Increasing our understanding of pigmentary disorders - Antonio ...

Increasing our understanding of pigmentary disorders - Antonio ...

Increasing our understanding ofpigmentary disordersPearl Grimes, MD, a James J. Nordlund, MD, b Amit G. Pandya, MD, c Susan Taylor, MD, dMarta Rendon, MD, e and Jean-Paul Ortonne, MD fLos Angeles, California; Dayton and Mason, Ohio; Dallas, Texas;New York, New York; Boca Raton, Florida; and Nice, FranceThis article focuses on developments in pigmentary disorders that extend dermatologists’ understandingof the field. Areas that are reviewed include the basic biochemistry, pharmacology, and physiology of themelanocortin system; melanosome development; genetic diseases associated with pigmentary disorders;pigmentary disorders secondary to systemic disease; drug-induced hyperpigmentation; environmentalexposure to chemicals; and primary disorders of hyperpigmentation such as melasma and lentigines. Basic,clinical, and epidemiological research, along with a number of clinical case reports, were included in thereview. This article also reports on the new health-related quality-of-life instrument (MELASQOL) that hasbeen developed for women with melasma. ( J Am Acad Dermatol 2006;54:S255-61.)This article reviews published work ondevelopments in pigmentary disorders. Basicscience and epidemiological and clinicalresearch articles are reviewed in addition to a numberof illustrative clinical case reports.The article is split into 3 main sections—molecularbiology, causes of dyschromias, and primary causesof hyperpigmentation—and a conclusion. Each ofthe main sections lists articles that were consideredof particular interest by members of the PigmentaryDisorders Academy (PDA). These articles are describedand PDA members’ thoughts on the significanceof the findings added.MOLECULAR BIOLOGYArticles discussed in this section include researchon a number of receptors involved in skin pigmen-From the Vitiligo & Pigmentation Institute of Southern California,Los Angeles, and Division of Dermatology, University ofCalifornia, Los Angeles a ; the Division of Dermatology, WrightState University, Dayton, and Group Health Associates, Mason bDepartment of Dermatology, University of Texas SouthwesternMedical Center, Dallas c ; Department of Dermatology, ColumbiaUniversity, and the Skin of Color Center, St. Luke’s-RooseveltHospital Center, New York d ; Dermatology and Aesthetic Center,Boca Raton e ; and the Department of Dermatology, Universityof Nice-Sophia Antipolis. fSupported by Galderma International.Disclosure: All authors are members of the Pigmentary DisordersAcademy (PDA) and receive honoraria from Galderma for theirwork on behalf of the Academy.Reprint requests: Pearl Grimes, MD, Vitiligo & Pigmentation Institute,Suite 609, 321 N Larchmont, Los Angeles, CA 90004-6408.0190-9622/$32.00ª 2006 by the American Academy of Dermatology, Inc.doi:10.1016/j.jaad.2005.12.042Abbreviations used:APP: b-amyloid precursor proteinBLOC-1: biogenesis of lysosome-relatedorganelles complex 1DLQI: Dermatology Life Quality IndexHCV: hepatitis C virusHPS: Hermansky-Pudlak syndromeHRQoL: health-related quality of lifeIM: imatinib mesylateLHS: Laugier-Hunziker syndromeLySD: lysosomal-storage diseaseMC1R: melanocortin 1 receptorMSH: melanocyte-stimulating hormonePDA: Pigmentary Disorders AcademyPJS: Peutz-Jeghers syndromesAPP: soluble amino-terminal ectodomainof APPUV: ultraviolettation, including the melanocortin 1 receptor (MC1R)and the b-endorphin/-opiate receptor, and on thedevelopment of skin pigmentation.A review of the basic biochemistry, pharmacology,and physiology of the melanocortin system hasrecently been published. 1 The melanocortin systemconsists of melanocortin peptides (a-, b- and g-melanocyte-stimulating hormone [MSH]) derivedfrom the proopiomelanocortin gene, 5 melanocortinreceptors, 2 endogenous antagonists (agouti andagouti-related protein), and 2 ancillary proteins(mahogany and syndecan-3). Recent pharmacologicaland genetic studies have confirmed the roleof melanocortins in pigmentation, inflammation,energy homeostasis, and sexual function. Developmentof selective agonists and antagonists isexpected to assist research on these complex physiologicalfunctions and provide an experimentalS255

