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Origin, Clinical Presentation, and Diagnosis of Hypomelanotic Skin Disorders
Dermatol Clin 25 (2007) 363–371
Origin, Clinical Presentation, and Diagnosis of Hypomelanotic Skin Disorders Ilse Mollet, MD, MSc, Katia Ongenae, MD, PhD*, Jean-Marie Naeyaert, MD, PhD Department of Dermatology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
Hypomelanotic skin disorders are cutaneous pigmentary disorders characterized by a reduced melanin content in the skin that results in a lightening of the skin. Hypomelanoses can be congenital or acquired, and the hypopigmented or depigmented lesions may appear in a localized form or diffuse pattern. Establishing the correct diagnosis for hypomelanotic skin disorders requires a good history, a detailed physical examination, the use of special lighting techniques, such as Wood’s light, and sometimes a biopsy of the abnormally pigmented skin and the normally pigmented skin [1]. Wood’s lamp, first described in 1903, is an important diagnostic tool in dermatology, particularly in the examination of pigmentary disorders [2]. The Wood’s light is produced using a filter opaque to all light except for a band between 320 and 400 nm, in the ultraviolet (UV) range, with a peak at 365 nm. Melanin is responsible for absorbing most of the radiation to which the skin is exposed, especially that in the shorter wavelengths. Its natural tendency to absorb radiation in the UV range is exploited by the Wood’s light examination, because hypermelanotic skin lesions, which possess an increased concentration of epidermal melanin, appear darker by contrast to the surrounding normal skin, and hypomelanotic lesions, which possess decreased melanin, appear brighter [3]. For optimal use, the Wood’s lamp should be allowed to warm up for approximately 1 minute and the Wood’s light examination should be performed in a totally darkened room. It is also
* Corresponding author. E-mail address: [email protected] (K. Ongenae).
essential that the examiner adapt to the dark before examining the skin under Wood’s light illumination to see the contrasts clearly [2]. This article focuses on the origin, clinical presentation, and diagnosis of acquired hypomelanotic skin disorders. An algorithm for the diagnostic approach to these hypomelanoses is given in Fig. 1.
Acquired localized hypomelanotic skin disorders Infectious disorders Pityriasis versicolor Pityriasis versicolor is a common benign recurrent superficial fungal disease that is caused by Malassezia species. These yeasts are part of the normal human skin flora and occur predominantly in seborrheic areas because of their lipid dependency [4]. Research has postulated that pityriasis versicolor occurs when the yeasts change from the saprophytic or yeast phase to the parasitic or mycelial phase. The cause of this change remains unclear [5,6]. Although the prevalence of pityriasis versicolor tends to be much higher in hot and humid climates compared with temperate regions, evidence points to the importance of endogenous host factors in the development of the disease. These factors may include the use of oral anticoagulants and the use of systemic corticosteroids or immunosuppressive drugs [5]. Pityriasis versicolor is most commonly found in adolescents and young adults when sebaceous gland activity is maximal. The disease is characterized by the appearance of round to oval, slightly scaling macules that are most commonly
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Fig. 1. Algorithm for the diagnostic approach of acquired hypomelanotic skin disorders. (Data from Lapeere H, Boone B, De Schepper S, et al. Hypomelanoses and hypermelanoses. In: Gilchrest BA, editor. Fitzpatrick’s dermatology in general medicine. 7th edition. In preparation.)
found on the trunk, chest, back, and shoulders (Fig. 2). Pityriasis versicolor is usually asymptomatic, although pruritus does occur in some cases [6]. These lesions may vary in color. The depigmented form of pityriasis versicolor, also called pityriasis versicolor alba, presents as white macules, whereas the hyperpigmented form of pityriasis versicolor is associated with pink, tan, brown, or black lesions. Recently, a variant with red maculae (pityriasis versicolor rubra) and another with black ones (pityriasis versicolor nigra) were described [5]. Pityriasis versicolor is diagnosed on the basis of its typical clinical appearance. The diagnosis always should be confirmed by microscopy. Direct examination of the scaling edge of a lesion is possible using a solution of potassium hydroxide at 10% to 20% and Parker ink in equal parts. This examination reveals the typical ‘‘spaghetti and meatballs’’ pattern, which reflects the presence of hyphae and blastospores. In general, it seems that the most common Malassezia species cultured from lesions of pityriasis versicolor are M globosa and M sympodialis [5,6]. In addition to microscopic examination, Wood’s light examination of
Fig. 2. Pityriasis versicolor presenting hypopigmented round to oval macules on the back and right shoulder of a young male adult.
