Classification of atopic hand eczema and the filaggrin ... - copsac
Classification of atopic hand eczema and the filaggrin ... - copsac
Classification of atopic hand eczema and the filaggrin ... - copsac
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Contact Dermatitis 2008: 59: 257–260Printed in Singapore. All rights reserved# 2008 The AuthorsJournal compilation # 2008 Blackwell MunksgaardCONTACT DERMATITISReview Article<strong>Classification</strong> <strong>of</strong> <strong>atopic</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong> <strong>and</strong><strong>the</strong> <strong>filaggrin</strong> mutationsCHARLOTTE GIWERCMAN 1 ,ANNE LERBAEK 1 ,HANS BISGAARD 2 AND TORKIL MENNE´11 Department <strong>of</strong> Dermatology, <strong>and</strong> 2 Danish Pediatric Asthma Centre, Copenhagen UniversityHospital Gent<strong>of</strong>te, DK-2900 Hellerup, DenmarkH<strong>and</strong> <strong>eczema</strong> is a common disease with various risk factors <strong>of</strong> which <strong>atopic</strong> dermatitis is known to beone <strong>of</strong> <strong>the</strong> most important. Recently, two mutations in <strong>the</strong> gene coding for <strong>filaggrin</strong>, a proteinimportant for <strong>the</strong> skin barrier, have repeatedly been shown to be associated with <strong>atopic</strong> dermatitis.Moreover, one study point towards an association between <strong>the</strong> <strong>filaggrin</strong> null alleles <strong>and</strong> <strong>the</strong> subgroup<strong>of</strong> patients having both <strong>h<strong>and</strong></strong> <strong>eczema</strong> <strong>and</strong> <strong>atopic</strong> dermatitis. For <strong>the</strong> remainder <strong>of</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong>patients, still unknown genetic risk factors exist. We propose that in future, classification <strong>of</strong> <strong>atopic</strong><strong>h<strong>and</strong></strong> <strong>eczema</strong> should distinguish between patients with <strong>and</strong> without <strong>the</strong> <strong>filaggrin</strong> null alleles <strong>and</strong> t<strong>of</strong>ur<strong>the</strong>r differentiate between associations with type I allergy, type IV allergy <strong>and</strong> exposure to irritants,respectively. Fur<strong>the</strong>rmore, we suggest future studies <strong>of</strong> <strong>atopic</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong> to analyse for <strong>the</strong><strong>filaggrin</strong> mutations. We believe this will increase <strong>the</strong> possibility <strong>of</strong> subgrouping this o<strong>the</strong>rwise heterogenicdisease <strong>and</strong> <strong>the</strong>reby enable a better phenotype–genotype characterization <strong>of</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong>.This could improve <strong>the</strong> preventive initiatives, secure better information <strong>of</strong> patients about <strong>the</strong> prognosisfor <strong>the</strong>ir disease, <strong>and</strong> possibly enable targeted treatment.Key words: <strong>atopic</strong> dermatitis; classification; contact allergy; <strong>filaggrin</strong> mutation; <strong>h<strong>and</strong></strong> <strong>eczema</strong>.# Blackwell Munksgaard, 2008.Accepted for publication 23 May 2008Filaggrin is a protein essential for aggregating keratinfilaments, which lead to keratinocyte compaction<strong>and</strong> formation <strong>of</strong> <strong>the</strong> stratum corneum.Pr<strong>of</strong>ilaggrin, <strong>the</strong> precursor <strong>of</strong> <strong>filaggrin</strong>, is locatedin <strong>the</strong> keratohyalin granules in <strong>the</strong> granular layer <strong>of</strong><strong>the</strong> epidermis. The formation <strong>of</strong> <strong>the</strong> cornified cellenvelope is crucial for <strong>the</strong> skin barrier function as itprevents epidermal water loss <strong>and</strong> penetration <strong>of</strong>infectious agents, toxic chemicals, <strong>and</strong> allergens (1).Two polymorphisms in <strong>the</strong> <strong>filaggrin</strong> gene,R501X <strong>and</strong> 2282del4, both result in a loss <strong>of</strong> function<strong>of</strong> <strong>the</strong> <strong>filaggrin</strong> protein. Homozygotes orcompound heterozygotes for <strong>the</strong> genetic variantshave a total loss <strong>of</strong> <strong>filaggrin</strong> products <strong>and</strong> <strong>the</strong>reforea dry, scaly skin (ichthyosis vulgaris), whereasheterozygotes present with a milder form or withoutsymptoms at all (2). The two loss-<strong>of</strong>-functiongenetic variants in <strong>the</strong> <strong>filaggrin</strong> gene were recentlyidentified as major predisposing factors for <strong>atopic</strong><strong>eczema</strong> (3), an association confirmed by severalstudies (4–6). No genetic markers for <strong>h<strong>and</strong></strong> <strong>eczema</strong>have yet been identified <strong>and</strong> only a few studiespublished so far have investigated a possible relationshipbetween <strong>the</strong> <strong>filaggrin</strong> loss-<strong>of</strong>-functionmutations <strong>and</strong> <strong>the</strong> development <strong>of</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong><strong>and</strong>/or contact allergy (7–9).H<strong>and</strong> <strong>eczema</strong> is a common disease <strong>of</strong>ten knownto have a chronic relapsing course. Risk factorsinclude <strong>atopic</strong> dermatitis <strong>and</strong> exposure to allergens<strong>and</strong> irritants (10, 11). A twin study has shownthat genetic factors influence <strong>the</strong> risk <strong>of</strong> developing<strong>h<strong>and</strong></strong> <strong>eczema</strong> (12).There is no universally accepted classification <strong>of</strong><strong>h<strong>and</strong></strong> <strong>eczema</strong>. Traditionally classification is basedon aetiological factors (irritant, allergic, <strong>and</strong><strong>atopic</strong> disease), <strong>the</strong> localization <strong>of</strong> <strong>the</strong> <strong>eczema</strong>(dorsum, palmar, fingers, <strong>and</strong> wrist), or morphologicalfeatures (vesicular, hyperkeratotic, lichenification,<strong>and</strong> recurrent vesicular <strong>h<strong>and</strong></strong> dermatitis).It is generally believed that this classification systemis insufficient, which makes comparison <strong>of</strong>studies <strong>and</strong> <strong>the</strong>rapeutic strategies difficult, <strong>and</strong>hampers <strong>the</strong> possibilities for better underst<strong>and</strong>ing<strong>and</strong> treating <strong>the</strong> disease (13, 14). It seems likelythat <strong>h<strong>and</strong></strong> <strong>eczema</strong> is a common phenotype expressinga variety <strong>of</strong> underlying diseases.
258 GIWERCMAN ET AL. Contact Dermatitis 2008: 59: 257–260We propose a revised classification for <strong>the</strong> subgroup<strong>of</strong> patients having <strong>atopic</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong>based on concurrent <strong>atopic</strong> dermatitis <strong>and</strong> <strong>filaggrin</strong>loss-<strong>of</strong>-function mutations.Risk Factors for H<strong>and</strong> EczemaDuring <strong>the</strong> last three decades, research has, asmentioned above, shown <strong>atopic</strong> dermatitis, contactallergy, <strong>and</strong> irritants, e.g. wet work, to be <strong>the</strong>most important risk factors for <strong>the</strong> development<strong>of</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong>.Atopic dermatitisMost studies agree that <strong>the</strong> frequency <strong>of</strong> <strong>atopic</strong>dermatitis is increased in patients with <strong>h<strong>and</strong></strong><strong>eczema</strong> (10, 15–18). The explanation is an <strong>atopic</strong>skin dia<strong>the</strong>sis, an endogenous risk factor not wellunderstood. The risk <strong>of</strong> developing <strong>h<strong>and</strong></strong> <strong>eczema</strong>can be predicted by means <strong>of</strong> a scoring system <strong>of</strong><strong>atopic</strong> dermatitis (19, 20).Contact allergyThe development <strong>of</strong> contact allergy requiresa combination <strong>of</strong> genetic susceptibility <strong>and</strong> environmentalexposure (21). Contact allergy is anindependent risk factor for developing <strong>h<strong>and</strong></strong><strong>eczema</strong> as <strong>the</strong> <strong>h<strong>and</strong></strong>s are <strong>the</strong> prime site for exposureto allergens, occupational as well as domestic(17, 18, 22).Wet workSeveral studies have verified wet work as a majorexternal risk factor for <strong>the</strong> development <strong>of</strong> <strong>h<strong>and</strong></strong><strong>eczema</strong>, probably because water decreases <strong>the</strong>protectiveness <strong>of</strong> <strong>the</strong> skin <strong>and</strong> occlusion increasesits irritant effect (23, 24). Bryld et al. (17) did notfind wet work to be an independent risk factor in<strong>the</strong>ir twin study. Instead, <strong>the</strong> authors suggest thatwet work is a risk factor only for a subgroup <strong>of</strong> <strong>the</strong>population, in accordance with <strong>the</strong> general observationthat only some people develop <strong>h<strong>and</strong></strong><strong>eczema</strong> although many more are heavily exposed.Genetic StudiesBased on a twin study, Bryld et al. (17) found thatgenetics influence <strong>the</strong> risk <strong>of</strong> acquiring <strong>h<strong>and</strong></strong><strong>eczema</strong>. Fur<strong>the</strong>rmore, <strong>the</strong>y concluded that anunknown genetic risk factor independent <strong>of</strong> <strong>atopic</strong>dermatitis <strong>and</strong> contact allergy is important fordeveloping <strong>h<strong>and</strong></strong> <strong>eczema</strong>. In a follow-up studyon <strong>the</strong> same twin population, Lerbaek et al. (25)found that genetic risk factors explain 41% <strong>of</strong> <strong>the</strong>variance in liability to develop <strong>h<strong>and</strong></strong> <strong>eczema</strong> <strong>and</strong>monozygotic twins to have a doubled risk fordeveloping <strong>h<strong>and</strong></strong> <strong>eczema</strong> if <strong>the</strong>ir co-twin havehad <strong>h<strong>and</strong></strong> <strong>eczema</strong> compared with a dizygotic twinindividual having a co-twin with <strong>h<strong>and</strong></strong> <strong>eczema</strong>,<strong>and</strong> fur<strong>the</strong>r document this risk factor to be independent<strong>of</strong> <strong>atopic</strong> dermatitis.Filaggrin Mutations <strong>and</strong> Atopic DermatitisIn 2006, Palmer et al. (3) documented for <strong>the</strong> firsttime <strong>the</strong> two <strong>filaggrin</strong> mutations, R501X <strong>and</strong>2282del4, to be associated with <strong>the</strong> development<strong>of</strong> <strong>atopic</strong> dermatitis. Several studies have confirmedthis finding, <strong>and</strong> <strong>the</strong> mutations are currently<strong>the</strong> most strongly associated genetic factorsknown to confer susceptibility to <strong>atopic</strong> dermatitisin European populations (6, 26). Odds ratios varybetween 3.73 <strong>and</strong> 7.1 (4, 27). No negative or equivocalstudies have been reported.The two mutations, R501X <strong>and</strong> 2282del4, arecarried by 16.7–56 % <strong>of</strong> all individuals with <strong>atopic</strong>dermatitis (6) <strong>and</strong> are inherited in a semidominantmode (2). The high frequencies <strong>of</strong> <strong>filaggrin</strong> mutationsare seen in studies investigating adults withboth persisting <strong>and</strong> early onset <strong>of</strong> <strong>atopic</strong> dermatitis.The mutations are associated with asthma <strong>and</strong>allergy as well as early onset <strong>of</strong> <strong>atopic</strong> dermatitis<strong>and</strong> persistence into adulthood as well as certainphenotypic characteristics, e.g. hyperlinearity <strong>of</strong><strong>the</strong> <strong>h<strong>and</strong></strong>s (3, 4, 28). O<strong>the</strong>r mutations in or nearby<strong>the</strong> <strong>filaggrin</strong> gene have been documented. In onepopulation, a third mutation, R2447X, was asstrongly <strong>and</strong> independently associated with <strong>atopic</strong>dermatitis as <strong>the</strong> mutations R501X <strong>and</strong> 2282del4(29). Besides R2447X, two o<strong>the</strong>r mutations,S3247X <strong>and</strong> 3702delG as well as o<strong>the</strong>r lesser frequentmutations, have recently been shown to beassociated with <strong>atopic</strong> dermatitis. These mutationsare qualitatively different from <strong>the</strong> previouslyreported mutations with some residualfunction, as demonstrated by a significantly lowerpenetrance <strong>of</strong> <strong>eczema</strong>. Generally, <strong>the</strong>se new mutationsreported are nei<strong>the</strong>r as prevalent nor asstrongly associated with <strong>atopic</strong> dermatitis (29, 30).Filaggrin Mutations <strong>and</strong> H<strong>and</strong> EczemaLerbaek et al. investigated a possible associationbetween <strong>the</strong> <strong>filaggrin</strong> mutations <strong>and</strong> <strong>atopic</strong> <strong>h<strong>and</strong></strong><strong>eczema</strong> (7). They