S256Grimes et alJAM ACAD DERMATOLMAY 2006Fig 1. Expression of b-amyloid precursor protein (APP)and secretion of its soluble amino-terminal ectodomain(sAPP) including its physiological effects. (Reproduced fromQuast T, Wehner S, Kirfel G, Jaeger K, de Luca M, Herzog V.sAPP as a regulator of dendrite motility and melanin releasein epidermal melanocytes and melanoma cells. FASEBJ 2003;17:1739-41 with permission of the FASEB.)basis for new pharmacotherapies. Scott, Suzuki, andAbdel-Malek 2 assessed this further in their in vitrostudy on the regulation of human MC1R usingnormal human melanocytes from neonatal foreskins.The study reported that MC1R is regulated by paracrinefactors, such as a-MSH and agouti signalingprotein, by specific endocrine sex hormones andby ultraviolet (UV) radiation. a-MSH has been shownto up-regulate expression of MC1R, whereas agoutisignaling protein has the opposite effect. Differencesin the responses of normal human melanocytes invitro to some of these factors suggest differentialregulation of MC1R gene expression, which maycontribute to the variation in constitutive and UVinducedcutaneous pigmentation in humans.Although there is no direct evidence of an interactionbetween melanotropin peptides and opioidreceptors or between opioid peptides and melanocortinreceptors, scientific evidence suggests thepossibility. In a study from Han et al, 3 19 a-melanotropinanalogues were designed from the d-opioidreceptor antagonist deltorphin-II. These moleculeswere designed by a hybrid approach, which incorporatedthe hydrophobic tail and the addresssequence of deltorphin-II (Glu-Val-Val-Gly-NH 2 )and key pharmacophore elements of melanotropins.After assaying for agonist activity for the MC1Rfrom Xenopus frog skin, selected potent analogueswere subsequently examined against recombinanthuman MC1, MC3, and MC4 receptors expressed inhuman embryonic kidney cells. The potent MC1Rantagonist was also found to have a high affinity forthe MC3R but low affinity for the MC4R. The significanceof the activity of MC3R and MC4R is currentlynot understood. It is hoped that the development ofspecific agonists and antagonists for these receptorswill shed light in this area. The techniques used haveallowed the development of the first potent MC1Rantagonist, and it is hoped that by using the sametechniques more selective and potent agonists andantagonists of different human melanocortin receptorscan be developed.In a study by Berson et al, 4 the authors assessedmechanisms involved in the production of melanosomes.It was demonstrated that cleavage of theproprotein convertase enzyme is required for melanogenesisto be initiated. Melanosomes and theirprecursors are lysosome-related organelles that haveintraluminal fibrous striations upon which melaninsare polymerized. The formation of intraluminalfibrils requires cleavage of Pmel17 by a furin-likeproprotein convertase. Pmel17 itself is a type 1 integralmembrane protein that is uniquely expressedby melanocytes and retinal pigment epithelialcells. Proper cleavage of Pmel17 generates a luminaldomain fragment that is incorporated into the fibrils.In the absence of proprotein convertase activity,longer Pmel17 fragments are created and these areunable to form organized fibrils.Quastetal 5 described the role of b amyloid precursorprotein (APP) isoforms in melanogenesis, wheretheyarethoughtto regulate dendrite motilityandmelaninrelease (Fig 1). The mode of action of its solubleamino-terminal ectodomain (sAPP) in the epidermis iscomparable to other growth factors in the epidermalmelaninunit, paracrine when sAPP is derived from keratinocytesand autocrine if released by melanocytes.Inoue et al 6 studied the induction of hyperpigmentation.Some hormones or prohormones,including adrenocorticotropic hormone and MSH,are overexpressed at times of stress. Both hormonesplay important roles in pigmentation. Increasednumbers of dopa-positive melanocytes were foundin stressed mice subjected to UV irradiation. Pretreatmentwith an inhibitor of adrenocorticotropichormone, however, led to a reduction in the numbersof dopa-positive melanocytes (and thus thestress pigmentary response).The role of neuropeptides in the control of skincolor was demonstrated in an article by Kauseret al. 7 They demonstrated that both the b-endorphinand -opiate receptors are expressed in epidermal

