Mutation of the genes encoding components of the TNFα-like (tumour necrosis factor α) pathway involved in signal transduction between the ectoderm and the mesenchyme during embryonic development causes hypohidrotic ectodermal dysplasia (HED), resulting from the abnormal differentiation of tooth buds, hair follicles and eccrine sweat glands. Two phenotypically indistinguishable forms of HED, X-linked recessive and autosomal (dominant or recessive), have been discerned in mice and humans.1 The X-linked form (OMIM #305100) is caused by mutations in the ED1 gene, which encodes two principal ectodysplasins. EDA-A1 is recognized by receptor EDA1R (ectodysplasin A1 receptor), causing the recruitment of an adaptor, EDARADD (EDA1R-associated death domain), which interacts with TRAF6 (tumour necrosis factor receptor-associated factor 6) leading to translocation of NFκB (nuclear factor κB) to the nucleus.2 Thus EDA-A1 ultimately activates NFκB to stimulate transcription of genes whose protein products are involved in the differentiation of skin appendages.1 In patients with HED, more than 100 different mutations in ED1, approximately 30 in EDA1R, and several in EDARADD have been reported (http://www.hgmd.cf.ac.uk). Studies conducted in mice have demonstrated that mutations in the tabby, downless or crinkled, genes, encoding the orthologues of EDA, EDAR1, and EDARADD, respectively, cause symptoms of HED.1 Furthermore, Naito et al.3 have shown that TRAF6–deficient mice also display symptoms of HED. To date, however, mutations in TRAF6, another component of the same signal transduction pathway, have not been reported in HED patients. In the present report is described the first mutation ever reported in TRAF6 in a female patient with symptoms typical of HED.

This review investigates the effectiveness of ablative and non-ablative Fractional Photothermolysis (FP) lasers for treating facial acne scars. 26 studies (13=ablative FP; 13=non-ablative FP) published between year-2003 to January 2011 were reviewed. Quantitative and qualitative data from each article were examined and analysed. 4 studies were split-face randomised controlled studies (RCTs). Whilst the data analysed where all clinically relevant and significant, there were some methodological differences between the studies. Outcomes included subjective and objective assessment of scar appearance, pre- and postoperative treatment, side effects and pain scores. A small number of studies used 3D Optical Profiling Imaging and histology for objective assessment. Even allowing for methodological variability, ablative FP seems to have an improvement range of 26-83% whereas non-ablative FP demonstrates an improvement range of 26-50%. Patients who undergo ablative FP laser experience erythema for 3-14 days and it resolves by 12 weeks, whereas patients who opt for the non-ablative FP laser experience erythema between 1-3 days and this resolves within a week. A higher proportion of patients (up to 92.3%) who undertake ablative FP experience post inflammatory hyperpigmentation (PIH) than those who have non-ablative FP (up to 13%). The maximum duration of PIH in ablative FP is up to 6 months whereas in non-ablative FP it lasts up to 1 week. Ablative FP and the procedure can be relatively uncomfortable in comparison to non-ablative FP. Ablative pain score range from 5.90-8.10 (scale 1-10) and the non-ablative FP pain score range from 3.90-5.66 (scale 1-10).

Background:  Dermoscopy is useful in evaluating skin tumours, but its applicability expands also in the field of inflammatory skin disorders. Plaque psoriasis (PP), dermatitis, lichen planus (LP) and pityriasis rosea (PR) are common inflammatory skin diseases, but little is currently known about their dermoscopic features.

Objective:  To determine and compare the dermoscopic patterns associated with of PP, dermatitis, LP and PR and to assess the validity of certain dermoscopic criteria in the diagnosis of PP.

Methods:  Patients with PP, dermatitis, LP and PR were prospectively enrolled. The single most recently developed lesion was dermoscopically and histopathologically examined. Variables included vascular morphology, vascular arrangement, background colour, scale colour, scale distribution and presence of Wickham striae. Univariate and adjusted odds ratios were calculated. Discriminant functions were used to plot ROC curves.