found a borderline statistical significancepointing towards an association between<strong>the</strong> subgroup <strong>of</strong> patients with <strong>h<strong>and</strong></strong> <strong>eczema</strong>, <strong>atopic</strong>dermatitis, <strong>and</strong> <strong>the</strong> <strong>filaggrin</strong> mutations. All individualshaving <strong>h<strong>and</strong></strong> <strong>eczema</strong> <strong>and</strong> <strong>atopic</strong> dermatitisalso had <strong>the</strong> <strong>filaggrin</strong> mutations, but <strong>the</strong> grouponly included 26 individuals <strong>and</strong> <strong>the</strong>re was nocomparable control group with <strong>atopic</strong> dermatitis,
Contact Dermatitis 2008: 59: 257–260 HAND ECZEMA AND FILAGGRIN MUTATIONS 259but without <strong>h<strong>and</strong></strong> <strong>eczema</strong>. No association between<strong>the</strong> <strong>filaggrin</strong> mutations <strong>and</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong> in generalor contact allergy was found, but this mightbe because <strong>of</strong> lack <strong>of</strong> statistical power <strong>and</strong> a possibleassociation could not be excluded. A recentstudy by de Jongh et al. has confirmed <strong>the</strong>se findingsbut is hampered by <strong>the</strong> same problem <strong>of</strong> statisticalpower (9).A single study <strong>of</strong> <strong>the</strong> <strong>filaggrin</strong> mutations <strong>and</strong>nickel allergy has been published. Novak et al.(8) confirm earlier findings <strong>of</strong> an associationbetween <strong>the</strong> <strong>filaggrin</strong> mutations <strong>and</strong> <strong>atopic</strong> dermatitis.They observed an association between contactsensitization to nickel <strong>and</strong> contact sensitization tonickel combined with intolerance to fashion jewellery.The positive association between <strong>the</strong> <strong>filaggrin</strong>null alleles <strong>and</strong> contact sensitization to nickelcould be explained in different ways. One possibilityis that because <strong>the</strong> mutations induce a skinbarrier dysfunction, nickel could act as an irritantinstead <strong>of</strong> an allergen <strong>and</strong> thus result in falsepositivepatch results, which in particular wouldapply to <strong>the</strong> <strong>atopic</strong> individuals. But, in <strong>the</strong> populationinvestigated by Novak et al. (8), nickelallergy occurs with <strong>the</strong> same frequency in both<strong>atopic</strong> <strong>and</strong> non-<strong>atopic</strong> individuals. Ano<strong>the</strong>r explanationcould be nickel accumulation in <strong>the</strong> skin <strong>of</strong><strong>filaggrin</strong> mutation-positive individuals because <strong>of</strong>increased ability to bind to <strong>the</strong> <strong>filaggrin</strong>-mutatedepidermis.Fur<strong>the</strong>r studies, including twin studies <strong>and</strong> populationstudies, are needed to investigate whe<strong>the</strong>rcontact sensitization to nickel itself is associatedwith <strong>the</strong> <strong>filaggrin</strong> mutations or <strong>the</strong> observed associationis biased because <strong>of</strong> <strong>the</strong> above-mentionedexplanations.DiscussionSo far, only two studies have been published concerning<strong>filaggrin</strong> mutations <strong>and</strong> <strong>atopic</strong> <strong>h<strong>and</strong></strong><strong>eczema</strong>. The tendency towards an associationbetween <strong>atopic</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong> <strong>and</strong> <strong>the</strong> allele variantsis plausible because <strong>atopic</strong> dermatitis is <strong>the</strong>most frequent risk factor for developing <strong>h<strong>and</strong></strong><strong>eczema</strong>, <strong>and</strong> previous work has suggested that<strong>atopic</strong> dermatitis is <strong>the</strong> core phenotype associatedwith <strong>the</strong> <strong>filaggrin</strong> mutations. Fur<strong>the</strong>r studies withmore statistical power are needed to better investigatethis topic.The gene for <strong>filaggrin</strong> is probably not <strong>the</strong> onlyresponsible carrier <strong>of</strong> barrier-deficiency. Accordingto Bryld et al. (12, 17) <strong>and</strong> Lerbaek et al. (7, 18,25), genetic risk factors independent <strong>of</strong> <strong>atopic</strong>dermatitis <strong>and</strong> contact allergy exists. Twin studiesdocument that genes account for up to 82% <strong>of</strong><strong>the</strong> individual susceptibility to develop <strong>atopic</strong>dermatitis (31–33) but only 16.7–56% <strong>of</strong> individualswith <strong>atopic</strong> dermatitis carry <strong>the</strong> <strong>filaggrin</strong>mutations. Obviously o<strong>the</strong>r genes must be <strong>of</strong> relevance,which might be genes coding for o<strong>the</strong>rimportant substances in <strong>the</strong> epidermal skin barrier,both proteins <strong>and</strong> lipids. Fur<strong>the</strong>r studies areneeded, including extended genetic studies.The possible association between <strong>the</strong> <strong>atopic</strong><strong>h<strong>and</strong></strong> <strong>eczema</strong> <strong>and</strong> <strong>the</strong> <strong>filaggrin</strong> mutations is interestingas it raises <strong>the</strong> possibility <strong>of</strong> subgroupingthis o<strong>the</strong>rwise heterogenic disease <strong>and</strong> <strong>the</strong>rebyenables a better phenotype–genotype characterization<strong>of</strong> <strong>atopic</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong>. This could improve<strong>the</strong> preventive initiatives, secure better information<strong>of</strong> patients about <strong>the</strong> prognosis for <strong>the</strong>ir disease,<strong>and</strong> possibly enable targeted treatment.Also, as it seems that <strong>the</strong> <strong>filaggrin</strong> mutations areassociated with both a prolonged course <strong>of</strong> <strong>atopic</strong>dermatitis <strong>and</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong>, being able to screenfor <strong>the</strong> mutations could help to better inform <strong>the</strong>patients about <strong>the</strong> prognosis for <strong>the</strong>ir diseaseincluding carrier guidance.In a future classification <strong>of</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong>, wesuggest subgrouping patients having <strong>atopic</strong> <strong>h<strong>and</strong></strong><strong>eczema</strong>. We propose a distinction betweenpatients with <strong>and</strong> without <strong>the</strong> <strong>filaggrin</strong> loss-<strong>of</strong>functionpolymorphisms <strong>and</strong> a fur<strong>the</strong>r differentiationbetween associations with type I allergy,type IV allergy <strong>and</strong> exposure to irritants, respectively.Fur<strong>the</strong>rmore, we suggest future studies <strong>of</strong><strong>h<strong>and</strong></strong> <strong>eczema</strong> to analyse for inherited barrier deficienciessuch as <strong>the</strong> <strong>filaggrin</strong> mutations.References1. C<strong>and</strong>i E, Schmidt R, Melino G. The cornified envelope:a model <strong>of</strong> cell death in <strong>the</strong> skin. Nat Rev Mol Cell Biol2005: 6: 328–340.2. Smith F J, Irvine A D, Terron-Kwiatkowski A et al. Loss-<strong>of</strong>functionmutations in <strong>the</strong> gene encoding <strong>filaggrin</strong> cause ichthyosisvulgaris. Nat Genet 2006: 38: 337–342.3. Palmer C N, Irvine A D, Terron-Kwiatkowski A et al. Commonloss-<strong>of</strong>-function variants <strong>of</strong> <strong>the</strong> epidermal barrier protein<strong>filaggrin</strong> are a major predisposing factor for <strong>atopic</strong>dermatitis. Nat Genet 2006: 38: 441–446.4. Marenholz I, Nickel R, Ruschendorf F et al. Filaggrin loss-<strong>of</strong>functionmutations predispose to phenotypes involved in <strong>the</strong><strong>atopic</strong> march. J Allergy Clin Immunol 2006: 118: 866–871.5. Weidinger S, Illig T, Baurecht H et al. Loss-<strong>of</strong>-function variationswithin <strong>the</strong> <strong>filaggrin</strong> gene predispose for <strong>atopic</strong> dermatitiswith allergic sensitizations. J Allergy Clin Immunol 2006:118: 214–219.6. Irvine A D. Fleshing out <strong>filaggrin</strong> phenotypes. J Invest Dermatol2007: 127: 504–507.7. Lerbaek A, Bisgaard H, Agner T, Ohm K K, Palmer C N,Menne T. Filaggrin null alleles are not associated with <strong>h<strong>and</strong></strong><strong>eczema</strong> or contact allergy. Br J Dermatol 2007: 157: 1199–1204.8. Novak N, Baurecht H, Schafer T et al. Loss-<strong>of</strong>-functionmutations in <strong>the</strong> <strong>filaggrin</strong> gene <strong>and</strong> allergic contact sensitizationto nickel. J Invest Dermatol 2007: 128: 430–1435.
