CORRESPONDENCE Topical tacrolimus for facial psoriasis SIR, We report four patients with extensive facial psoriasis who responded to treatment with topical tacrolimus. Tacrolimus, a calcineurin inhibitor, is effective against a wide range of inflammatory dermatoses including psoriasis, when given systemically. 1 Topical tacrolimus has been shown to be ineffective in treating psoriasis, 2 although one report from Japan claimed benefit in facial psoriasis, 3 and descaling and occlusive dressings have been shown to increase the effects of topical pimecrolimus on psoriatic lesions. 4 More recently, animal models have shown that a liposomal tacrolimus lotion may increase the penetration of tacrolimus into the skin and allow for slow release of the active compound locally. 5 Facial skin is highly sensitive due to its anatomy which includes a high density of append- ages, an elaborate network of sensory nerves and a more permeable horny layer, 6 and studies have demonstrated increased penetration in persons with sensitive skin. Facial and intertriginous skin is more susceptible to corticosteroid- induced atrophy, 7 a problem not associated with use of topical tacrolimus. The first patient, a 65-year-old woman with chronic psoriasis who had been previously treated with psoralen plus ultraviolet (UV)A, UVB, methotrexate, ciclosporin and acitre- tin at various times, was admitted with an acute exacerbation of psoriasis. It was noted on admission that she had marked facial psoriasis that had proven resistant to treatment with various topical agents. During her admission she was commenced on 0Æ1% topical tacrolimus for facial psoriasis. At 1-month follow-up the facial psoriasis had improved considerably (Figs 1 and 2). The second patient was a 20- year-old man with extensive psoriasis, who is maintained on ciclosporin 150 mg twice daily. He continued to have marked facial psoriasis and this proved to be psychologically disabling. He was commenced on 0Æ1% topical tacrolimus for the facial psoriasis and at 2-month follow-up his facial psoriasis had improved dramatically and for the first time in many years his face was clear from psoriasis. The third patient was a 30-year- old woman with chronic psoriasis who also had severe facial involvement. During an admission she was commenced on 0Æ1% topical tacrolimus for her facial psoriasis. The response to tacrolimus was dramatic, leading to complete clearance of the skin condition. The fourth patient was a 6-year-old girl Figure 2. Patient after treatment with 0Æ1% topical tacrolimus. Figure 1. Facial psoriasis before treatment. British Journal of Dermatology 2003; 149: 419–446. Ó 2003 British Association of Dermatologists 419
Transcript
CORRESPONDENCE
Topical tacrolimus for facial psoriasis
SIR, We report four patients with extensive facial psoriasiswho responded to treatment with topical tacrolimus.Tacrolimus, a calcineurin inhibitor, is effective against awide range of inflammatory dermatoses including psoriasis,when given systemically.1 Topical tacrolimus has beenshown to be ineffective in treating psoriasis,2 although onereport from Japan claimed benefit in facial psoriasis,3 anddescaling and occlusive dressings have been shown toincrease the effects of topical pimecrolimus on psoriaticlesions.4 More recently, animal models have shown that aliposomal tacrolimus lotion may increase the penetration oftacrolimus into the skin and allow for slow release of theactive compound locally.5 Facial skin is highly sensitive dueto its anatomy which includes a high density of append-ages, an elaborate network of sensory nerves and a morepermeable horny layer,6 and studies have demonstratedincreased penetration in persons with sensitive skin. Facialand intertriginous skin is more susceptible to corticosteroid-induced atrophy,7 a problem not associated with use oftopical tacrolimus.
The first patient, a 65-year-old woman with chronicpsoriasis who had been previously treated with psoralen plusultraviolet (UV)A, UVB, methotrexate, ciclosporin and acitre-tin at various times, was admitted with an acute exacerbationof psoriasis. It was noted on admission that she had markedfacial psoriasis that had proven resistant to treatment withvarious topical agents. During her admission she wascommenced on 0Æ1% topical tacrolimus for facial psoriasis.At 1-month follow-up the facial psoriasis had improvedconsiderably (Figs 1 and 2). The second patient was a 20-year-old man with extensive psoriasis, who is maintained onciclosporin 150 mg twice daily. He continued to have markedfacial psoriasis and this proved to be psychologically disabling.He was commenced on 0Æ1% topical tacrolimus for the facialpsoriasis and at 2-month follow-up his facial psoriasis hadimproved dramatically and for the first time in many years hisface was clear from psoriasis. The third patient was a 30-year-old woman with chronic psoriasis who also had severe facialinvolvement. During an admission she was commenced on0Æ1% topical tacrolimus for her facial psoriasis. The responseto tacrolimus was dramatic, leading to complete clearance ofthe skin condition. The fourth patient was a 6-year-old girl
Figure 2. Patient after treatment with 0Æ1% topical tacrolimus.Figure 1. Facial psoriasis before treatment.
British Journal of Dermatology 2003; 149: 419–446.
� 2003 British Association of Dermatologists 419
with extensive psoriasis with severe facial involvement. Shewas also commenced upon 0Æ1% topical tacrolimus, whichhad a profound and almost immediate effect, resulting incomplete clearance of her facial psoriasis within 72 h.
All of these patients exhibited marked facial psoriasisinvolving > 70% facial area, and the skin condition improvedrapidly with 0Æ1% topical tacrolimus ointment. We would sug-gest that topical tacrolimus is an agent that may have a limitedplace in the treatment of psoriasis, when a specific site such asthe face is involved, where there may be local factors enhancingtacrolimus absorption. Our results suggest that the beneficialeffect of topical tacrolimus in lesions of facial psoriasis maynot be unique to any one particular ethnic or age group.
T . H . C l a y t o n
P . V . H a r r i s o n
R . N i c h o l l s
M . D e l a p
Department of Dermatology,Lancaster Royal Infirmary,Lancaster, Lancs, U.K.E-mail: [email protected]
References
1 The European FK506 Multicentre Psoriasis Study Group. Systemic
tacrolimus (FK506) is effective for the treatment of psoriasis in a
2 Zonneveld IM, Rubins A, Jablonska S et al. Topical tacrolimus is not
effective in chronic plaque psoriasis. A pilot study. Arch Dermatol
1998; 134: 1101–2.
3 Yamamoto T, Nishioka K. Topical tacrolimus is effective for facial
lesions of psoriasis. Acta Derm Venereol 2000; 80: 451.
4 Mrowietz U, Graeber M, Brautigam M et al. The novel ascomycin
derivative SDZ ASM 981 is effective for psoriasis when used top-
ically under occlusion. Br J Dermatol 1998; 139: 992–6.
5 Erdogan M, Wright JR Jr, McAlister VC. Liposomal tacrolimus
lotion as a novel topical agent for the treatment of immune-me-
diated skin disorders: experimental studies in a murine model. Br J
Dermatol 2002; 146: 964–7.
6 Issachar N, Gall Y, Borrel MT, Poelman MC. Correlation between
percutaneous penetration of methyl nicotinate and sensitive skin,
using laser Doppler imaging. Contact Dermatitis 1998; 39: 182–6.
7 Lebwohl MG, Tan MH, Meador SL, Singer G. Limited application of
fluticasone propionate ointment, 0.005% patients with psoriasis of
the face and intertriginous areas. J Am Acad Dermatol 2001; 44:
77–82.
Pemphigoid gestationis: maternal sera recognizeepitopes restricted to the N-terminal portion of theextracellular domain of BP180 not present on its shedectodomain
SIR, Pemphigoid (herpes) gestationis (PG) is an autoimmunesubepidermal blistering disease associated with pregnancyand characterized by linear deposition of C3 and, lessfrequently, of immunoglobulin (Ig)G along the dermal–epidermal junction (DEJ).1 Complement-fixing circulatingIgG autoantibodies to the DEJ in serum of PG patients aremainly directed to the 180-kDa bullous pemphigoid antigen(BP180), a transmembrane hemidesmosomal glycoprotein.2
BP180 consists of an intracellular N-terminal globular head,a transmembrane region, and a C-terminal ectodomain. The
extracellular domain of BP180 consists of 15 collagenous and16 noncollagenous (NC) regions harbouring different anti-genic sites recognized by autoantibodies from patients withvarious subepidermal blistering diseases.2 The ectodomain ofBP180 may be shed from the surface of basal keratinocytes by
NC16A
Figure 1. Schematic diagram of cell-derived forms of 180-kDa bullous
pemphigoid antigen (BP180). From left to right, full-length BP180, its
shed ectodomain (LAD-1, 120-kDa fragment), and LABD97 (antigenic
fragment of 97 kDa) are shown (BK, basal keratinocyte; TM, trans-
membrane domain). NC16A, the immunodominant region of BP180,
is located immediately adjacent to the cell membrane (arrow). Num-
bers indicate amino acid position with reference to the amino acid
sequence of BP180 (numbering system adapted from Zillikens et al.9).
The N- and C-terminal sequence of LAD-1 as well as the C-terminus of
LABD97 are not yet fully characterized.
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cleavage within the NC16A domain resulting in a 120-kDafragment (LAD-1) that lacks a short juxtamembranousportion of the extracellular domain of BP180 (Fig. 1).3,4 Inhuman skin, the cleavage of BP180 results in anotherantigenic fragment of 97 kDa (LABD97) that can be extractedfrom epidermis.5 Recent findings from our laboratory suggestthat LAD-1 and LABD97 have different N-termini.6
Autoantibodies of patients with PG have been shown totarget distinct epitopes within the membrane-proximalNC16A domain of BP180.7,8 In the present study, we aimedat characterizing the reactivity of PG sera with LAD-1. Serumsamples from 34 PG patients with linear deposition of C3and ⁄ or IgG by direct immunofluorescence (IF) microscopywere analysed by immunoblotting of recombinant NC16A andLAD-1 from concentrated supernatant of cultured keratino-cytes.9 Complement-fixing autoantibodies to the DEJ werepresent in serum from 33 of 34 PG patients as revealed byindirect IF microscopy. By immunoblotting, autoantibodies
from 32 of 34 PG patients reacted with recombinant NC16A.Serum from one patient, which did not reveal complement-fixing autoantibodies by indirect IF microscopy, did react withrecombinant NC16A. Interestingly, serum samples from 33 of34 patients did not recognize cell-derived LAD-1 (Fig. 2).Previously, it was demonstrated that autoantibodies to BP180from patients with PG react with epitopes predominantlylocated between amino acids 507 and 520.7,8 The results ofthe present study therefore suggest that the N-terminus ofLAD-1 may be located at or downstream from amino acid 521.This assumption is in line with previous work demonstratingby preadsorption studies, that rabbit antibodies to NC16Aregion 4 (covering amino acids 535–548), but not to regions2, 2.5 and 3 (together covering amino acids 507–534),appear to be relevant for binding to LAD-1.9
One may hypothesize that the autoimmune response in BPpatients is initiated against the immunodominant NC16Aregion of BP180 and the development of autoantibodies to
Figure 2. Most pemphigoid gestationis (PG) sera do not react with the shed ectodomain (LAD-1, 120-kDa fragment) of the 180-kDa bullous
pemphigoid antigen (BP180). Serum samples from rabbits SA8009 (generated against the NC16A domain, lane 1) and R136 (directed to the
C-terminus of BP180, lane 2), control LAD (lanes 3–5, immunoglobulin (Ig)A reactivity) and BP patients (lanes 6–8), PG patients (lanes 9–14),
and sera from healthy controls (lanes 15 and 16, IgA and IgG reactivity, respectively) were reacted with concentrated supernatants of cultured
HaCaT cells as a source of the soluble BP180 ectodomain (LAD-1). Serum samples from some BP patients, rabbit sera SA8010, and R136 reacted
with LAD-1. In contrast, except for one (lane 13) out of 34 serum samples, PG sera, like sera from healthy controls, did not recognize the 120-kDa
LAD-1 fragment of BP180. Migration positions of molecular weight markers (kDa) are shown on the left.
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LAD-1 and to LABD97 may represent the immunologicalphenomenon of ‘epitope spreading’. Similar to BP, the NC16Adomain of BP180 was shown to contain the immunodomi-nant epitopes recognized by autoantibodies in virtually all PGpatients.7,8 In this study, we show that the vast majority ofPG sera do not react with the soluble form of BP180. Thisobservation is compatible with the hypothesis that theautoimmune response is initiated against epitopes withinthe NC16A domain and, in contrast to BP, remains restrictedto this immunodominant stretch of BP180. In PG, theautoimmune response to BP180 is associated with pruriticpapules, urticarial plaques and eczematous skin lesions butoften not with blisters.1 Similarly, BP, in the premonitorynonbullous stage, may also present with such pruritic lesionsfor weeks and months. PG, usually abrupt in onset, is short-lived and occurs in the setting of physiological immunosup-pression and therefore epitope spreading may not occur.
In conclusion, this study demonstrates on a large numberof patients that the epitopes recognized by PG sera are notpresent on the shed ectodomain of BP180 lacking thejuxtamembranous N-terminal portion of NC16A. This obser-vation confirms that the autoimmune response in PG patientsis restricted to epitopes within the N-terminus of theextracellular domain of BP180. The use of a short recom-binant peptide containing the major epitopes in PG maytherefore facilitate specific immunoadsorption therapy inpatients with a severe form of this disease.
