Anna E. Martinez

A consensus approach to wound care in epidermolysis bullosa

BACKGROUND Wound care is the cornerstone of treatment for patients with epidermolysis bullosa (EB); however, there are currently no guidelines to help practitioners care for these patients. OBJECTIVES The objective of this study was to generate a list of recommendations that will enable practitioners to better care for patients with EB. METHODS An expert panel generated a list of recommendations based on the best evidence available. The recommendations were translated into a survey, and sent to other EB experts to generate consensus using an online-based modified Delphi method. The list was refined and grouped into themes and specific recommendations. RESULTS There were 15 respondents (45% response rate), with significant experience in the EB field (>10 years [67%]). Respondents included physicians (67%), nurses (17%), and allied health professionals (7%). There was more than 85% agreement for all the proposed items. These were further refined and grouped into 5 main themes (assessment and management of factors that impair healing, patient-centered concerns, local wound care, development of an individualized care plan, and organizational support) and 17 specific recommendations. LIMITATIONS There is a paucity of scientific evidence with most recommendations based on expert opinion. CONCLUSIONS These recommendations will provide practitioners with a framework for caring for these patients. Additional scientific research including effectiveness studies for everyday practice and expert consensus, may further refine these recommendations.

Gastrointestinal complications of epidermolysis bullosa in children

Background  Epidermolysis bullosa (EB) is a group of inherited disorders characterized by skin and mucous membrane fragility. Gastrointestinal (GI) complications have been described in many types of EB and are responsible for significant morbidity.

Bone mineralization in children with epidermolysis bullosa.

Background  Various factors may have deleterious effects on bone health in patients with epidermolysis bullosa (EB).

Vascular anomalies in Proteus syndrome

Proteus syndrome (PS) is a complex hamartomatous disorder defined by local overgrowth (macrodactyly or hemihypertrophy), subcutaneous tumours and various bone, cutaneous and/or vascular anomalies (VA). VA are manifold in PS, but their prevalence is unknown so far. In order to further characterize PS, we studied the prevalence of VA in 22 PS patients presenting to our outpatient clinic and reviewed 100 PS patients previously reported between 1983 and 2001. The diagnosis of vascular abnormalities was made on clinical grounds and supported with imaging studies and/or histology in 12 and seven patients out of 22, respectively. Thirty‐five VA were identified in 22/22 (100%) of our patients, and more than one type of VA were present in 10 of them. Vascular tumours, portwine stains (PWS), and venous anomalies (varicosities, prominent veins) were equally common. A total of 118 VA were previously reported in 70/100 (70%) PS patients; vascular hamartomas were more prevalent (56/118 = 47.5%), whilst PWS (21.2%) and venous anomalies (22.9%) were slightly less common than in our series, but there is the possibility of under‐reporting. Unlike Klippel–Trenaunay syndrome, where VA are mostly confined to the hypertrophic limb, major arteriovenous anomalies are rare, and – similar to the other hamartomas and naevi observed in PS (pigmentary naevi, epidermal naevi, subcutaneous tumours, exostoses) − VA appear to be distributed at random sites on the body. We conclude that VA are among the most common findings in PS. Their varying type and distribution lend further support to the concept of somatic mosaicism.

Spontaneous remission of congenital leukemia : A case for conservative treatment

A newborn infant with spontaneous remission of congenital leukemia cutis is described and a literature review of this uncommon phenomenon is provided. In view of the unusual and unpredictable behavior of this disease, chemotherapy should be withheld unless there is evidence of an 11q23 translocation or progressive disease. Otherwise, overall survival does not appear to be affected by adopting a conservative approach. Because of occasional late relapses, long-term follow-up is recommended. The biologic basis underlying spontaneous remission of congenital leukemia is unknown; therefore, molecular or molecular cytogenetic analysis of DNA obtained from a skin biopsy is recommended.

Germline Mutation in EXPH5 Implicates the Rab27B Effector Protein Slac2-b in Inherited Skin Fragility

The Rab GTPase Rab27B and one of its effector proteins, Slac2-b (also known as EXPH5, exophilin-5), have putative roles in intracellular vesicle trafficking but their relevance to human disease is not known. By using whole-exome sequencing, we identified a homozygous frameshift mutation in EXPH5 in three siblings with inherited skin fragility born to consanguineous Iraqi parents. All three individuals harbor the mutation c.5786delC (p.Pro1929Leufs(∗)8) in EXPH5, which truncates the 1,989 amino acid Slac2-b protein by 52 residues. The clinical features comprised generalized scale-crusts and occasional blisters, mostly induced by trauma, as well as mild diffuse pigmentary mottling on the trunk and proximal limbs. There was no increased bleeding tendency, no neurologic abnormalities, and no increased incidence of infection. Analysis of an affected persons skin showed loss of Slac2-b immunostaining (C-terminal antibody), disruption of keratinocyte adhesion within the lower epidermis, and an increased number of perinuclear vesicles. A role for Slac2-b in keratinocyte biology was supported by findings of cytoskeletal disruption (mainly keratin intermediate filaments) and decreased keratinocyte adhesion in both keratinocytes from an affected subject and after shRNA knockdown of Slac2-b in normal keratinocytes. Slac2-b was also shown to colocalize with Rab27B and β4 integrin to early adhesion initiation sites in spreading normal keratinocytes. Collectively, our findings identify an unexpected role for Slac2-b in inherited skin fragility and expand the clinical spectrum of human disorders of GTPase effector proteins.

