1/6. Non-Herlitz junctional epidermolysis bullosa without hair involvement associated with BP180 deficiency.Junctional epidermolysis bullosa (JEB) is a clinically and genetically heterogeneous recessively inherited blistering disease of the skin and mucous membranes due to impaired epithelial adhesion. In particular, defective expression of the 180-kD bullous pemphigoid antigen (BP180) has been correlated to a non-lethal (non-Herlitz) form of JEB, generalized atrophic benign epidermolysis bullosa (GABEB), characterized by widespread skin blistering healing with atrophy and by atrophic alopecia with onset in childhood. We report the case of a 33-year-old man suffering from a generalized blistering skin disorder since birth. He also presented nail dystrophy and tooth abnormalities. Mucosal involvement was limited to gingival erosion. alopecia was absent and body, axillary and pubic hair were normal. Immunofluorescence analysis showed a markedly reduced expression of BP180, electron microscopy studies evidenced hypoplastic hemidesmosomes and Northern blot analysis confirmed a striking decrease in the amount of BP180 mRNA. The clinical features of our patient confirm that BP180 deficiency usually results in a non-Herlitz JEB form. However, the degree of skin, mucous membranes and hair involvement appears more variable and less typical than originally described for GABEB.- - - - - - - - - - ranking = 1keywords = suffering (Clic here for more details about this article) |
2/6. Junctional epidermolysis bullosa gravis (Herlitz): diagnostic and genetic aspects.We report on a boy suffering from lethal junctional epidermolysis bullosa gravis (JEBH) (Herlitz-type) (OMIM 226700). Screening for mutations of LAMB3 gene with polymerase chain reaction (PCR) amplification of all exons from genomic dna and subsequent heteroduplex analysis and dideoxynucleotide sequencing of heteroduplex forming PCR products disclosed two mutations: the recurrent maternal mutation R635X and the novel paternal mutation 1629insG, both in exon 14 of LAMB3. Both mutations lead to a premature termination code, non-sense mediated mRNA decay and to absence of the synthesis of the beta3 chain of laminin 5. During the mutation screening of the index patient a second pregnancy was ascertained. After amniocentesis (14 1 week of pregnancy), prenatal diagnosis from fetal cells was performed and compound heterozygosity for both mutations was evident. The consultants decided to have a termination of pregnancy shortly after the diagnosis. Remarkable skin fragility of the fetus was evident by clinical examination. Complete absence of laminin 5 could be demonstrated by immunofluorescence staining. By the third pregnancy of this couple so far screened for mutations by chorionic villus sampling for prenatal molecular diagnosis a healthy but heterozygous child is expected.- - - - - - - - - - ranking = 1keywords = suffering (Clic here for more details about this article) |
3/6. Squamous cell carcinoma in junctional and dystrophic epidermolysis bullosa.We report here on three patients suffering from recessive dystrophic epidermolysis bullosa and one suffering from generalized atrophic benign epidermolysis bullosa, all of whom developed cutaneous squamous cell carcinoma. Our observations and a review of the literature suggest that squamous cell carcinoma in generalized atrophic benign epidermolysis bullosa is very infrequent and has a better outcome compared to skin cancer in recessive dystrophic epidermolysis bullosa. These differences could be explained by the distinct pathophysiology and clinical course of each of these variants of epidermolysis bullosa. In contrast to UV-induced skin cancer, the tumours in epidermolysis bullosa develop on distal extremities at sites of chronic wound healing. The cases reported here underline the exceptional importance of early histopathological assessment of suspicious skin lesions in patients with epidermolysis bullosa.- - - - - - - - - - ranking = 2keywords = suffering (Clic here for more details about this article) |