Results:  Eighty-three patients with PP and 86 patients with either dermatitis, LP or PR were included in the study. Dotted vessels in a regular arrangement over a light red background and white scales were highly predictive of the diagnosis of PP, whereas dermatitis more commonly showed yellow scales and dotted vessels in a patchy arrangement. PR was characterized by yellowish background, dotted vessels and peripheral scales; whitish lines (Wickham striae) were exclusively seen in LP.

Conclusions:  PP, LP, PR and dermatitis show specific dermoscopic patterns that may aid their clinical diagnosis. Certain combinations of dermoscopic features can reliably predict the diagnosis of PP.

Segmental vitiligo and generalized vitiligo are in general considered to be separate entities. The aetiopathogenesis of segmental vitiligo remains unclear, although several hypotheses have been put forward including mainly neuronal mechanisms. The typical association with other autoimmune diseases, as seen in generalized vitiligo, seems to be significantly less in segmental vitiligo, although recent insights point towards a possible immune-mediated overlap between the two subtypes. In this article, we describe a case with simultaneous presence of segmental vitiligo, alopecia areata, psoriasis and a halo naevus. To our knowledge, this is the first case with this exceptional combination. This concomitant presence could support the involvement of a shared autoimmune-mediated process, and may provide new insights into the pathogenesis of segmental vitiligo and direct future research. In the light of this remarkable case, different possible aetiopathogenetic mechanisms leading to the clinical presentation of segmental vitiligo are discussed and a new three-step theory is proposed.

The Centre of Evidence Based Dermatology, University of Nottingham, U.K. holds an annual Evidence Based Update (EBU) Meeting focused on important dermatological topics, which have in the past included eczema, urticaria, blistering disorders, skin infections, skin cancer and hair disorders. These one-day meetings aim to summarize the most recent evidence in the form of systematic reviews and recently completed clinical trials. This year, the 9th EBU meeting took place in Loughborough, U.K. on 12 May 2011 and was devoted to psoriasis. The latest updates on topical treatments, nail psoriasis, genetics and clinical implications, rational use of biologics, new and unpublished studies on combination of phototherapy and biologics for psoriasis, and on treatments of palmoplantar pustular psoriasis were discussed by a panel of renowned international speakers.

Background  Variegate porphyria (VP) is due to a partial deficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in the haem biosynthetic pathway. Clinically, VP is characterized by photosensitivity and acute neurovisceral attacks that can manifest separately or together in affected individuals. The disease is inherited in an autosomal dominant fashion with incomplete penetrance and PPOX gene mutations associated with VP are usually unique to patients and their families. In South Africa, however, VP is highly prevalent as the result of a founder mutation, designated p.R59W. Previous genealogical and haplotype studies showed a link between South African and Dutch carriers of p.R59W and it was suggested that this mutation was introduced to South Africa by Dutch settlers at the end of the 17th century.

Objectives  To perform extended haplotype analysis in six South African and Dutch VP families with the p.R59W mutation.

Methods  Haplotyping of 13 microsatellite markers flanking the PPOX gene on chromosome 1q22-23 and five informative single nucleotide polymorphisms within and around the gene.

Results  A core haplotype cosegregated in all families studied.

Conclusions  Our data deliver further confirmation that the South African and Dutch VP families carrying mutation p.R59W shared a common ancestor.

Background  Alopecia areata (AA) is a hair loss disease caused by T-cell-mediated autoimmune reactions against anagen-stage hair follicles. Although the exact aetiology is poorly understood, there is evidence to suggest that both genetic and environmental factors are involved in AA pathogenesis.

Objectives  To analyse DNA methylation and histone modification patterns in peripheral blood mononuclear cells (PBMCs) of patients with AA.

Methods  PBMC samples were obtained from 25 patients with AA and 20 healthy controls. Global DNA methylcytosine levels, as well as histone acetylation and methylation levels, were measured by enzyme-linked immunosorbent assay. mRNA expression levels were determined using real-time quantitative reverse transcription–polymerase chain reaction.

