Locally advanced tongue squamous cell carcinoma in epidermolysis simplex bullosa patient: a therapeutic conundrum.

Epidermolysis bullosa simplex (EBS) is a debilitating condition affecting the skin and mucous membranes that is characterised by frequent ulceration and blistering on trivial trauma. In EBS, oral cavity mucosal injuries lead to a high propensity for developing squamous cell carcinomas. Locally advanced tongue carcinoma arising in this background presents a challenging therapeutic conundrum. To our knowledge, this is the first case of aggressive locally advanced tongue carcinoma that has developed sporadically in a patient with EBS and no family history. Routine screening of oral mucosal lesions will lead to early detection and timely management of this debilitating condition.

Next generation sequencing identifies double homozygous mutations in two distinct genes (EXPH5 and COL17A1) in a patient with concomitant simplex and junctional epidermolysis bullosa.

Epidermolysis bullosa (EB) is a heterogeneous group of heritable blistering diseases. We developed a next generation sequencing (NGS) panel covering 21 genes associated with skin fragility disorders, and it was applied to DNA from 91 probands with the diagnosis of EB. In one patient, novel homozygous mutations were disclosed in two different, unlinked EB-associated genes: EXPH5, chr11 g.108510085G > A; p.Arg1808Ter and COL17A1, chr10 g.104077423delT; p.Thr68LeufsTer106. Consequences of the COL17A1 mutation were examined by RNAseq which revealed a complex splicing pattern predicting synthesis of a truncated polypeptide (85%) or in-frame deletion of exon 4 (15% of transcripts). Transmission electron microscopy (TEM) and immunostaining revealed findings consistent with EB simplex (EBS) and junctional EB (JEB), and clinical examination revealed a complex phenotype with features of both subtypes. This case illustrates the power of next generation sequencing in identifying mutations in patients with complex EB phenotype, with implications for genotype-phenotype correlations, prenatal testing, and genetic counseling of families at risk for recurrence.

IL-6/IL-10 Ratio as A Prognostic and Predictive Marker of the Severity of Inherited Epidermolysis Bullosa.

BACKGROUND: Recent studies have shown that cytokines have an important role in the pathogenesis of inflammatory diseases and can be used as prognostic markers. OBJECTIVE: To evaluate the IL-6/IL-10 ratio in patients with Inherited Epidermolysis Bullosa (EB) as a prognostic marker. METHODS: Serum levels of IL-6 and IL-10 were measured in 13 patients with recessive dystrophic EB (RDEB) as well as 10 with EB Simplex (EBS), and in 18 healthy subjects. Receiver Operating Characteristics (ROC) analyses were used to assess the diagnostic accuracy of the IL-6/IL-10 ratio for detecting severe form of EB. RESULTS: The IL-6/IL-10 ratio was statistically higher in RDEB patients than in EBS patients and healthy subjects. The IL-6/IL-10 ratio significantly correlated with BEBS score. CONCLUSION: Our findings suggest that IL-6/IL-10 ratio >5.6 has a good diagnostic accuracy to identify patients with the highest severity of disease.

T-lymphocytes are directly involved in the clinical expression of migratory circinate erythema in epidermolysis bullosa simplex patients.

Epidermolysis bullosa simplex with migratory circinate erythema (EBS-MCE) is a rare EBS subtype characterised by migratory blistering lesions that resolve with brownish pigmentation. It is caused by a recurrent readthrough mutation, c.1649delG, in the tail of keratin 5. Here, we report a child with EBS-MCE and investigated the immunologic mechanisms underlying the migratory lesions in this patient. A skin biopsy from the patient from an active border of an erythematous lesion was used for the immunohistochemical characterisation of the inflammatory infiltrate and for TUNEL assay to detect apoptotic cells. We found abundant CD4+ and CD8+ T lymphocytes infiltrating the papillary dermis and lining the dermal-epidermal junction. A number of these cells expressed the activation marker CD69. CD83+ dendritic cells were present both in the epidermis and papillary dermis. Finally, TUNEL staining showed apoptosis of basal and suprabasal keratinocytes. These findings suggest a critical role of the cellular immunity in determining the EBS-MCE phenotype.

