M. El Hachem

Epidermolysis bullosa simplex with PLEC mutations: new phenotypes and new mutations.

Background  Genetic mutations in the plectin gene (PLEC) cause autosomal recessive forms of epidermolysis bullosa simplex (EBS) associated with either muscular dystrophy (EBS‐MD) or pyloric atresia (EBS‐PA). Phenotype–genotype analysis has suggested that EBS‐MD is due mostly to genetic mutations affecting the central rod domain of plectin, and EBS‐PA to mutations outside this domain.

Herlitz junctional epidermolysis bullosa : laminin-5 mutational profile and carrier frequency in the Italian population

Background  Herlitz junctional epidermolysis bullosa (HJEB; MIM 226700) is a rare epithelial adhesion disorder caused by null mutations in any of the three genes encoding the α3, β3 and γ2 chains of laminin‐5, and is mainly characterized by extensive mucocutaneous blistering, recurrent infections and early lethality.

A truncating mutation in the laminin-332α chain highlights the role of the LG45 proteolytic domain in regulating keratinocyte adhesion and migration.

Altered function of laminin‐332 (α3β3γ2) consequent to mutations in the LAMA3, LAMB3 and LAMC2 genes causes junctional epidermolysis bullosa non‐Herlitz (JEB‐nH). JEB‐nH patients suffer from skin blistering and have an increased risk of developing aggressive skin carcinomas in adulthood. Laminin‐332 is proteolytically processed and its extracellular mature form lacks the α3 chain C‐terminal globules 4 and 5 (LG45). The LG45 tandem has cell adhesion and protumorigenic properties. However, mutations that affect this domain are very rare and their functional effects in patients have not been explored to date.

Electrochemotherapy, a potential new treatment for the management of squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa: report of three cases.

Editor Epidermolysis bullosa (EB) is a rare congenital disorder caused by mutations in structural proteins of the dermal/epidermal junction and defined by high skin fragility and impaired wound healing. Generalized Severe Recessive Dystrophic EB (RDEB-sev gen) is a severe form, and squamous cell carcinoma (SCC) is one of the most feared complication. To date, surgery is the primary treatment option. Frequent relapses and metastasis require radiotherapy and chemotherapy. Despite this multimodal approach, in some cases, excisional surgery is not a possible option, and amputation is inevitable; over two-third of RDEB patients die from SCC. Therefore, alternative approaches should be considered. Electrochemotherapy (ECT) is a local treatment that combines low-dose systemic or intralesional cytotoxic drugs (bleomycin or cisplatin) and the application of high-intensity electric pulses. The electric fields temporarily increase the cell permeability allowing the delivery of drugs into tumour cells. ECT has been successfully used to treat cutaneous and subcutaneous metastasis and non-melanoma skin cancer, including SCC. We report the cases of three patients with SCC in RDEB-sev gen treated with ECT (Table 1). They were unsuitable for standard treatments because of tumour characteristics and general status. The ethics committee of the Bambino Ges u Children’s Hospital approved an expanded access program. Written consent was obtained from the patients. Inclusion criteria and technical procedures followed the European Standard Operating Procedures for ECT (ESOPE). Before treatment, a digital mapping of all lesions was performed and the tumour areas were calculated. A history, clinical examination, biopsy of the lesions, routine blood and instrumental exams were required for all patients. The procedures were performed under general anaesthesia, using the CliniporatorTM device (IGEA, Italy) and variable length hexagonal needle electrodes. Bleomycin was injected in an i.v. bolus at a dose of 15 mg/m for two of the three patients, 5 mg/m for one of them because of renal failure. Electrical pulses started 8 minutes after the drug administration and continued for 25 min (8 square wave pulses 1000 V/cm for 100 ms at 5 kHz). A simple dressing was used to cover the treated areas. The patients were seen at 1, 2, 4 weeks and then every month after ECT; the lesions were examined and measured to determine the response. We assessed the efficacy according to the Response Evaluation Criteria in Solid Tumours (RECIST).

Novel PNPLA1 mutations in two Italian siblings with autosomal recessive congenital ichthyosis

Autosomal recessive congenital ichthyoses (ARCI) are a clinically and genetically heterogeneous group of non-syndromic ichthyoses due to mutations in at least 9 genes, including PNPLA1 (1). PNPLA1 (Patatin-Like Phospholipase Domain-Containing Protein 1) is strongly expressed in the epidermal granular cell layer (1), and has been recently shown to play a crucial role in epidermal ω-O-acylceramide biosynthesis and skin barrier integrity both in mice and humans (2-5). Concomitantly several ARCI families carrying PNPLA1 mutations have been described confirming that most mutations occur in the highly conserved patatin core domain (1, 5-10). We report the identification of two novel missense mutations in PNPLA1 in two Italian sisters affected with ARCI characterized by a cyclic disease course. This article is protected by copyright. All rights reserved.