JAM ACAD DERMATOLVOLUME 54, NUMBER 5Grimes et alS257Table I. Classification of depigmenting agents according to mode of action*Stage of melanin synthesis/depositionCompoundsBefore melanin synthesis Tyrosinase transcription C 2 -ceramide, tretinoinTyrosinase glycosylationPaSSO 3 CaDuring melanin synthesis Tyrosinase inhibition Hydroquinone, 4-hydroxy-anisole4-S-CAP and derivatives, arbutinAloesin, azelaic acidKojic acid, methyl gentisateEllagic acid, resveratrolOxyresveratrolPeroxidase inhibitionMethimazole, phenols/catecholsProduct reduction and ROSscavengersAscorbic acid, ascorbic acid palmitateVC-PMG, thioctic acida-TOC, dl-a-TF, hydrocumarinsAfter melanin synthesis Tyrosinase degradation Linoleic acid, a-linoleic acidInhibition of melanosomes transferSkin turnover accelerationSerine protease inhibitors, lecithinsand neoglycoproteinsSoybean milk extracts, niacinamideRW-50353Lactic acid, glycolic acidLiquiritin, retinoic acidLinoleic acida-TF, a-Tocopherol ferulate; a-TOC, a-tocopherol; PaSSO 3 Ca, calcium d-pantetheine-S-sulfonate; ROS, reactive oxygen species; 4-S-CAP,4-S-cystaminylphenol; VC-PMG, magnesium-L-ascorbyl-2-phosphate.*Adapted from Briganti S, Camera E, Picardo M. Pigment Cell Res 2003;16:101-10.melanocytes. The team used a cultured melanocytesystem to show that b-endorphin has potentmelanogenic, mitogenic, and dendritogenic effects.The b-endorphin/-opiate receptor system is likelyto become an important area of research in the futurebecause it offers potential for developing therapeuticagents to interact with these neuropeptides.An interesting publication by Briganti, Camera,and Picardo 8 listed the various stages of melaninproduction that can be interrupted to producedepigmentation and the possible agents that canact at the different steps (Table I). The evidence forthe effectiveness of these therapies ranges from invitro studies through to clinical trials.Bovine retinas exposed to blue/green light at 390to 520 nm produced quantities of hydrogen peroxideassociated with a marked decrease in the amount ofmelanin present in the retinal pigment epithelium. 9It has been shown that oxidation of melanin and itsirreversible bleaching occurs after aerobic irradiationof melanin with UV or visible light because of theformation of superoxide anion or hydrogen peroxide.The observation may have implications fortreating dermal melanosis.CAUSES OF DYSCHROMIASDyschromias can be linked with a variety of causalfactors—genetic predisposition, contact with variousagents in the environment, as a sequel to chronicdisease, or as a result of drugs prescribed for anexisting condition.Genetic disordersKanitakis et al 10 provided a pathophysiologicalbasis for the understanding of the development ofpigmentary lesions in chromosome-linked focaldermal hypoplasia. They described a 19-year-oldwoman with atrophic lesions with adipocytic herniationthrough the dermis, papillomatous lesions, andbone anomalies. Biopsy results of the hyperpigmentedlesions showed higher melanin levels inthe basal layer and large dermal macrophages.Unusually, the hyperpigmentation presented as multiplelentigo-like macules at the periphery of atrophicareas. These macules first appeared at puberty anddeveloped progressively during adolescence. Theauthors noted that the melanocyte stimulation withintypical atrophic lesions supports the hypothesis thatfocal dermal hypoplasia lesions may be progressive.Ochiai et al 11 focused on the association betweenextrasacral mongolian spots and Hunter’s syndrome.Ultrastructural findings were similar to those seen inaberrant or persistent mongolian spots or nevus ofOta, both of which persist lifelong and suggest thelong-lasting nature of the hyperpigmentation. Thesefindings are relevant for the early diagnosis of a mild