Malignant melanoma arising in the setting of epidermolysis bullosa simplex: an important distinction from epidermolysis bullosa nevus.

IMPORTANCE: Patients with epidermolysis bullosa (EB) do not carry a significantly increased risk of melanoma but are prone to developing large, markedly atypical melanocytic nevi (EB nevi), which may mimic melanoma clinically and histologically. Many authors now favor a conservative approach in managing atypical pigmented lesions in patients with EB. OBSERVATIONS: We present the case of a 30-year-old woman with severe EB simplex who sought care for a large red and black ulcerated plaque. The clinical differential diagnosis included EB nevus and melanoma. An incisional punch biopsy specimen revealed an atypical melanocytic proliferation with focal florid pagetoid spread and involving elongated rete ridges, consistent with invasive acral lentiginous melanoma. The subsequent amputation was confirmatory. Micrometastasis was detected in 1 of 5 sentinel lymph nodes. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first reported case of melanoma arising in EB simplex-affected skin. It highlights the difficulty in differentiating melanoma from an EB nevus. Despite the increasing awareness of EB nevi, a high index of suspicion for melanoma should be maintained, and early biopsy is recommended when evaluating large pigmented lesions in patients with EB.

Verrucous carcinoma in epidermolysis bullosa simplex is possibly associated with a novel mutation in the keratin 5 gene.

Epidermolysis bullosa simplex (EBS) is mainly caused by mutations in the KRT5 and KRT14 genes. Squamous cell carcinoma (SCC) represents the second most frequent skin neoplasia with complex aetiology. The molecular events disrupting the orchestrated interplay between the cytoskeleton, cell adhesion molecules and signalling proteins are ill understood in SCC. We describe the molecular background and the unusual course of the disease in a patient with EBS Dowling-Meara, severe keratoderma and a massive verrucous carcinoma. Skin and tumour samples from the patient were analysed using light microscopy, immunohistochemistry and immunofluorescence mapping. Mutation analysis of the KRT5 and KRT14 genes identified the novel KRT5 mutation p.E477D. Invasive tumour areas were characterized by downregulation of keratins 5 and 14, reduced and irregular desmocollin-2 expression and increased expression of keratins 6, 16 and 17. Levels of Ki-67 were increased and levels of E-cadherin strongly reduced in the tumour tissue. In this case a novel KRT5 mutation led to increased fragility of keratinocytes. Desmosome and adherens junctions were destabilized, which may trigger keratinocyte-mediated inflammation, possibly via p120-catenin-dependent signalling, suggesting a link between a keratin mutation and SCC, which adds weight to the hypothesis that disturbance of the cytoskeleton represents a major cause in the appearance of the malignant phenotype. Some individuals with EBS may be at risk of developing secondary SCC.

[Immunofluorescence mapping for diagnosis of congenital epidermolysis bullosa]. / Mapeo por inmunofluorescencia para el diagnóstico de epidermólisis ampollosa congénita.

The tools for diagnosis of epidermolysis bullosa have advanced greatly since Hintner's group introduced antigen mapping as a diagnostic test for this family of genodermatoses. Monoclonal or polyclonal antibodies raised against some of the specific proteins found in the epidermis and basement membrane of the epidermis have allowed 4 types of epidermolysis bullosa de be identified and all variants to be classified. When a newborn baby presents with blisters, many conditions are implicated in the differential diagnosis. Examination under an optical microscope can suggest epidermolysis bullosa, but immunofluorescence mapping and electron microscopy are required for confirmation of the diagnosis and further classification of congenital epidermolysis bullosa. This article explains the importance of immunofluorescence antigen mapping and describes the methods employed for classification and subclassification of epidermolysis bullosa.

Ptosis and ophthalmoplegia associated with epidermolysis bullosa simplex-muscular dystrophy.

The association of epidermolysis bullosa simplex and muscular dystrophy (EBS-MD) has rarely been discussed in ophthalmology literature. This case report offers a brief summary of epidermolysis bullosa and describes what is known about EBS-MD. The case involves a patient with EBS-MD who presented with ptosis and ophthalmoplegia, suggesting that these may be complications of EBS-MD.

Case of mistaken identity: bullous congenital ichthyosiform erythroderma mistaken as epidermolysis bullosa simplex.

