Epidermolysis Bullosa Dystrophica-Recessive: a Possible Role of Anchoring Fibrils in the Pathogenesis
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T E JOU RNAL Of I NVESTIGATIV E D ERMATOLOGY, 65: 203- 211, 1975 Vo l. 65, No. 2 C:pyrig h t © 1975 by The Willia ms & Wilkins Co. Printed ill U.S.A . REPORTS EPIDERMOLYSIS BULLOSA DYSTROPHICA-RECESSIVE: A POSSIBLE ROLE OF ANCHORING FIBRILS IN THE PATHOGENESIS ROBERT A. BRIGGA MA N, M.D., AND CLA YTON E. WHE ELER, JR. , M.D. Department of Dermatology, The University of North Carolina Schoo l of Medicine, Chapel Hill, North Caro lina The purpose of t his study was to define the ultrastructura l defects and pathogenesis of e pidermolysis bullosa dystrophica- recessive (EBD- R ). The only consisten t ultrastructural alteration found in EBD- R was an a bsence of anchoring fibrils. In many specimens of n on blistered , nontraumatized E BD- R skin, absence of anchoring fibrils was t he only ultrastructura l a bnormali ty observed . The possibility that lack of anchoring fibrils was a secondary change result ing from previous bli stering and scarring was eliminated by our o bservation that anchoring fibrils were consistently absent in the never previously blistered s kin of two newborns wi th E BD- R. In experimentally traumatized skin, the epidermis and d ermis separated in the region of the epidermal- derma l junction normall y occupied by a n choring fibrils. Basal la mina and derma l microfibril bundles appeared to be norma l. Using recom binant grafts, we demonstrated t hat a nchoring fibrils were not fo rmed by EBD- R d ermis when combined wi th E BD- R epidermis or normal epidermis. Anchoring fibrils were formed when normal dermis was co mbined wi th norma l and EBD- R epidermis. These s tudies indicate that the defect in EBD- R resides in the dermis and that the defect may be associated with impa ired formation of anchoring fibrils. Epid ermolysiS bullosa dystrophica- recessive, pharynx, esophagus, and anal canal are involved. termed epidermolyse bullouse polydyspl asique by In t hese sites, scarring leads to mouth and tongue Touraine [1 ], congenita l, ge nera li zed , subletha l deformities and fr equent esophageal stenosis. Im epidermolysis bullosa dystrophica by Gedde-Da hl pa i'red growth, anemia, fr equent cutaneous infec [2 ] and d ermolytic bullous dermatosis- recessive by tion, and den tal a bnorma li ties are common . Pear son [3], is an autosomal recessive disease T he purpose of t hi s paper is to define the which begin s at birth or soon thereafter and pat hologic defect in epidermolysis bullosa dys pursu es a n unrelenting course throughout li fe , trophica-recessive (E BD-R) and to co nsider its occasio n a lly terminating fatall y at an earl y age. pathogenesis. Pearson [4 ] found a consistent ult ra The clinical defect is a fa ilure of epiderma l- derma l structural separation in the dermis just beneath the adherence resul ting in blisters and subsequent basal lamina (basemen t membrane) . In addition, erosio n s which involve t he entire skin surface wi t h he poin ted ou t a marked reduction of fine fibers a predilection for sites of frequent tra uma, part icu just beneath the basal lamina (subsequently iden larly t h e neck, shoulders, elbows, knees, buttocks, tifi ed as anchoring fibrils) and varying degrees of hands, a nd fee t . Dystrophic scarring, a ha llmark of co llagen degradation. Subsequent reports on the the disease, is most severe in sites of recurrent ultrastructura l abnorma li ty in EBD- R have pre blister ing a nd leads to a vari ety of functional sen ted a more confused pi cture. Vogel and Schny impair m en ts including mitten-like epiderma l en de l' [5,6] observed separation beneath the basal casemen ts of t he hands and feet, disfi gurement, la mina in so me patients and in the in termembra and jo int contractures. Ha ir and nails are co m- ' nous space in others. Kobayasi [7] fo und blisters monly lost. Mucous membranes of the ora l cavi ty, located in the in termembranous space in one patien t wi th recessive epidermolysis bullosa . From Manuscript received Dece mber 26, 1974; in rev ised the clinical descript ions in these patien ts, it is fo rm March 5, 1975 ; accepted for publication March 10, diffi cul t to obtain a cl ear view of the diseases being 1975. studied . It is possible that severa l types of epider T hi s stud y was supported by Resea rch Grant 2 ROl AM 10546 and Derm atology Training Grant 5 ROl AM molysis bullosa we re