Three Hong Kong Chinese cases of pretibial epidermolysis bullosa:a genodermatosis that can masquerade as an acquiredinflammatory disease

W. Y. M. Tang, K. C. Lee*, T. C. Chow* and K. K. LoSocial Hygiene Service, Department of Health, the Government of the Hong Kong Special Administrative Region, Hong Kong. *Department of Pathology,Princess Margaret Hospital, Kowloon, Hong Kong

Summary Three patients in two families presented with many years’ history of fragile skin, blisters,erosions and scars affecting almost exclusively the shin areas, accompanied by a variabledegree of itching. Two of the patients also had toenail dystrophy. Skin biopsy revealeddermal–epidermal blister formation and milia but no immunohistochemical evidence ofimmunoglobulin or complement deposition. Electron microscopic study of the lesionaland perilesional skin showed very sparse or absent anchoring fibrils. Immunolabellingfor type VII collagen using LH 7.2 monoclonal antibody revealed a bright, linearstaining pattern at the dermal–epidermal junction. The clinicopathological featureswere thus compatible with pretibial epidermolysis bullosa, a subtype of dystrophicepidermolysis bullosa. Of note, the inflammatory nature of the skin lesions, and theirresemblance to nodular prurigo and hypertrophic lichen planus, had caused diagnosticdifficulties in all cases in the past. A high degree of awareness of this rare subtype ofepidermolysis bullosa is important to establish the correct diagnosis, to allow for geneticcounselling and to plan clinical management.

Introduction

Pretibial epidermolysis bullosa (PEB) is a rare subtype ofdystrophic epidermolysis bullosa (DEB).1 Clinically, PEBis characterized and possibly distinguished from othersubtypes of DEB by a milder and more localized diseasewith early or late onset trauma-related blisters anderosions, milia, scars and frequent pruritic lichenoid orprurigo papules predominantly affecting the pretibialregion. The first example of this disorder was describedin 1946 by Kuske who reported abrasions and scarringof shins affecting three patients in three generations ofone family.2 We present three patients who had featurescompatible with PEB but who were initially misdiag-nosed as other unrelated inflammatory dermatoses.

Case reports

Case 1

A 17-year-old male student had a history sincechildhood of itchy, easily induced blisters and abrasionswhich occurred following minor trauma to both shinsand to a lesser extent the elbows. The lesions healedslowly to form itchy scars. Previous diagnoses of his skindisorder included eczema, fungal infections and lichenplanus. He enjoyed otherwise good health apart fromabnormal-looking toenails. The patient is the eldest sonof the family and his clinically normal parents are notknown to be related. He has a 12-year-old brother (Case2) who suffers from a similar skin problem, but his10-year-old sister is not affected.

Examination of his shins revealed flat lichenoid scars,healed erosions and a few small vesicles. Close inspectionof a larger vesicle also showed underlying milia (Fig. 1a).Atrophic scars were also noted on the knees and to alesser extent, on the elbows. Toenails were atrophic and

Clinical dermatology • Original article

q 1999 Blackwell Science Ltd • Clinical and Experimental Dermatology, 24, 149–153 149

Paper No.: 440

Correspondence: W.Y.M. Tang, social Hygiene Clinic, 3/F Lek Yuen HealthCentre, Lek Yuen Street, Shatin, NT, Hong Kong. Tel: þ 852 26928179.Fax: þ 852 26020305.

Accepted for publication 2 December 1998

rudimentary (Fig. 1b). A systemic examination wasnormal.