Acknowledgments
This work was supported by grant 98.073.2 from theWilhelm Sander Stiftung, Munich (D.Z.). We thank Dr GeorgeJ. Giudice, Milwaukee, WI, U.S.A., for providing us withrabbit serum R-136 and Silvana Noll (Wurzburg) and JillAllan (Oxford) for technical assistance.
C . S i t a r u
J . P o w e l l *
I . S h i m a n o v i c h
S . J a i n t a
G . K i r t s c h i g *�F . W o j n a r o w s k a *
D . Z i l l i k e n s
Department of Dermatology,University of Wurzburg, Wurzburg,Germany*Department of Dermatology, OxfordRadcliffe Hospital, Oxford, U.K�Department of Dermatology, VrijeUniversiteit Medical Centre,Amsterdam, the NetherlandsCorresponding author: D. ZillikenE-mail: [email protected]
References
1 Shimanovich I, Brocker EB, Zillikens D. Pemphigoid gestationis:
new insights into the pathogenesis lead to novel diagnostic tools.
BJOG 2002; 109: 970–6.
2 Zillikens D. BP180 as the common autoantigen in blistering diseases
with different clinical phenotypes. Keyo J Med 2002; 51: 21–8.
3 Hirako Y, Usukura J, Uematsu J et al. Cleavage of BP180, a
180-kDa bullous pemphigoid antigen, yields a 120-kDa collagen-
4 Schacke H, Schumann H, Hammami-Hauasli N et al. Two forms of
collagen XVII in keratinocytes. A full-length transmembrane pro-
tein and soluble ectodomain. J Biol Chem 1998; 273: 25937–43.
5 Zone JJ, Taylor TB, Meyer LJ, Petersen MJ. The 97 kDa linear IgA
bullous disease antigen is identical to a portion of the extracellular
domain of the 180 kDa bullous pemphigoid antigen, BPAg2.
J Invest Dermatol 1998; 110: 207–10.
6 Hirako Y, Nishizawa Y, Sitaru C et al. The 97 kDa (LABD97) and
120 kDa (LAD-1) fragments of type XVII/BP180 have different
N-termini. J Invest Dermatol, in press.
7 Chimanovitch I, Schmidt E, Messer G et al. IgG1 and IgG3 are the
major immunoglobulin subclasses targeting epitopes within the
NC16A domain of BP180 in pemphigoid gestationis. J Invest Der-
matol 1999; 113: 140–2.
8 Lin MS, Gharia M, Fu CL et al. Molecular mapping of the major
epitopes of BP180 recognized by herpes gestationis autoantibodies.
Clin Immunol 1999; 92: 285–92.
9 Zillikens D, Herzele K, Georgi M et al. Autoantibodies in a subgroup
of patients with linear IgA disease react with the NC16A domain of
BP1801. J Invest Dermatol 1999; 113: 947–53.
Decreased CGRP staining in alopecia areata
SIR, Alopecia areata is an autoimmune disease with geneticand psychosomatic factors. The role of the cutaneous nervoussystem remains unclear, whereas interactions between skin,immunity and the nervous system, defined as the neuro–immuno–cutaneous system (NICS),1 have been frequentlyreported in skin disorders. The nervous system is probablystrongly involved in alopecia areata lesions as the denerva-tion can induce hair growth in affected skin territories.2
Nonetheless, there are very few studies on the cutaneousnervous system in alopecia areata. In this study, our aim wasto determine if there is any modification of NICS in alopeciaareata lesions compared with normal skin.
The study was approved by the ethics committee of Rhone-Alpes ⁄ Loire. Fifteen patients gave written consent. They did nothave any treatment for alopecia areata or any other conditionfor 1 month before taking the biopsies. They were 18–47 yearsold (eight males and seven females). Two biopsies wereperformed on the scalp of all patients: one from the border ofan alopecia areata lesion, and the other one from healthy scalp.
All specimens were immediately frozen in isopentane at)180 �C then preserved at )80 �C. Standard histologicalexamination and immunohistochemistry were performed. Wehave used the three-step immunoperoxidase technique asdescribed by Mason and Sammons.3 Specific monoclonalantibodies were used to recognize CGRP (1 ⁄ 2000, Sigma,Saint Quentin-Fallavier, France), Substance P (1 ⁄ 1000,Sigma) somatostatin (1 ⁄ 100, Chemicon, Hampshire, U.K.),NGF (1 ⁄ 12, Sigma) and NGFR (1 ⁄ 25, Chemicon). Stainingswere revealed by biotinylated secondary antibodies using themethod of Graham and Karnovsky.4 Negative controls wereset up for each immunostaining procedure omitting theprimary antibody. The proportion of positive epidermal cellsfor each neurotransmitter was evaluated using a semiquan-titative grading system as follows: 0, no staining; 1, weakstaining; 2, strong staining. For lymphocyte infiltrates, thegrades were defined as follows: 0, no infiltrate; 1, slight
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infiltration, 2 moderate or heavy infiltration. The stainings onscalp slides were compared with those on brain slides.
In normal scalp as well as in normal skin, CGRP stainingwas detected on nerve fibres and on the basal and suprabasallayers of epidermis and hair follicles (Fig. 1), as strong asbrain controls. In the lesions, the expression of CGRP wasdiminished (grades 0 or 1) in 10 cases (Fig. 2). In three cases,
there was no difference. CGRP expression was greater inlesions than in healthy scalp in two cases.
Substance P expression was found on nerve endings and inthe whole epidermis (mainly suprabasal layers) and hairfollicles. This expression was weakly diminished in alopeciaareara lesions in six patients, not modified in seven cases andenhanced in two patients. Somatostatin, NGF and NGFRimmunostainings were not significantly different betweenhealthy and unhealthy scalp.
We have shown that CGRP expression is decreased inalopecia areata lesions. A previous study indicated that CGRPimmunoreactivity is increased in nerves around eccrineglands of alopecia areata patients.5 A previous work founddecreased CGRP blood amounts in these patients.6 Thesethree studies suggest that CGRP is involved in the patho-physiogeny of alopecia areata. A vasoconstriction, as CGRP isa powerful vasodilator, could favour hair loss. Laser-Dopplerflowmetry was used to study microcirculation of the scalp.Results indicated that patients with alopecia areata havelower basal blood flow and greater vasodilatation followingintradermal CGRP injection than control subjects. A vascularhyperreactivity to vasodilatatory substances such as neuro-peptides, probably because of the lack of these substances,was hypothesized.7 Another hypothesis is that CGRP defici-ency might annihilate a CGRP-promoted tolerance to ahapten or antigen responsible for the autoimmune destruc-tion of hairs in alopecia areata. Indeed, CGRP is able to inducea hapten-specific tolerance.8 The therapeutic effects of ultra-violet radiation (UVR) on alopecia areata could be due to therestoration of CGRP cutaneous amounts through its releaseby cutaneous nerve endings in response to UVR.9
Hence, the role of CGRP deficiency in alopecia areataappears to be related to vascular and immune properties of thisneurotransmitter. Nonetheless, the mechanisms of the CGRPdecrease in alopecia areata remain unknown. We suggest thatCGRP deficiency could be induced by CD10 (or neutralendopeptidase, NEP). CD10 is a membrane-bound peptidase,which cleaves many peptides including CGRP, thereby limit-ing their biological actions. In alopecia areata, affected hairfollicles strongly express this enzyme10 at the margins of areasof hair loss, in the inner portion of the outer root sheath and insome of the outermost cells of the outer root sheath.
CGRP could be used for the treatment of alopecia areatabut, as a neurotransmitter, CGRP could be very rapidlymetabolized. Agonists with a long half-life might be moreinteresting.
Acknowledgment
We thank the Association Alopecia Areata for financialsupport.
D . M e y r o n e t
K . J a b e r *
A . G e n t i l - P e r r e t
F . C a m b a z a r d *
L . M i s e r y *
Departments of Pathology and*Dermatology, University Hospital,Saint-Etienne, FranceCorresponding author: L. MiseryE-mail: [email protected]
Figure 1. Strong expression of CGRP in the epidermis and in hair
follicles in noninvolved scalp.
Figure 2. Dramatic decrease of CGRP expression in the epidermis
and hair follicles in involved scalp.
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References
1 Misery L. Skin, immunity and the nervous system. Br J Dermatol
1997; 137: 843–50.
2 Atkin DH, Levine N, Walter FG. Single patch of hair at a dener-
vated site in a patient with alopecia universalis. J Am Acad Der-
matol 1997; 37: 796–7.
3 Mason DY, Sammons RE. The labeled antigen method of
Milia en plaque: a novel manifestation of chroniccutaneous lupus erythematosus
SIR, The specific cutaneous manifestations of lupus erythe-matosus (LE) are manifold and encompass those of subacutecutaneous LE (SCLE) and discoid LE (DLE) as well as thoseseen in systemic LE. Milia en plaque, occurring de novo, hasnot been described as a manifestation of LE. We present theclinical and histopathological findings of such a case anddiscuss the therapeutic challenges associated with treatingour patient.
A 44-year-old white woman presented with a 5-yearhistory of chronic, progressive facial lesions which beganinsidiously as a solitary yellow papule on an erythematousbase. Over time, they slowly enlarged and become indurated.Several milium-studded plaques were excised without subse-quent recurrence, but new lesions appeared on the chin1 year before presentation. She denied sicca syndromesymptoms or Raynaud’s phenomenon, ulcers, oral aphthae,alopecia, fever or weight loss. She did, however, havearthralgia of the large joints without myalgia or arthritis.
Her past medical history was significant for juvenilerheumatoid arthritis, primary hypothyroidism and mildobesity. Examination revealed two discrete, indurated, disfig-uring, erythematous plaques on the chin, with overlyingyellow papules (Fig. 1a,b). There was prominent follicularplugging in the left conchal bowl. There were no periungualtelangiectases, aphthae, alopecia or evidence of vasculitis.
Full blood count, aminotransferases, alkaline phosphatase,albumin, creatinine, blood urea nitrogen, activated partialthromboplastin time, Westergren erythrocyte sedimentationrate, complements and serum and urine protein electrophor-esis were all within normal limits. Serologies for syphilis(rapid plasma reagin), antinuclear antibodies, precipitins andanticardiolipin antibodies were all negative. Tissue culturesfor mycobacteria, bacteria and fungi were negative.
Skin biopsy (Fig. 2a) revealed numerous milium-like cysticstructures present in follicles, associated with an inter-face ⁄ lichenoid infiltrate. In the dermis there was a perivas-cular and periappendageal inflammatory lymphocyticinfiltrate. Alcian blue staining demonstrated pronouncedinterstitial mucin. Direct immunofluorescence showed heavygranular IgM and weaker IgA, IgG and C3 deposition, mostpronounced along the follicular basement membrane zone(Fig. 2b) without fibrin deposition.
Initial therapy included hydroxychloroquine 200 mg twicedaily and intralesional injection of triamcinolone. She wasmaintained on hydroxychloroquine and later placed on a
papules clustered within a large, indurated, ulcerated and erythe-
matous plaque. (b) Smaller erythematous plaque with clustered milia
at the mental crease.
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10-week tapering dose of oral prednisone starting at0Æ4 mg kg)1 daily, as well as isotretinoin 1 mg kg)1 dailyin divided doses. She then showed rapid improvement in theinflamed and indurated nature of the plaques and in thenumber and size of the milia. Hydroxychloroquine wasmaintained and isotretinoin was discontinued. Smaller resid-ual lesions were treated with tazarotene 0Æ1% cream daily.
While the specific and nonspecific cutaneous manifesta-tions of LE are extensive, the features of the chroniccutaneous LE (CCLE) subset are more limited, encompassingnot only DLE but also hypertrophic LE, as well as lupustumidus and lupus profundus (panniculitis).
Pathological alteration of adnexal structures is frequentlyobserved secondary to a lichenoid ⁄ interface dermatitis asso-ciated with the follicular epithelium, and is a common featureof DLE. These changes manifest clinically by folliculardistortion with dilation, and plugging. Advanced stages offollicular alteration in DLE are associated with surroundingscar formation and drop-out of the pilosebaceous apparatus,
manifesting as cicatricial alopecia, which is a commonmanifestation of DLE.1
DLE and SCLE share many histopathological features, butthe effects on the pilosebaceous units are more pronounced inDLE and pilosebaceous atrophy is the main predictor ofDLE.2,3 Accordingly, follicular plugging is a clinical featurenot seen in SCLE.4 Milium formation is often induced bycutaneous scarring disorders that disrupt the integrity of thebasilar epidermis, basement membrane zone or papillarydermis, as in porphyria cutanea tarda, bullous pemphigoid,epidermolysis bullosa acquisita,5 lichen sclerosus et atrophi-cus6 and lichen planus.7,8
Although histopathologically there was both a lichenoidinfiltrate and mucin present, the pronounced interstitialmucin deposition helps in differentiating this case from bothlichen planopilaris (LPP) and follicular mucinosis. In com-parison with LE, LPP characteristically shows less, if any,interstitial mucin deposition. Further, the mucin seen infollicular mucinosis often involves the outer root sheath of thehair follicle and replacement of the sebaceous apparatus, afinding not present in our case. Our patient’s biopsy showedheavy granular IgM deposition at the basement membranezone without fibrin deposition. These findings are character-istic for lupus, especially DLE.