lumped together as EBD- R. 5298 from the National Institutes of Health, and Grant It is a lso possible that EBD- R is actuall y a group of RR 46 fr om the General Clinical Research Centers different diseases whi ch have a similar clinical Branch of the Division of Resea rch Resour ces, U. S. appearance. Public Health Service. Reprint requests to : Dr. R. A. Bri gga man, Department In the presen t study, we sha ll presen t evidence of Dermatology, The Uni ve rsity of North Caro lina Sc hoo l t hat the most consistent and often the only ul tra of Medicine, Chapel Hill , North Carolina 275 14. structUl" a l defect noted in EBD- R is an absence of 203 204 BRiGGAMAN AND WHEELEIl Vol. 65, NO. 2 anchoring fibr il s. Using a system in which anchor was chosen for biopsy. These were away from any exist' ing fibri ls norma ll y re-form in recombin a nt grafts blisters or obvious scarring, although it should be no~n~ grown for a period of time on the chorioallantoic t hat t he skin of older patients had a crinkled, atroPh~c membrane of embryonated chicken eggs [8], we appea.!·a nce even In these areas. In two cases (patients Iii sha ll present evidence t hat formation of these a nd EO), biopSies were obtatned soon al ter birth f completely normal-appearing skin which had never structures may be impaired in EBD- R a nd that ;Olll blI' stere d prevIo. us I y. B"l opsles were d one under 10een I the defect resides in the EBD- R dermis. lidocain e anesthesia using a scalpel to obta in a t~a MATERIALS AND METHODS sp li~ - thickness skin specimen. Special care was taken :~ aVOid traumatizing t he blOP.sy sites. Sen a l biopsies wer~ Patient, done over a 3-year penod 111 patient Bl a nd a 2-v The patients comprising this study constitute a clini period inpatients Sl, S2, H1,H 2, and H3. Biopsies ~:~: call y homogenous group which conforms to the clinical also obtalne? trom multiple Sites, II1ciudlng t high , abdo_ features of EBD- R described above. All patients have a men, back, lor~a rm , and upper a r~l to determine whether generalized bullous disorder resulting in severe dys pathologiC dll/erences cou ld be found III different an trophic scarring. Famili al cases consistent with an auto tomic sites. a- somal recessive mode of inheritance make up the bulk of M inimal frictional trauma. An area of skin free r the patient group. obvious blisters and scarring was subjected to minirn 0 Familial cases. Family B is of Turkish extraction with trauma insufficient to produce an overt blister a 1 2 of 5 siblings involv ed. No other family members are epidermal- dermal separation. Five to 10 strokes with Or affected. The parents are second co usins. Patient Bl is an ordinary pen~iJ eraser with li ght application of pr essu~: 18-year-old male of small stature who has mitten-li ke were used, al ter whlGh the area was blopsied as previ enclosures of the hands and feet and severe esophageal ously described. stenosis. Patient B2 is a 7-year-old male who has simi lar M echanically separated epidermis and dermis p but milder involvement. lions of split-thickness skin specimens obtained ~s ~r. Family S is a Negro family in which 2 of 5 siblings are scribed above were placed in tissue culture mediu e· involved. No other fami ly members are affected. Patient (Medium 199 with 10% fetal calf serum) and imm ed i ate;~ Sl is a 13-year-old male of small stature with severe transported to t he laboratory (lapsed time less t han 5 mitten-like enclosures of the hands and feet, Ilexure min) .. Under a. dissecting microscope, epidermis and contractures of the elbows and knees, and esophageal dermiS were easd y separated USIng Jeweler's forceps a d stenosis. Patient S2 is an ll-year-old female of small di secting needles to tease the components apart. Th~ stature manifesting severe scarring about the face, scar specimens will be referred to hereafter as " mecha nicall , ring alopecia of the scalp, scarring of the conjunctivae separated" epidermis and dermis. ~ with ectropion of the lower lids, and esophageal stenosis. Family H is a Caucasian fa mily in which 3 of 4 siblings Recombination Studies Usi /t{{ Normal and Abnormal are involved. Other members of the family are normal. Epidermis and Dermis Patient HI is a 21-year- old male with very severe Preparation of skin component,. An area of skin free or dystrophic scarring on his arms, legs, and face. Patient obV IOUS bltsters or scarrIng was chosen on patients with H2 is a 20-year-old j'')male with esophageal stenosis and EBD-R.