Results  Genomic DNA methylation in PBMCs of patients with AA was increased relative to controls. DNMT1, MBD1 and MBD4 expression levels were significantly higher in AA PBMCs than in controls, and DNMT1 transcription levels positively correlated with global DNA methylation levels in patient samples. Histone H3 acetylation was significantly increased and histone H3 lysine 4 methylation was significantly decreased in patient PBMCs compared with healthy controls. Histone H3 acetylation levels were positively correlated with AA disease severity, and with RANTES (CCL5) mRNA expression in PBMCs of patients with AA. These changes were accompanied by increased p300 (EP300), histone deacetylase 1 (HDAC1), myeloid/lymphoid or mixed lineage leukemia (MLL), SET7/9 (SETD7), G9A (EHMT2), JMJD2C (KDM4C) and JARID1A (KDM5A) expression, as well as reduced HDAC2, HDAC7, LSD1 (KDM1A), JMJD2A (KDM4A) and JMJD2B (KDM4B) expression.

Conclusions  DNA methylation and histone modification status are altered in PBMCs of patients with AA, possibly due to the deregulation of epigenetic regulatory genes. These changes may contribute to the activation of pathological immune responses in AA.

Background  Irritant contact dermatitis (ICD) is a frequent and often underrated problem for which the major efficacious therapy is still local glucocorticoids, although they have known adverse effects due to their wide spectrum of action. A more focused therapeutic strategy would be the inhibition of a key enzyme for biosynthesis of the lipid mediators, cytosolic phospholipase A2α (cPLA2α), in ICD. We are analysing the pharmacological and biological effects of a selective cPLA2α inhibitor.

Objectives  To examine the usefulness of the potent and selective cPLA2α inhibitor 3-(5-carboxypentanoyl)-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (compound 1) for therapy of inflammatory skin disorders.

Methods  We examined clinical and cellular effects of a selective cPLA2α inhibitor (compound 1) on ICD in mice.

Results  Topical application of the compound significantly reduced ear swelling after induction by the irritant benzalkonium chloride. Concomitantly, compound 1 inhibited the accumulation of granulocytes as well as the expression of inflammatory proteins such as tumour necrosis factor-α, interleukin-1β and macrophage inflammatory proteins 1α and 1β in the ear tissue. In primary murine keratinocytes, the benzalkonium chloride-induced expression of these proteins was also downregulated after treatment with compound 1 in vitro.

Conclusions  Compound 1 is a well-aimed agent for the treatment of nonspecific skin inflammation as it selectively inhibits cPLA2α and as it acts on an early stage of skin inflammation after its elicitation.

Background  Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are characterized by keratinocyte apoptosis and necrosis, resulting in epidermal detachment. Although monocytes abundantly infiltrate the epidermis in SJS/TEN skin lesions, the properties and functions of these cells have not been fully examined.

Objectives  To determine the properties of monocytes infiltrating into the epidermis in SJS/TEN.

Methods  Immunostaining of skin sections was performed to examine the membrane markers of monocytes infiltrating into skin lesions.

Results  Immunostaining of cryosections from 11 SJS/TEN skin lesions revealed numerous CD14+ monocytes located along the dermoepidermal junction and throughout the epidermis. The cells coexpressed CD16, CD11c and HLA-DR. CD14+ CD16+ cells were identified in very early lesions without epidermal damage, suggesting that their infiltration is a cause, rather than a result, of epidermal damage. Moreover, these cells expressed CD80, CD86 and CD137 ligand, indicative of their ability to facilitate the proliferation and cytotoxicity of CD8+ T cells. CD16+ cells infiltrating the epidermis and detected at the dermoepidermal junction were immunostained and counted in paraffin-embedded skin sections obtained from 47 patients with drug rash manifested as TEN, SJS, maculopapular-type rash or erythema multiform-type rash. The number of CD16+ monocytes infiltrating the epidermis increased significantly, depending on the grade of epidermal damage.

Conclusions  These findings suggest that the appearance of CD14+ CD16+ cells of monocyte lineage plays an important role in the epidermal damage associated with SJS/TEN, most probably by enhancing the cytotoxicity of CD8+ T cells.