S258Grimes et alJAM ACAD DERMATOLMAY 2006Table II. Laugier-Hunziker syndrome: An important differential diagnosis for Peutz-Jeghers syndrome*Peutz-Jeghers syndromeLaugier-Hunziker syndromeInheritance Autosomal dominant SporadicAge at onset Infancy or early childhood Early to mid-lifeCutaneous lesions Oral and labial pigmentation Oral, labial, and fingertippigmentation; longitudinalmelanonychiaPigmented mucosal lesions Lips, oral mucosa Buccal mucosa, lower lips,hard and soft palateGermline mutations onMay be present in 40%-60% ofNone identifiedchromosome 19p13.3patients with conditionGI abnormalitiesHamartomatous GI polyposis,NoneGI cancerSurveillance recommendationsUpper and lower GI endoscopywith small bowel follow-upevery two years, early breastscreening every five years.Gynecological exams every 3 yNoneGI, Gastrointestinal.*Based on Wirtzfeld DA, Petrelli NJ, Rodriguez-Bigas MA. Ann Surg Oncol 2001;8:319-27 12 ; Scott RJ, Crooks R, Meldrum CJ, Thomas L, SmithCKA, Mowat D, et al. Clin Genet 2002;62:282-7 13 ; Lampe AK, Hampton PJ, Woodford-Richens K, Tomlinson I, Lawrence CM, Douglas FS.J Med Genet 2003;40:e77. 14form of Hunter’s syndrome in order to improve thepatient’s prognosis.Table II 12,13 highlights the differences betweenLaugier-Hunziker syndrome (LHS) and Peutz-Jegherssyndrome (PJS). LHS is an important differentialdiagnosis for PJS. Although there are commondermatological features within the two syndromes,PJS is associated with hamartomatous gastrointestinalpolyposis and any risk of malignancy can be assessedby regular surveillance. In contrast, LHS is a benigndisease with no systemic manifestations requiring nointerventions. 14Widespread dermal melanocytosis as a marker forlysosomal-storage disease (LySD) was reported in acase study of two infants presenting with extensiveblue cutaneous patches in the posterior and anteriortrunk region. 15 The article also included a literaturereview of widespread dermal melanocytosis withassociated LySD that identified 46 patients, 24 (52%)of which had Hurler syndrome. GM1 gangliosidosis,Niemann-Pick disease, Hunter syndrome, and a-mannosidosis are also featured in the list. Dermalmelanocytosis occurred more commonly in darkerskinned infants. 15Hermansky-Pudlak syndrome (HPS) is a group ofgenetic diseases resulting from abnormal movementof vesicles to and among subcellular organelles,including melanosomes, platelet-dense granules,and lysosomes. At the time of the review, 4 geneticvariants of HPS were known to exist (HPS-1, HPS-2,HPS-3, and HPS-4). All are associated with bleedingdiathesis from abnormal platelets. Huizing, Boissy,and Gahl 16 reviewed the roles played by the genesresponsible for HPS, which are key to understandingprotein formation and transport in people with thesyndrome. Subsequently, 3 more genetic subtypesof HPS have been identified; HPS-5, HPS-6, andHPS-7. 17 Discovery of the HPS-7 variant is of particularinterest as it provides the first evidence that amutation affecting a biogenesis of lysosome-relatedorganelles complex 1 (BLOC-1) component causesHPS in humans. 18 HPS-associated genes participatein at least 4 distinct protein complexes: the adaptorcomplex AP-3; BLOC-1, consisting of 4 HPS proteins(pallidin, muted, cappuccino, HPS7/sandy); BLOC-2, consisting of HPS6/ruby-eye, HPS5/ruby-eye-2,and HPS3/cocoa; and BLOC-3, consisting of HPS1/pale ear and HPS4/light ear. 19Systemic diseaseHyperpigmentation is commonly found in patientswith chronic renal failure and is also one ofthe most evident features of porphyria cutanea tarda.Hepatitis C virus (HCV) is an important precipitatingagent of this disease, which has been described inpatients undergoing hemodialysis. A study of 47patients undergoing hemodialysis divided patientsinto two groups: group 1, anti-HCV positives (n = 17),and group 2, anti-HCV negatives (n = 30). Tenpatients in group 1 and 7 in group 2 developedhyperpigmentation (P \ .05). 20 The authorsconcluded that dialysis patients with HCV andchronic renal failure were more likely to exhibithyperpigmentation.

