Evaluation of Anchoring Fibrils and Other Components of the Dermal
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0022-202X/ 85/8405- 0374$02.00/0 THE ,)O ltNAI. OF INVESTIGATIV E DEitMATOLOr.Y, 84:374- 377, 1985 Vol. 84, No.5 Copyrighl 1985 by T he Williams & Wilkins Co. Printed in U.S .A. REPORTS Evaluation of Anchoring Fibrils and Other Components of the Dermal Epidermal Junction in Dystrophic Epidermolysis Bullosa by a Quantitative Ultrastructural Technique* MICHAEL J. TIDMAN, M.B., B .Sc., M.R.C.P.t AND ROBIN A. J. EADY, M.B., F.R.C.P. Department of Electron Microscopy and Ce ll Pathology, Institute of De rmatology, London, U.K. To examine the possibility that differences in the may be indistinguishable from the dominant condition (DDEB) structure and population density of anchoring fibrils [2]. Severe RDEB, however, is a much more aggressive disease (AF) and other components of the dermal-epidermal characterized by generalized fragility of the skin and wide junction might distinguish between genetically and clin spread scarring of the skin and mucous membranes, associated ically distinct varieties of dystrophic epidermolysis bul with stunted growth , c hronic anemia, esophageal strictures, losa (DEB), a controlled ultrastructural morphometric dental decay, pseudosyndactyly, and fl exion contractures (1] . study of nonseparated keratinocyte-associated dermal This typical clinical picture all ows ready distinction from the epidermal junction was undertaken in a total of 17 localized form. patients with DEB. Seven patients had dominant DEB, In all variants of DEB, blisters arise immediately beneath 3 had localized recessive DEB, and 7 had severe, gen the lamina densa of t he dermal-epidermal junction (DEJ) in eralized · recessive DEB. Nonlesional, unscarred skin the most superficial region of the dermis [3], where anchoring was obtained from standard body regions. Criteria for fibrils (AF) are normally located. The biochemical nature and the identification of AF were a mandatory union with function of AF are still not known, but the strong union that the lamina densa and the presence of central banding normall y exists between the lamina densa a nd AF (4], which and/or fanning of the extremities. are derived from epidermis and dermis respectiv ely [5], suggests No AF were detected in 9 technically suitable samples that AF serve as attachment devices. In DDEB the AF have from patients with severe recessive DEB. Structurally been reported to be reduced in number (6] and abnormal in normal AF were present, but significantly reduced in structure [7,8]. Furthermore, in the Pasini type of DDEB the number, in both dominant a nd localized recessive DEB, reduction in AF numbers was found in both bli ster predilection compared with site-matched samples from 12 healthy and nonpredilection sites [7], whereas in t he milder Cockayne adults. There was no difference in AF characteristics Touraine form, AF numbers were noted to be decreased only between dominant and localized recessive DEB, or be in predilection sites (8] . Some workers have found that AF tween sites of predilection and non predilection for blis were present, but reduced in number, in both locali zed and ters. The presence or absence of albopapuloid lesions in ge neralized forms of RDEB [9], whereas others have described dominant DEB did not influe nce AF counts. There was a total absence of AF in severe generalized RDEB [10,11]. no difference in numbers of hemidesmosomes, basal cell Quantitative data on the AF in DEB are limited, but a plasmalemma) vesicles, or dermal microfibril bundles in morphometric analysis of the components of normal DEJ has any g roup of DEB patients compared with controls. demonstrated that AF numbers vary widely among individuals, Thus, a lthough severe mutilating DEB can be distin between body regions in the same individual, and even within guished by routine transmission electron microscopy, a s ingle s kin sample, and has highlighted the potential pitfalls the dominant and localized recessive forms cannot be in evaluating AF numbers from isolated microscopic fields differentiated on the basis of AF structure or numbers. [1 2]. The aim of t he present investigation was to use the same morphomet ri c technique on skin from patients with DEB to quantify AF a nd other components of the DEJ, and to ascertain Dystrophic epidermolysis bullosa (DEB) may be inherited whether DDEB and RDEB can be distinguished using ultra· autosomall y in either a dominant o r a recessive manner, each structural criteria. This would have o bvious implications for type having a wide spectrum of severi ty [1 ]. This distinction both prognostication and ge netic counseling, and may fa cilitate often proves difficult