4/6. Genetic bases of severe junctional epidermolysis bullosa presenting spontaneous amelioration with aging.Change of the clinical picture with aging is noted in some patients suffering from junctional epidermolysis bullosa (JEB), an inherited blistering disorder caused by extensive disadhesion of the epithelia. We have studied a patient born with severe JEB associated with absent expression of laminin 5. A remarkable reduction of the blistering tendency was observed with aging that correlated with a restored expression of immunoreactive laminin 5 molecules. Genetic analysis of the gene LAMB3 detected compound heterozygosity for the nonsense mutation R635X and a novel 2 bp deletion (1587delAG) resulting in a downstream premature termination codon. RT-PCR amplification of total rna purified from skin biopsies demonstrated that the mutated beta3 mRNAs underwent rapid decay shortly after birth, and that illegitimate splicing of the mRNA carrying mutation 1587delAG generated a new internally shortened beta3 transcript with advancing age. Our genetic and biochemical data show that (i) the illegitimate splicing of the beta3 pre-mRNA results in synthesis and secretion of a laminin 5 heterotrimer with an internally deleted beta3 polypeptide, (ii) expression of the mutated beta3 polypeptide is up-regulated in the basal keratinocytes with high proliferative potential, (iii) absence of the N-terminal region of the beta3 rod domain II thought to stabilize the tertiary structure of the laminin 5 is not required for the assembly of the protein and (iv) the mutant laminin 5 retains its adhesive potential. Our results demonstrate that mRNA rescue may underlie the evolution of the clinical phenotype in inherited skin conditions.- - - - - - - - - - ranking = 1keywords = suffering (Clic here for more details about this article) |
5/6. Analysis of the LAMB3 gene in a junctional epidermolysis bullosa patient reveals exonic splicing and allele-specific nonsense-mediated mRNA decay.How splicing, the process of intron removal in pre-messenger rna (mRNA), is carried out with such fidelity in human cells is still not understood, although some general rules are being proposed mainly by in vitro experiments. These rules are currently being redefined by analysis of splicing mechanisms in patients presenting splicing defects. We analysed material of a patient suffering from junctional epidermolysis bullosa, a heritable blistering skin disease. Absence of laminin-5 protein together with hypoplastic hemidesmosomes at the dermo-epidermal junction in the patient's skin was shown by immunohistochemical analysis and immunoelectron microscopy. Subsequent dna analysis revealed heterozygosity for the mutations R635X and 3009C-->T in the LAMB3 gene. The latter did not alter codon translation, but introduced an exonic splice site in exon 20. Interestingly, this exonic splice site, which presented a splice score of only 68.6, was preferentially used by the spliceosome over the wild-type splice site at the exon 20-intron 20 border, which showed a splice score of 92.2. LAMB3 mRNA was still detectable in RT-PCR analysis although the aberrantly spliced mRNA leads to a stop codon in exon 21, 5' of the commonly assumed 3' border for nonsense-mediated mRNA decay. These results describe an exception to the proposed rules of pre-mRNA splicing and rna degradation.- - - - - - - - - - ranking = 1keywords = suffering (Clic here for more details about this article) |
6/6. Congenital pyloric atresia and junctional epidermolysis bullosa: a report of long-term survival and a review of the literature.The coexistence of congenital pyloric atresia (PA) and epidermolysis bullosa (EB) in newborns is a rare but distinct association. mortality is high. In particular, a universally fatal outcome has been reported in neonates born with the junctional type of EB and PA. This has led some investigators to advocate that surgical correction of PA be withheld to obviate needless suffering. We treated five patients, including one set of siblings. Maternal hydramnios and nonbilious vomiting were constant features. Delayed passage of meconium was found in four. Plain x-rays demonstrated gastric dilatation in an otherwise gasless abdomen. Blistering skin lesions were noted at birth in four and developed soon after in the last patient. All lesions were determined to be junctional EB based on electronmicroscopy. The clinical course for these children has been far better than the literature predicts. Successful repair of PA was performed after appropriate stabilization. One infant died at 4 months of age of staphyloccal septicemia, malnutrition, and sepsis from chronic urinary tract obstruction. Another child, born with dysmorphic features to consanguineous parents, is 9 years old and has a seizure disorder. The remaining three are alive and well at 17 months, and 9 and 16 years. The oldest two are siblings. In all four surviving patients, the blistering nonscarring lesions were found to significantly improve in severity, duration, and occurrence with age. Presently, these lesions are mild and require little therapy. Their nails, initially normal at birth, have become discoloured, thickened, and dystrophic. The management of pitted, carious, and yellow teeth is currently the major problem.(ABSTRACT TRUNCATED AT 250 WORDS)- - - - - - - - - - ranking = 1keywords = suffering (Clic here for more details about this article) |