R Mallipeddi

Epidermolysis bullosa and cancer

Summary Epidermolysis bullosa (EB) encompasses a group of inherited blistering skin disorders classified into three main subtypes of simplex, junctional and dystrophic. In recent years there have been substantial advances in our understanding of the molecular basis of these conditions and in the management of such patients. In spite of this progress, squamous cell carcinoma (SCC) is still a major cause of morbidity and mortality, particularly in Hallopeau‐‐Siemens recessive dystrophic EB. The reason why dystrophic EB patients readily develop SCC with such a poor prognosis remains a mystery. This article reviews the epidemiology of cancer in inherited EB and also discusses the clinical features, histological assessment and treatment options of SCC in EB.

Increased risk of squamous cell carcinoma in junctional epidermolysis bullosa.

Non‐Herlitz junctional epidermolysis bullosa (JEB) is an autosomal recessive genodermatosis characterized by skin fragility and blistering. It is usually caused by mutations in the genes encoding the basement membrane proteins laminin 5 or type XVII collagen. Clinically, impaired wound healing and chronic erosions cause major morbidity in affected patients. Previously it was thought that these individuals, unlike patients with dystrophic EB, did not have an increased risk of developing skin cancer. However, we describe three patients with non‐Herlitz JEB (aged 42, 56 and 75 years) who developed cutaneous squamous cell carcinomas (SCCs). The tumours were well‐differentiated in two cases, but one patient had multiple primary SCCs that were either well‐ or moderately differentiated. Most cases of SCC in non‐Herlitz JEB described have occurred in those with laminin 5 defects and on the lower limbs. These clinicopathological observations have important implications for the management of patients with this mechanobullous disorder as well as providing further insight into the biology of skin cancer associated with chronic inflammation and scarring.

Dermatofibrosarcoma protuberans: 35 patients treated with Mohs micrographic surgery using paraffin sections.

Background  Dermatofibrosarcoma protuberans (DFSP) has conventionally been treated with wide local excision. More recently Mohs micrographic surgery (MMS) has been advocated.

Dilemmas in distinguishing between dominant and recessive forms of dystrophic epidermolysis bullosa

Background  Dystrophic epidermolysis bullosa (DEB) is a heterogeneous inherited blistering skin disorder. The mode of inheritance may be autosomal dominant or recessive but all forms of DEB result from mutations in the gene encoding the anchoring fibril protein, type VII collagen, COL7A1. Consequently, in spite of careful clinical and skin biopsy examination, it may be difficult to distinguish mild recessive cases from de novo dominant disease in families with clinically normal parents and no other affected siblings; this distinction has significant implications for the accuracy of genetic counselling.

Psoriasis bullosa acquisita

Summary We report a 51‐year‐old man with a 20‐year history of chronic plaque psoriasis who developed an autoimmune subepidermal blistering eruption that had clinical features of bullous pemphigoid, erythema multiforme and epidermolysis bullosa acquisita. Investigations revealed a 1 : 400 titre circulating and in vivo bound IgG autoantibody that mapped to the dermal side of 1 m NaCl‐split skin and localized to the lower lamina lucida/upper lamina densa on immunogold electron microscopy. Immunoblotting, using dermal extracts, showed serum binding to antigens of ≈ 200‐ and ≈ 260 kDa. Indirect immunofluorescence microscopy, using the patients serum on archival skin sections taken from selected individuals with different forms of inherited epidermolysis bullosa as substrate, showed normal basement membrane labelling on all samples apart from recessive dystrophic epidermolysis bullosa skin (with inherent mutations in the type VII collagen gene): in these cases there was a complete absence of immunostaining. Clinically, the patient responded rapidly to combination treatment with intravenous immunoglobulin and oral corticosteroids, dapsone and mycophenolate mofetil. Autoimmune subepidermal blistering has been reported in other patients with psoriasis, although no specific target antigen has ever been determined. Our study provides preliminary evidence that, for this patient at least, the autoantibody may be targeted against a skin component closely associated with type VII collagen (the epidermolysis bullosa acquisita antigen). Therefore, we propose the term ‘psoriasis bullosa acquisita’ for this and possibly other patients with similar skin eruptions.