While one report of milia arising within a previouslyidentified plaque of DLE has been documented,9 the occur-rence of milia en plaque as a de novo manifestation of CCLEhas, to the best of our knowledge, not been reported in theliterature. In our case, histopathological evaluation demon-strated milium cyst formation from follicles affected bypronounced interface ⁄ lichenoid dermatitis of the folliculardermal–epidermal junction. Milium formation in this case ismost likely to be attributable to alteration of the infundibularportion of the follicle, resulting in dysfunctional keratinizationand outlet obstruction.
In summary, we report a new clinical variant of CCLE thatpresents de novo with inflamed milia en plaque lesions on sun-exposed surfaces. Although lacking evidence of systemicdisease, our patient required temporary oral immunosup-pressive therapy. In addition, oral retinoids appeared to play asynergistic role in concert with immunomodulation. Milia enplaque should be considered as a specific manifestation ofCCLE, and LE should be included in the differential diagnosisof such lesions arising de novo on sun-exposed skin.
D . J . K o u b a
N . M . O w e n s
D . M i m o u n i
W . K l e i n *
C . H . N o u s a r i�
Departments of Dermatology and*Pathology, Johns HopkinsUniversity, Baltimore, MD, U.S.A.�Department of Dermatology,Division of Dermatopathology,University of Pennsylvania, 2 RhoadsPavilion, 3600 Spruce Street,Philadelphia, PA 19104-4283,U.S.A.Correspondence: Carlos H.Nousari.E-mail:[email protected]
Figure 2. (a) Photomicrograph of chin biopsy specimen demonstra-
ting a solitary milium cyst with associated basilar vaculopathy and
periappendageal lymphocytic infiltrate (haematoxylin and eosin;
original magnification · 40). (b) Direct immunofluorescence staining
of chin biopsy specimen showing granular IgG deposition at the
basement membrane zone of a dilated and plugged follicle.
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References
1 de Berker D, Dissaneyeka M, Burge S. The sequelae of chronic
Primary cutaneous large cell CD30+ lymphomain a renal transplant recipient
SIR, Solid organ transplant recipients are more at risk ofdeveloping a wide range of viral-associated malignanciesincluding skin tumours and lymphoproliferative disorders.The risk of post-transplant lymphoproliferative disorder(PTLD) is 28–49 times the risk of lymphoproliferative disorderin the normal population.1 Most cases are of B-cell phenotypeand are associated with Epstein–Barr virus (EBV) infection.1–3
We describe a rare primary cutaneous T-cell lymphomaarising in a renal transplant patient.
A 60-year-old man presented with a multinodular, asymp-tomatic lesion on the upper, outer right arm. Over the6 months before presentation, new nodules had appeared andothers had regressed. Examination revealed deep nodularsubcutaneous lesions varying in diameter from 1 to 2 cm,with some smaller more superficial nodules with overlyingerythema (Fig. 1a). There were no discrete erythematousplaques. He had received a cadaveric renal transplant66 months previously for end stage renal failure of unknownorigin and his graft was maintained by mycophenolatemofetil, prednisolone and ciclosporin. He was in good generalhealth at the time of presentation and a blood film wasnormal.
One of the deep nodules was biopsied. Lymphoid nodulesextended from the reticular dermis into the superficial fat(Fig. 1b). The nodules were composed predominantly of largeblast cells displaying an anaplastic morphology (Fig. 1c).Numerous mitoses were present. The atypical lymphocytesinfiltrated and destroyed skin appendages but there was noangioinvasion or epidermotropism.
Immunohistochemical staining of the tumour cells waspositive for CD2 and CD43 but negative for the B-cell markersCD20 and CD79a. They also showed strong expression of
CD30 (Fig. 1d) and were weakly positive for intracytoplasmicCD3. Staining for CD4, CD8, CD56, TIA-1, ALK-1 andepithelial membrane antigen was negative. The proliferationmarker Ki-67 showed positive staining in 70–80% of tumourcells, indicating a high proliferation fraction. Immunostainingfor EBV (latent membrane protein cocktail) was negative.Therefore, the morphology and the immunohistochemicalfindings were consistent with a CD30+ anaplastic large celllymphoma with a T-cell phenotype.
Staging investigations including a bone marrow aspirateand trephine biopsy and staging computed tomography (CT)of the chest, abdomen and pelvis were all negative.Consequently, a primary cutaneous lymphoma was diag-nosed. An unsuccessful attempt was made to induce tumourremission by stopping mycophenolate mofetil to reduceimmunosuppression. Renal function quickly deterioratedand mycophenolate mofetil was reintroduced before it waspossible to determine the effect on the lymphoma. It wasdecided to watch and wait, but 6 months after diagnosisthere was progression of the skin lesions. A course of localradiotherapy resulted in regression of the lesions, but a fewmonths later, and 9 months after presentation, there wasrecurrence of nodules on the arm plus axillary lymphaden-opathy. A right axillary lymph node biopsy confirmed thepresence of T-cell lymphoma at this site and, in addition,suspicious lesions were detected in the right kidney and liver(although not biopsied). Chemotherapy was commencedwith prednisolone, cyclophosphamide, mitoxantrone, etopo-side and vincristine. The initial response, as assessed byclinical examination and repeat CT, was encouraging, butafter six cycles new liver lesions developed and weeklyCAMPATH 1H (anti-CD52 antibody) was commenced. After11 weeks, and 18 months after the original diagnosis oflymphoma, he died of congestive cardiac failure, probablyaggravated by the lymphoma deposits in the myocardiumfound at postmortem.
Knowledge of this rare T-cell PTLD is limited, although fromreports so far it seems that T-cell lymphomas have apredilection for extranodal sites including the graft itself, withthe cutaneous site being very unusual. Most T-cell lymphomasdevelop as a late complication of transplantation, but mayoccur as early as 1 month after transplantation.4 Reportedcases of primary cutaneous T-cell PTLD include a pleomorphicprimary cutaneous lymphoma arising on the lower leg,5 twocases of mycosis fungoides6 and one of Sezary syndrome.7
There has been a recent report of a post-transplantationprimary cutaneous CD30+ large cell lymphoma.8
CD30+ cutaneous lymphomas can be divided into primarycutaneous or secondary types (representing spread of nodallymphoma or transformation of mycosis fungoides). CD30+large cell tumours may be further divided, on the basis ofmorphology, into anaplastic, large pleomorphic and immu-noblastic types and are of T-cell or null-cell phenotype. TheCD30+ primary cutaneous large cell lymphomas, irrespect-ive of the cytomorphology, form a distinct subgroupcharacterized by a male preponderance, a propensity forspontaneous regression and a favourable prognosis,9,10 but
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� 2003 British Association of Dermatologists, British Journal of Dermatology, 149, 419–446
whether this holds true in the immunosuppressed patient isunknown.
Our patient presented some management difficulties for tworeasons. First, the optimum treatment of T-cell PTLD remainsundefined. Although some B-cell PTLDs have been shown toundergo partial or complete regression by reduction ofimmunosuppression, T-cell tumours probably respond lesswell. Secondly, was it justifiable to risk the loss of the renalallograft by reducing immunosuppression in a tumour withan excellent prognosis in a non-transplant setting? Ourpatient was therefore treated with radiotherapy, which is theconventional treatment for such tumours. There are insuffi-cient data to comment on whether such tumours have apoorer prognosis in renal transplant recipients, as in aminority of cases, non-immunosuppression-related tumourskill the patient. Nevertheless, the tumour followed anaggressive course in our patient.
S . M . C o o p e r
G . D . H . T u r n e r *
K . H o l l o w o o d *
K . G a t t e r *
C . H a t t o n�D . G r a y�
R . R u s s e l l - J o n e s §
F . W o j n a r o w s k a
Departments of Dermatology,*Pathology, �Haematology and�Renal Transplantation, OxfordRadcliffe Hospitals, Oxford OX3 7LJ,U.K.§Skin Tumour Unit, St John’sInstitute of Dermatology, St Thomas’Hospital,London SE1 7EH,U.K.Correspondence: Dr S.M.Cooper,Department of Dermatology,Churchill Hospital,Headington,Oxford OX3 7LJ,U.K.E-mail: [email protected]
Figure 1. (a) Nodular lesions involving the skin of the upper arm. (b) Photomicrograph showing nodules within the reticular dermis (haema-
toxylin and eosin; original magnification ·25). (c) Nodules are composed of large anaplastic cells, including some with reniform nuclei (so-called
hallmark cells) (haematoxylin and eosin; original magnification ·400). (d) Immunostaining for CD30 (original magnification ·400).
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References
1 Penn I. Lymphoproliferative diseases in disorders of the immune
system. Cancer Detect Prev 1990; 14: 415–21.
2 Penn I. The changing pattern of posttransplant malignancies.
Transplant Proc 1991; 23: 1101–3.
3 Dockrell DH, Strickler JG, Paya CV. Epstein-Barr virus-induced T
cell lymphoma in solid organ transplant recipients. Clin Infect Dis
1998; 26: 180–2.
4 Yasunaga C, Kasai T, Nishihara G et al. Early development of
Epstein-Barr associated T-cell lymphoma after a living-related
occurrence of T-cell and B-cell lymphomas after renal transplan-
tation in a patient with multiple cutaneous squamous-cell carci-
nomas. N Engl J Med 1992; 27: 1924–6.
8 Seckin D, Demirhan B, Oguz Gulec T et al. Posttransplantation
primary cutaneous CD30 (Ki-1)-positive large cell lymphoma. J
Am Acad Dermatol 2001; 45 (Suppl. 6): 196–9.
9 Stein H, Foss HD, Durkop H et al. CD30+ anaplastic large cell
lymphoma: a review of its histopathologic, genetic, and clinical
features. Blood 2000; 96: 3681–95.
10 Bekkenk MW, van Geelen FAMJ, Voorst Vader PC et al. Primary
and secondary cutaneous CD30+ lymphoproliferative disorders: a
report from the Dutch Cutaneous Lymphoma Group on the long-
term follow up data of 219 patients and guidelines for treatment.
Blood 2000; 95: 3653–61.
Significance of iron status in hair loss in women
SIR, We read with interest Sinclair’s recent study1 concludingthat there is no clear association between chronic diffusetelogen hair loss in women and low iron stores. At a recentinternational meeting attended by many of the worldauthorities on hair disorders (European Hair Research Soci-ety, Brussels, 27–30 June 2002) we hosted an open debate onthe topic of diffuse hair loss in women, particularly concen-trating on the role of iron.2 Sinclair’s findings are in supportof our clinical experience and interpretation of the litera-ture—that the significance of iron deficiency in hair loss isdubious, despite textbook references to the contrary.3,4 In ouropinion, there are several limitations with respect to theliterature concerning this possible association and theseinclude: (i) variation in the biochemical definition of irondeficiency by gender and between laboratories; (ii) difficulty inisolating iron status from other variables that affect hairgrowth; (iii) lack of confirmation of iron deficiency as arelevant cause of hair loss by replacement therapy withmeaningful follow-up over time; and (iv) lack of consensusregarding the ideal means of measuring hair growth andresponse to therapy.5 Indeed, the first limitation has been thesubject of hot debate just recently.6,7 It must also be pointedout that some of the more emphatic papers suggesting asignificance for iron status in hair loss have really onlyexamined small numbers of women.8 While one may arguethat Sinclair’s period of follow-up is too short to detectmeaningful regrowth (which he acknowledges), one would
certainly expect a reduction in shedding in those women inwhom iron status was relevant (and this was not observed inhis study). For the reasons stated above, in our hair clinic wetoo are reluctant to attribute chronic and diffuse hair loss inwomen to iron deficiency too readily when, in reality, this isusually more likely to be due to androgenetic alopecia orchronic telogen effluvium. It is equally curious to us whyyoung women and even girls with iron deficiency due tomenorrhagia rarely present to dermatologists with hair loss!
A . J . C h a m b e r l a i n ,
R . P . R . D a w b e r
Department of Dermatology,Churchill Hospital, Old Road,Headington, Oxford OX3 7LJ, U.K.E-mail: [email protected]
References
1 Sinclair R. There is no clear association between low serum ferritin
5 Chamberlain AJ, Dawber RPR. Methods of evaluating hair growth.
Australas J Dermatol 2003; 44: 10–18.
6 Rushton DH, Dover R, Sainsbury AW et al. Why should women
have lower reference limits for haemoglobin and ferritin concen-
trations than men? Br Med J 2001; 322: 1355–7.
7 Waalen J, Felitti V, Beutler E. Haemoglobin and ferritin concen-
trations in men and women: cross sectional study. Br Med J 2002;
325: 137.
8 Rushton DH, Ramsay ID. The importance of adequate serum
ferritin levels during oral cyproterone acetate and ethinyl oestra-
diol treatment of diffuse androgen-dependent alopecia in women.
Clin Endocrinol 1992; 36: 421–7.
Factors affecting the choice of a ceiling on the numberof exposures with TL01 ultraviolet B phototherapy
SIR, Recommending the maximum number of lifetimeexposures in order to limit the risk of phototherapy-inducedskin cancer is best achieved from recorded incidence data as aconsequence of the therapy. These data are not yet availableand it will be a decade or more before we can expect them.In the meantime, the most defensible approach is to incor-porate mathematical models of skin cancer incidence withestimates of human exposure to both sunlight and thera-peutic ultraviolet (UV) B in order to arrive at risk estimates.
