Anna Zampetti

Angiokeratoma: Decision-making aid for the diagnosis of Fabry disease

Isolated angiokeratomas are common benign cutaneous lesions, generally deemed unworthy of further investigation. In contrast, diffuse angiokeratomas should alert the physician to a possible diagnosis of Fabry disease, a rare X‐linked lysosomal storage disorder, characterized by α‐galactosidase deficiency. Glycosphingolipids accumulate in cells throughout the body resulting in progressive multi‐organ failure. Difficulties are encountered when trying to interpret the significance of angiokeratomas because they may also occur in other lysosomal storage disorders and rarely in an isolated manner in Fabry disease. We present an algorithm for the classification of angiokeratomas which might prove useful for the diagnosis and management of Fabry disease. Assessment of the clinical features and location of the lesions, personal and family history, skin biopsy, dermoscopy and electron microscopy imaging are sequential steps in the diagnostic process. Assessing the deficiency of α‐galactosidase enzyme activity is essential to confirm the diagnosis in males, while mutation analysis is always needed in females. Potentially this algorithm can change the current approach to patients when Fabry disease is suspected, thus improving the diagnostic strategy and management of this disorder. It remains to be decided whether the use of an algorithm might reduce the number of genetic consultations. As evidence has shown the efficacy of enzyme replacement therapy in halting progression of the disease before the onset of irreversible organ damage, it is advisable to aim at an early diagnosis in order to achieve timely initiation of effective treatment with benefits for patients and appropriate use of medical resources.

Polymerase chain reaction-reverse cross-blot hybridization assay in the diagnosis of sporotrichoid Mycobacterium marinum infection

In this paper, we report a patient in whom Mycobacterium marinum sporotrichoid infection was diagnosed using polymerase chain reaction (PCR) amplification of the 16S rRNA gene and subsequent analysis of the amplified product in a reverse cross‐blot hybridization assay with mycobacterial species‐specific probes. This molecular method allowed us rapidly to detect and identify this organism directly in the patients lesional skin biopsy rather than in cultures in conventional media. The identification provided by PCR–reverse cross‐blot hybridization assay was confirmed by examination of the morphological and biochemical features and by high‐performance liquid chromatography analysis of mycolic acid from the clinical isolate, suggesting the validity of our molecular approach.

Acquired Epidermodysplasia Verruciformis: A Comprehensive Review and a Proposal for Treatment

BACKGROUND Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by immunologic abnormalities, disseminated human papilloma virus infection, and early development of skin cancers. Acquired forms have been rarely reported and usually occur with immunosuppression. The therapeutic management of the acquired forms is not standardized, and several therapies have been tried, with variable outcomes. OBJECTIVES To provide updated clinical and experimental information on the treatment of acquired EV. METHODS A Medline literature search was performed for relevant Medical Subject Heading terms, reviewing publications on strategies for management of acquired EV. We also report a case successfully treated using a combination of photodynamic therapy and oral retinoids. CONCLUSION Data from the literature show that a standardized approach to this condition is lacking; the combination treatment chosen in our case may be proposed because it led to an excellent clinical outcome and a long‐lasting remission.

Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene

Ferri L, Guido C, la Marca G, Malvagia S, Cavicchi C, Fiumara A, Barone R, Parini R, Antuzzi D, Feliciani C, Zampetti A, Manna R, Giglio S, Della Valle CM, Wu X, Valenzano KJ, Benjamin ER, Donati MA, Guerrini R, Genuardi M, Morrone A. Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene.

Onset of lichen planopilaris during treatment with etanercept.