JAM ACAD DERMATOLVOLUME 54, NUMBER 5Grimes et alS259An article discussing vitamin B 12 deficiency describeda 54-year-old man who had distinct hyperpigmentationof the hands, feet, and tongue alongwith shortness of breath and weakness. 21 He hada medical history that included diabetes, alcoholabuse, liver disease, and vitamin B 12 deficiency secondaryto malnutrition. The exact mechanism ofhyperpigmentation is unknown, but a number ofhypotheses have previously been put forward. Adeficiency in vitamin B 12 might cause a decrease inintracellular-reduced glutathione. This results in anincrease in tyrosinase activity and allows an increasein melanogenesis, resulting in clinical hyperpigmentation.A decrease in hyperpigmentation usually occurswithin 2 weeks of starting vitamin B 12 treatment.High and Costner 22 reported the case of a 12-year-old girl who presented with forehead, glabellar,preauricular, and periotic hyperpigmentation; telangiectases;and atrophic scars. The patient had beendiagnosed in infancy with neonatal lupus erythematosus—anautoimmune disease with a distinctivecutaneous appearance. The condition is usually selflimiting,as the causative antibodies are maternallyderived. Chronic cutaneous sequelae, as in this case,are rare. The areas of hyperpigmentation were successfullytreated with hydroquinone (4%) and tretinoin(0.025%).Environmental chemical exposureIn a study of the effects of consuming arseniccontaminatedwater, 7683 persons from India wereassessed for skin disease. 23 Two hundred forty-eight(3.2%) showed clinical characteristics of arsenicosis,including raindrop (spotty) pigmentation/depigmentationof the body and extremities (94.35% of sufferers)and keratoses of the hand (65.3%). Pigmentedabnormalities were observed in more than 80% ofpersons who drank water containing more than 50g/L of arsenic. The study also reported that arseniclevels in the water were very high (3.4 mg/L).Drug-induced skin diseaseMahé et al 24 surveyed a total of 599 Senegalesewomen presenting with a variety of skin diseases,including dermatophyte infections (n = 105), scabies(n = 69), acne (n = 42), and dyschromias (n = 26).Seventy-one percent of these women (425 patients)used bleaching agents. Ninety-two percent of theseapplied the products to their whole body at leastonce a day. The cost of the products accounted forapproximately 7% of their monthly income. Mostwere hydroquinone-based compounds (89%), followedby corticosteroid (70%), mercury salts (10%),and caustic agents (17%). They concluded that atleast 55% of the diseases prompting a visit to theclinic could be classified as complications of usingcosmetic bleaching agents. They suggested that theextensive use of topical steroids was responsible forconditions such as scabies and acne. Eczema, irritantdermatitis, and a lupus-like facial eruption wereassociated with hydroquinone use.Tosti et al 25 reported a lentiginous eruption followingtreatment with topical squaric acid dibutylester(0.001%-0.1%) in a 16-year-old boy withalopecia universalis on the scalp and eyebrows.The hair regrew after 9 months, but subsequentrelapses were treated similarly over the next 26months. A lentiginous eruption developed aroundthe treated areas 3 years after the first treatmentand the hyperpigmented macules resembled thoseof psoralen-UVA-induced lentigines, although thistreatment or exposure to sunlamps or excessivesunlight had not occurred. The authors suggestthat possible mechanisms could be antigenic competition,nonspecific systemic suppression of delayed-typehypersensitivity, and interference withpostinflammatory cytokine activity.Bellet et al 26 described a 20-year-old whitewoman diagnosed with Diamond-Blackfan anemiaat 2 months of age. She had been receiving monthlyexchange transfusions which had resulted in ironoverload. Stem cell factor was used to reduce thenumber of transfusions required, which has a directstimulatory effect on melanocytes and promotesmast cell hyperplasia. As a result she suffered extensivehyperpigmentation at the many injection sites,including the buttocks.Two studies showing contrasting effects oftyrosine kinase inhibition on gray hair werereviewed. 