In vivo and in vitro evidence for an association between the route-specific transmission of HHV-8 and the virus genotype.

The study was performed to determine if there is an association between the genotype and transmission of HHV-8 types A and C. These HHV-8 subtypes are prevalent in the area of North of Sardinia, which is an island off west Italy's mainland that has a high HHV-8 seroprevalence (35%). Blood and saliva samples from 30 patients with classic Kaposi's sarcoma who were lifetime residents of North Sardinia were analyzed to identify the HHV-8 genotype and quantitate the viral load. Genotype A, especially A1 subtype, was found more frequently (9/30 patients) and had a significantly higher viral load in saliva compared to blood (P = 0.029), where type C was found more frequently but with a viral load lower than 10(3) copies/ml. To determine if there is a correlation between the viral genotype and cellular tropism, type A1 and C3 HHV-8 viral particles were obtained from cell lines BCBL1 and BC3 infected chronically with HHV-8 A1 and C3 genotypes respectively and used to infect HEK293 epithelial origin cells and PBMCs in vitro. The data indicate that the A1 HHV-8 genotype is tropic and replicates at higher levels in the epithelial cell lines.

COL7A1 Recessive mutations in two siblings with distinct subtypes of dystrophic epidermolysis bullosa: pruriginosa versus nails only.

Dystrophic epidermolysis bullosa (DEB) is a rare, clinically heterogeneous, blistering genodermatosis inherited as either autosomal dominant or recessive trait. All DEB forms are caused by mutations in the COL7A1 gene, which encodes for type VII collagen, the major component of the anchoring fibrils ensuring epithelial-mesenchymal adhesion. Major determinants of clinical heterogeneity in DEB are COL7A1 mutation types and their consequences at mRNA and protein levels; nevertheless, siblings with the same genetic alterations can manifest highly variable clinical signs. Here, we report novel compound heterozygous recessive COL7A1 missense mutations in 2 siblings presenting different DEB clinical subtypes. Our findings document the rare occurrence of recessive inheritance for the nails only DEB variant and emphasize the role of acquired phenotype-modifying factors in DEB pruriginosa pathogenesis.

Environmental factors influence the rate of human herpesvirus type 8 infection in a population with high incidence of classic Kaposi sarcoma.

High prevalence of human herpesvirus type 8 (HHV-8) infection has been reported on the island of Sardinia. Among emigrants from Sardinia, rates of HHV-8 infection are lower than they are in Sardinia and are similar to those observed in the local population. Thus, environmental factors seem to play a relevant role in affecting the prevalence of HHV-8 infection.

Classic Kaposi sarcoma in northern Sardinia: a prospective epidemiologic overview (1977-2003) correlated with malaria prevalence (1934).

BACKGROUND: Studies have demonstrated considerable variations in classic Kaposi sarcoma (CKS) incidence within Europe, with some of the highest incidences found in the Mediterranean area. As a Mediterranean area, northern Sardinia has a high CKS frequency. OBJECTIVE: In order to determine CKS incidence in people born in and residing in northern Sardinia, a clinical prospective epidemiologic study was carried out between 1977 and 2003 by the Department of Dermatology, University of Sassari. We also evaluated a correlation between malaria prevalence in 1934, estimated on the eight historical sub-areas of the Sassari province, and the standardized morbidity ratio from 1977 to 2003. RESULTS: A total of 332 patients with CKS were identified. Incidence among the northern Sardinian population > or =40 years of age was 4.06/100,000 persons/year and it was almost stable through the years. The male to female ratio showed a significant decline from 3.6 to 2.5 (P = .03). Females had a statistically decreased risk of developing CKS compared to males (adjusted incidence rate ratio = 0.27; 95% CI: 0.21-0.34), and the risk of developing CKS increased exponentially with age. The prevalence of malaria in each sub-area ranged from 9% to 91%. The standardized morbidity ratio for CKS in the years between 1977 and 2003 ranged from 0.27 to 1.76; the regression coefficient was -0.85 (95% CI: -2.94-1.24), yielding a nonsignificant relationship between the two diseases. LIMITATIONS: These results were obtained from patients with CKS in northern Sardinia and may not be applicable to other populations. CONCLUSIONS: The northern Sardinian population consistently has a very high incidence of CKS, while in our data, the correlation between malaria and CKS remains open to question.