in sporadic cases because the clinical the prenatal diagnosis of DEB. features of the mild locali zed form of recessive DEB (RDEB) MATERIALS AND METHODS ManuRcript received July 24 , 1984; accepted for publication Novem· ber 2, 1984. Patients and Co ntrols Thi s work was supported hy grants from the Dystrophic Epidermo· Seventee n patients with DEB were studied, comp ri sing 7 with lysis Bu ll osa Research Association and the Dunhill Trust. DDEB, 3 with mi ld locali zed RDEB , a nd 7 with severe generali zed *Presented in part at the Join t International Meeting of The Society RDEB. In each case the diagnosis was unequivocal and based on clinical for Investigative Dermatology, In c. and t~e European Society for and ge netic features. Electron microsco py was used to establish that Dermatological Research, Washingto n, D.C., Apr il 27- May 1, 1983. blisterin g occurred beneath the lamina densa. All the subjects with Abstract in J Invest Dermatol 80:342, 1983. DDEB had affected fam ily members in 2 or more ge nerations, and each 1' Dr. Tidman is a Medical Research Coun cil Training Fell ow. of th e 3 patients with the mild loca lized form of RDEB had a simi larly Reprint requests to: Robin A. J. Eady, M.S. , Institute of Dermatol affected sibling in the abse nce of parental involvement. Five of the ogy, Homerton Grove, London E9 6BX, England. patients with seve re genera lized RDEB were s poradic cases and the Abbreviations: other 2 were siblin gs (CH and SH). AF: anchorin g fibril(s) The DDEB group included a father and daughter (DP and SG) and DDEB: dominant dystrophic epidermolysis bu llosa a grandmother and grandso n (BB and KM) . In 6 of the 7 patients the DEB: dyRtroph ic ep idermolys is bu llosa co ndition was localized, with blistering, sca rring, and mi lia formation DEJ: derm al-epide rmal junction co nfined to bony prominences on the extremiti es, and with typical RDEB: recessive dystrophic epidermo lysis bullosa dystrophic changes of the nai ls. The seventh patient (KB) had a more 374 May 1985 ANCHORING FIBRILS IN DYSTROPHIC EPIDERMOLYSIS BULLOSA 375 widespread invo lvement wi th extensive scarring of his trunk a nd limbs, and basal plasma membrane, excluding DEJ associated with melano a nd acLi ve bli stering co ntinuing in t hese a reas despite his advanced cytes. The numerical densities of AF and dermal mi crofibril bundles age. He occasionally s uffered with bli stering of t he buccal mucous wi t h respect t.o lamina den sa, a nd of hemidesmosomes and plasmalem: membranes and episodes of dysphagia had been associated with radio mal vesicles, with respect to basal plasma membrane, were determined, logic evidence of an esophageal web. However, t he co ndition could be using the criteria previously defin ed [1 2], by the same observer. An AF t r aced through 3 ge nerations a nd there was no evidence of fin ge r was counted only if it united with the la mina densa and demonstrated webbing. In this group t he presence or absence of albopapul oid lesions, irregular banding of the central portion or fanning of its extremities or which a re thought to be a dist inguishing feature of t he Pasini variant both these characteristics, thus excluding wisp like structures normally of DDEB [1 ,13], was recorded (Table 1). Albopapuloid lesions were present beneath t he la mina densa, and avoiding confusion with other defined as hypopigmented macules or papules, with a wrinkled surface, fibrillar structures such as elastic mi crolibrils a nd co ll agen fibrils. u s ually located over the lower back. The absence of fresh, natural blisters in all 7 subjects wi th DDEB at the t ime of co nsultation and RESULTS t h e inability to experimentally provoke blister formation by vigorous friction with a pencil eraser, as is often the case [1 4], prevented the The c linical details a nd AF counts for the DDEB group are ult rastructural confirmation of a sub-lamina densa separation, al recorded in Table I. The presence o f albopapuloid lesions did t h ough clinically the diagnosis in each patient was beyond doubt. not appear to bear a direct relationship to the clinical severity The 3 s ubjects with mi ld locali zed RDEB included 2 sisters (MD of the co ndition, and it is of interest that 1 of the subjects (IH) a nd BB). In both, s kin lesions were confined to bony prominences on with the mild locali zed form of RDEB also had albopapuloid t h e extremities and consisted of old scarring as blisters had occurred lesions over the lumbar r egion, as did his 7-year-old brother. o nly infrequently s ince c hildhood. Both had suffered episodes of dys The possession of albopapuloid lesions does, however, seem to phagia a nd mild iron-defi ciency anemia, and an esophageal web h ad be a familial trait.