1 EMEA Committee for Proprietary Medicinal Products (CPMP). Note for Guidance on Clinical Investigation of Medicinal Products Indicated for the Treatment of Psoriasis. CPMP ⁄EWP ⁄2454 ⁄02. London: EMEA, 2004. 2 LABAG. Landelijk beoordelingsinstituut voor aanvragen groeihormoon en biologicals voor reumatologische en dermatologische indicaties. Home page at http://www.labag.nl/ (last accessed 13 January 2008). 3 Nijsten T, Lambert J. Dermatologists’ views and opinions about photo(chemo)therapy and conventional systemic psoriasis therapies: results from a Belgian survey. Dermatology 2006; 213:123–33. 4 Nijsten TE, Stern RS. The increased risk of skin cancer is persistent after discontinuation of psoralen + ultraviolet A: a cohort study. J Invest Dermatol 2003; 121:252–8. 5 Lim JL, Stern RS. High levels of ultraviolet B exposure increase the risk of non-melanoma skin cancer in psoralen and ultraviolet Atreated patients. J Invest Dermatol 2005; 124:505–13. 6 Marcil I, Stern RS. Squamous-cell cancer of the skin in patients given PUVA and ciclosporin: nested cohort crossover study. Lancet 2001; 358:1042–5. 7 Paul CF, Ho VC, McGeown C et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study. J Invest Dermatol 2003; 120:211–16.

Tannic acid induces in vitro acantholysis of keratinocytes via IL-1alpha and TNF-alpha.

The mechanism of acantholysis in pemphigus vulgaris (PV) is an intriguing argument since several chemical mediators are implicated. We previously reported a central role for IL-1α and TNF-α, both able to regulate complement activation and plasminogen activators. Very little is known about what triggers the disease (drugs, viruses or food). In this study, we evaluate the molecular role of tannins in acantholysis. By HPLC chromatography we measured tannic acid (TA) and gallic acid (GA) in blister fluid of 4 groups of patients divided according to their dietary habits, including a regular diet, a diet rich in tannins, a diet free of tannins, and a group of pemphigus patients. Blister fluid was obtained from patients using a suction blister apparatus. We show that people with a diet rich in tannins have increased tannin metabolites (TA and GA) in the skin in respect to controls (tannin-rich diet: GA = 194.52±2.39 nmol/ml; TA = 348.28±1.4 nmol/ml versus tannin-Mediterranean diet: GA = 15.28±1.63 nmol/ml; TA = 22.81±1.68 nmol/ml). PV patients showed similar values to the Mediterranean diet population (PV patients: GA = 95.8±1.97 nmol/ml; TA = 199.09±4.15 nmol/ml versus Mediterranean diet: GA = 83.53±2.35 nmol/ml; TA = 195.1±2.50 nmol/ml). In an in vitro acantholysis system using TA and PV-IgG we show that TA 0.1 mM in NHEK culture is able to induce acantholysis. This effect was able to amplify the acantholytic action of PV-IgG in vitro. A blocking study using anti IL-1α and anti TNF-α antibodies showed a reduction in TA-induced acantholysis. Taken together, these results suggest that a diet rich in tannins could be a trigger in genetically predisposed patients. If these data are confirmed, a complementary diet poor in tannins may be useful in patients affected by PV.

Exacerbation of pemphigus after influenza vaccination.

Pemphigus is a rare autoimmune disease characterized by flaccid blisters and erosions on skin and mucous epithelia. A critical event in its pathogenesis is production of antidesmoglein antibodies, which mediate the loss of intercellular adhesion in epithelia, leading to blister formation. Multiple environmental factors (ultraviolet radiation, trauma, drugs, infective agents) have been suggested as possible triggers of pemphigus. Occasionally, the disease has been reported to follow viral and bacterial vaccination. We describe a patient who experienced exacerbation of pemphigus shortly after administration of the influenza vaccination on two separate occasions. We review the literature, suggest possible explanations for a causal relationship, and discuss the administration of vaccination to these patients.

