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follicles from 13-cis retinoic acid-treated tive intracellular isomerization to all-trans blind vehicle-controlled study. JAMA acne patients. Br J Dermatol 133:241–8 retinoic acid and binding to retinoid 259:527–32 Stewart ME, Benoit AM, Stranieri AM, Rapini RP, acid receptors. J Invest Dermatol Wingender E, Dietze P, Karas H, Knuppel R (1996) Strauss JS, Downing DT (1983) Effect of oral 115:321–7 TRANSFAC: a database on transcription 13-cis Retinoic Acid at three dose levels on Wang Q, Chen Q, Zhao K, Wang L, Wang L, factors and their DNA binding sites. Nucleic sustainable rates of sebum secretion and on Traboulsi EI (2001) Update on the molecular Acids Res 24:238–41 acne. J Am Acad Dermatol 8:532–8 genetics of retinitis pigmentosa. Ophthalmic Yedgar S, Cohen Y, Shoseyov D (2006) Tsukada M, Schroder M, Roos TC, Chandraratna Genet 22:133–54 Control of phospholipase A2 activities RA, Reichert U, Merk HF et al. (2000) Weiss JS, Ellis CN, Headington JT, Tincoff T, for the treatment of inflammatory 13-cis retinoic acid exerts its specific Hamilton TA, Voorhees JJ (1988) Topical conditions. Biochim Biophys Acta 1761: activity on human sebocytes through selec- tretinoin improves photoaged skin. A double- 1373–1382

Heterozygous Null Alleles in Filaggrin Contribute to Clinical Dry Skin in Young Adults and the Elderly

Journal of Investigative Dermatology (2009) 129, 1042–1045; doi:10.1038/jid.2008.324; published online 6 November 2008;

TO THE EDITOR protocol was approved by the South (Palmer et al., 2006; Sandilands et al., Null mutations in the epidermal barrier Glasgow Research Ethics Committee, 2007) with minor refinements (Table filaggrin (FLG) cause conformed to the Declaration of Hel- S1). Statistical comparisons were vulgaris (IV, Smith et al., 2006) and are sinki Principles, and written informed made in 284 patients in whom all a major risk factor for eczema and other consent was obtained. The study took four mutations were successfully atopic diseases (Palmer et al., 2006; place in all months of the year, in a typed, between those wild-type se- Baurecht et al., 2007; Brown et al., climate without extreme variation in quence at all loci (wt) and patients 2008a; Henderson et al., 2008). About humidity, and all assessments took heterozygous for only one of the muta- 10% of European patients are place before genotyping. A question- tions (null). heterozygous for such null mutations naire asked patients whether they Of 284, 252 (89%) patients were (Sandilands et al., 2006), but clinical considered they had dry skin (possible wild type for all four mutations; 29 details of their skin phenotype are responses, coded 0–3, were not at all, a (10.2%) were heterozygous for one null sparse. A recent study of 811 English little, moderately, or a lot), sensitive mutation, and 3 (1%) were compound children reported that mild ichthyosis, skin (same responses) and how often heterozygotes, R501X/R2447X, 2282del4/ palmar hyperlinearity, and keratosis they used a moisturizer for the body S3247X, and R2447X/S3247X. The fre- pilaris were commoner in carriers of (never, now and again, more than once quency of these alleles was consistent null mutations (Brown et al., 2008a). a week, or daily), and sought a history with the previous UK data (Table S2; We report the effect of heterozygosity of childhood eczema or other diseases. Sandilands et al., 2007; Brown et al., for FLG null alleles, and age, on the Trained observers made objective as- 2008b). Four patients in whom the prevalence of simple subjective or sessments of visible fine scale and of assessors commented on marked objective clinical features of ‘‘dry skin’’ roughness in each of three body sites scaling consistent with IV included all in adults and elderly patients not (volar forearms, lower legs, and lower three compound heterozygotes; the selected for inflammatory skin disease. back), of (upper arms fourth was heterozygous only for Patients referred for diagnosis of a only), and of increased palmar mark- R501X but on biopsy showed a reduced discrete skin lesion to dermatology ings and texture. A simple scoring scale granular layer, consistent with previous clinics in Glasgow were recruited in for each parameter was used: absent immunohistochemical analysis indica- two age cohorts: young adults 18–40 (0), just perceptible (1), obvious (2), and tive of an undetected second null years (192 patients; 82 men, 110 marked (3). The total score of these mutation (Sandilands et al., 2007); for women), and the elderly 60–75 years parameters (maximum 27) was used as financial reasons, this patient was not (99 patients; 55 men, 44 women). a summary measure of ‘‘dry skin’’. subjected to full sequencing. Patients were asked not to apply body DNA, extracted from whole blood Questionnaire results are shown in moisturizers for 48 hours before their using standard procedures, was geno- Figure 1a and Table S3. Women were appointment; sunbed users or those typed for four FLG null mutations highly significantly more likely than who had been on a sunny holiday common in the UK (R501X, 2282del4, men to consider they had dry skin (39 within 6 weeks were excluded. The R2447X, and S3247X) as described vs 11%) or use body moisturizers regularly (43 vs 7%). Heterozygous carriers of null mutations were more Abbreviation: FLG, filaggrin; IV, ichthyosis vulgaris likely to think they had dry skin

