Segmental neurofibromatosis 1 (SNF1) is a rare genodermatosis caused by somatic mutations in the NF1 gene. It consists of localized characteristic pigmentary lesions (i.e. café-au-lait spots and ...freckling) and/or neurofibromas intermingled with areas of unaffected skin, often configuring specific mosaic patterns. Oculo-auriculo-vertebral spectrum (OAVS) is a developmental field defect primarily affecting the 1st and 2nd branchial arch derivatives. This condition recognizes a wide range of environmental and genetic causes, including postzygotic mutations. We report on a 24-year-old female presenting with a constellation of features fitting both with SNF1 and OAVS. Neurofibromatosis 1 pigmentary lesions are confined to the left arm and adjacent trunk skin surface with sharp midline demarcation. OAVS characteristic craniofacial anomalies, including neurosensorial hearing loss, hemimandibular and tongue underdevelopment, are homolateral to the SNF1 features. Additional findings, such as prearicular tags and multiple costo-vertebral segmentation defects, mainly involving the cervical and upper thoracic metameres, support the diagnosis of OAVS. To our knowledge, this is the first published patient who presents with an association of SNF1 and OAVS. The spatial relationship between craniofacial and skin pigmentary anomalies has prompted us to speculate about the possible underlying pathogenetic mechanism (s).
Recent studies suggest that skin keratinocytes from patients with atopic dermatitis (AD) and nonatopic subjects differ in their intrinsic ability to respond to proinflammatory stimuli. In this study ...keratinocyte cultures established from the normal-looking skin of six adult patients with AD and six healthy, nonatopic control subjects were compared in their response to interferon (IFN)-γ, a potent proinflammatory lymphokine whose expression is increased in chronic AD lesions. Basal expression of IFN-γ receptor as well as IFN-γ–induced membrane expression of HLA-DR and intercellular adhesion molecule (ICAM)-1 were evaluated by flow cytometry. Keratinocyte release of IL-1α, IL-1 receptor antagonist (IL-1ra), granulocyte-macrophage colony stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-α were measured by ELISA on culture supernatants after treatment with IFN-γ or medium alone. Expression of membrane IFN-γ receptor was similar in keratinocytes cultured from nonatopic subjects and subjects with AD. IFN-γ (10 to 500 U/ml) induced comparable levels of membrane HLA-DR and ICAM-1 in both groups of keratinocytes. In contrast, spontaneous release of IL-1α, IL-1ra, GM-CSF, and TNF-α was increased in the supernatants of unstimulated keratinocytes from patients with AD compared with keratinocytes from control subjects, with IL-1ra and GM-CSF reaching statistically significant difference. Moreover, IFN-γ–induced release of all the cytokines tested was much higher for keratinocytes from patients with AD, but the IL-1ra/IL-1α ratio for the two groups of keratinocytes was not substantially different, either basally or after IFN-γ stimulation. The results indicate that keratinocytes from patients with AD are hyperresponsive to IFN-γ in terms of cytokine release.
Acne fulminans following isotretinoin therapy Didona, Dario; Paolino, Giovanni; Cantisani, Carmen ...
Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia,
02/2019, Volume:
154, Issue:
1
Journal Article
In this study we describe six Italian patients presenting an unusually mild variant of non-Herlitz junctional epidermolysis bullosa associated with a reduced expression of type XVII collagen. All ...patients are homozygous for a novel nonsense mutation (R795X) within exon 33 of COL17A1 and show a common haplotype, attesting propagation of an ancestral allele within the Italian population. Analysis of patients' COL17A1 transcripts showed the presence of two mRNA species: a normal-sized mRNA carrying mutation R795X that undergoes rapid decay, and a transcript generated by in-frame skipping of exon 33. Patients keratinocytes were shown to synthesize minute amounts of type XVII collagen, which appeared correctly localized along the cutaneous basement membrane. We therefore suggest that the exon 33-deleted COL17A1 splice variant encodes for type XVII collagen molecules that maintain a functional role and account for the mild phenotype of our patients.
Molecular analysis of p53 and patched (PTCH), two candidate tumor suppressor genes for non-melanocytic skin cancer, was performed in skin tumors from six patients affected by the cancer-prone disease ...xeroderma pigmentosum (XP). UV-specific p53 mutations were detected at a frequency of 38-50% in all the tumor types analysed, including melanomas. Additional analysis of PTCH mutations in the subset of eight basal call carcinomas (BCC) revealed a very high mutation frequency of this gene (90%) which exceeded that detected in the p53 gene in the same tumors (38%). PTCH mutations were predominantly UV-specific C>T transitions. This mutation pattern is different from that reported in BCC from normal donors where PTCH mutation frequency is 27% and mutations are frequently deletions and insertions. These findings suggest that PTCH mutations represent an earlier event in BCC development than p53 alterations and that the inability of XP patients to repair UV-induced PTCH mutations might significantly contribute to the early and frequent appearance of BCC observed in these patients.