Alteration of Cholinergic System in Keratinocytes Cells Produces Acantholysis: A Possible Use of Cholinergic Drugs in Pemphigus Vulgaris

Human epidermis shows a non-neuronal cholinergic system including keratinocyte (kc) acetylcholine (Ach) axis which is composed by enzymes and two families of Ach receptors (muscarinic and nicotinic receptors). The activity of these two receptors can regulate the interkeratinocytes and kcs-extracellular matrix adhesion modifying the regulation of intercellular adhesion molecules like cadherins and integrins. Some authors demonstrate that acantholysis in pemphigus depends not only on anti desmogleins antibodies (abs) (mostly IgG) but even on other abs directed against kc membrane antigens (e.g. anti Ach receptors Abs). In the early phase of pemphigus pathogenesis, anti Ach receptors Abs block Ach signaling essential for cell shape and intercellular adhesion and increase the phosphorylation of adhesion molecules. Combined with the action of abs antidesmogleins, anti Ach receptors Abs cause the acantholytic phenomenon. In vitro experiments show that high doses of Ach in acantholytic kcs can rapidly reverse this pathologic event. In vivo experiments using neonatal mice model of Pemphigus have demonstrated that cholinergic agonists reduce these lesions. Therapy with pyridostigmine bromide and Nicotinamide per os or pilocarpine used topically, drugs that present cholinomimetic effects, has lead to encouraging results in patients affected by Pemphigus disease. Cholinergic agents could have a strategic role in the therapy of pemphigus since they could be responsible for the early stage of acantholytic diseases.

Dysplastic nevi, cutaneous melanoma, and other skin neoplasms in patients with myotonic dystrophy type 1: A cross-sectional study

BACKGROUND Myotonic dystrophy type 1 (MD1) is reported to be associated with internal malignancies. The association of myotonic dystrophy with cutaneous tumors is not fully understood. OBJECTIVE We sought to explore the total nevi count and the presence of atypical nevi, cutaneous melanoma, and other skin neoplasms in a representative cohort of patients with MD1 and to compare the findings with age- and sex-matched control subjects. METHODS In all, 90 patients with MD1 and 103 age- and sex-matched control subjects were assessed for cutaneous neoplasms by clinical skin and epiluminescence examination (dermoscopy). Where indicated, subsequent excisions were performed. In patients with MD1, leukocyte n(CTG) expansion was measured. RESULTS Patients with MD1 showed significantly higher numbers of nevi, dysplastic nevi, and melanomas despite a significantly greater proportion of the control subjects reporting sunburns. In addition, we found a significantly greater number of pilomatrixoma in patients with MD1. LIMITATIONS Our study is limited by the fact that there is no agreed-upon standardized technique to assess for prior sun exposure. Further research in the association of cutaneous neoplasms and MD1 including vitamin D and molecular biological techniques are also recommended. CONCLUSION MD1 itself may predispose to development of skin tumors.

Serum interleukin-18 in children with Henoch-Schonlein purpura: a promising marker of disease activity?

Henoch-Schönlein purpura (HSp) is the most common systemic vasculitis of childhood with typical skin involvement and concurrent signs involving joints, gastrointestinal tract, and kidney. HSp pathogenesis is still far from being completely understood, though a knotty cytokine complex is believed to contribute to its intimate processes. The aim of our evaluation is to establish the relationship between serum levels of interleukin (IL)-18 and disease outcome and establish its feasibility to provide a marker of disease activity or even a prognostic tool in clinical practice. We examined clinical/laboratory variables and serum IL-18 in 17 children hospitalized during a year for HSp, diagnosed by EULAR/PRINTO/PRES criteria; the same patients were re-evaluated after 6 months. All results were compared with 25 age-matched healthy controls. IL-12 and IL-6 were also evaluated in a cohort of the same patients and compared with controls. General and clinical variables (sex, edema of the extremities, gastrointestinal or renal complications, relapses and renal involvement at 6 months) had no relationship with cytokine levels. Serum IL-18 and IL-6 levels were found significantly increased at diagnosis in HSp patients when compared with healthy controls. After 6 months, serum IL-18 and IL-12 levels were significantly decreased in patients, while IL-12 and IL-6 levels were significantly increased compared to healthy controls. Though preliminary and expecting further confirmation on a larger sample, our data support the conclusion that serum IL-18 levels reflect HSp activity.