1042 Journal of Investigative Dermatology (2009), Volume 129 A Sergeant et al. Filaggrin Null Alleles and Dry Skin

History of other disorders FINE SCALE: Arms Childhood eczema Legs Trunk Hay fever Acne ROUGHNESS: Arms Legs Self-reported features Trunk WOMEN: “Sensitive skin” “Dry skin” Keratosis pilaris Body moisturizer ≥2 × week PALMS: Hyperlinearity MEN: “Sensitive skin” Roughness “Dry skin” Body moisturizer ≥2 × week TOTAL SKIN SCORE > 4

0.1 1 10 100 0.1 1 10 100 Log odds ratio Log odds ratio

Figure 1. Symptoms and signs of dry skin are more likely in carriers of null alleles. Effect of heterozygosity for one null mutation in filaggrin on (a) subjective dry skin and history of eczema and other disorders and (b) the presence of clinical signs of dry skin. In each case the odds ratios (shown with 95% confidence intervals) represent the likelihood of a heterozygous carrier displaying the feature, compared with individuals with wild-type sequence at all four polymorphisms tested. No carriers gave a history of psoriasis, so the odds ratio has not been calculated.

Wild type Null mutation 18 18

Male Female Male Female 16 16

14 14

12 * 12

10 10 *

8 8 Total score Total

6 6

4 4

2 2

0 0

6006060 0 6 Number of subjects Number of subjects Young cohort Old cohort

Figure 2. Total scores for signs of dry skin are increased in carries of null alleles. Population distribution of individual total scores for features of dry skin in 238 patients with (left) wild-type sequence at all four polymorphisms tested and (right) 27 patients carrying one null mutation in FLG and two compound heterozygotes (the latter shown by *); note the 10-fold difference in scale. 18 patients typed, including two heterozygotes and one compound heterozygote, were excluded from assessment of signs because they had used body moisturizer within 48 hours. The subject who scored 18 was thought clinically to have IV, and granular layer was absent on biopsy. He may be carrying a second mutant allele not identified in this study.