Investigations including complete blood picture, liverand renal functions, iron and total iron binding capacity,serum total thyroxine, antinuclear antibody, anti-double-stranded DNA antibody and immunoglobulin patternswere normal or negative. Skin biopsies were taken froma fresh vesicle, perilesional normal-looking skin on theshin and normal-looking skin from the abdomen forhistopathology, direct immunofluorescence (DIF) andtransmission electron microscopy (TEM). Histopathologyof the abdominal skin was unremarkable but that fromthe shin vesicles showed an upper dermal dense band ofinflammatory cells, increased dermal fibrosis and keratincysts consistent with milia (Fig. 2, a and b). DIF of thelesional and normal-looking skin revealed no depositionof immunoglobulins or complement. TEM of theabdominal skin revealed normal looking fan-shapedanchoring fibrils demonstrating central cross-banding

and insertion into the lamina densa (Fig. 3a). TEM of ablister confirmed a sublamina densa plane of tissuecleavage (Fig. 3b). Assessment of perilesional skinrevealed a greatly reduced number of anchoring fibrils(Fig. 3c). DIF using monoclonal anti-collagen type VIImonoclonal antibody (Clone LH7.2, Sigma) on the peri-lesional skin was also performed which showed normallinear staining at the basement membrane zone.

Case 2

The patient is the 12-year-old younger brother of Case 1and shares the same but milder clinical features as hisbrother. Examination of the shins revealed a 5 mmdiameter vesicle with adjacent milia, lichenoid papulesand atrophic scars. Toenails were dystrophic but finger-nails were normal. Systemic examination wasunremarkable. Blood investigations as in Case 1 werenormal. Histopathology and DIF of the lesional andperilesional skin showed similar abnormalities to thoseof Case 1. TEM confirmed sublamina blister formationand absence of anchoring fibrils (AF) in the perilesionalskin.

Case 3

An unrelated 22-year-old female reported recurrentitchy skin and vesicles on her legs since the age of4 years. Scratching led to abrasions which healedslowly with papules and pigmentation. She was theonly daughter of nonconsanguineous asymptomaticparents and all enjoyed good physical health. Prior toher dermatologic consultation, she was treated foreczema and prurigo without improvement.Examination revealed lichenoid papules andpigmentary changes on her legs confined mainly tothe extensor aspect. A vesicle with adjacent milia wasnoted on the right shin. Her skin elsewhere was normalwithout albopapuloid papules. The teeth, hair andnails were normal. Results of blood tests (as in Case 1)were normal except for a slightly elevated immunoglo-bulin IgE. Her skin biopsies for histopathology, TEMand DIF staining using anticollagen type VIImonoclonal antibodies (Clone LH7.2, Sigma) showedsimilar findings as in Cases 1 and 2 compatible withPEB.

Discussion

In PEB, and as in all other types of DEB, the clinical andultrastructural features are accounted for byquantitatively reduced or morphologically abnormal

Pretibial epidermolysis bullosa • W. Y. M. Tang et al.

q 1999 Blackwell Science Ltd • Clinical and Experimental Dermatology, 24, 149–153150

Figure 1 (A) Close up view of the right shin of Case 1 showingflat lichenoid scars, healed erosions and a blister with underlyingmilia. (B) The toenails of Case 1 were atrophic and rudimentary.Superficial ulcers of the toe skin are discernible in the right bigand second toes.

AF3,4; this was found in the three cases presented here.Type VII collagen molecules constitute a major compo-nent of AF5,6 whose structure provides a firm attachmentof the basement membrane to the underlying dermis. Thegene for type VII collagen (COL7A1) is located on thechromosome 3p21.7–9 and mutations in COL7A1 areknown to impede the synthesis of type VII procollagen orits subsequent assembly into homotrimers and hence AF.Comprehensive mutation analyses have shown that theclinical expression and inheritance of DEB depend on thenature of the specific underlying mutations.10

The clinical features in our three patients with PEB

show striking similarities to the phenotype describedas epidermolysis bullosa pruriginosa (EBP).11 SomeCOL7A1 mutations have now been reported in bothPEB and EBP. Specifically, Christiano et al. described anautosomal dominant pedigree from Taiwan with PEB inwhich a glycine substitution mutation in COL7A1 wasfound.12 Tamai et al. recently described three Japanesepatients with EBP with prominent shin lesions in whomglycine substitution mutations in exon 85 of COL7A1were identified.13 One of these mutations was verysimilar to that described in a Chinese family with EBPby Lee et al.14 Thus all of these patients, who are of Asian

Pretibial epidermolysis bullosa • W. Y. M. Tang et al.

