids 46-59 of domain NC16A, a protein segment that was previously shown to be unreactive with bullous pemphigoid sera. Two lichen planus pemphigoides sera, in addition, reacted with the immunodominant antigenic region associated with bullous pemphigoid. In conclusion, there are now five bullous diseases that are associated with an autoimmune response to BP180: bullous pemphigoid; pemphigoid/herpes gestationis; cicatricial pemphigoid; linear immunoglobulin A disease; and lichen planus pemphigoides. In addition, we have identified a novel epitope within the BP180 NC16A domain, designated MCW-4, that appears to be uniquely recognized by sera from patients with lichen planus pemphigoides.

A randomized, multicentre, investigator-masked study was conducted in 105 patients with mild to moderate acne vulgaris to compare the efficacy and safety of adapalene 0.1% gel with tretinoin 0.025% gel after three months of treatment, with particular emphasis on reduction in inflammatory lesion counts after one week of treatment and impact on quality of life. In terms of efficacy, adapalene gel was found to be superior to tretinoin gel after one week of treatment, with respect to reduction in inflammatory lesion counts (32% vs. 17%, respectively; P = 0.001), total lesion counts (28% vs. 22%, respectively; P = 0.042) and global severity grade (28% vs. 16%, respectively; P = 0.001). No significant difference between the two treatments was found after 12 weeks of treatment for any of these variables. Evaluation of facial skin tolerance parameters showed significant differences between the two treatments in favour of adapalene for dryness, erythema, immediate and persistent burning and pruritus for at least one time point. One patient in the adapalene group and three patients in the tretinoin group experienced medical events which lead to discontinuation of treatment (skin irritation; NS). Quality of life scores improved more rapidly in the adapalene group than in the tretinoin group, with significant differences (P < 0.05) appearing at week 1 for questions related to problems with partners, close friends or relatives and to skin symptoms. There was also a significantly greater improvement in social and leisure activity in the adapalene group at week 12. Adapalene 0.1% gel reduced inflammatory and total lesion counts more rapidly than tretinoin 0.025% gel, and was also better tolerated. These differences appear to result in an earlier and greater quality of life improvement for the patients receiving adapalene.

Erythropoietic protoporphyria is a hereditary disorder of porphyrin metabolism caused by mutations in the ferrochelatase gene. Ferrochelatase catalyzes the chelation of ferrous iron into protoporphyrin IX to form heme. Mutation analysis was performed in four Spanish erythropoietic protoporphyria families resulting in the identification of four different mutations in the ferrochelatase gene. Two of them were novel mutations, a missense mutation (1157 A-->C, H386P) and a frameshift mutation (843delC) found in two Spanish families, respectively. The third and the forth Spanish patients carried already published ferrochelatase gene mutations, a nonsense mutation (343C-->T, R115X) and a missense mutation (557T-->C, I186T), respectively. The newly described frameshift mutation (843delC) predicted formation of an abrupt mRNA. The deleterious effect of His386 to Pro substitution as a result of mutation 1157 A-->C on the ferrochelatase activity was investigated by expressing the mutant ferrochelatase in Escherichia coli. The mutant ferrochelatase exhibited only 0.8% of the wild-type ferrochelatase activity. Prediction of the secondary structure of ferrochelatase suggested that the H386P mutation disrupted the original alpha-helical structure by way of introducing a turn, a rather drastic structural change of the enzyme sufficient to cause activity loss.

We present a 66-year-old man who had maculopapular pigmented lesions on the skin of the head, neck and trunk suggesting generalized eruptive histiocytoma (GEH). These lesions had a yellowish centre in a target-like pattern that has not been previously described. The patient suffered from diplopia and had a severe sensorimotor polyneuropathy causing progressive paresis of the limbs. The explorations performed disclosed the presence of specific xanthomatous infiltrates in the skin, lungs, respiratory tract, peripheral nerves and meninges, suggesting xanthoma disseminatum (XD) or juvenile xanthogranuloma. Multiple osteolytic lesions of large bones were also found. The infiltrate was CD68, MAC 387 and factor XIIIa positive and S-100 and CD1 negative. Some cells contained worm-like bodies visible by electron microscopy. Our patient presented clinical and immunohistochemical findings suggestive of GEH, juvenile xanthogranuloma or XD, supporting the idea of a wide spectrum of non-Langerhans cell histiocytosis. These specific target-like xanthomatous lesions seem to be unique for this new variant of XD.