www.jidonline.org 1043 A Sergeant et al. Filaggrin Null Alleles and Dry Skin

‘‘moderately’’ or ‘‘a lot’’ (Fisher’s exact the prevalence of null mutations was CONFLICT OF INTEREST test; P ¼ 0.024), to due principally men, identical to previous UK populations Irwin McLean and Frances Smith have filed patents relating to genetic testing and therapy and not significant in women alone. who had not been ascertained. We development aimed at the FLG . The other Use of body moisturizers twice a week chose to study patient perception and authors state no conflict of interest. or more was commoner among carriers, simple clinically assessed surface but again this finding was significant changes, to reflect the usage of the ACKNOWLEDGMENTS only in men (P ¼ 0.035). Self-perceived term ‘‘dry skin’’ by patients and practi- We are grateful to Sarah Brown, Department of sensitive skin (‘‘moderately’’ or ‘‘a lot’’) tioners in everyday life. This is less Dermatology, University of Newcastle upon Tyne, was no more common among carriers. objective than physiological correlates for recalculating mutant allele frequency data in her population study (Table S2) to permit compar- Carriers were more likely to give a of altered skin surface such as transepi- ison of the four polymorphisms studied. Clinical history of childhood eczema dermal water loss and stratum corneum costs were met by the South Glasgow Dermatol- (P ¼ 0.009), but asthma and hay fever hydration. Despite this, there was a ogy Fund. Filaggrin research in the McLean/Smith were not significantly more common in clear effect of FLG mutation on the laboratory is supported by grants from the British Skin Foundation, the National Eczema Society, this study. Trends to fewer cases of acne clinical measures. The finding that and the Medical Research Council (reference no. and psoriasis in carriers were not heterozygous carriers have an in- G0700314) and by donations from anonymous significant. creased prevalence of dry skin is also families affected by eczema in the Tayside region of Scotland. In the objective assessments, the consistent with studies with potential 1 2 prevalence of fine scaling and rough- recruitment bias (for example, Novak Ann Sergeant , Linda E. Campbell , 2 1 ness of the skin, keratosis pilaris, and of et al., 2008, ascertained for contact Peter R. Hull , Martin Porter , 3 2 palmar hyperlinearity and roughness (a eczema; Kezic et al., 2008, recruited by Colin N.A. Palmer , Frances J.D. Smith , 2 score of 1 or more) were all increased advertisement). We also confirm the W.H. Irwin McLean and 1 in carriers (Figure 1b). For most para- recent population survey in English Colin S. Munro meters this was significant by Fisher’s schoolchildren showing increased dry 1Alan Lyell Centre for Dermatology, Southern 2 exact test (Table S3). Distribution of skin, an increased incidence of child- General Hospital, Glasgow, UK; Epithelial total skin signs in wild-type and carrier hood eczema, and a surprisingly high Genetics Group, Division of Molecular Medicine, University of Dundee, Dundee, UK populations is shown in Figure 2; 94% prevalence of clinical IV (Brown et al., and 3Population Pharmacogenetics Group, of young non-carriers had a score of 4 2008a). Biomedical Research Centre, University of or less and thus a total score 44 was However, even with the loosest Dundee, Dundee, UK chosen to define clinical ‘‘dry skin’’. By criteria for dry skin, penetrance is at E-mail: [email protected] this criterion, using binary logistic most 70% in young patients and nearly regression, heterozygous carriers were 50% of non-carriers have some positive SUPPLEMENTARY MATERIAL more likely than non-carriers to have findings. Signs such as keratosis pilaris Table S1. Primers and probes for FLG mutation dry skin (odds ratio 7.3, 95% confi- and palmar hyperlinearity are sugges- screening by TaqMan allelic discrimination. dence interval 2.9–18.6, P ¼ 0.00002; tive but nonspecific, and though sum- Table S2. Allele frequencies. P ¼ 0.003 in each age cohort). Inde- mary skin scores were highly Table S3. Subjective features, history, and clinical pendently of genotype, the elderly were significantly different between groups signs. more likely to have dry skin than they have poor predictive values at an younger adults (odds ratio 2.9, 95% individual level. Less than a third gave a REFERENCES confidence interval 1.3–6.3, P ¼ 0.007). history of eczema. Thus, although null Baurecht H, Irvine AD, Novak N, Illig T, Buhler B, Seventy percent of young adult carriers mutations in FLG are a major contribut- Ring J et al. (2007) Toward a major risk factor for atopic eczema: meta-analysis of filaggrin exhibited some features of dry skin (a ing factor to clinical dry skin and polymorphism data. J Clin Immunol score of 1 or more in any parameter) eczema in the population, additional 120:1406–12 but so did 47% of young non-carriers. factors influence expression of these Brown SJ, Relton CL, Liao H, Zhao Y, Sandilands All the older carriers had some phenotypes. These may include the A, Wilson IJ et al. (2008a) Filaggrin null evidence of dry skin, but so did 70% number of FLG repeats per allele, which mutations and childhood atopic eczema: a population-based case–control study. J of non-carriers. In identifying young varies from 10 to 12 (Ginger et al., Allergy Clin Immunol 121:940–6 carriers clinically, fine scale on the 2005), or variations in the expression of Brown SJ, Sandilands A, Zhao Y, Liao H, Relton legs was helpful (53% of carriers vs FLG or other protein or lipid components CL, Meggitt SJ et al. (2008b) Prevalent and 22% of non-carriers) but most older of the cornified layer. The latter include low-frequency null mutations in the filaggrin patients had scaling on the legs irre- ceramides, whose decline may be gene are with early-onset and persistent atopic eczema. J Invest Dermatol 128:1591–4 spective of genotype. In the latter responsible for increasingly dry skin Ginger RS, Blachford S, Rowland J, Rowson M, group, fine scaling on the arms, or with age (Rogers et al., 1996). Further Harding CR (2005) Filaggrin repeat number palmar hyperlinearity (63 vs 27%, and study of protein and lipid expression in polymorphism is associated with a dry skin. 50 vs 11%, respectively) provided the skin is required to identify the Arch Dermatol Res 297:235–41 better opportunities to make a clinical molecular correlates of clinical dry skin, Henderson J, Northstone K, Lee SP, Liao H, Zhao distinction. impaired barrier function, and predispo- Y, Pembrey M et al. (2008) The burden of disease associated with filaggrin mutations: a In this adult population, ascertained sition to eczema in carriers of FLG null population-longitudinal birth cohort study. independently of dry or inflamed skin, mutations. J Allergy Clin Immunol 121:872–7