Risk analysis of human skin cancer. Estimates of the risk ofinducing skin cancer from exposure to UV radiation demandknowledge of dose–response relationships and the relativeeffectiveness of different wavelengths (known as an action
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� 2003 British Association of Dermatologists, British Journal of Dermatology, 149, 419–446
spectrum) in inducing skin cancer. Data on dose–responserelationships and action spectra are available to some extentto allow quantitative estimates of the effects of TL01phototherapy on nonmelanoma skin cancer (NMSC) inci-dence, but remain unknown for malignant melanoma.
Application of multivariate analysis to population-basedepidemiology of NMSC, combined with data from a mousephototumorigenesis model, has shown that, for a group ofsubjects with a given genetic susceptibility, age and environ-mental UV exposure are the two most important factors indetermining the relative risk. The risk of NMSC at age T canbe expressed mathematically as:
Risk � ðcumulative UV dose at age T Þ��1Xt¼T
t¼0
ðannual dose at age½T � t�Þt���
The symbols a and b are numerical constants associatedwith the specific type of NMSC and are normally derived fromsurveys of skin cancer incidence and UV climatology. Inkeeping with other model estimates, exemplary values ofa and b are 5 and 2, respectively,2 and these values will beused here for NMSC considered as a single entity.
Human exposure to sunlight. Personal dosimetry studiesindicate that indoor workers in northern Europe receive anannual exposure of about 200 standard erythema doses(SED), mainly from sun exposure during summer weekendsand vacations.3 Children have a greater opportunity foroutdoor exposure and receive an annual dose in the U.K. ofabout 300 SED.3 One SED is equivalent to an erythemalweighted exposure dose of 100 J m)2; a minimal erythemaon unexposed skin in subjects with skin types I–IV would beexpected to require an exposure of between 1Æ5 and 6 SED. Inthe analysis presented here it is assumed that the erythemaaction spectrum is an adequate surrogate for NMSC and sodoses expressed in SED from both sunlight and TL01 lampsare used in risk calculations.
TL01 phototherapy exposure. Broadly speaking, clinicalstudies indicate that two-thirds of patients clear in 15–30treatments over a period of 5–10 weeks with a cumulativeUV dose of 10–40 J cm)2. For the purpose of estimatingthe risk of TL01 phototherapy, assume an exemplary value
of 25 J cm)2 per course (equivalent to 140 SED as 1 J cm)2
of TL01 radiation results in an erythemal effective exposure of5Æ7 SED). This exposure is generally to the whole body, incontrast to sun exposure, which is normally to exposed sites(hands, face and neck), estimated to be 10% of the bodysurface area. Treatment courses are normally given eitheronce or twice a year, and this has an effect on the lifetime riskof skin cancer as illustrated below.
Many centres recognize the need to shield the face (if it isnot involved with psoriasis) during UVB phototherapy, as itreceives frequent exposure to sunlight and is the mostcommon site for NMSC. Risk calculations have been made,therefore, for the face both shielded and unshielded duringTL01 exposure.
How many treatments? In recommending a ceiling num-ber of treatments, we need to consider what is an‘acceptable’ increased risk of NMSC resulting from TL01phototherapy. It might be reasonable to presume that arisk-averse patient would only accept a 20% increase inlifetime risk of NMSC as a consequence of their photother-apy, with risk factors of 1Æ5-fold and 2-fold for patientswith an ‘average’ attitude to risk and a those who are risk-takers, respectively. So using the model described abovewith the input factors of exposure due to sunlight andTL01 lamps, and with appropriate allowance for differencesin the area of the body normally exposed to sunlight andwhole body phototherapy, we arrive at the results shownin Table 1.
These estimates presume that TL01 radiation is equallyeffective as sunlight in inducing NMSC for the same erythe-mal exposure. Suppose that this is not the case and that,erythema-for-erythema, TL01 is twice as carcinogenic assunlight, as may be inferred from animal studies compar-ing response to broad-band and narrow-band exposure.4
Repeating the risk calculations gives the results shown inTable 2.
In conclusion, the choice of a maximum number oftreatment exposures for patients undergoing TL01 narrow-band UVB phototherapy depends not only on objectiveestimates of skin cancer risk (and the uncertainties associated
Table 1. Risk calculations made assuming
that TL01 radiation is as equally carcinogenic
as sunlight Attitude
to risk
Relative
lifetime riska
Maximum no. treatments Years of treatmentb
Face
shielded
Face
unshielded
Face
shielded
Face
unshielded
One treatment course per year
Risk-averse 1Æ2 500 200 20 8
Average 1Æ5 > 1000 450 > 40 18
Risk-taker 2Æ0 > 1000 1000 > 40 40
Two treatment courses per year
Risk-averse 1Æ2 400 150 8 3
Average 1Æ5 700 350 14 7
Risk-taker 2Æ0 1200 700 24 14
aThis is the risk of nonmelanoma skin cancer relative to someone not undergoing TL01 phot-
otherapy. bEstimated assuming 25 treatments per course.
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with these estimates for narrow-band UVB exposure) but alsoon factors such as whether or not the face is shielded duringphototherapy, the frequency with which treatment coursesare repeated and, not least, each patient’s attitude to therisks of the treatment. Strategies for reducing the lifetimerisk of NMSC consequent to TL01 phototherapy are to limittreatment courses to once per year, if possible, and toshield the face during phototherapy, if clinically appropri-ate.5
It should be emphasized that these figures should be treatedwith caution until epidemiological data emerge from humanTL01 cancer studies currently under way. However, it wouldbe prudent to identify those patients whose cumulativetreatment has exceeded the ceilings estimated above forrisk-takers and to follow them up for evidence of skin cancer.Finally, it should be recognized that these ceiling estimatesmust be used in conjunction with clinical judgement in casesof severe psoriasis where the alternative to phototherapymight be potent systemic agents such as methotrexate andciclosporin.
B . L . D i f f e yRegional Medical PhysicsDepartment, Newcastle GeneralHospital, Newcastle upon TyneNE4 6BE, U.K.E-mail: [email protected]
References
1 National Radiological Protection Board. Health Effects from Ultra-
violet Radiation. Report of an Advisory Group on Non-ionising
Radiation. Documents NRPB 1995; 6(2): 143.
2 Diffey BL. Cosmetic tanning and human skin cancer. In: Skin
Cancer: Mechanisms and Human Relevance (Mukhtar H, ed.). Boca
Raton, FL: CRC Press, 1995; 31–7.
3 Diffey BL. Human exposure to ultraviolet radiation. In: Photoder-
A unique case of sarcoidosis: coexistence of sarcoidalgranuloma and histological changes consistent withdermatomyositis
SIR, Sarcoidosis is a systemic granulomatous disease ofunknown aetiology that sometimes accompanies variousautoimmune diseases. Aronson et al. reported a case ofsarcoidosis coexisting with collagen vascular disease.1 Intheir case, histopathological features of sarcoidal granulomasand lupus erythematosus occurred in the same lesion. Theysuggested that the coexistence of sarcoidosis with autoim-mune collagen vascular disease might be more than coinci-dence. We report a patient who had both sarcoid granulomaand the findings of dermatomyositis in the same rash. This isthe first report of a case showing histological changes of bothsarcoidosis and dermatomyositis in the same skin lesion.
A 62-year-old woman had had erythema on her face anddorsal hands for 18 months and muscle weakness in theproximal part of the lower extremities for a year. She wasdiagnosed as having uveitis 1 year previously; however, chestX-ray and serum level of angiotensin-converting enzyme(ACE) at that time were normal. When she visited our clinic,we found telangiectasia on her cheeks and small brownpapules on her bilateral temples (Fig. 1A), and erythemawithout infiltration on the dorsum of her hands (Fig. 1B).Laboratory evaluation was as follows: erythrocyte sedimen-tation rate 20 ⁄ 54 mm, C-reactive protein 0Æ5 mg dL)1, ACE31Æ1 U L)1 (normal 7Æ0–25Æ0), serum Ca 10Æ3 mg dL)1
(normal 3Æ6–31Æ2), antinuclear antibody 64Æ7 index (normal< 12). Anticentromere protein-B antibody was 158Æ9 index(normal < 20), whereas rheumatoid factor and anti-DNA,anti-SS-A, anti-SS-B, anti-Jo-1, anti-Sm, anti-RNP and anti-Scl-70 antibodies were normal. The creatine phosphokinase(CPK) level was normal. Chest X-ray and chest computed
Attitude to
risk
Relative
lifetime riska
Maximum no. treatments Years of treatmentb
Face
shielded
Face
unshielded
Face
shielded
Face
unshielded
One treatment course per year
Risk-averse 1Æ2 200 75 8 3
Average 1Æ5 350 175 14 7
Risk-taker 2Æ0 600 350 24 14
Two treatment courses per year
Risk-averse 1Æ2 150 50 3 1
Average 1Æ5 275 150 5 3
Risk-taker 2Æ0 450 275 9 5
aThis is the risk of nonmelanoma skin cancer relative to someone not undergoing TL01
phototherapy. bEstimated assuming 25 treatments per course.
Table 2. Risk calculations made assuming
that TL01 radiation is twice as carcinogenic
as sunlight
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tomography revealed bilateral lymphadenopathy, but therewere no findings of interstitial pneumonia.
Skin biopsies were taken from her temple and dorsal hand.The specimen from a papule on her temple showed sarcoidalgranuloma in the dermis (Fig. 2A). The specimen from theerythema of her dorsal hand showed small epithelial gran-uloma accompanied by epidermal atrophy, vacuolar alterna-tion of basal layer keratinocytes and a lymphocyticinflammatory infiltrate around blood vessels in the upperdermis (Fig. 2B). Direct immunofluorescence of the erythe-matous lesion of her dorsal hand displayed deposits ofcomplement C3, IgA and IgM, but no IgG at the dermoep-idermal junction. Although a muscle biopsy specimen showedneither sarcoidal granuloma nor findings of myositis, anelectromyogram was indicative of sarcoid myopathy and wasnot indicative of dermatomyositis. A diagnosis of sarcoidosiswith sarcoid myopathy and amyopathic dermatomyositis wasmade.
Sarcoidosis is rarely associated with dermatomyositis.2–7
In 1976 Ogawa et al. reported the first case of sarcoidosiswith dermatomyositis.2 In 1980, Itoh et al. reported a caseof a sarcoid myopathy with a rash of dermatomyositis. Inboth reports, skin biopsy showed the histological changes of
dermatomyositis only and muscle biopsy showed sarcoidalgranuloma. In other reports, detailed histological findings ofthe skin rash were not mentioned. Brateanu et al. reviewedsix cases of dermatomyositis associated with sarcoidosispreviously reported in the world literature;7 they assumedthe possibility of genetic predisposition because three of thesix cases were in Japanese patients. In four of the casesACE level was normal and in five cases serum CPK levelwas low, although it is usually significantly increased indermatomyositis. Two of the cases were negative for musclegranuloma. Also in our case, the patient was Japanese andnegative for muscle granuloma, the serum ACE was mildlyincreased and the CPK level was low. The authorssuggested that steroid treatment for the myositis couldhave normalized the ACE; however, our patient’s ACE wasnot high before treatment with steroids.
In summary, sarcoidosis shows various types of clinicalfeatures. One of our biopsy specimens showed the histolog-ical finding of sarcoidosis simply, but the other biopsyspecimen revealed dermatomyositis in our patient. Thus it isimportant to examine each rash when one patient hasvarious clinical features. Especially in cases of sarcoidosisassociated with dermatomyositis with low ACE, low CPK and
Figure 1. (A) Papules on the temple; (B) erythema on the dorsum of the hands.
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negativity for muscle granuloma, skin biopsy is useful fordiagnosis.
Acknowledgment
We thank Mr T.Imai for technical assistance.
A . I t o
T . K a z a m a
M . I t o
Department of Dermatology, NiigataUniversity School of Medicine, 1-757Asahimachi-dori, Niigata 951-8510,JapanE-mail: [email protected]
References
1 Aronson PJ, Fretzin DF, Morgan NE. A unique case of sarcoidosis
with coexistent collagen vascular disease. Possible result of a
compatible disease-sustaining immunologic environment. J Am
Acad Dermatol 1985; 13: 886–91.
2 Ogawa K, Hongo O, Sekiguchi T. Dermatomyositis-like symptoms
by muscle sarcoidosis. Rinshyo Derm (Tokyo) 1976; 18: 993–9.
3 Itoh J, Akiguchi I, Midorikawa R et al. Sarcoid myopathy with
typical rash of dermatomyositis. Neurology 1980; 30: 1118–21.
4 Hart Y, Schwartz MS, Bruckner F et al. Relapsing dermatomyositis
associated with sarcoidosis. J Neurol Neurosurg Psychiatry 1988;
51: 311–13 (Letter).
5 Takano Y, Oida K, Kohri Y et al. [Dermatomyositis complicated by
6 Lipton JH, McLeod BD, Brownell AK. Dermatomyositis and gran-
ulomatous myopathy associated with sarcoidosis. Can J Neurol Sci
1988; 15: 426–9.