Genetic predisposition plays an important role in the development of nearly 10% of cases of cutaneous malignant melanoma (CMM). The CDKN2A gene has been described as responsible for melanoma susceptibility in a proportion of families with CMM linked to 9p. CDKN2A encodes a cyclin-dependent kinase inhibitor also implicated in the carcinogenesis of several sporadic tumors. Even though the incidence of other cancers is higher in CMM families, pancreatic adenocarcinoma is the only other well demonstrated cancer associated with CDKN2A mutations in some CMM pedigrees. We describe a family with four cases of CMM, eight patients affected by other cancers, and nine patients affected by dysplastic nevus (DN) syndrome. A CDKN2A frameshift mutation (358delG) was present in all the CMM patients, in at least three of the patients with other cancers (CDKN2A status is unknown in four patients), and in only two of the DN patients (CDKN2A status is unknown in one patient). An absence of linkage between chromosome 9p markers and the 358delG CDKN2A mutation and DN was detected, indicating genetic heterogeneity for DN and CMM in this family. The study strongly suggests that CDKN2A mutations are involved not only in the predisposition to CMM but also to several other types of cancer.

The BP180 antigen, a component of the epidermal anchoring complex, has been identified as one of the major antigenic targets of autoantibodies associated with the blistering skin disease, bullous pemphigoid. Our research group has recently demonstrated that reactivity of bullous pemphigoid autoantibodies to the BP180 ectodomain is almost entirely restricted to a set of four antigenic sites clustered within the membrane-proximal noncollagenous stretch (NC16A). Using a passive transfer mouse model, antibodies to the corresponding noncollagenous region of murine BP180 were shown to trigger an inflammatory subepidermal blistering disease that closely mimics bullous pemphigoid. We now report the development of an enzyme-linked immunoabsorbent assay system that is extremely sensitive in detecting disease-specific autoantibodies in the sera of bullous pemphigoid patients. The target antigen in this assay is a recombinant form of the BP180 NC16A domain that contains all four of the well-defined bullous pemphigoid-associated antigenic sites. Of 50 randomly selected bullous pemphigoid sera tested, 47 (94%) were positive in this assay, whereas no specific reactivity was detected in any of the 107 controls. Interestingly, all three of the bullous pemphigoid sera that were negative in this assay had been obtained from patients who were already undergoing treatment. The NC16A enzyme-linked immunosorbent assay is more sensitive than any of the standard techniques for detecting circulating bullous pemphigoid autoantibodies, including other enzyme-linked immunosorbent assays, immunoblotting, and indirect immunofluorescence. Finally, the NC16A enzyme-linked immunosorbent assay provides immunologic information that cannot be obtained from direct immunofluorescence studies of skin biopsies, and that may well be relevant in the diagnosis and treatment of bullous pemphigoid.

Pemphigus vulgaris is an autoimmune bullous disorder characterized by autoantibodies directed against desmoglein 3. A group of 19 pemphigus vulgaris sera were characterized by immunoblotting, immunofluorescence, immunoprecipitation, and the passive transfer mouse model. The aim of these studies was to determine the specificity of the autoantibody response in these patients. All patients had clinical and histologic evidence of pemphigus vulgaris. Fogo selvagem sera (n = 8), bullous pemphigoid sera (n = 8), antinuclear antibodies positive sera from patients with lupus erythematosus (n = 2), and normal human sera (n = 8) were used as controls. All pemphigus vulgaris patients showed titers of IgG autoantibodies by indirect immunofluorescence > or = 1:60, predominantly of the IgG4 subclass and immunoprecipitated recombinant desmoglein 3 expressed in the baculovirus system. Patients with disease localized to the mucous membranes showed no reactivity with desmoglein 1 and only one had weak reactivity with mouse skin by indirect immunofluorescence (titer = 1:20). Sera of four of these mucosal patients were tested in the mouse model and three of four did not elicit skin or mucosal disease in the animals. In contrast, sera from all seven patients with disease involving the skin and mucous membranes (generalized disease) produced disease in neonatal mice. In one patient the disease evolved from pure mucosal involvement associated with anti-desmoglein 3 antibodies to a disorder involving mucosas and skin. This transition was associated with the appearance of anti-desmoglein 1 antibodies in the patient's serum. These studies indicate that the autoantibody response in pemphigus vulgaris is heterogeneous. Epitopes recognized by some pemphigus vulgaris sera are species specific and others may be mucosal specific.