260 GIWERCMAN ET AL. Contact Dermatitis 2008: 59: 257–2609. de Jongh C M, Verberk M M, Calkoen F, van Dijk F J H,John S M, Khrenova L, Kezic S. Loss-<strong>of</strong>-function polymorphismsin <strong>the</strong> <strong>filaggrin</strong> gene <strong>and</strong> susceptibility to chronicirritant contact dermatitis: a case-control study. Br J Dermatol2008: 159: 621–627.10. Rystedt I. H<strong>and</strong> <strong>eczema</strong> <strong>and</strong> long-term prognosis in <strong>atopic</strong>dermatitis. Acta Derm Venereol Suppl (Stockh) 1985: 117:1–59.11. Meding B, Wrangsjo K, Jarvholm B. Fifteen-year follow-up<strong>of</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong>: predictive factors. J Invest Dermatol 2005:124: 893–897.12. Bryld L E, Agner T, Kyvik K O, Brondsted L, HindsbergerC, Menne T. H<strong>and</strong> <strong>eczema</strong> in twins: a questionnaire investigation.Br J Dermatol 2000: 142: 298–305.13. Diepgen T L, Agner T, Aberer W, Berth-Jones J, CambazardF, Elsner P, McFadden J, Coenraads P J. Management <strong>of</strong>chronic <strong>h<strong>and</strong></strong> <strong>eczema</strong>. Contact Dermatitis 2007: 57: 203–210.14. Storrs F J. Acute <strong>and</strong> recurrent vesicular <strong>h<strong>and</strong></strong> dermatitis notpompholyx or dyshidrosis. Arch Dermatol 2007: 143: 1578–1580.15. Glickman F S, Silvers S H. H<strong>and</strong> <strong>eczema</strong> <strong>and</strong> atopy in housewives.Arch Dermatol 1967: 95: 487–489.16. Cronin E. Clinical patterns <strong>of</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong> in women. ContactDermatitis 1985: 13: 153–161.17. Bryld L E, Hindsberger C, Kyvik K O, Agner T, Menne´ T.Risk factors influencing <strong>the</strong> development <strong>of</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong> ina population-based twin sample. Br J Dermatol 2003: 149:1214–1220.18. Lerbaek A, Kyvik K O, Ravn H, Menné T, Agner T. Incidence<strong>of</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong> in a population-based twin cohort:genetic <strong>and</strong> environmental risk factors. Br J Dermatol2007: 157: 552–557.19. Diepgen T L, Fartasch M, Hornstein O P. Evaluation <strong>and</strong>relevance <strong>of</strong> <strong>atopic</strong> basic <strong>and</strong> minor features in patients with<strong>atopic</strong> dermatitis <strong>and</strong> in <strong>the</strong> general population. Acta DermVenereol Suppl (Stockh) 1989: 144: 50–54.20. Diepgen T L, Sauerbrei W, Fartasch M. Development <strong>and</strong>validation <strong>of</strong> diagnostic scores for <strong>atopic</strong> dermatitis incorporatingcriteria <strong>of</strong> data quality <strong>and</strong> practical usefulness. J ClinEpidemiol 1996: 49: 1031–1038.21. Frosch P J, Menne´ T, Lepoittevin J P. Contact Dermatitis(Springer-Verlag Berlin Heidelberg), 4th edition. 