Potential of Systemic Allogeneic Mesenchymal Stromal Cell Therapy for Children with Recessive Dystrophic Epidermolysis Bullosa

TO THE EDITOR The skin fragility disorder, recessive dystrophic epidermolysis bullosa (RDEB) results from mutations in COL7A1, leading to reduced or absent type VII collagen (C7) and defective anchoring fibrils at the dermal–epidermal junction (Fine et al., 2014). Currently, there is no cure, and most individuals develop lifeshortening squamous cell carcinomas (Fine and Mellerio, 2009). RDEB also has a major health economic burden; wound dressings for a 10-year-old child can cost

New vascular classification of port-wine stains: improving prediction of Sturge–Weber risk

680 per day (Kirkorian et al., 2014), which equates to 4

Cutaneous manifestations of tuberculosis

250,000 annually. Reported clinical trials of cell-based therapies for RDEB comprise intradermal allogeneic fibroblasts (Petrof et al., 2013; Venugopal et al., 2013), bone marrow transplantation (Wagner et al., 2010), intradermal bone marrow– derived mesenchymal stromal cells (BM-MSCs) (Conget et al., 2010), and intravenous BM-MSCs in RDEB adults (El-Darouti et al., 2013; abstract only). Ex vivo COL7A1 keratinocyte gene therapy is also being evaluated (Siprashvili et al., 2014). MSCs are heterogeneous cells that undergo self-renewal or differentiate into mesenchymal lineages (Caplan, 1991). MSCs also have non-progenitor functions in immune regulation, cell growth, and tissue repair (Phinney and Prockop, 2007; Chen et al., 2008). Nevertheless, healing is not associated with large numbers of therapeutic MSCs in injured tissues, suggesting that paracrine benefits may modulate inflammatory and immune responses (Baraniak and McDevitt, 2010). Our interest focuses on the potential of intravenous allogeneic BM-MSCs to help people living with RDEB. Ten children were included in the clinical trial and are detailed in Supplementary Table S1 online, with the trial protocol shown in Supplementary Figure S1 online. The trial was approved by the UK Medicines and Healthcare Products Regulatory Agency, with EudraCT number: 2012-001394-87; the UK National Research Ethics Committee London-Bloomsbury provided ethics approval (Ref:12/LO/1258), and the trial was registered prospectively with www. controlled-trials.com ISRCTN46615946. Written informed consent was obtained for each subject. Inclusion/exclusion criteria are presented in Supplementary Table S2 online, and study interventions are listed in Supplementary Table S3 online. Details of the BM-MSCs are provided in Supplementary Table S4 online. Each participant received three intravenous infusions of BM-MSCs (day 0, 7, and 28; each dose 1–3×10 cells kg) with no HLA matching or pre-conditioning. With regard to safety, there were 163 adverse events (AEs; Supplementary Tables S5–S7 online). Initially, two serious AEs, esophageal dilatation and skin infection, were reported but were subsequently downgraded (protocol version 4.0, 1 August 2014), as they were considered to be complications of RDEB and not the cells. Indeed, 127/163 (78%) of AEs were either unlikely or not related to the BM-MSCs. Concerning the severity of MSCrelated AEs, there were two severe events of DMSO odor, although odor was noted following 28/30 infusions (lasting up to 48 hours). Mild nausea occurred during two infusions, and abdominal pain and bradycardia were observed during two other infusions; all resolved within 15 minutes without treatment or hemodynamic compromise. No AEs resulted in discontinuation of MSCs. Laboratory assessments did not reveal any adverse impact of the BM-MSCs on renal, liver, or bone marrow function. Anti-C7 antibodies were detected by ELISA at baseline in 9/10 participants, but no sera bound to the dermal–epidermal junction by indirect immunofluorescence microscopy. Following MSCs, there were no changes in ELISA or indirect immunofluorescence microscopy data (Supplementary Table S8 online). Collectively, the tolerance data appear encouraging, although it should be noted that a zero event rate for a serious AE in just 10 patients is compatible with an upper 95% confidence interval of over 30%. With regard to secondary outcome measures, the data are summarized in Supplementary Table S9 online. Skin biopsies revealed no increase in C7 and no new anchoring fibrils at day 60. Fluorescence in situ hybridization analysis did not show donor-cell chimerism. Birmingham epidermolysis bullosa severity score (BEBSS) and global severity score questionnaires were completed for all the 10 participants (Supplementary Figures S2 and S3 online). Mean parentreported pain score was lower at 60 days than at baseline (mean difference: −5.5 points; 95% confidence interval (CI): LETTERS TO THE EDITOR

High-dose systemic corticosteroids can arrest recurrences of severe mucocutaneous erythema multiforme.

Facial port‐wine stains (PWSs) are usually isolated findings; however, when associated with cerebral and ocular vascular malformations they form part of the classical triad of Sturge–Weber syndrome (SWS).