1044 Journal of Investigative Dermatology (2009), Volume 129 M Tanioka et al. Circumscribed Palmo-Plantar Hypokeratosis

Kezic S, Kemperman PM, Koster ES, de Jongh CM, Common loss-of-function variants of the atopic . J Invest Dermatol 126: Thio HB, Campbell LE et al. (2008) Loss-of- epidermal barrier protein major predisposing 1770–1775 function mutations in the filaggrin gene lead factor for . Nat Genet Sandilands A, Terron-Kwiatkowski A, Hull PR, to reduced level moisturizing factor in the 38:441–6 O’Regan GM, Clayton TH, Watson RM et al. stratum corneum. J Invest Dermatol Rogers J, Harding C, Mayo A, Banks J, Rawlings A (2007) Comprehensive analysis of the gene 128:2117–9 (1996) Stratum corneum lipids: the effect of encoding filaggrin uncovers prevalent Novak N, Baurecht H, Schafer T, Rodriguez E, ageing and the seasons. Arch Dermatol Res mutations in ichthyosis vulgaris and atopic Wagenpfeil S, Klopp N et al. (2008) Loss-of- 288:765–70 eczema. Nat Genet 39:650–4 function mutations in the filaggrin gene Sandilands A, O’Regan GM, Liao H, Zhao Y, Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandi- and allergic contact sensitization to nickel. Terron-Kwiatkowski A, Watson RM et al. lands A, Campbell LE, Zhao Y et al. (2006) J Invest Dermatol 128:1430–5 (2006) Prevalent and rare mutations in Loss-of-function mutations in the gene en- Palmer CN, Irvine AD, Terron-Kwiatkowski the gene encoding filaggrin cause ichthyosis coding filaggrin cause ichthyosis vulgaris. A, Zhao Y, Liao H, Lee SP et al. (2006) vulgaris and predispose individuals to Nat Genet 38:337–42