Distinguishing clinically similar dermatologic disorders can be challenging and the differential diagnosis of a blistering eruption in the newborn period can be extensive. Several genodermatosis, such as bullous congenital ichthyosiform erythroderma (BCIE) and epidermolysis bullosa simplex (EBS), autoimmune bullous disorders, infectious diseases, sucking blisters, and bullous mastocytosis must be considered. We present a case of BCIE misdiagnosed as EBS and review characteristic clinical and histopathological features of each disorder as well as the basic approach to treatment.

The molecular genetics of keratin disorders.

Keratins are the type I and II intermediate filament proteins which form a cytoskeletal network within all epithelial cells. They are expressed in pairs in a tissue- and differentiation-specific fashion. Epidermolysis bullosa simplex (EBS) was the first human disorder to be associated with keratin mutations. The abnormal keratin filament aggregates observed in basal cell keratinocytes of some EBS patients are composed of keratins K5 and K14. Dominant mutations in the genes encoding these proteins were shown to disrupt the keratin filament cytoskeleton resulting in cells that are less resilient and blister with mild physical trauma. Identification of mutations in other keratin genes soon followed with attention focussed on disorders showing abnormal clumping of keratin filaments in specific cells. For example, in bullous congenital ichthyosiform erythroderma, clumping of filaments in the suprabasal cells led to the identification of mutations in the suprabasal keratins, K1 and K10. Mutations have now been identified in 18 keratins, all of which produce a fragile cell phenotype. These include ichthyosis bullosa of Siemens (K2e), epidermolytic palmoplantar keratoderma (K1, K9), pachyonychia congenita (K6a, K6b, K16, K17), white sponge nevus (K4, K13), Meesmann's corneal dystrophy (K3, K12), cryptogenic cirrhosis (K8, K18) and monilethrix (hHb6, hHb1).In general, these disorders are inherited as autosomal dominant traits and the mutations act in a dominant-negative manner. Therefore, treatment in the form of gene therapy is difficult, as the mutant gene needs to be inactivated. Ways of achieving this are actively being studied. Reliable mutation detection methods from genomic DNA are now available. This enables rapid screening of patients for keratin mutations. For some of the more severe phenotypes, prenatal diagnosis may be requested and this can now be performed from chorionic villus samples at an early stage of the pregnancy. This review article describes the discovery of, to date, mutations in 18 keratin genes associated with inherited human diseases.

Epidermolysis bullosa simplex Dowling-Meara due to an arginine to cysteine substitution in exon 1 of keratin 14.

Epidermolysis bullosa simplex (EBS) is a blistering disorder affecting the basal layer of the epidermis usually inherited in an autosomal dominant fashion. Most cases are caused by mutations in the genes encoding keratin 5 (K5) and keratin 14 (K14) and are characterized by cytolysis within the basal layer of the epidermis. We report a patient manifesting the Dowling-Meara variant of EBS in whom we characterized a cytosine to thymine transition at codon 125 (R125C) in K14. This missense mutation is located at the amino terminus of the helical rod domain of the keratin 14 molecule, resulting in defective pairing with K5, thereby disrupting keratin tonofibril integrity.

DNA based prenatal testing for the skin blistering disorder epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is a skin fragility disorder in which mild physical trauma leads to blistering. The phenotype of the disorder is variable, from relatively mild affecting only the hands and/or feet, to very severe with widespread blistering. For the severest forms of EBS there is a demand for prenatal diagnosis which until now has involved a fetal skin biopsy in the second trimester. The identification of mutations in the genes encoding keratins K5 and K14 as the cause of EBS opens up the possibility of much earlier diagnosis of the disease. We report here four cases in which prenatal testing was performed. In three of the cases the genetic lesions were unknown at the start of the pregnancy, requiring the identification of the causative mutation prior to testing fetal DNA. In two of the four cases novel mutations were identified in K14 and in the two remaining families, a previously identified type of mutation was found. Fetal DNA, obtained by chorionic villus sampling or amniocentesis, was analysed for the identified mutations. Three of the DNA samples were found to be normal; a mutant K14 allele was identified in the fourth case and the pregnancy was terminated. These results demonstrate the feasibility of DNA-based prenatal testing for EBS in families where causative mutations can be found.