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the patient may be used to confirm the diagnosis of pityriasis versicolor, but the yellow-green fluorescence of affected skin areas is visible in only approximately one third of the cases [6]. The characteristic pityriasiform scaling should clinically differentiate pityriasis versicolor from the nonscaling depigmented lesions of vitiligo. Vitiligo frequently affects hands and feet of a patient, whereas pityriasis versicolor predominates on the trunk. Pityriasis alba mainly affects the face and limbs and produces diffuse patches that are slightly scaling and nonfluorescent. Other differential diagnoses include tinea corporis, pityriasis rosea of Gibert, pityriasis rotunda, erythrasma, seborrheic dermatitis, confluent and reticulated papillomatosis of Gougerot and Carteaud, and secondary syphilis [6]. Other infectious diseases that may be associated with hypopigmented patches are treponematosis and onchocerciasis [7,8]. The development of hypopigmented skin lesions with altered sensitivity is a characteristic and diagnostic feature of leprosy [9]. Postinflammatory disorders Pityriasis alba Pityriasis alba is a common benign dermatosis usually seen in preadolescent children. It is characterized by the presence of pale white or pink irregular, slightly scaling plaques with well-defined borders that vary from 0.5 to 6 cm in diameter. It affects the head and neck region, trunk, and limbs. It is usually asymptomatic. Male subjects are thought to be affected more frequently, as are patients with darker skin color [10,11]. The etiology and pathogenesis of pityriasis alba are still poorly understood. Excessive and unprotected sun exposure, frequent bathing, hot baths, and cutaneous signs of atopy are strongly related to the development of pityriasis alba [10,11]. Most cases of pityriasis alba are diagnosed clinically [10,11]. Chemical and physical agents Exposure to chemical agents, such as monobenzylether of hydroquinone and hydroquinone, which destroy melanocytes, may result in hypopigmentation or depigmentation. The latter may be difficult to distinguish from vitiligo [12]. Physical agents, such as heat and cold and UV and laser light, may damage melanocytes and give rise to localized depigmentation [13].
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Lupus erythematosus Depigmentation is commonly seen in lupus erythematosus as a result of the destruction of the basal layer homing melanocytes. In discoid lupus erythematosus, the skin is atrophic and depigmented. In systemic lupus erythematosus, cutaneous depigmentation is often secondary to inflammatory skin lesions [14]. Scleroderma Hypopigmented lesions may be seen in morphea or localized scleroderma. Depigmented patches seeded with perifollicular hypopigmentation that mimic repigmenting vitiligo patches are also seen in scleroderma [15,16]. Lichen sclerosus Lichen sclerosus (LS) is a chronic skin disease predominantly found in the anogenital area. It may occur in patients of any age, sex, or race, but it is most commonly observed in white peri- and postmenopausal women [17–19]. In women, LS can affect the perineum, labia majora, labia minora, fourchette, and clitoris. Perianal involvement is characterized by the ‘‘figure of eight’’ shape. Vaginal involvement is not a feature of LS. Typical lesions of LS are milky white, atrophic papules that may coalesce into plaques. Follicular plugging is present in early lesions. Its atrophic form can lead to loss of the labia minora and entrapment of the clitoris [18]. In men, LS can affect the foreskin and glans but not the perianal region [18,19]. Patients who have LS may complain of pruritus, dysuria, dyspareunia, and a burning sensation. There is not always a correlation between disease severity and the severity of symptoms [18]. Extragenital lesions of LS are asymptomatic and occur most commonly on the neck and shoulders [18,19]. The true incidence of LS remains unknown, because many cases are left unreported [19]. Over the years, many terms have been used to describe this condition, such as lichen plan atrophique, kraurosis vulvae, hypoplastic dystrophy, weissflecken dermatose, balanitis xerotica obliterans, and lichen planus sclerosus et atrophicus. With time, the terminology has been redefined and the term ‘‘lichen sclerosus’’ has been adopted, excluding all other terms [18,19]. Although the cause of LS is still unknown, several mechanisms have been suggested to play a role in the pathogenesis of LS, including genetic, autoimmune, hormonal, infectious, and local factors. Studies of genetic factors in LS have focused on the role of the human leukocyte