2004: 127–134.22. Elston D M, Ahmed D D, Watsky K L, Schwarzenberger K.H<strong>and</strong> dermatitis. J Am Acad Dermatol 2002: 47: 291–299.23. Lammintausta K, Kalimo¨ K. Atopy <strong>and</strong> <strong>h<strong>and</strong></strong> dermatitis inhospital wet work. Contact Dermatitis 1981: 7: 301–308.24. Nilsson E, Mikaelsson B, Andersson S. Atopy, occupation<strong>and</strong> domestic work as risk factors for <strong>h<strong>and</strong></strong> <strong>eczema</strong> in hospitalworkers. Contact Dermatitis 1985: 13: 216–223.25. Lerbaek A, Kyvik K O, Mortensen J, Bryld L E, Menné T,Agner T. Heritability <strong>of</strong> <strong>h<strong>and</strong></strong> <strong>eczema</strong> is not explained bycomorbidity with <strong>atopic</strong> dermatitis. J Invest Dermatol2007: 127: 1632–1640.26. Baurecht H, Irvine A D, Novak N, Illig T, Buhler B,Ring J, Wagenpfeil S, Weidinger S. Toward a major riskfactor for <strong>atopic</strong> <strong>eczema</strong>: meta-analysis <strong>of</strong> <strong>filaggrin</strong>polymorphism data. J Allergy Clin Immunol 2007: 120:1406–1412.27. Rue<strong>the</strong>r A, Stoll M, Schwarz T, Schreiber S, Folster-HolstR. Filaggrin loss-<strong>of</strong>-function variant contributes to <strong>atopic</strong>dermatitis risk in <strong>the</strong> population <strong>of</strong> Nor<strong>the</strong>rn Germany.Br J Dermatol 2006: 155: 1093–1094.28. Barker J N, Palmer C N, Zhao Y et al. Null mutations in <strong>the</strong><strong>filaggrin</strong> gene (FLG) determine major susceptibility to earlyonset<strong>atopic</strong> dermatitis that persists into adulthood. J InvestDermatol 2007: 127: 564–567.29. Brown S J, S<strong>and</strong>il<strong>and</strong>s A, Zhao Y et al. Prevalent <strong>and</strong> lowfrequencynull mutations in <strong>the</strong> <strong>filaggrin</strong> gene are associatedwith early-onset <strong>and</strong> persistent <strong>atopic</strong> <strong>eczema</strong>. J Invest Dermatol2008: 128: 1591–1594.30. S<strong>and</strong>il<strong>and</strong>s A, Terron-Kwiatkowski A, Hull P R et al. Comprehensiveanalysis <strong>of</strong> <strong>the</strong> gene encoding <strong>filaggrin</strong> uncoversprevalent <strong>and</strong> rare mutations in ichthyosis vulgaris <strong>and</strong><strong>atopic</strong> <strong>eczema</strong>. Nat Genet 2007: 39: 650–654.31. Thomsen S F, Ulrik C S, Kyvik K O, Hjelmborg J B,Skadhauge L R, Steffensen I, Backer V. Importance <strong>of</strong>genetic factors in <strong>the</strong> etiology <strong>of</strong> <strong>atopic</strong> dermatitis: a twinstudy. Allergy Asthma Proc 2007: 28: 535–539.32. Thomsen S F, Ulrik C S, Kyvik K O, Skadhauge L R,Steffensen I, Backer V. Findings on <strong>the</strong> <strong>atopic</strong> triad froma Danish twin registry. Int J Tuberc Lung Dis 2006: 10:1268–1272.33. Nystad W, Roysamb E, Magnus P, Tambs K, Harris J R.A comparison <strong>of</strong> genetic <strong>and</strong> environmental variance structuresfor asthma, hay fever <strong>and</strong> <strong>eczema</strong> with symptoms <strong>of</strong> <strong>the</strong>same diseases: a study <strong>of</strong> Norwegian twins. Int J Epidemiol2005: 34: 1302–1309.Address:Charlotte GiwercmanDepartment <strong>of</strong> DermatologyCopenhagen University Hospital Gent<strong>of</strong>teNiels Andersens Vej 65DK-2900 HellerupDenmarkTel: þ45 39773200Fax: þ45 39657137e-mail: c_giwercman@hotmail.com