Primary cutaneous B-cell lymphomas (CBCL) are a group of malignant lymphomas with apparently distinct clinicopathological and immunophenotypical features. As in other B-cell lymphomas, the accompanying benign cell population in CBCL includes a variable number of T lymphocytes whose role is not well understood. In the present study we characterized the immunophenotype of these T cells and compared it with that of the reactive T-cell population in specific skin involvement by noncutaneous B-cell malignancies. Our results indicated that most T cells in both primary and secondary B-cell lymphomas were CLA+ memory/effector helper T cells which differed from the currently known CLA+ memory/effector helper T lymphocytes of the skin-associated lymphoid tissue (SALT) system. However, the endothelial CLA ligand, E-selectin, was expressed on dermal vessels. These results suggest that a B cell environment and/or a lack of epidermal involvement promote(s) the recruitment into the skin of a different, apparently less specific, subset of memory helper T cells from those seen in T-cell-mediated dermatoses.

Cutaneous manifestations of lupus erythematosus (LE) are, usually, characteristic enough to permit an easy diagnosis. However, some patients may present less typical lesions, associated or not to the classic ones. Therefore, irrespectively of the variety of LE (acute, subacute and chronic), in absence of the typical butterfly rash, erythematosquamous papules or plaques, or any of the characteristic cutaneous alterations, it is important (even though not always easy) to recognize the uncommon and/or atypical changes of the skin.

The porphyrias are uncommon diseases caused by enzymatic deficiencies in the heme pathway. In the 25 year period 1969-1994, the Department of Dermatology of the Hospital Clinic of Barcelona has been able to study 793 cases of porphyria (724 cases of PCT, 27 of EPP, 26 of PV, 5 of CEP, 5 of HEP, 5 of AIP, 1 of HCP). Homozygous expression of an enzymatic deficiency in the heme pathway produces severe disease. Commonly, clinical manifestations appear in the homozygous state (the autosomal recessive porphyrias). However, homozygous forms of autosomal dominant porphyrias may occur exceptionally. Moreover, there are cutaneous porphyrias whose clinical manifestations do not permit dermatologists to classify them clearly into one of the well-defined syndromes. These uncommon and atypical forms are difficult to recognize without biochemical and enzyme studies. The porphyrias have a wide clinico-biochemical spectrum, including a large proportion of well defined diseases. Nevertheless, atypical forms occur and may be difficult to evaluate. It is important to note the genetic heterogeneicity of porphyrias, which accounts for the varying phenotypic expression.

We have analyzed 12 microsatellite markers on chromosome 9p in 54 paired cutaneous malignant melanoma (CMM) tumors and normal tissues. Forty-six percent of the tumors, including two in situ CMMs, showed loss of heterozygosity (LOH) at 9p. Only one tumor was homozygously deleted for 9p markers. The smallest deleted region was defined by five tumors and included markers D9S126 to D9S259. Loss of eight or more markers correlated significantly with worse prognosis (P < .002). Among the primary tumors, 87.5% of those with large deletions have a high risk of metastasis, as compared with only 18% of those without deletions or with loss of fewer than 8 markers (P < .001). It was not possible to demonstrate homozygous deletions of p16 in any of the CMM tumors. In four tumors, the LOH for 9p markers did not involve p16. The reported data suggest the existence of several tumor suppressor genes at 9p that are involved in the predisposition to and/or progression of CMM and exclude p16 from involvement in the early development of some melanoma tumors.

Hepatoerythropoietic porphyria is a severe cutaneous porphyria caused by deficiency of uroporphyrinogen decarboxylase and is considered to be the homozygous form of familial (type II) porphyria cutanea tarda. To elucidate further the relation between these conditions, we studied five Spanish families with hepatoerythropoietic porphyria and nine unrelated Spanish patients with familial porphyria cutanea tarda. Immunoreactive and catalytic uroporphyrinogen decarboxylase was decreased by greater than 95% in the five patients with hepatoerythropoietic porphyria. Hepatic uroporphyrinogen decarboxylase activity was decreased to 22% of normal. Four patients were homozygous for a mutation (G281E) originally identified in a Tunisian family; the fifth patient was a compound heterozygote for this mutation. The calculated carrier frequency for G281E in Spain is one in 1800. None of the nine familial porphyria cutanea tarda patients carried the G281E mutation. However, one G281E heterozygote in a family with hepatoerythropoietic porphyria had overt porphyria cutanea tarda. These findings suggest that the G281E mutation is functionally less severe than erythrocyte measurements indicate, that its clinical penetrance is very low in heterozygotes, and that, for this particular mutation, hepatoerythropoietic porphyria is the homozygous form of familial porphyria cutanea tarda.