7 Brateanu AC, Caracioni A, Smith HR. Sarcoidosis and derma-
tomyositis in a patient with hemoglobin SC. A case report and
literature review. Sarcoidosis Vasc Diffuse Lung Dis 2000; 17:
190–3.
Exacerbation of psoriasis by thalidomide in Behcet’ssyndrome
SIR, We report a 46-year-old woman with severe orogenitalulceration as the dominant feature of Behcet’s syndrome. Thiswas unresponsive to a variety of topical and systemic agents,including dapsone and colchicine. She also exhibited minorstable chronic plaque psoriasis of the elbows only [PsoriasisArea and Severity Index (PASI) score < 5], which wasuntreated and had not flared significantly in its 5-yearduration. Due to the severity of her orogenital symptoms, atrial of low-dose thalidomide (50 mg daily) was commenced.Within 4 days this was stopped by the patient, due to a severeand progressive eruption of her psoriasis. This took the formof small plaque psoriasis (PASI score 15). There was nochange in her orogenital symptoms, as expected during thisshort time. She was started on methotrexate 7Æ5 mg weeklyand her psoriasis became stable again on methotrexate15 mg weekly after 3 months. This also had no effect on herorogenital symptoms, and she is currently being assessedwith a view to ciclosporin treatment of her Behcet’ssyndrome.
Thalidomide has been shown to have anti-inflammatory,immunomodulatory and antiangiogenic properties.1
Thalidomide modifies T-cell function. A decrease in theCD4 ⁄ CD8 ratio has been demonstrated in the blood ofhealthy men treated with thalidomide.2 In vitro, thalidomideconverts lymphocyte responses from T-helper cell type (Th)1 [interferon-c, tumour necrosis factor (TNF)-a, interleukin(IL)-2] to Th2 (IL-4, IL-5).2,3 However, in vivo there areconflicting reports on the effect of thalidomide on the pivotalcytokine TNF-a. TNF-a acts by regulating the host immuneand inflammatory responses to infection. It is also felt toplay a crucial role in a variety of inflammatory diseases,such as psoriasis and rheumatoid arthritis, for which theanti-TNF-a antibody infliximab, and the soluble TNF-areceptor etanercept, have been shown to be therapeuticallypromising.4,5 By enhancing the degradation of mRNA,thalidomide was initially found to act as a potent inhibitorof TNF-a production in vitro and in vivo.6 Recent reportssuggest that the effect of thalidomide on TNF-a is bidirec-tional, with both enhancing and inhibitory effects onproduction reported.
Figure 2. (A) Photomicrograph of a papule showing sarcoidal
granuloma (haematoxylin and eosin; original magnification · 10).
(B) Photomicrograph of erythema showing granuloma and vacuolar
alternation of basal layer keratinocytes (haematoxylin and eosin;
original magnification · 10).
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Thalidomide has been used in the treatment of Behcet’sdisease7 and other inflammatory dermatoses.8 Its beneficaleffect has been attributed to its known suppressive actionon TNF-a production.8 However, Wolkenstein et al. showedincreased mortality in toxic epidermal necrolysis, associatedwith increased TNF-a levels,9 and Oliver et al. showedincreased TNF-a levels in scleroderma treated with thalido-mide.10 Only one previous report of thalidomide treatmentof psoriasis is documented in an open trial of 35 patientswith a variety of dermatological conditions, in whichtreatment of two patients with psoriasis was unsuccessful.11
We hypothesize that the flare in our patient’s psoriasis wasmediated by a thalidomide-induced increase in TNF-awithin the psoriatic lesions. Our observation is importantin that it provides further evidence of a bidirectional effectof thalidomide on TNF-a, and illustrates that even mildstable chronic plaque psoriasis can undergo a dramaticflare with thalidomide. The factors that determine whetherthalidomide stimulates or suppresses TNF-a in a particulardisease are not yet clear: differential effects of thalidomideon TNF-a production have been described, respectively,during inflammatory stimulation and the subsequentT-lymphocyte response.12 TNF-a levels in response tothalidomide have also been observed to vary in differenttissues.13 Polymorphisms of the TNF-a gene have beenreported as influencing the response to thalidomide in thetreatment of myeloma.14 It is noteworthy that the absenceof flaring of psoriasis in response to thalidomide in twopreviously reported cases11 was equally associated with alack of improvement. It may be that thalidomide has aTNF-a-stimulatory effect in all patients with psoriasis, butthat TNF-a polymorphisms lessen or minimize this effect insome patients.
We suggest that clinicians proceed with extreme caution ifthalidomide is clinically indicated in a patient with coexistentpsoriasis.
C . M . D o b s o n
R . A . P a r s l e w *
Departments of Histopathology and*Dermatology, Royal LiverpoolHospitalLiverpool L7 8XPU.K.
References
1 Tseng S, Pak G, Washenik K et al. Rediscovering thalidomide:
a review of its mechanism of action, side effects, and potential
ison of thalidomide versus placebo in toxic epidermal necrolysis.
Lancet 1998; 352: 1586–9.
10 Oliver SJ, Moreira A, Kaplan G. Immune stimulation in sclero-
derma patients treated with thalidomide. Clin Immunol 2000; 97:
109–20.
11 Naafs B, Faber WR. Thalidomide therapy. An open trial. Int J
Dermatol 1985; 24: 131–4.
12 Marriott JB, Clarke IA, Dredge K et al. Thalidomide and its ana-
logues have distinct and opposing effects on TNF-alpha and
TNFR2 during co-stimulation of both CD4 (+) and CD8 (+) T cells.
Clin Exp Immunol 2002; 130: 75–84.
13 Cao Z, Joseph WR, Browne WL et al. Thalidomide increases both
intra-tumoural tumour necrosis factor-alpha production and anti-
tumour activity in response to 5,6-dimethylxanthenone-4-acetic
acid. Br J Cancer 1999; 80: 716–23.
14 Neben K, Mytilineos J, Moehler TM et al. Polymorphisms of the
tumor necrosis factor-alpha gene promoter predict for outcome
after thalidomide therapy in relapsed and refractory multiple
myeloma. Blood 2002; 100: 2263–5.
Solitary sclerotic fibroma of the lip
SIR, Sclerotic fibroma (SF) is a rare peculiar type of dermalfibroma. SF was first described to be associated with Cowden’sdisease by Weary et al.1 and is now considered to be acutaneous hallmark of this cancer-prone genodermatosis onlywhen it is multiple.2,3 Consequently, the occurrence of asolitary SF may not allow the dermatologists to suggest thediagnosis of Cowden’s disease. Although oral manifestationsare common in Cowden’s disease, multiple mucosal papulesand nodules typically are simple fibroepithelial hyperplasia4
and SF is a very rare complication.1 To our knowledge, noneof the cases of sporadic SF described in the British literatureinvolved the oral mucosa. We observed a solitary mucosaltumour of the lip that fulfilled the diagnostic criteria of SF in apatient without Cowden’s disease.
A 64-year-old woman had a painless, slowly enlargingmass on the lower lip of 1-year duration. There were no signsof Cowden’s disease in the patient and her family members.On examination, a solitary, 7 · 6 · 5 mm, firm, mobilenodule was found (Fig. 1a). At operation, three small lobulesof salivary glands were attached to the tumour. There wasno evidence of recurrence or a new lesion. Histologicalexamination showed a rounded, sharply demarcated fibro-collagenous tumour in the submucosa (Fig. 1b). A denseproliferation of hypocellular hyalinized bands of collagen withprominent empty clefts were arranged in a peculiar whorledor plywood pattern (Fig. 1c). A few spindle-shaped tumourcells were entrapped among the thick bundles, but the major
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part of the lesion was acellular. These cells were immunore-active with vimentin, factor XIIIa and CD34 (Fig. 1d). Bcl-2,factor VIII-related antigen, smooth muscle actin, S-100protein and Ki-67 were uniformly negative in tumour cells.
In 2000, Lombardi et al.5 presented two cases of oral SF inpatients not affected by Cowden’s disease; one of themoccurred in the lower lip. Because it was a poster abstract,corroborative pathological data were not available. Therefore,this report is the first to describe a solitary SF involving themucosal surface of the lip.
The nature and pathogenesis of SF are still in dispute. Theoccurrence of identical lesions in patients with Cowden’sdisease presents evidence to support the concept that SF is adistinct hamartoma of a specialized fibroblastic lineage withdifferentiation toward the dermal dendrocyte. In contrast, theclinicopathological features of sporadic SF are somewhatdifferent in many aspects. Some tumours recurred afterexcision,6,7 while others did not. It is well-known that focalareas of SF have been observed in other neoplastic orinflammatory lesions,6–9 such as fibroma of the tendonsheath, dermatofibroma, neurofibroma, pleomorphic fibromaand folliculitis. Moreover, inconsistent expression of CD34,
proliferating cell nuclear antigen and Ki-67 has beenreported.6,8,9 Marked differences in biological, histologicaland immunohistochemical profiles may account for theheterogeneity of the published SF.
The lower lip is the most common site of salivary mucoceles(mucous cysts). More interesting is that organizing mucocelessometimes showed features reminiscent of fibroma of thetendon sheath.10 On the other hand, clear similaritiesbetween SF and dermal nodules of fibroma of the tendonsheath have been discussed repeatedly.7,11 On the basis ofthese observations, together with the lack of proliferationactivity in the present lesion, the possibility that our SF is apeculiar form of fully organized mucocele cannot be com-pletely ruled out.
F . I d e
K . M i s h i m a
I . S a i t o
Department of Pathology, TsurumiUniversity, School of DentalMedicine, 2-1-3 Tsurumi,Tsurumi-ku, Yokohama 230-8501,JapanCorrespondence: Fumio Ide.E-mail: [email protected]
Figure 1. (a) Normal coloured tumour of 7-mm diameter on the mucosal surface of the lower lip. (b) A well-circumscribed collagenous tumour
(haematoxylin and eosin, original magnification ·10). (c) Hypocellular hyalinized collagen bundles arranged in a plywood pattern (haematoxylin
and eosin, original magnification ·100). (d) Tumour cells are positive for CD34 (immunostaining, original magnification ·200).
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sclerotic fibroma of the skin. Am J Dermatopathol 1999; 21: 571–4.
8 Chen TM, Purohit SK, Wang AR. Pleomorphic sclerotic fibroma. A
case report and literature review. Am J Dermatopathol 2002; 24:
54–8.
9 Chang S-N, Chun SII, Moon TK, Park W-H. Solitary sclerotic
fibroma of the skin: degenerated sclerotic change of inflammatory
conditions, especially folliculitis. Am J Dermatopathol 2000; 22:
22–5.
10 Pulitzer DR, Martin PC, Reed RJ. Fibroma of tendon sheath. A
clinicopathologic study of 32 cases. Am J Surg Pathol 1989; 13:
472–9.
11 Watanabe T, Sasaki T, Ogata F et al. Sclerotic fibroma of tendon
sheath. Dermatology 1997; 195: 263–5.
Eruptive seborrhoeic keratosis in humanimmunodeficiency virus infection: a coincidenceor ‘the sign of Leser-Trelat’?
SIR, Seborrhoeic keratosis is a very frequent pigmentedgrowth seen mostly among the elderly population.1 Althougha benign entity, showers of seborrhoeic keratoses may eruptconcomitantly with internal malignancies.1 We describe apatient with human immunodeficiency virus (HIV) infectionwho presented with eruptive seborrhoeic keratosis withoutdemonstrable evidence of internal malignancy.
A 32-year-old male office worker with promiscuousbehaviour was referred for dermatological consultationregarding sudden-onset, multiple, pruritic, hyperpigmentedpapular lesions over the head, chest and back of 3 weeks’duration. In the past, he had had repeated, unprotected,heterosexual contact with commercial sex workers. Hedenied habits of any substance abuse. He had been sufferingfrom pyrexia of unknown origin with significant weight lossfor the previous 6 months, for which he sought medicaladvice. On investigation, he was found to be HIV positivewith a CD4+ T-cell count of 300 mm)3. He was started on afixed-dose combination of nevirapine, stavudine and lami-vudine which he had taken regularly for the past 2 monthswithout significant side-effects. Presently, the rapid increasein number and size of the skin lesions had caused concern tothe patient.
On local cutaneous examination, multiple, brownish-black papules with a dull, hyperkeratotic surface were
found scattered over the vertex, frontal scalp, forehead(Fig. 1), upper back and chest. Individual lesions had atypical ‘stuck-on’ appearance, clinically suggestive ofseborrhoeic keratosis. Close grouping and koebnerizationwere not observed in the distribution of the lesions.Thorough clinical examination did not reveal the presenceof any internal malignancy. Complete haemogram, chestX-ray, upper gastrointestinal endoscopy and barium enemaruled out the possibility of common occult malignancies.Histopathological examination of the lesions showed epi-dermal changes in the form of marked hyperkeratosis andacanthosis in a church spire pattern, consistent withseborrhoeic keratosis. A diagnosis of multiple eruptiveseborrhoeic keratosis was made and the patient was keptunder surveillance.
