Deficient Plakophilin-1 Expression Due to a Mutation in PKP1 Causes Ectodermal Dysplasia-Skin Fragility Syndrome in Chesapeake Bay Retriever Dogs

In humans, congenital and hereditary skin diseases associated with epidermal cell-cell separation (acantholysis) are very rare, and spontaneous animal models of these diseases are exceptional. Our objectives are to report a novel congenital acantholytic dermatosis that developed in Chesapeake Bay retriever dogs. Nine affected puppies in four different litters were born to eight closely related clinically normal dogs. The disease transmission was consistent with an autosomal recessive mode of inheritance. Clinical signs occurred immediately after birth with superficial epidermal layers sloughing upon pressure. At three month of age, dogs exhibited recurrent superficial skin sloughing and erosions at areas of friction and mucocutaneous junctions; their coat was also finer than normal and there were patches of partial hair loss. At birth, histopathology revealed severe suprabasal acantholysis, which became less severe with ageing. Electron microscopy demonstrated a reduced number of partially formed desmosomes with detached and aggregated keratin intermediate filaments. Immunostaining for desmosomal adhesion molecules revealed a complete lack of staining for plakophilin-1 and anomalies in the distribution of desmoplakin and keratins 10 and 14. Sequencing revealed a homozygous splice donor site mutation within the first intron of PKP1 resulting in a premature stop codon, thereby explaining the inability to detect plakophilin-1 in the skin. Altogether, the clinical and pathological findings, along with the PKP1 mutation, were consistent with the diagnosis of ectodermal dysplasia-skin fragility syndrome with plakophilin-1 deficiency. This is the first occurrence of ectodermal dysplasia-skin fragility syndrome in an animal species. Controlled mating of carrier dogs would yield puppies that could, in theory, be tested for gene therapy of this rare but severe skin disease of children

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Long-Term Skin Findings İn Patients With Fanconi Anemia After Allogeneic Hematopoietic Stem Cell Transplantation

Long-term skin findings in patients with Fanconi anemia after allogeneic hematopoietic stem cell transplantationWo

A newborn with overlapping features of AEC and EEC syndromes

Item does not contain fulltextEctrodactyly, ectodermal dysplasia, clefting (EEC) syndrome is the prototype of several p63 conditions, which include ankyloblepharon, ectodermal dysplasia, clefting (AEC) syndrome, limb-mammary syndrome (LMS), Rapp-Hodgkin syndrome (RHS), ADULT syndrome, and others. All these disorders include combinations of ectodermal dysplasia, orofacial clefting and limb malformations in variable severity. A newborn patient is presented with diffuse erythematous and desquamating skin lesions and anal atresia. She also had sparse and lightly colored thin hair, deeply set eyes, hypoplastic alae nasi, and a short philtrum. Cleft lip/palate and ankyloblepharon were not present. Complete cutaneous syndactyly was present on both hands in between the third and fourth fingers. Mild ectrodactyly was evident on all four extremities in between first and second digits. There was post-axial polydactyly on both feet. Anal atresia was present and defecation occurred through a rectovaginal fistula. The patient represented an interesting overlapping clinical condition between AEC and EEC syndromes. Diffuse skin lesions with excoriation and desquamation suggest AEC syndrome, despite the absence of ankyloblepharon, however; ectrodactyly and polydactyly strongly suggest the EEC syndrome. C308Y mutation in exon 8 of TP63 gene was detected, which was previously described to lead only to EEC syndrome and not to any of the other allelic conditions. These data emphasize the large degree of clinical variability that may be seen for specific TP63 mutations. (c) 2011 Wiley Periodicals, Inc