27,28 Imatinib mesylate (IM) (Gleevec) isa tyrosine kinase inhibitor that targets the BCR-ABLprotein in chronic myelogenous leukemia, c-Kit, andplatelet-derived growth factor receptors. Etienne,Cony-Makhoul, and Mahon 27 studied 133 patientswith chronic myeloid leukemia to see how IMtherapy affected hair color. Nine patients had grayhair before treatment and hair repigmentation occurredafter a median of 5 months of treatment. Theauthors of the report offered no explanation for theeffects seen. By contrast, Robert et al 28 found that 18of their 28 patients being treated for chronic myelocyticleukemia with SU11428—which also blocks thereceptors for vascular endothelial growth factor,platelet-derived growth factor, and stem cell factor—developed gray hair. They suggested that the repigmentationeffect seen in the first study couldbe related to c-Kit; IM is known to inhibit c-Kit, atyrosine kinase receptor. Blocking of various combinationsof 3 tyrosine kinase receptors can result invery different effects on hair pigmentation.

S260Grimes et alJAM ACAD DERMATOLMAY 2006PRIMARY DISORDERS OFHYPERPIGMENTATIONMelasmaSarker, Jain, and Puri 29 reported a review of 120Indian melasma patients. Thirty-one (26%) weremale, which is greater than that usually reported inmelasma studies. Among these, malar melasma wasobserved in 16 (52%)—higher than is generally foundin females. Etiology involved sunlight (45%), familyhistory (perhaps surprisingly low at 16%), and exposureto phenytoin (6%). The authors noted that theprevalence of melasma in the men could be linked togreater exposure to the sun, more cosmetic awareness,and the use of mustard seed oil as a moisturizer.Larger studies are called for to confirm this finding.The MELASQOL scale is a new 10-item qualityof-lifeinstrument for melasma patients. 30 It wasderived from existing health-related quality-of-life(HRQoL) assessments, and validation tests found theMELASQOL to be well correlated with the DermatologyLife Quality Index (DQLI) and Skindex indexin terms of psychometric properties and with otherHRQoL measures. The new instrument highlights the3 life domains considered by patients to be mostaffected by melasma—social life, recreational andleisure life, and emotional well-being.Balkrishnan et al 30 randomly sampled 102 women,aged 18 to 65 years, identified as having melasma.These women were evaluated using the MelasmaArea and Severity Index and then asked to completethe DLQI, the Skindex-16, a 7-point skin discolorationquestionnaire, and the Fear of Negative EvaluationQuestionnaire. The women were also asked torate their perceived quality of life in 8 aspects of theirlives (emotional well-being, family relationships,money matters, physical health, recreation and leisureactivities, sexual relationships, social life, andwork) first with melasma and then without melasma,so that an assessment of the patient’s increasedquality-of-life perceptions could be made. All ofthese data were utilized in the selection of the itemsto make up the MELASQOL. The 10 items choseninclude 7 from Skindex-16 and 3 from the skindiscoloration questionnaire, which was created forstudy purposes using a focus group of melasmaexperts. Patients are asked to rate how they feelabout the following items on a scale of 1 (not bothered)to 7 (bothered all the time):1. The appearance of your skin condition2. Frustration about your skin condition3. Embarrassment about your skin condition4. Feeling depressed about your skin condition5. The effects of your skin condition on yourinteractions with family, friends, close relationships,etc6. The effects of your skin condition on yourdesire to be with people7. Your skin condition making it hard to showaffection8. Skin discoloration making you feel unattractiveto others9. Skin discoloration making you feel less vital orproductive10. Skin discoloration affecting your sense of freedomThe MELASQUOL’s discriminatory power is similarto that of Skindex 16 and DLQI for melasma.Absent lentiginesThe development of lentigines within psoriaticplaques is a known clinical phenomenon, but thereverse was described in a paper by Mendonça,Holmes, and Burden. 