Background  Systemic scleroderma (SSc) is a rare disease and knowledge about the relationship between clinical signs, disability, quality of life and depressive symptoms is still limited. Although patients with SSc are frequently treated by dermatologists, the vast majority of published evidence is based on rheumatological samples.

Objectives  To identify determinants of disability, decreased quality of life, and depression in a sample of dermatological patients with SSc.

Methods  This was a cross-sectional study on consecutive patients with SSc attending one specialist dermatological centre between April 2008 and November 2009. Validated questionnaires, the Health Assessment Questionnaire (HAQ), EuroQol (EQ-5D) and the Center for Epidemiologic Studies Depression scale (CES-D) were utilized to measure disability, quality of life and depressive symptoms. Additionally, disease characteristics (SSc subtype, skin thickness, organ involvement), subjective symptoms of SSc, treatment and socioeconomic characteristics were collected by trained investigators. Based on an a priori hypothesized causal model, multivariate logistic regression models were used to analyse determinants of disability, quality of life and depression in patients with SSc.

Results  A total of 72 patients [59 female (82%), mean age 59 years] were enrolled. According to the CES-D, 69% (48 out of 70) were screened positive for depression. Quality of life impairment and female sex and were independent risk factors for depressive symptoms. Disease-specific disability was the main determinant of quality of life impairment in SSc. Pain involvement of the musculoskeletal system and male sex were the main determinants of disability in our sample of patients with SSc.

Conclusions  The high psychosomatic morbidity in our sample of consecutive patients with SSc calls for the investigation of interdisciplinary models of care.

Background  Generalized recessive dystrophic epidermolysis bullosa (RDEB) is often complicated by high nutritional difficulties with risks of malnutrition.

Objectives  To provide information regarding the benefits of enteral feeding by gastrostomy (GTF), energy and protein requirements, tolerance, growth and pubertal development in children with RDEB.

Methods  Twenty-four patients were referred over a 7-year period in a retrospective study. Gastrostomy placement was decided in patients unable to feed orally and/or presenting loss in weight and height of at least 1 SD compared with their best growth level, despite regular nutritional advice. Weight and height were expressed as Z-scores. Catch-up growth following GTF onset was studied.

Results  Gastrostomies were performed in 11 children (aged 9·0 ± 5·8 years), and one young man aged 18 years. The body weight Z-score was −2·3 ± 1·0, height Z-score 1·1 ± 1·1, weight-for-height was 81 ± 11% and height-for-age 95 ± 4%. At onset, GTF provided 74 ± 21% and 180 ± 81% of the recommended dietary allowance (RDA) for energy and proteins, respectively. At study update (53 ± 20 months), GTF provided 91 ± 29% and 205 ± 100% of RDA for energy and proteins, respectively. Weight-for-height reached 92 ± 15% and height-for-age 98 ± 5%. A normal puberty was obtained when GT was performed before the age of 10 years. Skin was not improved.

Conclusion  Malnutrition was observed in 50% of the children with generalized RDEB. Protein and energy needs are particularly high. GTF is well tolerated and helps with catch-up growth and puberty. It must be considered before malnutrition onset, and, if necessary, before puberty.

Background  Exposure to ultraviolet radiation (UVR) and the familial melanoma susceptibility gene p16 (CDKN2A) are among the major risk factors which have been identified to contribute to the development of melanoma, and also significantly contribute to squamous cell carcinoma. We have previously shown that UVR induces p16CDKN2A expression in melanoma and keratinocyte cell lines and human skin, but the regulatory mechanisms controlling this expression are unknown.

Objectives  To determine the mechanism by which UVR induces p16CDKN2A expression in melanocytes and keratinocytes in the epidermis.

Methods  We have used an in vitro cell lines model of the UVR response in skin to assess the changes in p16CDKN2A expression and the signalling pathways regulating these changes, and validated these findings in whole human skin cultures.

Results  We show that UVR-induced ERK signalling, mediated by BRAF, regulates p16CDKN2A expression at the transcriptional, and possibly translational level.

Conclusions  This study demonstrates the biological connection between the known melanoma genes p16 (CDKN2A) and BRAF in a normal physiological response to UVR in the skin, and highlights the importance of defects in this biological pathway to melanoma and squamous cell carcinoma development.