q 1999 Blackwell Science Ltd • Clinical and Experimental Dermatology, 24, 149–153 151

Figure 2 (A) Histopathology of a vesicleat the shin revealed a subepidermal blisterand a dense band of inflammatory cells inthe upper dermis (haematoxylin & eosin× 40). (B) Histopathology of a vesicleshowing its subepidermal locationassociated with underlying keratin cysts.(haematoxylin & eosin × 100).

origin, have the same types of mutation clustered in thesame region of COL7A1. In a study of white Europeanpatients with EBP, however, Mellerio et al. demonstratedallelic heterogeneity in five patients, suggesting thatseveral different mutations may give rise to this type ofepidermolysis bullosa.15 Nevertheless, the current datasuggest that in Asian patients the site of the COL7A1mutation may have some direct relevance to the clinicalphenotype. Mutational studies have not been performedin our patients because of lack of facilities; we anticipatethat should such service be available, the results wouldcertainly enlighten this aspect and assist understandingof PEB in Asians.

At present, epidemiological data on the various typesof EB in Hong Kong are lacking, but we believe thatcases of PEB or EBP do exist, but that the correctdiagnosis has not been ascertained in most instances,as seen in our three cases. The exact mode of inheri-tance in our three patients is not certain. The occur-rence of a single case in a pedigree could be consideredas sporadic and accounted for by spontaneous muta-tion. However, de novo cases of dominant DEB have beenshown to be rare events,16 and the presence of twoaffected siblings in a family where no skin lesions haveever been reported in the previous generations wouldtend to suggest a recessive inheritance. If this is true,the two siblings in this series (Cases 1 and 2) wouldhave localized recessive DEB and indeed, autosomalrecessive cases of EBP with prominent shin lesionshave been reported.11 Alternatively, it cannot be dis-counted that the inheritance could be autosomal domi-nant where one of the parents carries the mutant genewithout manifesting the disease. This could be due toincomplete penetrance or subtle clinical expression (forexample, mild toenail dystrophy that might escapediagnosis if one relies only on clinical evaluation)or one of the parents having gonadal mosaicism forthe mutant gene. Precise determination of the mode ofinheritance in our patients will depend on futuremutational analysis of COL7A1.

In summary, we believe that this first report of theoccurrence of PEB in Hong Kong Chinese serves tohighlight the importance of a high level of awarenessof this inherited skin condition. The features of fragilevesicles and erosions, which are often overshadowed byitchy lichenoid-papule-like scars in the pretibial regionsof PEB patients can easily be misdiagnosed as lichenplanus, prurigo nodularis or dermatitis artefacta asexemplified by our three cases. Such clinical similaritiesto acquired dermatoses together with the mild severityare very likely to lead to an incorrect diagnosis andinappropriate advice and management.

Pretibial epidermolysis bullosa • W. Y. M. Tang et al.

q 1999 Blackwell Science Ltd • Clinical and Experimental Dermatology, 24, 149–153152

Figure 3 (a) TEM of normal abdominal skin. The basal cell cyto-plasm and basement membrane are intact. The hemidesmosomes(H), subbasal dense plates and lamina densa (L) are normal andclearly shown. Anchoring fibrils (arrowheads) are normal andfan-shaped, and exhibit alternating dense and lucent bands andinsertion into the lamina densa (original magnification × 45 000).B, Basal keratinocyte; D, dermis. (b) TEM of a vesicle showing asublamina densa plane of cleavage with intact hemidesmosomes,lamina lucida, sub-basal dense plate and lamina densa. Fibrinousmaterial (F) is evident and anchoring fibrils are not discernible(original magnification × 45 000). (c) TEM of the perilesional skinshowing normal basal keratinocytes, lamina lucida, sub-basaldense plate and lamina densa. Compared with the findings inFig. 3(a), anchoring fibrils (arrowheads) are greatly reduced andhypoplastic (original magnification × 45 000).