Altered expression of l‐arginine metabolism pathway genes in chronic wounds in recessive dystrophic epidermolysis bullosa

Individuals with the severe, mutilating Hallopeau–Siemens form of recessive dystrophic epidermolysis bullosa (HS‐RDEB) have trauma‐induced blisters and skin erosions which often progress to wounds that are slow to heal. These chronic wounds cause considerable morbidity and there is an increased risk of squamous cell carcinoma arising in the wound margins. Currently, little is known about the keratinocyte cell biology in these wounds. Therefore, we compared the gene expression profiles of wound edge with nonwounded skin from two individuals with HS‐RDEB. Trauma‐induced wound sites had been present in both patients for more than 3 months. Hybridizations using DermArrayTM gene expression filters showed relative differences in gene expression between wounded and unwounded skin. Notably, there was a fivefold increase in expression of arginase‐1 (ARG1) in the chronic wound samples. Expression of seven other genes relevant to l‐arginine metabolism also showed differences greater than twofold. l‐Arginine is known to have a critical role in the synthesis of nitric oxide as part of normal tissue repair. Although alterations in arginase isoenzymes have been detected previously in other chronic wounds (human and animal models), this is the first study to demonstrate differences in several components of the l‐arginine metabolism pathway in chronic wounds, and the first to examine chronic wounds in HS‐RDEB. The data show that the cascade of l‐arginine metabolites is altered in HS‐RDEB and the findings may provide new insight into the pathology of chronic wounds in this genodermatosis.

Genomic localization, organization and amplification of the human zinc transporter protein gene, ZNT4, and exclusion as a candidate gene in different clinical variants of acrodermatitis enteropathica

Abstract Acrodermatitis enteropathica is an inherited disorder of zinc metabolism, the molecular basis of which is currently unknown. Recent transgenic mouse studies have highlighted the potential significance of certain zinc transport proteins, for example ZnT4, in providing clues to the pathogenesis of zinc-related disorders such as acrodermatitis enteropathica. Specifically, mice of any genotype suckled on ZnT4-deficient mice fail to absorb intestinal zinc and ZnT4-deficient mice also develop dermatitis, alopecia and stunted growth. Therefore, to assess human ZnT4 as a candidate gene/protein in acrodermatitis enteropathica or related disorders, we characterized the intron-exon organization of the human ZNT4 gene, which comprises seven distinct exons spanning approximately 38.7 kb. High-resolution radiation hybrid mapping placed ZNT4 on 15q21.1. We also developed a PCR-based mutation detection strategy using primers placed on flanking introns followed by direct sequencing of the PCR products. Using this approach, we sequenced DNA from five individuals with acrodermatitis enteropathica; no mutations were identified. Thus, ZNT4 is unlikely to be the correct candidate gene for this disorder. We also identified and characterized two common single nucleotide polymorphisms in exon 5 and in the 3′ UTR of ZNT4 , which will be useful for future genetic linkage studies in assessing ZNT4 as a candidate gene for other inherited disorders of zinc metabolism.

Safety, complications and patients’ acceptance of Mohs micrographic surgery under local anaesthesia: results from the U.K. MAPS (Mohs Acceptance and Patient Safety) Collaboration Group

By virtue of its tissue sparing properties and assessment of 100% of the margin of excised specimens, MMS is regarded as the gold-standard surgical treatment of high-risk non-melanoma skin cancers of the head and neck. From its original inception in the 1940s, modern day MMS has evolved to become a fresh tissue surgical technique, using frozen section margin control performed under local anaesthesia in an out-patient or day-case setting. In the UK, the increasing burden of skin cancer has resulted in a greater demand for MMS with over 32 units across the country providing the technique. This article is protected by copyright. All rights reserved.

Hemorrhoid cushions for chondrodermatitis nodularis helicis (CNH): Piling off the pressure

THERAPEUTIC CHALLENGE Chondrodermatitis nodularis helicis (CNH) results from inflamed cartilage of the ear, most commonly because the patient persistently sleeps on the affected side. CNH often recurs unless the patient can avoid repeated trauma to that ear in future, by reducing pressure applied over the cartilage. Methods suggested previously include strapping bespoke ear-protective devices to the head, or simply advising the patient to alter their sleeping position; both these methods are seldom adhered to, although frequently advised.