Summary Background  Photodynamic therapy (PDT) is a nonsurgical alternative to conventional tumour excision for nonmelanoma skin cancers (NMSCs).

Objectives  We evaluated whether patients with field cancerization (multiple NMSCs) treated with aminolaevulinic acid (ALA) or its methylester (MAL) for that indication had PDT-induced changes in surgical scars in the treatment field.

Methods  Six adult patients with multiple NMSCs and a total of 21 scars from previous excisions were studied in a retrospective blinded evaluation from clinical photographs of scar response to ALA/MAL-PDT. After a 3-h application of topical 20% ALA or 16·8% MAL under occlusion, each field was irradiated with 635-nm light-emitting diode light at the fluence of 200 J cm−2. Patients underwent one to three PDT sessions per field at ∼1 month intervals, to fields that included scars on the back, thigh, arms and neck. Pre- and post-treatment digital photographs of scars were combined into 92 pairs that were independently and blindly evaluated by three board-certified dermatologists. This study was performed at our academic practice at the Massachusetts General Hospital.

Results  PDT produced a statistically significant improvement in scar appearance. The degree of improvement correlated with the number of treatment sessions (two or three treatments; P < 0·05). Improvement after a single treatment was not statistically different from baseline ratings (P = 0·99).

Conclusions  Surgical scar remodelling and clinical improvement may be accomplished via ALA/MAL-PDT, but may require repeated treatment sessions. Larger, prospective studies are necessary to confirm the effectiveness of PDT for this indication.

Background  Bosentan is an oral dual endothelin receptor antagonist, which has been shown to be efficacious for preventing new digital ulcers in patients with systemic sclerosis (SSc) in two high-quality randomized controlled trials. However, its efficacy for nondigital ulcers in SSc remains unknown.

Objectives  To evaluate the efficacy of bosentan on nondigital ulcers in patients with SSc.

Methods  Bosentan was administered to five patients with SSc with pulmonary arterial hypertension, who also had nondigital ulcers refractory to conventional treatments. The efficacy of bosentan on nondigital ulcers and its association with clinical features of ulcers were analysed.

Results  The nondigital ulcers refractory to conventional treatments were significantly improved by the administration of bosentan in cases surrounded with severe cyanosis. In contrast, nondigital ulcers without cyanosis were still refractory to bosentan therapy.

Conclusions  Bosentan may be efficacious for accelerating the healing of nondigital ulcers with severe cyanosis, suggesting that nondigital ulcers caused by severely impaired peripheral circulation are highly responsive to this treatment.

Summary Background  Recent studies suggest that patients on mammalian target of rapamycin (mTOR) inhibitors experience a reduction in cutaneous carcinogenesis by an estimated 50% or more compared with calcineurin inhibitors. While randomized trials are running, organ transplant recipients are frequently switched from calcineurin inhibitors to mTOR inhibitors when cutaneous carcinogenesis increases.

Objectives  To slow carcinogenesis in our patient, a heart transplant recipient with a neuropathic diabetic foot syndrome who had developed cutaneous carcinogenesis at a rate of more than 20 squamous cell carcinomas (SCC) annually.

Methods  The patient’s immunosuppression was switched from the calcineurin inhibitor ciclosporin to the mTOR inhibitor everolimus.

Results  Carcinogenesis slowed to six SCC annually; however, he developed recalcitrant diabetic foot ulcers which were purely neuropathic and nonangiopathic, and a limb-threatening fistulating necrotic erysipelas of the right leg. Both sites responded poorly to antibiotic therapy, offloading and debridement. This skin fistula became chronic and some toes were at risk for minor amputation. In view of the propensity for mTOR inhibitors to impair would healing, immunosuppression was switched back to ciclosporin. All wounds healed rapidly, but skin carcinogenesis rose to former levels.

Conclusions  This case impressively illustrates the clinical dilemma for mTOR inhibitor use where benefit in carcinogenesis is counterbalanced by impairment in wound healing. Changes in immunosuppressive regimens should thus be made on an individual basis with careful consideration of the relative risks.