The sign of Leser-Trelat describes the concomitantoccurrence of visceral malignancy and sudden-onset erup-tive seborrhoeic keratosis.1 Although there is controversyabout the validity of this sign, it is considered as aparaneoplastic syndrome.1,2 However, this clinical entitycan also be encountered in association with other inflam-matory dermatoses, generalized dermatitis,2 benign neo-plasms3 and pregnancy.4 Our patient did not have anyother obvious skin lesions, nor was there evidence ofvisceral or haematological malignancies. Although uncom-mon, other eruptive dermatoses in HIV-infected patientshave been described. Duvic et al.5 have reported sevensymptomatic HIV-infected patients with eruptive dysplasticnaevi, which appeared as multiple new moles. Multipleeruptive dermatofibromas6 have also been described in HIV-infected patients.
In the pathogenesis of the sign of Leser-Trelat, the role oftumour-derived circulating epidermal growth factors such astransforming growth factors (TGFs) and melanocyte-derivedgrowth factors acting on keratinocytes has been proposed.2,3
The role of platelet-derived growth factor, TGF-a and TGF-b inthe genesis of neoplasms such as Kaposi’s sarcoma in HIV-
Figure 1. Multiple lesions of seborrhoeic keratosis over the forehead.
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� 2003 British Association of Dermatologists, British Journal of Dermatology, 149, 419–446
infected persons is well known.7 There is the possibility of asimilar phenomenon giving rise to this clinical feature in ourpatient.
Another potential mechanism for these lesions relates tothe possible role of human papillomavirus (HPV) as anaetiological factor in seborrhoeic keratosis.2 HPV DNA hasbeen isolated from seborrhoeic keratosis in the genital area,and rarely from lesions at other sites.8 It is possible thatimmunosuppression due to HIV may allow overgrowth oflatent HPV and contribute to development of seborrhoeickeratosis, although the histological examination did not showviral changes and we were unable to probe for HPV DNA inour patient’s lesions. Whether there is a true causative linkbetween HIV and seborrhoeic keratoses, and the mechanismfor such an association, must therefore remain uncertain atpresent.
A . C . I n a m a d a r
A . P a l i t
Department of Dermatology,Venereology and Leprology, BLDEA’sSBMP Medical College, Hospital andResearch Centre, Bijapur 586103,Karnataka, IndiaE-mail: [email protected]
References
1 MacKie RM. Epidermal skin tumours. In: Textbook of Dermatology
(Champion RH, Burton JL, Burns DA, Breathnach SM, eds), 6th
with human immunodeficiency virus infection. Arch Dermatol
1989; 125: 397–401.
6 Kanitakis J, Carbonnel E, Delmonte S et al. Multiple eruptive der-
matofibromas in a patient with HIV infection: case report and lit-
erature review. J Cutan Pathol 2000; 27: 54–6.
7 Roth WK, Brandstetter H, Sturzl M. Cellular and molecular features
of HIV associated Kaposi’s sarcoma. AIDS 1992; 6: 895–913.
8 Zhu WY, Leonardi C, Penneys NS. Detection of human papilloma
virus DNA in seborrheic keratosis by polymerase chain reaction.
J Dermatol Sci 1992; 4: 166–71.
Raised limb bands developing in infancy
SIR, We read with interest the recent article by Meggitt et al.1
which described two patients with raised limb bands thatbecame apparent postnatally. We too have seen an infantwith similar ‘raised limb bands’, and agree that this distinctcutaneous finding probably represents an entity different from‘amniotic bands’.
A 13-month-old boy was referred for consultation regard-ing linear lesions on the back of his lower legs. He had had anormal perinatal period and was not born prematurely. Thebands were first noted within the first 2 months of life, butwere not present at birth. They were asymptomatic and hadnot changed since their initial appearance. The patient wasotherwise healthy, except for transient hyperbilirubinaemiaduring the first few days of life and recurrent episodes of otitismedia. There was no family history of similar lesions,although his mother reported that she had a tendency toform keloids. No known trauma preceded the development ofthe lesions.
Examination showed thin, raised, linear skin-colouredbands on the posterior lower legs (Fig. 1A,B). The lesionsfelt infiltrated, but not hard. The bands were bilaterallysymmetrical, and partially encircled the limbs. No areas ofconstriction or folding of excess skin were noted. Full physicalexamination revealed no other abnormalities. Follow-upexamination of our patient at 3Æ3 years of age showed nochange in the appearance of the raised linear bands.
Based on our familiarity with the two patients reported byMeggitt et al.1 who showed an identical clinical appearanceand normal skin on microscopic examination of biopsiedtissue, we avoided biopsy and suggested a diagnosis of raisedlimb bands. The lack of any areas of constriction in ourpatient further distinguishes this entity from the group of
Figure 1. Posterior aspects of the left (A) and right (B) legs of the patient at 13 months of age, showing raised limb bands.
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� 2003 British Association of Dermatologists, British Journal of Dermatology, 149, 419–446
disorders that has been called ‘amniotic bands’ or ‘congenitalpseudoainhum’. Of note, our patient differs from the patientsdescribed by Meggitt et al. in that our patient was a full-terminfant, whereas the previously described patients were bornafter 31 and 29 weeks’ gestation. This discrepancy suggeststhat prematurity is not an association with raised limb bands.
D . C . R u s s i
A . D . I r v i n e
A . S . P a l l e r
Division of Pediatric Dermatology,Children’s Memorial Hospital,Northwestern University, 2300Children’s Plaza, Box 107, Chicago,IL 60614, U.S.A.Corresponding author: Amy S. Paller,E-mail: [email protected]
Reference
1 Meggitt SJ, Harper J, Lacour M, Taylor AEM. Raised limb bands
developing in infancy. Br J Dermatol 2002; 147: 359–63.
A case of disseminated granuloma annulare treatedwith defibrotide: complete clinical remission andprogressive hair darkening
SIR, Defibrotide is a drug with an interesting spectrum ofpharmacological properties that make it useful for thetreatment of arterial and venous thrombotic diseases. Theseproperties include profibrinolytic, antithrombotic–thrombo-lytic, anti-ischaemic and antiatherosclerotic activity, as wellas protective activity in shock.1 Like low molecular weightheparins, it also seems to have anti-inflammatory properties.1
We report a 73-year-old man with disseminated granulomaannulare (GA) treated with defibrotide. The lesions had
appeared 2 months earlier on the neck and nape of the neck,spreading slowly to the scalp, trunk, back and arms. Thepatient complained of moderate pruritus. His family historywas negative for similar skin diseases and diabetes mellitus.The patient’s previous medical history included chronicautoimmune gastritis (15-year history) and deep vein throm-bosis of the lower limbs (10-year history). Skin examinationshowed large plaques of dermatitis, predominantly on thenape of the neck, back, chest and extensor surface of the arms(Fig. 1a,b). The face and scalp were also involved.The plaques consisted of small, slightly raised erythematouspapules with diameters of 1–3 mm, with clear margins buttending to flow together. The plaque peripheries were annularand ⁄ or polycyclic in form. Routine blood chemistry showedhyposideraemic hypochromic microcytic anaemia. ChestX-ray showed chronic obstructive pulmonary disease. Abdom-inal ultrasonography showed enlarged liver with grade Isteatosis. Histological examination of a biopsy specimen wasconsistent with the diagnosis of disseminated GA (Fig. 1c). Asthe patient was also susceptible to deep vein thrombosis,therapy with intramuscular defibrotide 400 mg daily wasbegun. The clotting profile was monitored every 15 days.After about 30 days of therapy, a clear-cut improvement inthe clinical picture was observed and the dose of the drug wasreduced to 200 mg daily. After about 90 days of therapy, thedermatitis had completely cleared (Fig. 2). The patient con-tinued maintenance therapy with oral defibrotide 400 mgdaily. At 7 months follow-up, no side-effects or relapse ofdisseminated GA were observed. Moreover, the patient com-mented that in the last year his hair, which had long been grey(> 10 years), had gradually reacquired its original colour.
Disseminated GA is a chronic skin disease associatedwith immunological predisposition (T-helper 1 type cytokine
Figure 1. Patient with disseminated granu-
loma annulare before treatment with defibro-
tide: large plaques of dermatitis predominantly
located (a) on the nape of the neck and (b) on
the back, consisting of small, slightly raised
erythematous papules with diameters of
1–3 mm, with clear margins but tending to
flow together. (c) Granulomatous infiltrate in
the superficial and middle dermis (haematox-
ylin and eosin; original magnification ·5).
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� 2003 British Association of Dermatologists, British Journal of Dermatology, 149, 419–446
pattern) but of unknown aetiology.2 Some authors havehypothesized that disseminated GA develops from vasculardamage due to deposition of immune complexes in predis-posed subjects.3 This hypothesis seems in line with frequentevidence of circulating immune complexes3 and microangi-opathy4 in patients with disseminated GA. The choice to treatour patient with defibrotide was made on the basis of both thevasculitic ⁄ microangiopathic aetiopathogenic hypothesis ofdisseminated GA and the patient’s severe chronic venousinsufficiency. Defibrotide is the sodium salt of single-strandedDNA isolated from porcine tissues by controlled depolymer-ization.1 It is used to prevent deep vein thrombosis and totreat vascular disorders such as peripheral obliterativearterial disease and acute thrombophlebitis.5 No severehaemorrhage or other serious toxicity related to defibrotidehas been reported.6 It has fibrinolytic activity, reducingplasminogen activator inhibitor levels and inhibiting mono-cyte proclotting function.1 It also has anti-ischaemic activitythrough inhibition of a lymphocyte function-associated anti-gen-1-dependent mechanism of neutrophil adhesion toendothelial cells.7 Last but not least, defibrotide appears to
protect the endothelium directly, by preserving endothelialcapacity to generate prostacyclin (PGI2) and nitric oxide(NO), conserving the endothelial glycosaminoglycan layer,and deactivating platelets.8 Increased generation of PGI2
causes a rise in platelet cAMP, which is a signal for plateletsto disaggregate. Moreover, NO causes inhibition of plateletaggregation and activation. Platelets are regarded as beingsomehow proinflammatory, because when activated theyrelease substances such as serotonin, adenosine diphosphate,platelet-activating factor, platelet-derived growth factor,transforming growth factor-b, cationic proteins and proteo-lytic enzymes (collagenase and elastase) that modify tissueintegrity.9 Defibrotide is therefore considered in some wayanti-inflammatory.
Although disseminated GA is usually a persistent disease, itis also possible for it to develop and settle quickly. Thereforethe resolution of the rash in our case may be coincidentalwith the use of defibrotide treatment. However, we canspeculate that the efficacy of therapy may be due to thecombined effect of fibrinolytic, anti-ischaemic, cytoprotectiveand anti-inflammatory properties of the drug. Besides remis-sion of the skin disease, the patient’s hair, which had beengrey for about 20 years, gradually began to acquire itsoriginal colour. This phenomenon has also been described inother circumstances, usually as a postinflammatory effect,but several drugs are also reported to induce hair colourchanges, albeit with few supporting data.10 These drugsinclude verapamil, tamoxifen, para-aminobenzoic acid, cisp-latin, ciclosporin, etretinate, levodopa and cyanocobalamin.Although in our case the mechanism of repigmentation isunclear, we believe that the main factor was a postinflam-matory effect because defibrotide is widely used in elderlypatients and this is the first report of hair repigmentation.Moreover, the hair darkening started shortly after thebeginning of treatment.
In conclusion, defibrotide may be a useful drug for treatingdisseminated GA. However, further studies are necessary toexplore fully the efficacy, optimal dosage and safety ofdefibrotide in treating patients with disseminated GA.
P . R u b e g n i
P . S b a n o
M . F i m i a n i
Istituto di Scienze Dermatologiche,Universita degli Studi di Siena,Policlinico ‘Le Scotte’, Viale Bracci,53100 Siena, ItalyE-mail: [email protected]
References
1 Pescador R, Porta R, Ferro L. An integrated view of the activities
of defibrotide. Semin Thromb Hemost 2000; 22: 71–5.
2 Fayyazi A, Schweyer S, Eichmeyer B et al. Expression of IFN-
gamma, coexpression of TNFalpha and matrix metalloproteinases
and apoptosis of T lymphocytes and macrophages in granuloma
annulare. Arch Dermatol Res 2000; 292: 384–90.
3 Peserico A, Ossi E, Salvador L et al. Circulating immune complexes
in granuloma annulare. Arch Dermatol Res 1988; 280: 325–6.