Circumscribed Palmo-Plantar Hypokeratosis: A Disease With Two Subtypes

Journal of Investigative Dermatology (2009) 129, 1045–1047; doi:10.1038/jid.2008.306; published online 25 September 2008

TO THE EDITOR circumscribed, round, nonerythema- papillary dermis. Connective tissue in Circumscribed palmo-plantar hypoker- tous macule on the plantar arch of the the dermis looked normal on heama- atosis (CPH) is a recently described right sole, which had persisted for 2 toxylin and eosin (HE) staining. The characterized by persis- years (Figure 1a). The lesion had density and shape of dermal fibroblasts tent asymptomatic, well-circumscribed, increased in size gradually, and the located beneath the affected depressed macules on the palm or diameter was 12 mm. Topical steroids did not differ from those in adjacent sole skin developing after middle age and antibiotics were of no benefit. normal dermis. Immunohistochemical (Perez et al., 2002). The characteristic Bacterial cultures were negative. examination revealed that K9 expres- pathological features are an abrupt Dermoscopic views using jelly immer- sion at the lesional epidermis dimin- step-down in the cornified layer and sion showed regularly distributed whit- ished abruptly at the transition from resulting hypokeratosis of the lesional ish spots with round pigmentation intact sole skin; however, the acrosyr- epidermis without notable changes corresponding to the pigmented acro- ingeal keratinocytes scattered in the in the underlying dermis. Several syringeum (data not shown). Furrows hypokeratotic macula continued to pathogeneses have been proposed, in- and ridges were obscure but main- show strong expression of K9 (Figure cluding clonal epidermal malformation, tained. Histological examination 2a and b). In contrast, lesional kerati- primary keratinizing disorder at the showed an abrupt and substantial de- nocytes showed robust 10 (K10) granular and horny layers, trauma and crease in the thickness of the stratum expression, as compared to the subtle papilloma-virus infection. However, corneum (Figure 1b). The corneum in K10 expression in the surrounding sole insufficient biological observations the involved skin showed typical bas- epidermis (Figure 2c and d). Expression have been reported to verify the nature ket-wave orthokeratosis. The lesional of K6 and K16 showed no marked of this unique keratoderma. epidermis was thinner and its granular difference between normal and lesional Here, we propose that the loss of layer was reduced when compared to skin (data not shown). Involucrin keratin 9 (K9) and 26 (Cx26) adjacent noninvolved skin. However, and filaggrin showed slightly decreased expression in lesional keratinocytes as a lesional sweat glands did not show expression in the involved epidermis pathogenetical alteration of CPH based these characteristic features. The acro- when compared to the adjacent on immunohistochemical observation of syringeal structures, including thick normal skin (data not shown). The our two additional cases affecting the sole cornified and granular layers, remained expression of Cx26, which is known and palm skin, respectively. The patients similar in appearance to the surround- to be abundant in the palm-plantar gave their consent to this study, which ing intact skin (Figure 1c). Multiple keratinocytes, also diminished notably was approved by Kyoto University Hos- slices detected no cornoid lamella. at the hypokeratotic lesional keratino- pital and conducted in accordance with Nuclear size and quality of cytoplasm cytes. The acrosyringeal keratinocytes the Declaration of Helsinki Principles. in keratinocytes from lesional skin was exclusively retained Cx26 expression Case 1 subtly disrupted, but there was no (Figure 2e and f ). A 62-year-old Japanese man presenting pleomorphism. There was no lympho- The number of Ki-67- (antibody with a solitary, asymptomatic, well- cyte infiltration or dilated vessels in the against the cell proliferation marker

www.jidonline.org 1045