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antigen (HLA). No significant association has been demonstrated between LS and HLA class I antigens. On the other hand, an important link between LS and HLA class II antigens has been found. Associated autoimmune diseases, particularly vitiligo, alopecia areata, thyroid disease, and diabetes, have been found in patients with LS, which suggests a possible autoimmune basis for the disease [18,19]. The highest incidence of LS is observed in prepubertal girls and postmenopausal women, who possess low estrogen levels. This finding leads to the hypothesis that sexual hormones might play a role in LS pathogenesis [19]. To date, no clear data have shown that LS is related to an infectious organism. The onset of LS has been recorded at sites of surgery, after repeated trauma, or as a result of irritation caused by sunburn and radiotherapy. The Koebner phenomenon also occurs in LS [18,19]. Three responsible mechanisms for the leukoderma in LS have been proposed: decreased melanin production, reduced transfer of melanosomes to keratinocytes, and melanocyte loss [20]. LS is associated with a 4% to 6% risk of progression to squamous cell carcinoma of the vulva, which makes long-term follow-up recommended in these patients [19]. Although diagnosis of LS can be suggested on its clinical evaluation, histologic confirmation should be sought [18]. The histologic aspects of LS depend on how long the disease has existed and changes that result from the act of scratching [19]. Typical LS cases show dermal sclerosis, vacuolar interface alterations, and a lymphocytic infiltrate underlying the sclerosis [21]. Vacuolar degeneration of the basal layer is usual, especially in earlier lesions [17]. Differential diagnosis includes lichen planus, vitiligo, psoriasis, and vulvar intraepithelial neoplasia [19].
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The depigmentation does not cross the midline and affects one segment of the integument. These types of vitiligo can be classified as localized vitiligo. Acrofacial vitiligo involves distal extremities and face, whereas vitiligo vulgaris (Fig. 3) is characterized by scattered macules over the entire body with a symmetrical distribution pattern. Both types are classified as generalized vitiligo [23,24]. The prevalence of vitiligo in the global population is estimated at approximately 0.5% to 1% [22]. The disease has no predilection for either sex or ethnic origin. Vitiligo usually begins in childhood or young adulthood and has an unpredictable but often progressive course, with phases of stability and spreading of lesions [25,26]. Segmental vitiligo usually affects younger people and has a rapid onset with a progression limited to months or a few years [27]. Various factors are suspected to affect the progression of vitiligo: emotional shock, sunburn, pregnancy, physical illness, and trauma. The latter is known as the Koebner phenomenon, which is defined as the development of macules at the site of trauma, such as cut, burn, or abrasion [23]. The diagnosis of vitiligo is mainly clinical. The current consensus on the histologic presentation in vitiligo is a complete absence of melanocytes in the amelanotic lesions. The perilesional area
Vitiligo Vitiligo is an acquired depigmenting disorder characterized by the progressive loss of melanocytes from the epidermis and epidermal appendages, which results in milky white macular lesions, usually on predilection sites such as extensor areas of extremities and hands or face [22]. According to the distribution of the lesions, several types of vitiligo have been distinguished. Focal vitiligo involves one or more maculae in one area but not clearly in a zosteriform or segmental distribution. Vitiligo segmentalis is characterized by one or more maculae in a quasidermatomal pattern.
Fig. 3. Vitiligo vulgaris involving the back of a woman.