Palmoplantar keratodermas are a group of heterogeneous diseases characterized by thickening, and marked hyperkeratosis, of the epidermis of the palms and soles. Palmoplantar keratodermas can be ...divided into four major classes: diffuse, focal, punctate, and palmoplantar ectodermal dysplasias. All forms are genetic diseases inherited as autosomal dominant disorders. We studied a patient exhibiting a localized thickening of the skin in parts of the right palm and the right sole, following Blaschko's lines, that does not fit into any classes already described. We sequenced the keratin 16 cDNA derived from skin biopsy material from affected and non affected palms. The keratin 16 cDNA sequence from lesional epidermis showed a 12 base pair deletion (309–320del), which deletes codons 104–107. The mutation is predicted to delete four amino acids, GGFA, from the V1 domain of the keratin 16 polypeptide, close to the 1A domain. Full-length keratin 16 cDNA sequence derived from the unaffected palm was completely normal, consistent with a postzygotic mutation as is suggested by the mosaicism observed. We defined this new clinical entity, ‘‘unilateral palmoplantar verrucous nevus’', rather than localized or focal epidermolytic palmoplantar keratodermas, as the lesions are present only on one side of the body and follow Blaschko's lines. This study is a report of a mosaic mutation in keratin 16 and also the association of a mutation in the V1 domain of a type I keratin associated with a human disease.
We created a relational database of patients with cutaneous T-cell lymphoma (CTCL) to collect in a standardised fashion, anagraphic variables, clinical history, clinical, histological, ...haematological, and immunological information on CTCL patients hospitalised at IDI-IRCCS, Rome, Italy. At present, there are data on 424 patients, hospitalised from 1983 to July 2005. Active follow-up is performed yearly to ensure a standardised ascertainment of survival time. For deceased patients, the actual date of death (for all causes) is recorded, while surviving patients are censored at the date of last contact.
The database includes 29 patients with Sezary syndrome (SS). Follow-up times ranged from 0 to 105 months. At first hospitalisation the median values of cells/mL were: white blood cells (WBC) 8750, neutrophils 4250, eosinophils 140, basophils 120, lymphocytes 2760, monocytes 500, CD3+ 2780, CD4+ 2431, CD8+ 192, CD19+ 96. Seventeen patients were deceased. We included in the Kaplan-Meier survival analysis only patients who were diagnosed before July 2004 (n=26). Median survival time from diagnosis was 52 months. No significant differences were observed in mortality for WBC (cutoff 9000 cells/uL), neutrophils (cutoff 4500 cells/uL), basophils (cutoff 200 cells/uL), lymphocytes (cutoff 3000 cells/uL), monocytes (cutoff 500 cells/uL), CD3+ (cutoff 2000 cells/uL), CD4+ (cutoff 2000 cells/uL), CD8+ (cutoff 200 cells/uL), CD19+ (cutoff 70 cells/uL). A lower survival was observed for patients with eosinophils <200 cells/uL (p=.08).
Survival in patients with SS does not seem to be influenced by haemathologic parameters. However, patients with long-term survival (>90 months) are observed, and their characteristics should be further investigated.
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Treatment of pemphigus vulgaris can be challenging. Systemic steroids associated with other immunosuppressant agents are the mainstay of therapy and have dramatically reduced morbidity and mortality ...from pemphigus vulgaris. In some patients, however, these agents are not able to control the disease or have severe adverse effects. Rituximab (MabThera; Roche, Basel, Switzerland), a chimeric monoclonal anti-CD20 antibody, induces depletion of B cells in vivo and has shown efficacy in patients with refractory antibody-mediated autoimmune disorders. We report 10 cases of pemphigus vulgaris and 2 cases of pemphigus foliaceous treated with rituximab--to our knowledge the largest series of patients so far--and review the existing literature on the topic.
The 12 patients were selected for treatment with the anti-CD20 antibody. Rituximab was administered intravenously at a dosage of 375 mg/m(2) once weekly for 4 weeks. The treatment was well tolerated, and all 12 patients showed a good clinical response during an 18-month follow-up period, along with a consensual decline of the serum antidesmoglein titers. No infectious complications were observed.
Rituximab is able to induce a prolonged clinical remission in patients with both pemphigus vulgaris and pemphigus foliaceous after a single course of 4 treatments. The preliminary experiences worldwide make rituximab a promising therapeutic option for patients with autoimmune diseases. The high costs and the limited knowledge of long-term adverse effects, however, limit its use to selected patients with treatment-resistant or life-threatening disease.
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