Epidermolysis bullosa (EB) is a heritable skin blistering disease caused by variants in genes coding for proteins that secure cell-cell adhesion and attachment of the epidermis to the dermis. Interestingly, several proteins involved in inherited EB are also associated with autoimmune blistering diseases (AIBD). In this study, we present a long-term follow-up of 15 patients suffering from recessive dystrophic or junctional EB. From these patients, 62 sera were analysed for the presence of autoantibodies associated with AIBD. We show that patients suffering from recessive dystrophic EB (RDEB) are more susceptible to developing autoantibodies against skin proteins than patients suffering from junctional EB (70% vs. 20%, respectively). Interestingly, no correlation with age was observed. Most patients showed reactivity to Type XVII collagen/linear IgA bullous dermatosis autoantigen (n = 5; 33%), followed by BP230 (n = 4; 27%), Type VII collagen (n = 4; 27%) and laminin-332 (n = 1; 7%). The pathogenicity of these autoantibodies remains a subject for future experiments.

Epidermolysis bullosa (EB) is a group of skin disorders with skin fragility characterized by blistering from minimal mechanical trauma with rupture at the dermoepidermal junction. There are four major classical heritable EB types, due to mutations in as many as 20 distinct genes: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler EB (KEB). This study is aimed at reporting case series on patients (N = 8; males, n = 5 and females, n = 3, age range 12-68 years) affected by EB and performs a review of the literature on this topic. This group of disorders can affect oral soft and hard tissues in various ways, resulting in various effects including enamel hypoplasia, dental caries, microstomia, ankyloglossia, oral blistering, and ulcerations early-onset periodontal disease. From the sample results, it can be concluded that the clinical manifestation of EB patients is highly variable and very different in prognosis. Oral health deeply influences the quality of life of EB patients. Dental management is essential to prevent the aggravation of soft tissue damage and tooth loss and to improve the quality of life through prosthetic and restorative therapies. Dentists should consider the oral alterations of EB subtypes to perform a personalized approach to the patients\' needs in a preventive and therapeutic point of view.

BACKGROUND: Epidermolysis bullosa (EB) comprises a heterogeneous group of skin fragility disorders, classified in four major types based on skin cleavage level, i.e. EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), Kindler EB, and in more than 30 subtypes defined by the combination of laboratory and clinical data, including disease course.
OBJECTIVE: Our aims were to address whether, in the age of genomics, electron microscopy (TEM) has still a role in diagnosing EB, and whether the genotype per se may be sufficient to sub-classify EB.
METHODS: A thoroughly characterized single-centre EB case series was retrospectively evaluated to compare the power of TEM with immunofluorescence mapping (IFM) in establishing the EB type, and the ability of TEM, IFM and genetics to predict selected EB subtypes, i.e. severe dominant EBS (DEBS), severe JEB, severe recessive DEB (RDEB) and DEB self-improving, using genetic and final diagnosis, respectively, as gold standard.
RESULTS: The series consisted of 87 patients, including 44 newborns, with a median follow-up of 54 months. Ninety-five mutations were identified in EB-associated genes, including 25 novel variants. Both IFM and TEM were diagnostic in about all cases of JEB (21/21 for both) and DEB (43/44 for IFM, 44/44 for TEM). TEM sensitivity was superior to IFM for EBS (19/20 vs. 16/19). As to EB subtyping, IFM performed better than genetics in identifying severe JEB cases due to laminin-332 defect (14/14 vs. 10/14) and severe RDEB (eight/nine vs. seven/nine). Genetics had no role in self-improving DEB diagnosis; it almost equalled TEM in predicting severe DEBS (eight/nine vs. nine/nine) and enabled to discriminate dominant from recessive non-severe DEB phenotypes and to identify special subtypes, e.g. DEBS with KLHL24 mutations.
CONCLUSIONS: Transmission electron microscopy remains relevant to the diagnosis of EBS. IFM and genetics are essential and complementary tools in the vast majority of EB cases.

To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS).
After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary.
Of the 200 participants, 52 (26%) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West.
A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.

Laminin 5 (kalinin/epiligrin/nicein) is an essential structural component of the dermal-epidermal junction, composed of three polypeptide subunits: laminin alpha3, beta3 and gamma2. Studies of the inherited skin fragility disorder junctional epidermolysis bullosa (JEB) have suggested that the major role of this heterotrimeric protein is to act as an adhesive ligand essential for binding the epidermis to the underlying dermis and thus maintaining the integrity of the skin. Protein interaction studies have shown that the C terminus of the alpha3 subunit binds to a range of integrin complexes depending on the motility status of keratinocytes. This allows laminin 5 to interact with either hemidesmosomes or the actin cytoskeleton. Recently we have reported that the absence of the N-terminal region of laminin alpha3a in laryngo-onchyo-cutaneous syndrome causes excessive granulation tissue production at wound sites. As granulation tissue production is also a problem in JEB, this implicates laminin 5 in control of this wound healing response.

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Prenatal diagnosis of epidermolysis bullosa (EB) using fetal skin biopsy specimens has been successfully performed in Europe and America, but this technique has not previously been attempted in Asia. For the first time in Asia, we attempted to make a prenatal diagnosis of EB in a high-risk fetus by fetal skin biopsy. A skin biopsy was obtained from the fetus at risk of gravis type junctional epidermolysis bullosa of Herlitz. The biopsy specimen was studied by electron microscopy and immunohistochemistry using various monoclonal antibodies against the epidermal basement membrane zone (BMZ). There were no ultrastructural abnormalities in the BMZ, including the hemidesmosomes. Indirect immunofluorescence showed normal expression of GB3 antigen. The pregnancy was continued, and a normal, healthy infant was born. The prenatal diagnosis of epidermolysis bullosa is now available in Tokyo. This clinical diagnostic service is available to families from various parts of Asia.

GB3 monoclonal antibody detects a normal basement membrane component (GB3 antigen) that is variably expressed in junctional epidermolysis bullosa. To assess the accuracy of GB3 in the diagnosis of junctional epidermolysis bullosa, we have reviewed its use in 250 cases of the major types of epidermolysis bullosa. In the majority of cases of the simplex and dystrophic forms of epidermolysis bullosa, GB3 antigen is normally expressed. In the Herlitz variant of junctional epidermolysis bullosa, GB3 antigen expression is consistently abnormal, but in the non-Herlitz and indeterminate forms of junctional epidermolysis bullosa, 40% of cases express GB3 antigen normally. We propose that GB3 monoclonal antibody is useful in the accurate identification of patients with Herlitz junctional epidermolysis bullosa and may prove equal to electron microscopy for the diagnosis of this disease. For the non-Herlitz variants, it should not be used as an alternative to electron microscopy but may be of special value in the determination of prognosis.