References1 Fine JD, Bauer EA, Briggaman RA et al. Revised clinical

and laboratory criteria for subtypes of inheritedepidermolysis bullosa. A consensus report by theSubcommittee on Diagnosis and Classification of theNational Epidermolysis Bullosa Registry. J Am AcadDermatol 1991; 24: 119–35.

2 Kuske H. Epidermolysis traumatica, regionar uber beidenTibiae zur Atrophie fuhrend mit dominanter Vererbung(in German). Dermatologica 1946; 91: 304–5.

3 Hanna W, Silverman E, Boxall L, Krafchik BR.Ultrastructural features of epidermolysis bullosa.Ultrastruct Pathol 1983; 5: 29–36.

4 Tidman MJ, Eady RA. Evaluation of anchoring fibrils andother components of the dermal–epidermal junction indystrophic epidermolysis bullosa by a quantitativeultrastructural technique. J Invest Dermatol 1985; 84:374–7.

5 Sakai LY, Keene DR, Morris NP, Burgeson RE. Type VIIcollagen is a major structural component of anchoringfibrils. J Cell Biol 1986; 103: 1577–86.

6 Keene DR, Sakai LY, Lunstrum GP, Morris NP, BurgesonRE. Type VII collagen forms an extended network ofanchoring fibrils. J Cell Biol 1987; 104: 611–21.

7 Parente MG, Chung LC, Ryynanen J et al. Human typeVII collagen: cDNA cloning and chromosomal mapping ofthe gene. Proc Natl Acad Sci USA 1991; 88: 6931–5.

8 Ryynanen M, Knowlton RG, Parente MG et al. Humantype VII collagen: genetic linkage of the gene (COL7A1)on chromosome 3 to dominant dystrophic epidermolysisbullosa. Am J Hum Genet 1991; 49: 797–803.

9 Dunnill MG, Richards AJ, Milana G et al. Genetic linkageto the type VII collagen gene (COL7A1) in 26 families

with generalised recessive dystrophic epidermolysisbullosa and anchoring fibril abnormalities. J Med Genet1994; 31: 745–8.

10 Christiano AM, Uitto J. Molecular diagnosis of inheritedskin diseases: The paradigm of dystrophic epidermolysisbullosa. Adv Dermatol 1996; 11: 199–213.

11 McGrath JA, Schofield OM, Eady RA. Epidermolysisbullosa pruriginosa: dystrophic epidermolysis bullosawith distinctive clinicopathological features. Br J Dermatol1994; 130: 617–25.

12 Christiano AM, Lee JY, Chen WJ, La Forgia S, Uitto J.Pretibial epidermolysis bullosa: genetic linkage toCOL7A1 and identification of a glycine-to-cysteinesubstitution in the triple-helical domain of type VIIcollagen. Hum Mol Genet 1995; 4: 1579–83.

13 Tamai K, Hashimoto I, Murai T et al. Particularmutations in exon 85 of type VII collagen gene (COL7A1)induce severe itch: Specific glycine substitutions fordominant forms of epidermolysis bullosa pruriginosa.J Invest Dermatol 1998; 110: 509 (abstract).

14 Lee JY, Pulkkinen L, Liu HS, Chen YF, Uitto J. Aglycine-to-arginine substitution in the triple-helicaldomain of type VII collagen in a family with dominantdystrophic epidermolysis bullosa pruriginosa. J InvestDermatol 1997; 108: 947–9.

15 Mellerio JE, Ashton GH, Salas-Alanis JC, Lyon CC,Griffiths WA. Allelic heterogeneity of type VII collagengene (COL7A1) mutations in epidermolysis bullosapruriginosa. J Invest Dermatol 1998; 110: 508 (abstract).

16 Kon A, McGrath JA, Pulkkinen L et al. Glycinesubstitution mutations in the type VII collagen gene(COL7A1) in dystrophic epidermolysis bullosa:implications for genetic counseling. J Invest Dermatol1997; 108: 224–8.

Pretibial epidermolysis bullosa • W. Y. M. Tang et al.

q 1999 Blackwell Science Ltd • Clinical and Experimental Dermatology, 24, 149–153 153