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exhibits melanocyte and keratinocyte damage with an occasional perivascular mononuclear leukocyte infiltrate. In early lesions some persistent melanocytes may be found, giving a partial depigmentation (hypopigmentation) [28,29]. The etiopathogenesis of vitiligo is still not completely elucidated. One hypothesis considers vitiligo an autoimmune disease [30]. The association with autoimmune disorders and organspecific antibodies and the fact that nonsurgical repigmenting therapies have immunomodulating effects indirectly support the idea of an autoimmune pathogenesis of the disease. The exact immune mechanism involved in vitiligo remains unknown, however. A humoral immune reaction is implicated through the detection of circulating antibodies against melanosomal and other melanocyte autoantigens. The variety of detected antibodies and the lack of melanocyte specificity points to a secondary phenomenon after melanocyte destruction and disruption of the melanocyte/ keratinocyte unit. In vitro assays demonstrate the melanocytotoxic capacity of some antibodies, however. Recent research focuses on a melanocytespecific cytotoxic T-cell immune reaction in the destruction of melanocytes. Analyses on the inflammatory infiltrate accompanying the depigmentation and high frequencies of circulating melanocyte-specific cytotoxic T cells further suggest the involvement of melanocyte-specific T cells recruited from the circulation in the disappearance of melanocytes. The neural hypothesis suggests that melanocyte death is caused directly or indirectly by mediators such as neuropeptides, catecholamines, or their metabolites or by an overactive sympathic system [31]. The biochemical hypothesis bases melanocyte death on an intrinsic increased sensitivity to oxidative stress that arises from autocytotoxic intermediate metabolites of the melanin synthesis or from other sources (eg, catecholamines). Defective homeostasis of pterins and essential cofactors in the hydroxylation of phenylalanine to tyrosine together with an increased hydrogen peroxide concentration and decreased catalase levels may contribute to the depigmenting process [22]. Other possible etiologic factors, such as deficiency in unidentified melanocyte growth factors, intrinsic defect of structure and function of melanocytes, or genetic factors, are proposed to be involved in the depigmentation process. The convergence theory suggests that the different causal factors could contribute in variable
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proportions to the destruction of melanocytes [32,33]. Different pathogenic pathways could be involved in the various clinical types of vitiligo. The neural hypothesis is probably involved in segmental vitiligo, whereas the autoimmune hypothesis is commonly related with generalized or focal nondermatomal vitiligo. In vivo morphologic studies recently demonstrated detachment of living melanocytes (melanocytorrhagy) in normal skin of patients with generalized vitiligo after friction. Detachment, followed by transepidermal migration and eventually melanocyte death, is suspected to be responsible for depigmentation in the Koebner phenomenon [34]. A chronic ‘‘melanocytorrhagy’’ caused by defective adhesion or loss of dendricity has been proposed as primary defect in a pathogenetic model integrating other known theories in nonsegmental vitiligo. Loss of dendricity could be mediated by oxyradicals or increased catecholamines, exaggerating transepidermal loss induced by minor trauma, whereas autoimmune phenomena could be triggered by antigen release and aggravate melanocyte detachment [31]. Halo nevus A halo nevus is a pigmented nevus surrounded by a ring of depigmentation. The nevus usually undergoes progressive regression over a period of several months. Halo nevi are estimated to affect 1% of the population. The lesions usually develop in children and young adults and are preferentially located on the back. A halo nevus may remain solitary, but up to half of patients may develop multiple lesions that develop simultaneously or successively. Complete regression of the nevus leaves a round- to oval-shaped depigmented macule (Fig. 4) [35]. The area of depigmentation may remain stable for months to years, but a considerable percentage repigments spontaneously [36]. Histologically, a moderate to dense mononuclear infiltrate with lymphocytes and marcophages is observed in close association with nevus cells [37]. In the depigmenting halo, melanocytes show degenerative signs, such as vacuolization of the cytoplasm [38]. The pathophysiology of halo nevi is not well known. A cytotoxic cell-mediated immune response is suspected to be involved in the destruction of nevomelanocytes [39]. A local proliferation of T-cell clones, activated by common nevus antigens, has been found in different halo nevi of the same patient [40]. Halo nevi and vitiligo seem to have different
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Fig. 4. Halo nevi on the lower back: Typical halo nevus adjacent to a depigmented macula after complete regression of the nevus.