31 They described a 44-year-oldwoman with a 10-year history of psoriasis. Shesunbathed regularly and had developed multiplesolar lentigines around the psoriatic plaques but notin the lesions themselves. Before this examinationshe had been treated with topical therapies and onecourse of narrowband UVB therapy. Histology of alentigo adjacent to a psoriatic plaque revealed anincrease in basal melanocytes and basal hyperpigmentation.The psoriasis was cleared with dithranoland this area remained free of lentigines 2 monthslater. A 10-year-old white boy had had psoriasis withmultiple lentigines outside the psoriatic plaquessince the age of 3 years. 31 The psoriasis was successfullytreated with coal tar and at 3 months aftertreatment, the areas remained free of psoriasis andlentigines. It is believed that there could be someT helper cell type 1 cytokines in psoriatic lesions,which can inhibit melanin production. Kang andKang 32 reported the case of a 30-year-old Koreanwoman with lentigines grouped on the left side ofher face without mucosal involvement, which shehad had from 7 years of age. The authors suggestedthat the segmental nature of the lesions could bediagnosed as agminated lentigines. However, thelack of symmetry, the early age at onset, the presenceof dermal melanocytes, and a lack of elongated reteridges led them to diagnose nevus of Ota in this case.CONCLUSIONThere has been much improvement in the understandingof the mechanisms underlying pigmentarydisorders. As our understanding grows, new treatmentstrategies are being developed and new areasof research assessed. The articles presented hereinare just a snapshot of this rapidly progressing area.Studying multiple different factors involved inthe production of melanin, its transfer, its degradation,and the various inhibitors of these steps, is key

JAM ACAD DERMATOLVOLUME 54, NUMBER 5Grimes et alS261to understanding pigmentary disorders—one can nolonger think only in terms of the action of tyrosinasein pigmentation. This understanding will enable thedevelopment of novel agents that enhance or suppressthe natural production of melanin.Moreover, the epidemiological studies and casereports reviewed herein suggest causes of pigmentarychanges and provide much food for thought andpossible areas for further research. The importanceof such studies lies not only in informing dermatologistsabout the more unusual dyschromias, but alsoin the opportunities they present to evaluate thedisorder—and its treatment—in a more effective way.Beyond the simple treatment of dyschromias, thedevelopment of a quality-of-life measure for melasmaindicates that the psychological effects of somepigmentary disorders are now being recognized andmeasured. Understanding the effects that dyschromiashave on patients’ lives will help practitionersprioritize therapy, which in turn will drive the need tofurther understand the mechanisms underlying thedisease and, thus, the development of new therapies.REFERENCES1. Gantz I, Fong TM. The melanocortin system. Am J PhysiolEndocrinol Metab 2003;284:E468-74.2. Scott MC, Suzuki I, Abdel-Malek ZA. Regulation of the humanmelanocortin 1 receptor expression in epidermal melanocytesby paracrine and endocrine factors and by ultraviolet radiation.Pigment Cell Res 2002;15:433-9.3. Han G, Quillan JM, Carlson K, Sadée W, Hruby VJ. Designof novel chimeric melanotrophin- deltorphin analogues. Discoveryof the first potent human melanocortin 1 receptorantagonist. J Med Chem 2003;46:810-9.4. Berson JF, Theos AC, Harper DC, Tenza D, Raposo G, Marks MS.Proprotein convertase cleavage liberates a fibrillogenic fragmentof a resident glycoprotein to initiate melanosomebiogenesis. J Cell Biol 2003;161:521-33.5. 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