Skin vasculitis during Creutzfeldt-Jakob's disease.

We report the case of a 72-year-old woman with sporadic Creutzfeldt-Jakob's disease who presented a large purplish erythematous and edematous lesion, with subsequent bullous detachment on the anterior right thigh. The lesion rapidly evolved into an ulcer covered by a blackish necrotic eschar. Histological examination showed intense necrotizing leukocytoclastic vasculitis in the deep and middle dermis. Direct immunofluorescence revealed C3 and IgM deposits around vessels of the middle and deep dermis. The diagnosis of sporadic Creutzfeldt-Jacob's was confirmed post-mortem by immunoblotting on frozen brain tissue which showed pathologic proteinase-resistant prion-related protein isoform glycotype 2A. In the literature, only two cases of Creutzfeldt-Jakob's disease and cutaneous manifestations are reported.

Antiphospholipid syndrome with subsequent chronic discoid lupus erythematosus: a case report.

Antiphospholipid syndrome is an immune-mediated acquired disorder characterized by vein and/or artery thromboses and obstetrical complications associated with the presence of antiphospholipid antibodies in the blood. aPL include anticardiolipin antibodies (aCL), antiß2glycoproteinI (antiß2GPI), and lupus anticoagulant (LAC). A primitive idiopathic form and a secondary form of APS are recognized. The latter, observed mostly in patients affected by systemic lupus erythmatosus (SLE), has been described in numerous other autoimmune diseases. The association between CDLE and APS in not frequent. Indeed, although the literature contains several reports of CDLE patients positive for aPL, only two of these present sufficient clinical and laboratory characteristics for a diagnosis of APS..We present a case of APS and CDLE present contemporaneously in the patient. In our case, CDLE arose after the diagnosis of APS. Therefore, ours constitutes the first case of CDLE in an APS-diagnosed patient.

Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome in the context of inherited lipodystrophies.

BACKGROUND: Lipodystrophies are a large heterogeneous group of genetic or acquired disorders characterized by generalized or partial fat loss, usually associated with metabolic complications such as diabetes mellitus, hypertriglyceridemia and hepatic steatosis. Many efforts have been made in the last years in identifying the genetic etiologies of several lipodystrophy forms, although some remain to be elucidated. METHODS: We report here the clinical description of a woman with a rare severe lipodystrophic and progeroid syndrome associated with hypertriglyceridemia and diabetes whose genetic bases have been clarified through whole-exome sequencing (WES) analysis. RESULTS: This article reports the 5th MDPL (Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome) patient with the same de novo p.S605del mutation in POLD1. We provided further genetic evidence that this is a disease-causing mutation along with a plausible molecular mechanism responsible for this recurring event. Moreover we overviewed the current classification of the inherited forms of lipodystrophy, along with their underlying molecular basis. CONCLUSIONS: Progress in the identification of lipodystrophy genes will help in better understanding the role of the pathways involved in the complex physiology of fat. This will lead to new targets towards develop innovative therapeutic strategies for treating the disorder and its metabolic complications, as well as more common forms of adipose tissue redistribution as observed in the metabolic syndrome and type 2 diabetes.

High rate of human herpesvirus-8 seroprevalence in thalassemic patients in Italy.

