Adrian Heagerty

The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB

BACKGROUND Since publication in 2000 of the Second International Consensus Report on Diagnosis and Classification of Epidermolysis Bullosa, many advances have been made to our understanding of this group of diseases, both clinically and molecularly. At the same time, new epidermolysis bullosa (EB) subtypes have been described and similarities with some other diseases have been identified. OBJECTIVE We sought to arrive at a new consensus of the classification of EB subtypes. RESULTS We now present a revised classification system that takes into account the new advances, as well as encompassing other inherited diseases that should also be included within the EB spectrum, based on the presence of blistering and mechanical fragility. Current recommendations are made on the use of specific diagnostic tests, with updates on the findings known to occur within each of the major EB subtypes. Electronic links are also provided to informational and laboratory resources of particular benefit to clinicians and their patients. LIMITATIONS As more becomes known about this disease, future modifications may be needed. The classification system has been designed with sufficient flexibility for these modifications. CONCLUSION This revised classification system should assist clinicians in accurately diagnosing and subclassifying patients with EB.

Identification of an epidermal basement membrane defect in recessive forms of dystrophic epidermolysis bullosa by LH 7:2 monoclonal antibody: use in diagnosis

LH 7:2 is a monoclonal antibody that was raised against an extract of human epidermal cells and identifies an epitope within the lamina densa of the basement membrane of stratified squamous epithelia. Using indirect immunofluorescence we found intense labelling with LH 7:2 at the epidermal basement membrane (EBM) of normal skin, and in skin samples from patients with simplex, junctional, dominantly inherited dystrophic and acquired forms of epidermolysis bullosa (EB), as well as bullous pemphigoid. Staining was absent or only very faint in generalized recessive dystrophic EB (RDEB), and patchily reduced in the localized form of RDEB.

GB3 monoclonal antibody for the diagnosis of junctional epidermolysis bullosa: Results of a multicenter study

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.

Detection of a novel basement membrane antigen by GDA‐J/F3 anti‐human sperm fibrous sheath monoclonal antibody

Summary Basement membrane zones (BMZ) of human epithelia were stained with GDA‐J/F3 monoclonal antibody, which was originally raised against sperm cells. Using indirect immunofluorescence and immunoperoxidase techniques, the antibody reacted with the BMZ of stratified squamous epithelia (skin and its appendages, tongue, lip, oesophagus and cervix). It also stained the BMZ of trachea, nasal ciliated mucosa, some mammary ducts of lactating and resting breast, amnion and ureter but failed to react with that of stomach, ileum. colon, rectum, kidney, liver, fallopian tube, lung or their blood vessels. In testes, the antibody did not react with the BMZ of the seminiferous tubules although the sperm tails were stained. Split‐skin immunofluorescence and immunoelectron microscopy localized GDA‐J/F3 antigen to the inferior border of the lamina densa of the BMZ. In human foetuses, the epidermally associated antigen was detected at an estimated gestational age of 9 weeks, and in the amnion at 1 5 weeks. The antibody reacted with tissues from monkey but not from mouse, rat, cow or pig suggesting the late appearance of the antigen during evolution. Although the GDA‐J/F3 was difficult to characterize biochemically, its tissue distribution, ontogeny and ultrastructural localization suggests that this antigen may be a type VII collagen‐associated protein, whose expression is altered in recessive dystrophic epidermolysis bullosa. This disease could represent abnormalities in type VII collagen structure, assembly, transport or interaction with associated proteins.

Somatic forward (nonrevertant) mosaicism in recessive dystrophic epidermolysis bullosa.

angiofibromas.4 Successful treatment of nonangiofibroma cutaneous manifestations of TSC has been sparse. To our knowledge, topical rapamycin has not been used successfully to treat the ungual fibromas of TSC. In our case, the use of topical rapamycin was well tolerated and resulted in the resolution of subungual tumors and rapid normalization of the overlying nail distortion. The pathogenesis of TSC is characterized by an autosomal dominant mutation in TSC1 or TSC2 resulting in aberrant functioning of hamartin or tuberin, respectively. Tuberin, a GTPase-activating protein for Rheb, functions in a complex formed with hamartin. Rheb, which in turn activates mTOR, is inhibited in the presence of a normal tuberin-hamartin complex.5 In TSC, the hamartin-tuberin complex is unable to form, resulting in the constitutive activation of the mitogenic mTOR pathway. Rapamycin suppresses this pathway through the direct inhibition of mTOR. While not entirely understood, an unrestrained mTOR pathway leads to upregulation of vascular endothelial growth factor (VEGF). It is suggested that rapamycin may exert its therapeutic effect on TSC lesions by directly killing tumor cells in addition to inhibiting VEGF production.6 Therefore, the same mechanism by which rapamycin reduces facial angiofibromas may also apply to nonangiofibroma cutaneous manifestations such as ungual tumors. Patients with periungual and subungual fibromas associated with TSC are often quite symptomatic and often have significant distortion of the nail plate. Their treatment options have been quite limited to date. While further study is necessary, the experience with our patient suggests that topical rapamycin is a safe, well-tolerated, and potentially efficacious treatment for patients with ungual tumors associated with TSC.

LH7:2, a new monoclonal antibody for use in the diagnosis of epidermolysis bullosa

Monoclonal antibodies provide unique opportunities to detect subtle changes in the structure of the basal lamina particularly in the diagnosis of different subgroups of epidermolysis bullosa. The monoclonal antibody LH7:2 was produced following immunization of Balb C mice with 1% NP40 extract of trypsin separated epidermal cells (predominantly basal cells). By indirect immunofluorescence of skin sections, strong staining of the basal laminae of interfollicular and follicular epidermis, sweat glands and sebaceous glands was obtained. The basal laminae of other stratified squamous epithelia such as oral, oesophageal and cervical epithelia react with LH7:2 but not those of most simple epithelia including gastric and renal epithelia. Weak placental staining is obtained.