4 Haim S, Shafrir A, Haim N, Lichtig C. Microangiopathy in cases of
The coexistence of cutaneous vasculitis andthrombosis in childhood-onset systemic lupuserythematosus with antiphospholipid antibodies
SIR, A 14-year-old girl presented with a sudden outbreak ofpurpuric macules on her legs. These had developed after herlegs had been hit while playing judo. They had started assimple bruises, and their size and number had increased1–2 days later, followed by blistering. On examination,purplish, stellate purpuric macules were seen on both legs,accompanied by blistering (Fig. 1). Both our patient and herfather had type 1 neurofibromatosis. The family history wasotherwise uninformative. Laboratory investigations were asfollows: white cell count 3Æ2 · 109 L)1, platelet count196 · 109 L)1, erythrocyte sedimentation rate 80 mm inthe first hour, activated partial thromboplastin time 48 s
(normal 30–40), C3 level 0Æ63 g L)1 (normal 0Æ7–1Æ6), C4level 0Æ03 g L)1 (normal 0Æ17–0Æ45), circulating immunecomplexes (C1q) 8Æ3 mg L)1 (normal < 3Æ0). Rheumatoidfactor and lupus anticoagulant were positive and venerealdisease research laboratory findings were negative. Anti-nuclear antibodies, anti-doublestranded DNA antibodies andantiphospholipid antibodies (aPLs) represented by IgG classanticardiolipin antibodies and anticardiolipin–b2-glycoproteinI complex antibodies reacted strongly. Anti-Ro ⁄ SS-A antibod-ies and anti-La ⁄ SS-B antibodies were also strongly reactive,but there were no clinical, X-ray or pathological abnormalitiessuggesting Sjogren’s syndrome. Anti-Sm antibodies, cytoplas-mic antineutrophil cytoplasmic antibodies (ANCA), perinu-clear ANCA and cryoglobulin were all negative. The serumcreatinine level was 44 lmol L)1, total urinary protein0Æ4 g day)1 and creatinine clearance 2Æ06 mL s)1 (normal1Æ24–2Æ08). Chest X-ray, electrocardiogram and echocardio-gram showed no abnormalities. Magnetic resonance imagingof the brain, performed because of the positive Babinski andChaddock sign on her left foot, showed small spotty abnormalsignals in the right cerebellum and pons.
Biopsy of a purpuric macule revealed that the blood vesselsin the centre of the lesion were remarkably dilated. They wereentirely occluded by erythrocytes intermingled with homo-geneous eosinophilic material to form thromboses (Fig. 2a).No inflammatory infiltrates were found around the throm-bosed vessels. The overlying epidermis was almost necrotic.The thrombosed vessels were surrounded by small bloodvessels with inflammatory changes. The walls of the inflam-matory vessels surrounding the large thrombosed vessels hadundergone fibrinoid degeneration with prominent inflamma-tory infiltrates and nuclear debris consistent with leucocy-toclastic vasculitis (Fig. 2b). Direct immunofluorescencetesting showed deposits of IgA, IgM, C3 and C1q in theinflammatory vessels, but not in the thrombosed vesselslocated in the centre of the lesion. Our patient was diagnosedas having systemic lupus erythematosus (SLE) with aPLs.Treatment was started with oral prednisolone 60 mg dailyand aspirin 162 mg daily. The cutaneous symptoms resolvedwithin 2 weeks, without recurrence. Three years after theinitial event, she remains without recurrence on a mainten-ance dose of oral prednisolone 20 mg daily supplementedwith aspirin 162 mg daily.
The hallmark of the present case is the distribution of thethrombosed vessels and the small vessels with leucocytoclas-tic vasculitis that appeared after the definite triggering event.In general, the two vascular pathologies are distinct. Inpatients with SLE, inflammatory vascular lesions includingvasculitis are associated with a local deposition of immunecomplexes,1,2 and thrombotic lesions are associated withcirculating aPLs.3–5 It is not yet clear why these two distinctpathologies occurred together.
In the present case, histology revealed that the thrombosisand leucocytoclastic vasculitis were closely associated witheach other. The thrombosed vessels located in the centre ofthe lesion did not show any histological or immunohisto-chemical evidence that the vasculitic process had precededFigure 1. Stellate purpuric macules with a haemorrhagic blister on
the leg.
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� 2003 British Association of Dermatologists, British Journal of Dermatology, 149, 419–446
thrombosis. On the other hand, the small blood vesselssurrounding the large thrombosed vessels showed leucocy-toclastic vasculitis. Direct immunofluorescence supports thatimmune complex vasculitis was present on the surroundingvessels. These observations suggest that the two vascularchanges resulted from different pathogenic mechanisms.Based on the clinical course, we hypothesize that the vascularchanges in the present case started with thrombosis and werefollowed by vasculitis: the stellate purpuric macules followedthe initial bruise without additional physical trauma. Thisexplanation may be contrary to the general consensus thatimmune complex vasculitis is followed by thrombosis becauseimmune complexes and the complement system promotedamage to endothelial cells which, in turn, lead to plateletaggregation.1
It is known that the normal thrombotic process in tissueinjury induces endothelial activation.6–8 Our patient devel-oped stellate purpuric macules beyond the bruised site.Physical injury in a healthy person, however, does not causea stellate purpuric macule beyond the bruised site, withhistological thrombosis and vasculitis. We think that thisunique condition may be explained by the fact that ourpatient had SLE with coexistent aPLs. She showed high levelsof serum aPLs reflecting antiphospholipid syndrome (APS),as well as high circulating immune complexes with hypo-complementaemia reflecting SLE. These laboratory findingsexplain the concurrence of thrombosis and vasculitis in thepresent case: in a condition of fully activated endothelial cellsdue to active SLE associated with aPLs, the incidentalphysical trauma and following haemostatic process arethought to have triggered the severe thrombosis. Thethrombotic process enhanced an already activated conditionwithin the endothelial cells6–8 to allow an increase invascular permeability required for immune complexes toleave the microcirculation and become deposited within oroutside the vessel walls.1 When enough immune complexes
were deposited to activate the complement cascade, immunecomplex vasculitis ensued. Thus, the pathophysiology of thetwo different vascular changes might be explained asconsecutive events. This idea is supported by the report thatSLE patients with APS had a much higher risk of cutaneousvasculitis than SLE patients without APS.9 However, it is stillpossible that the two pathologies, thrombosis and vasculitis,might be separate consequences of disease activities. Forexample, once a thrombosis has occurred and blood hasstopped flowing, that vessel may be refractory to thevasculitic process surrounding it. Our case suggests thatthe thrombotic process might trigger an outbreak of vascu-litis to a certain extent.
K . T o m i z a w a
K . C . S a t o -
M a t s u m u r a�N . K a j i i *
Departments of Dermatology and*Paediatrics, Ebetsu City Hospital,6 Wakakusa-Cho, Ebetsu 067-8585,and �Department of Dermatology,Hokkaido University Graduate Schoolof Medicine, Sapporo, JapanE-mail: [email protected]
Radiation therapy as a curative treatmentin extraocular sebaceous carcinoma
SIR, Sebaceous carcinoma is a rare malignant neoplasmderived from the sebaceous glands of the skin. Only 25% areextraocular. We report our experience in the treatment of anextraocular sebaceous carcinoma with radiation therapy.
An 87-year-old white male presented in February 1997with an irregular, ulcerative, exophitic and erythematoustumour extending to the left side of the face in the cheek. Thelesion had appeared 6 months previously, and had initiallybeen diagnosed as a nodular malignant hydroadenoma. It wasthen treated with radiation therapy with a single field directlyon the lesion to a total dose of 70 Gy ⁄ 35 fractions with Co60photons in another hospital, achieving a complete response.
In August 1997 the patient was referred because hepresented a marginal local recurrence. On physical examina-tion, he presented with large ulcerative, exophitic, firm anderythematous nodules on the left of the face from theperiorbital area to the labial comisure caudally, around theanterior border of the previous treatment (Fig. 1a).
An incisional biopsy of the lesion of the face was performed.Histological examination showed the presence of basaloidtumour lobules with prominent nuclear pleomorphism andscattered mitotic figures infiltrating the dermis. Most cellswithin the lobules had foamy and vacuolated cytoplasmsuggesting sebaceous differentiation (Fig. 2a). Immunohisto-chemical stains demonstrated that tumour cells wereintensely positive for epithelial membrane antigen (EMA;Fig. 2b) and negative for carcinoembryonic antigen (CEA).All these findings were diagnostic of sebaceous carcinoma.
No surgical treatment was carried out due to the extentand location of the neoplasm, so the patient was treated withorthovoltage radiotherapy (100 kV) up to a total dose of 50Gy ⁄ 25 fractions administered through a conformed singlefield with a 2-cm margin directly on the lesion.
A reduction in size and firmness of the lesion was observedduring treatment. Ten months after treatment, no local ordistal relapse has been observed (Fig. 1b).
Even though sebaceous carcinoma may arise from seba-ceous glands anywhere in the body, about 75% are located inthe periocular area, where these glands are concentrated. Inthe eyelids, the most frequent origin is from Meibomiosebaceous modified glands, and less frequently from Zeisglands.1 In the periocular area, sebaceous carcinoma presentsas an infiltrating malignancy with poor prognosis.
Clinically, mainly female patients between 60 and 80 yearsof age are affected.2 The tumour is generally a firm yellow ororange solitary nodule that is often ulcerated.3
Clinically it may resemble benign diseases, such as blepha-roconjuntivitis or chalazion. The histological differential diag-nosis includes clear cell carcinoma, squamous cell carcinoma,malignant melanoma and extramammary Paget’s disease, assebaceous carcinoma of the eyelid can present a pagetoidspread of malignant cells.
Figure 1. (a) An 87-year-old white male with large ulcerative,
exophitic and erythematous nodules in the left side of the face cau-
dally from the periorbital area to the labial comisure. (b) Complete
remission of the tumour after 10 months of follow-up.
Figure 2. (a) Histological examination showed the presence of
basaloid tumour lobules with prominent nuclear pleomorphism and
scattered mitotic figures infiltrating the dermis. Most cells within the
lobules had foamy and vacuolated cytoplasm, suggesting sebaceous
differentiation. (b) Immunohistochemical stains demonstrated that
tumour cells were intensely positive for epithelial membrane antigen.
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Although extraocular sebaceous carcinomas traditionallyhave been considered less aggressive neoplasms than those inthe ocular area, they have also been reported to lead todisseminated metastatic disease.4
The signs of poor prognosis described are: the simultaneousinvolvement of the upper and lower eyelids, of multicentricorigin with a size of more than 10 mm in diameter, a highlyinfiltrative pattern, vascular, lymphatic or pagetoid invasion,poor differentiation and delay in diagnosis of more than6 months.1,5 Early diagnosis must be considered vital inimproving the survival rate.6
Although surgery with wide excision, considering marginsof at least 5–6 mm, has obtained good curative results,7 Mohsmicrographic surgery is actually considered to be the besttreatment when used as the primary treatment for sebaceouscarcinoma.6,8
Sebaceous carcinoma has been reported as radioresistant.Radiation therapy has been considered a palliative methodrather than a curative treatment in patients who refuse orcannot withstand surgery. It has also been employed asadjuvant therapy in patients with lymph node metastases.Nevertheless, Yen et al.9 reported that radiation therapy withan appropriate delivery system is an effective treatment foreyelid sebaceous carcinoma.
extraocular sebaceous carcinoma. Am J Dermatopathol 2001; 23:
450–5.
5 Spencer JM, Nossa R, Tse DT, Sequeira M. Sebaceous carcinoma of
the eyelid treated with Mohs micrographic surgery. J Am Acad
Dermatol 2001; 44: 1004–9.
6 Boniuk M, Zimmerman LE. Sebaceous carcinoma of the eyelid,
eyebrow, caruncle and orbit. Int Ophthalmol Clin 1972; 12: 225–
57.
7 Nelson BR, Hamlet KR, Gillard M et al. Sebaceous carcinoma. J Am
Acad Dermatol 1995; 33: 1–15.
8 Pardo FS, Wang CC, Albert D, Stracher MA. Sebaceous carcinoma
of the ocular adnexa: radio-therapeutic management. Int J Radiat
Oncol Biol Phys 1989; 17: 643–7.
9 Yen MT, Tse DT, Wu X, Wolfson AH. Radiation therapy for local
control of eyelid sebaceous cell carcinoma: report of two cases and
review of the literature. Ophthal Plast Reconstr Surg 2000; 16:
211–15.
The first case of sarcoidosis treatedwith mycophenolate mofetil
SIR, In a recent fascinating and important paper Kouba et al.1
have found that the relatively novel immunosuppressantmycophenolate mofetil (MMF) was quite effective in treating anumber of patients with refractory sarcoidosis. Their fivepatients had about an 85% reduction in disease signs andsymptoms, and prednisone doses went from an averagemaximum dose of approximately 60 mg day)1 before MMF toabout 10 mg every other day. Kouba et al.1 also note thattheirs is the first description of successful treatment ofsarcoidosis with MMF. Interestingly, it is not.
In a 1998 paper, Kilmartin et al.2 found that seven of ninepatents treated with MMF as rescue therapy for uveitis ofvarious causes had clinical improvement. One of the patientswho improved was their case seven—a patient with refrac-tory uveitis secondary to sarcoidosis. At that time I triedunsuccessfully in a correspondence to the journal to point outthat this was the first case of treatment of sarcoidosis withMMF, and that MMF might be useful for patients withsarcoidosis affecting other organs. Fortunately, Kouba et al.have far superseded my mere suggestion. One can only hopeand expect that in larger trials MMF will continue to be auseful agent for sarcoidosis.
E . L . A l t s c h u l e rMt Sinai School of Medicine,1425 Madison Avenue,Box 1240, New York, NY 10029,and Brain and Perception Laboratory,University of California, San Diego,La Jolla, CA 92093–0109, U.S.A.E-mail: [email protected];[email protected]
References
1 Kouba DJ, Mimouni D, Rencic A, Nousari HC. Mycophenolate
mofetil may serve as a steroid-sparing agent for sarcoidosis. Br J
Dermatol 2003; 148: 147–8.
2 Kilmartin DJ, Forrester JV, Dick AD. Rescue therapy with myco-
phenolate mofetil in refractory uveitis. Lancet 1998; 352: 35–6.