BACKGROUND: The potential risk of acquiring infection by the novel human herpesvirus-8 (HHV-8) through blood derivatives is still debated. OBJECTIVES: In the present study, we determined HHV-8 seroprevalence in beta-thalassemic patients living in Italy. STUDY DESIGN: We have analysed 86 patients from Sardinia, an island characterised by a high diffusion of HHV-8, as well as 33 thalassemics from the area of Rome, where a lower rate of HHV-8 infection has been reported. These data have been compared with HHV-8 seroprevalence found in healthy controls living in the same areas of the assayed patients. RESULTS AND CONCLUSIONS: A three-fold increase in HHV-8 seroprevalence was found among thalassemic patients when compared to control groups taken from the same regions (17.6% versus 5.1%). This risk factor was statistically significant when considering the Sardinians alone (P = 0.01) and the entire population analysed in the present survey (P = 0.0006). In the Roman area also an increased seroprevalence in thalassemic subjects was found (12.1% versus 4.6%) but it was not statistically significant (P = 0.2). HHV-8 is sporadically present in the blood of healthy individuals and it is unknown whether the virus eventually present in donors' blood is completely cleared by the treatments which blood undergoes before red cells are transfused. Based on these considerations, we hypothesise that multiply transfused subjects living in areas at high HHV-8 prevalence present an increased risk of being infected.

CD4+ and CD8+ T-cell skewness in classic Kaposi sarcoma.

It is widely accepted that a deranged immune system plays a key role in the onset and evolution of classic Kaposi sarcoma (CKS). Nevertheless, the usage of the T-cell receptor (TCR) ß-variable (BV) chain repertoire expressed by peripheral blood lymphocytes in patients with CKS is still unknown. With the aim of providing some further insights into the complex role of the immune system in CKS pathogenesis, we performed an extensive analysis of the TCR BV repertoire in both CD4(+) and CD8(+) T cells in 30 human herpesvirus 8-positive Sardinian patients with CKS and an equal number of age-matched healthy controls. We used a panel of monoclonal antibodies covering approximately 70% of human BV subfamilies and third complementarity determining region (CDR3) spectratyping. Patients with CKS showed an increased frequency of BV expansions in both CD4(+) and CD8(+) lymphocytes, with no prevalent clones. On spectratyping analysis, most of the 720 BV CDR3 profiles obtained from both CD4(+) and CD8(+) T cells in patients with CKS were skewed. In particular, the surprising increase of BV skewing observed in CD4(+) lymphocytes mimics the pattern of progressive TCR BV narrowing described in responses to persistent viral antigen stimulations. Our findings support the hypothesis that CKS evolution is associated with inadequate activation rather than impairment of the immune system.

Keratitis-Ichthyosis-Deafness Syndrome, Atypical Connexin GJB2 Gene Mutation, and Peripheral T-Cell Lymphoma: More Than a Random Association?

Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital disorder characterized by skin lesions, neurosensorial hypoacusia, and keratitis, usually due to the c.148G → A mutation involving the connexin 26 gene. We report on a KID patient who showed the atypical c.101T → C mutation and developed a T-cell lymphoma so far never described in this group of patients.

Classic Kaposi's sarcoma in Sardinia: HLA positive and negative associations.

BACKGROUND: The incidence of classic Kaposi's sarcoma (CKS) in northern Sardinia is one of the highest in the world. METHODS: Sixty-two patients with CKS were typed for class I and class II antigens. All patients had been born and were living in northern Sardinia. RESULTS: In the Sardinian patients, we observed a positive CKS association with Cw7, DRB1*1104, DRB1*1302, DQA1*0302, and DQB1*0604, and a negative CKS association with A30, B58, Cw5, DRB1*1601, and DQB1*0502. CONCLUSIONS: The strong positive CKS association with DRB1*1104 and DQB1*0604 and negative association with B58 are particularly significant and further support the notion of a genetic predisposition to CKS.

Follicular spicules and multiple ulcers: cutaneous manifestations of multiple myeloma.

We describe 2 patients with multiple myeloma who had horn-like filiform spicules in the follicular orifices of the face, particularly on the nowe, and multiple small ulcerations on the trunk. In the first patient, histopathologic study of a specimen from the nose showed follicular plugs of compact homogeneous eosinophilic material filling the intercellular spaces surrounding the keratinocytes. The same eosinophilic deposits were seen in the ulcer. In the second patient, biochemical investigation revealed that skin matter from spicules and ulcers were made up of monoclonal dysprotein with electrophoretic characteristics identical to those found in patient serum.