Acral skin atrophy in an infant: an early clue to Kindler syndrome diagnosis

and lymphadenopathy disappeared within 3 months and systemic corticosteroids gradually decreased. Tattoos can induce allergic reactions like type IV T-cell mediated hypersensitivity, or cutaneous lymphoid hyperplasia, more often on red ink tattoos. They can also induce granulomatous reactions due to foreign body reactions or authentic sarcoidosis. Cutaneous manifestations occur in about one-third of patients with systemic sarcoidosis. The development of SG in old scars, traumatised skin sites and around foreign material is well known and may represent a K€ obner phenomenon. SG can appear on tattoos and be limited to them. Since the first of sarcoidosis revealed by granulomas on tattoo described in 1952, several cases of SG on tattoos have been reported. SG occur whatever the ink of the tattoo: red (cinnabar), black (ferric oxide) and blue-black. They can appear while an alreadyknown systemic sarcoidosis with or without previous skin involvement. They may also be the only manifestation of sarcoidosis or reveal a systemic sarcoidosis even asymptomatic as in our patient. In most reported cases, SG on tattoos occur spontaneously but triggering by medication, such as interferon alpha has been reported. The skin lesions appear several weeks to several decades after tattooing. In our case, SG developed 10 years later. Such prolonged delay has been rarely reported. Histological differentiation between sarcoidosis and a foreign body reaction can sometimes be difficult and the two can be associated. However, if foreign material is discovered in granulomas, investigations for sarcoidosis should still be led. The cause of sarcoidal reactions in tattoos remains unknown. In genetically predisposed patients, the ink of the tattoos could induce a chronic antigenic stimulation, resulting in a Th1/Th2 immunity imbalance with a predominant Th1 immune response. The systemic spread of the tattoo pigment could induce the same reaction in other sites, causing systemic manifestations. Sarcoidosis must be hypothesized when nodular lesions arise on tattoos, along benign lymphoid hyperplasia, infectious inoculation. Skin biopsy is required and systemic sarcoidosis has to be ruled out, even in the absence of systemic symptoms.

Autosomal recessive epidermolysis bullosa simplex due to KRT14 mutation: two large Palestinian families and literature review

c.2542delG might not regulate the severity of skin lesions independently. These findings lead to the possibility that c. 2542delG might be involved in the absence of skin lesions together with other modifying factors. A limitation of this study is that we performed blind skin biopsies from one predisposed area, and we could not perform medical examinations of the father of the patient in case 1 because he did not consent. Although further studies are needed, our report may add new information regarding the genotype– phenotype correlations of the uncommon PXE atypical phenotype.

Management of congenital ichthyoses: European guidelines of care: Part Two

These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016, and a consensus on the discussions. These guidelines summarize evidence and expert‐based recommendations and intend to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part two, covering the management of complications and the particularities of some forms of congenital ichthyosis.

IgA tracheobronchial deposits underlie respiratory compromise in neonatal linear IgA bullous dermatosis

rituximab. B-cell depletion was monitored by circulating CD19+ lymphocyte cell counts on flow cytometry, and patients were considered to have achieved B-cell depletion if absolute CD19+ B-lymphocyte count was <5 cells/mL. All patients were regularly assessed, and the data collected were Pemphigus Disease Activity Index (PDAI) score, lymphocyte subsets, antidesmoglein (Dsg) 1 and 3 antibody titres in patients with PV, while Dsg 1 antibody titre in patient with PS. Results are summarized in Figure 1. Rituximab, a chimeric murine/human anti-CD20 monoclonal IgG antibody, has shown efficacy in the treatment of severe and refractory cases of PV/PS. In the context of pregnancy, its placental passage is low in the first trimester, but may be extensive in the third trimester, and it can deplete fetal B-lymphocyte production, increasing the risk of infection. Complete elimination of rituximab from the bloodstream is expected to occur after 3–6 months. In the literature, a few cases on the use of rituximab during pregnancy have been reported, and there are no controlled trials. Recently, Lake et al reported successful treatment with rituximab and IVIG in two females affected by PV, allowing to discontinue immunosuppressive drugs before and during pregnancy. Also in our cases, we documented a successful pregnancy outcome in three women, two affected by severe PV and one PS, treated with rituximab. In our series, all patients were in remission at the time of conception as determined by PDAI score. All patients conceived after median of 11 months, which makes it unlikely that there was any residual rituximab in their circulation. The two patients affected by PV presented a postpartum flare of disease, with a subsequent long period of remission after rituximab infusion (500 mg). Moreover, we could observe a correspondence between antiDsg titres and clinical outcome, suggesting that the autoantibody level follow-up is worthwhile during pregnancy. Differently, the pregnancy did not worsen the disease in patient with PS; therefore, a long remission was documented. In conclusion, a multidisciplinary approach, stable disease at conception and during pregnancy with very close clinical and anti-Dsg titre monitoring, and the use of drugs compatible with pregnancy should be important goals when the diagnosis of PV/ PS in a fertile woman is made.

Severe osteoarticular involvement in isotretinoin‐triggered acne fulminans: two cases successfully treated with anakinra

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