SIR, We appreciate the astute observation of Dr Altschuler inbringing to our attention the article by Kilmartin et al.1
Indeed, we were not aware of their single patient whoapparently had sarcoidal uveitis successfully treated withmycophenolate mofetil (MMF) rescue therapy (our Medlinesearch for ‘sarcoidosis’ and ‘mycophenolate mofetil’ did notyield this reference).
However, as presented in Table 1 of our original article,2
we document the first description of MMF utilized in thetreatment of five patients with histologically proven, refract-ory cutaneous sarcoidosis, all of whom also had concurrentsystemic disease.
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� 2003 British Association of Dermatologists, British Journal of Dermatology, 149, 419–446
This unique observation is important for the practisingdermatologist treating cutaneous sarcoidosis, as the potentialmorbidity and mortality of long-term steroid use may eclipsethat of the disease being treated.
D . J . K o u b a
D . M i m o u n i
A . R e n c i c
C . H . N o u s a r i *
Department of Dermatology, TheJohns Hopkins University, Baltimore,MD, U.S.A., and *Department ofDermatology, Division ofDermatopathology, University ofPennsylvania, 2 Rhoads Pavilion,3600 Spruce Street, Philadelphia, PA19104-4283, U.S.A.Corresponding author: C.H.Nousari,[email protected]
References
1 Kilmartin DJ, Forrester JV, Dick AD. Rescue therapy with myco-
phenolate mofetil in refractory uveitis. Lancet 1998; 352: 35–6.
2 Kouba DJ, Mimouni D, Rencic A, Nousari HC. Mycophenolate
mofetil may serve as a steroid-sparing agent for sarcoidosis. Br J
Dermatol 2003; 148: 147–8.
A novel missense mutation (Gln306His) in exon 7 ofthe ED1 gene causing anhidrotic ectodermal dysplasiawith prominent milia-like facial sebaceous papules
SIR, Anhidrotic ectodermal dysplasia (EDA; OMIM 305100)is an X-linked recessive disorder that is clinically character-ized by the triad of anodontia, hypotrichosis and anhidrosis.The affected organs are of ectodermal origin, but thenervous system is unaffected. The gene encodes a trans-membrane protein of 391 amino acids (isoform II),1 whichplays a critical role in morphogenesis of teeth, hair andsweat glands.
Mutations in this gene were first reported in 1996.2 Todate, 76 mutations have been reported (Human GeneMutation Database, to 23 December 2002). These comprise51 nucleotide substitutions, 15 microlesions and 10 grossdeletions. Sebaceous papules on the face in EDA weredescribed in the early literature,3–8 when gene mutationscould not be specifically identified. We report a young manwith prominent facial sebaceous papules with a novelmutation in the ED1 gene.
Since birth, a 19-year-old Taiwanese man had hadcomplete absence of teeth and recurrent fever withoutinfection. He had had intolerance to heat since childhood,and usually avoided hot environments to prevent attacks offever. His nails were all normal and no mental retardation orother anomaly was found. He had no pubic or axillary hair,and scanty hair on the scalp. Examination showed acharacteristic facial appearance including a prominent fore-head and supraorbital ridges (frontal bossing), a depressednasal bridge (saddle nose) and protruding thick lips. Inaddition, many white milia-like papules, discrete or aggrega-ted in plaques, had been present on his forehead, cheeks andchin (Fig. 1a) since puberty. Skin biopsy from the palm
revealed no sweat glands at all, and skin biopsy from a milia-like papule revealed several sebaceous lobules surroundingvellus hair, which did not grow in a normal shape anddirection (Fig. 1b). His only brother was free from similar
Figure 1. (a) Numerous milia-like papules, discrete or aggregated in
plaques, on the forehead, cheeks and chin. (b) Photomicrograph
showing three immature sebaceous lobules surrounding vellus hair in
a milia-like papule (haematoxylin and eosin).
C O R R E S P O N D E N C E 4 4 3
� 2003 British Association of Dermatologists, British Journal of Dermatology, 149, 419–446
symptoms or signs. His parents refused history taking andphysical examination.
Genomic DNA was extracted from peripheral blood of thepatient, with informed consent. DNA samples were thensubjected to mutation screening by amplification of segmentsof ED1 spanning all eight exons of the gene using primerssynthesized on the basis of intronic sequences, and allamplified segments containing each exon were analysed withan ABI 377 autonomic sequencer (Advanced Biotechnolo-gies, Columbia, MD, U.S.A.). A missense mutation, designated918GfiC (Gln306His), was found in exon 7 of the ED1 gene(Fig. 2). Webcutter (URL:http://www.firstmarket.com/cutter/cut2.html) was used to find the BsaAI enzyme capable ofcutting the mutant gene only. None of the amplified segmentscontaining exon 7 from 50 unrelated normal Taiwanesecontrols in our laboratory was cut with BsaAI, and a truemutation was confirmed.
Milia-like sebaceous facial papules in EDA have beendescribed under different names: milia, adenoma sebaceum,xeroderma pigmentosum, sebaceous cyst, naevi and degener-ated sebaceous gland with hyperkeratosis.3–8 The only twobiopsies from these lesions described in the literature revealedsebaceous glands that were ‘large and degenerated’, andsurrounding vellus hair follicles. In our patient, threesebaceous lobules surrounding vellus hair were noted onbiopsy. However, the sebaceous lobules were not as mature asthose in normal facial skin. They seemed to be smaller, deeperand immature, without a well-formed vellus hair shaft invertical growth. According to the literature, these papulesgradually develop after puberty. This might be explained bythe presence of intact sexual maturation in EDA patients,starting at puberty with androgen exerting an effect on thepartially defective pilosebaceous units. Although the haircannot grow well due to an innate error, the sebaceous glandspresent at birth start to grow in due time. This may also implythat sebaceous glands may not be involved in EDA. In view of
the developmental inadequacy of hair, teeth and eccrineglands in EDA, as the triad implies, the term ‘immaturesebaceous lobules’ rather than ‘large and degenerative’sebaceous glands or ‘sebaceous gland hyperplasia’ may bemore appropriate, and this conveys the concept of pathogen-esis. From a brief review of EDA cases with descriptions offacial papules7,9 and our case, it seems that these lesions occurmainly in male patients. However, the scarcity of homozygousfemale patients or mild manifestations in female carriers ofX-linked genodermatoses could result in this difference.Nevertheless, the androgen excess in male patients could bean alternative explanation, as a similar effect of androgen canbe observed in neonatal sebaceous hyperplasia. More EDApatients with facial sebaceous papules need to be observed toclarify whether a sexual difference does exist.
The complete ED1 gene was not fully unveiled until 1998,when Monreal et al.1 identified a new splice form of the EDA1gene which permits detection of nearly all X-linked hypohid-rotic ectodermal dysplasia mutations. The exon numbers maybe confusing because a previous exon 2, mapped from isoformI,2 is not included in ectodysplasin A (391 aa), the completetranscript of ED1 (1173 bp). The most up-to-date gene mapmay be viewed using the Ensemble Human Genome Browser(GeneView: http://www.ensembl.org/Homo_sapiens/geneviewgene=ENSG00000158813). From this map, there areeight exons in ED1 (396, 106, 24, 180, 35, 52, 131 and249 bp in length, accordingly). In our patient, a missensemutation (918GfiC, substituting glutamine by histidine inthe penultimate amino acid of the 7th exon) in the tumournecrosis factor-like domain10 in ectodysplasin A interfereswith both isoforms (EDA-A1 and EDA-A2, the most commonand longest EDA splice isoforms) and probably results in allthe clinical manifestations. We suspect that the presence ofprominent sebaceous papules may be related to this muta-tion, because only a small number of EDA patients have thismanifestation.
A prominent and unique appearance of the facialsebaceous papules in some EDA patients has been reportedbut incompletely described. This is the first genetic muta-tion in ED1 reported to be associated with many prominentmilia-like facial sebaceous papules. Whether the lesionsare male-prone or mutation site-related remains to beclarified in further studies. Nevertheless, the easily recog-nized facial papules help in the understanding and diagno-sis of EDA.
M . M . L . H s u
S . C . C h a o
A . C . H . L u
Department of Dermatology, Collegeof Medicine, National Cheng-KungUniversity Hospital, 138 Sheng-LiRoad, 704 Tainan, TaiwanE-mail: [email protected]
References
1 Monreal AW, Zonana J, Ferguson B. Identification of a new splice
form of the EDA1 gene permits detection of nearly all X-linked
hypohidrotic ectodermal dysplasia mutations. Am J Hum Genet
1998; 63: 380–9.
Figure 2. Sequence analysis of the ED1 gene in this patient (upper
panel) and a control sequence from a normal individual (lower panel)
for comparison.
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� 2003 British Association of Dermatologists, British Journal of Dermatology, 149, 419–446
2 Kere J, Srivastava AK, Montonen O et al. X-linked anhidrotic
(hypohidrotic) ectodermal dysplasia is caused by mutation in a
plasia (X-recessive type)—a family report and review of the lit-
erature. Dermatol Sinica 1988; 6: 73–81.
10 Copley RR. The gene for X-linked anhidrotic ectodermal dysplasia
encodes a TNF-like domain. J Mol Med 1999; 77: 361–3.
Book Reviews
Atlas of Clinical Dermatology, 3rd edn. ANTHONY DU VIVIER.Amsterdam: Elsevier. 752 pp. ISBN 0-4430-7220-5. Hard-back, 2432 ills. Price: £149.
The Third Edition of this classic is even more splendid thanits predecessors. The illustrations are exceptional, as ever, andare now nearly 2500 of them. Dr du Vivier has expanded somekey areas, including cutaneous aspects of systemic disease andwhat the author, engagingly, describes as ‘female disorders’.The result is an even more comprehensive version of what wasalways a pretty comprehensive book. The text is clear andprecise, and continues the approach of the first two editions inmaking the teaching points gently and wisely. As a result, thisbook remains the benchmark against which all dermatolog-ical atlases will be judged. Even at £149 it is great value.
It is also very stylish and, if you do open the book idly in alibrary, I urge you to look, not only at the fabulous pictures,or to browse through the sharp, snappy text, picking out themany bon mots. Sample also the Acknowledgements. Thisparagraph, placed beneath the Preface inside the front cover,gives us more than a flavour of the man who wrote this book.It is apparent that you are in the company of a kind, witty
and charismatic educator. I guarantee that as a result youwill want to read what he has to say about the subject towhich he has devoted his professional life.
R . G r a h a m - B r o w n
Dermatology: Pocket picture book. ANTHONY DU VIVIER.Oxford: Blackwell Publishing. 312 pp. ISBN 0-6320-5428-X.Hardback. Price: £19.95.
This is a nice compact introductory text for those new toDermatology. As the author indicates, it can easily be slippedinto the pocket of a white coat and does adequately serve as‘a taster for the greater picture’. The book is nicely structuredwith a good index and covers many less common interestingdermatoses as well as the basics. The illustrations are goodeven if some of them are a bit small. Grouping them at theend of each chapter works well. In summary, this book can berecommended as an excellent introductory text for students,General Practitioners and those starting their first dermatol-ogy post.
J f B o u r k e
News and Notices
British Society of Paediatric Dermatology, 18th AnnualMeeting. 14–15 November 2003, Dublin, IrelandFor further details, including abstracts and registration forms,please contact: Ms Yvonne Thomson, Medical RecordsDepartment, Our Lady’s Hopsital for Sick Children, Crumlin,Dublin 12, Ireland. Tel: + 353 1 409 6537; Fax: +353 1 4553197; E-mail: [email protected]
Introductory Course on the Biology of the Skin,Cambridge, December 2003The annual introductory course on ‘The Biology of the Skin’will be held at Downing College, Cambridge, on 8–12December 2003.
This course is primarily for registrars and postgraduatestudents at an early stage of their training in dermatology butis open to other interested practitioners.
Closing date for applications is 7 November 2003.Further information may be obtained from the Postgradu-
ate Medical Centre, Clinical School, Addenbrooke’s Hospital,Hills Road, Cambridge, UK, CB2 2SP. Tel: 01223 216 376.E-mail: [email protected]
Lasercare Clinics 6th Annual Convention, Birming-ham, 2 December 2003The 6th Annual Lasercare Educational Day, which is open toall interested doctors and nurses, will take place at the
B O O K R E V I E W S 4 4 5
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Postgraduate Centre, City Hospital, Birmingham on Tuesday2 December 2003.
For further information please contact Dr Sean Lanigan on0121 507 6655 or E-mail: [email protected] AND NOTICESNEWS AND NOTICES
Paediatric dermatology Course, LiverpoolAmended NoticeThis clinical course is held annually in Liverpool and is aimedat Specialist Registrars and recently appointed Consultant
Dermatologists and Paediatricians. An important componentof the course is small group clinical teaching. Numbers arelimited to 12. The next two-day course will be held on 20 and21 November 2003. For further details contact: Dr G Sharpe,Course Organiser, The University of Liverpool, DermatologyUnit, Department of Medicine, UCD Building, Liverpool, L693GA. Tel: 0151 706 4030; Fax: 0151 706 5842; E-mail:[email protected].
� 2003 British Association of Dermatologists, British Journal of Dermatology, 149, 419–446