pathogenetic mechanisms. A recent case control study indicated that halo nevi are infrequent in symmetrical and unilateral vitiligo [41]. Differences in HLA association suggest that vitiligo vulgaris and halo nevi associated with vitiligo have distinct pathogenetic mechanisms [42]. Melanoma-associated leukoderma Three different types of hypomelanosis may occur in patients with melanoma: leukoderma within the primary tumor or its metastases due to regression, leukoderma acquisitum centrifugum around the primary tumor or its metastases, and vitiligo-like depigmentation remote from the tumor or its metastases. The latter is also called melanoma-associated leukoderma [43]. Clinically, melanoma-associated leukoderma is a diffuse patchy vitiligo-like macular hypomelanosis or depigmentation that often develops at sites distant to the location of the primary melanoma. In classic vitiligo, depigmentation is symmetrical, usually starts on hands, face, and feet, and spreads centripetally to the trunk. In melanoma-associated leukoderma, depigmentation is asymmetrical, starts more commonly on the trunk, and spreads centrifugally toward the neck, face, and extremities. The leukoderma may be hypomelanotic and mottled or amelanotic and milk white. The time of onset of the leukoderma and the finding of metastases in melanoma patients may be fairly close [43]. Patients with melanoma-associated leukoderma may have a better survival rate than patients with melanoma without leukoderma [43,44]. Diagnosis of melanoma-associated leukoderma is mainly clinical. Wood’s lamp examination enhances the numerous discrete, white macules and
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patches. Histologic examination of the hypopigmented skin shows a decrease or a complete absence of melanocytes. Hypertrophic macromelanocytes with stubby dendrites may be present [43]. Growing evidence suggests that melanomaassociated, vitiligo-like leukoderma results from an immune reaction against shared antigenic determinants on normal and malignant melanocytes. Although humoral immune responses are commonly found in patients with melanoma, increasing evidence points toward an important role for cellular immune responses [43,45]. The association between vitiligo-like leukoderma, which results from destruction of normal melanocytes, and melanoma regression, which results from destruction of cancer cells, in patients who have melanoma suggests that targets of immunotherapy involved in melanoma regression comprise normal melanocytic differentiation antigens [46]. Vitiligo-like lesions have been observed in melanoma patients after successful immunotherapy with tumor-infiltrating T lymphocytes specific for tyrosinase and gp100, two melanocytic differentiation antigens [45]. Research also has demonstrated that T cells involved in the destruction of neoplastic melanocytes are identical clones of those that accumulate in melanoma-associated leukoderma [47].
Acquired diffuse hypomelanotic skin disorders Idiopathic guttate hypomelanosis Idiopathic guttate hypomelanosis is a common acquired pigmentary disorder characterized by sharply defined white macules of approximately 2 to 6 mm in diameter that are most commonly located on the legs and forearms. The disease particularly affects middle-aged and elderly persons. Idiopathic guttate hypomelanosis develops equally in both sexes and no race is exempt [48]. The pathogenesis of idiopathic guttate hypomelanosis is uncertain. Because most idiopathic guttate hypomelanosis lesions occur in sunexposed skin, a possible etiologic role of chronic exposure to UV radiation could be of some importance. It has been suggested that idiopathic guttate hypomelanosis may represent an effect of the normal ageing process. The pathologic hallmark of idiopathic guttate hypomelanosis seems to be an absolute reduction in the number of melanocytes. Several mechanisms might be responsible for melanocyte loss in idiopathic guttate hypomelanosis. It may be due to a disturbance in
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the production of melanocyte growth factors by keratinocytes, or it may be due to direct cytotoxicity, as from chronic exposure to UV radiation [48]. Diagnosis is made clinical and can be confirmed by Wood’s light examination. Histologically, Idiopathic guttate hypomelanosis lesions are characterized by slight basket-weave hyperkeratosis with epidermal atrophy and loss of the ridge pattern. Hypopigmented macules show a decrease in melanocytes and melanin content within the basal layers of the epidermis [48]. Leukoderma punctata In 1988, Falabella and colleagues [49] first described leukoderma punctata as an entity with multiple punctate hypopigmented and achromic spots that developed after psoralen plus ultraviolet A (PUVA) treatment. Similar findings were described after UVB therapy in psoriasis patients and after topical PUVA in a patient with segmental vitiligo [50,51]. The typical skin lesions were usually numerous, distinct, sharply demarcated, round, or oval macules varying in diameter from 0.5 to 1.5 mm. They were predominantly present on the upper and lower extremities, upper back and chest, and occasionally the face (Fig. 5) [49].
Fig. 5. Leukoderma punctata with numerous round or oval hypopigmented macules on the lower leg of a woman.
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It has been postulated that the most likely cause of leukoderma punctata is UV phototoxicity [49,50]. Ultrastructural studies by Falabella and colleagues [49] showed varying degrees of cellular damage within keratinocytes and in melanocytes. Histologic findings revealed decreased numbers but not an absence of functional melanocytes and melanin granules [51]. The appearance of new punctate hypopigmented and achromic spots in a long-term PUVA treated patient in combination with characteristic histologic and ultrastructural findings may suggest the diagnosis [49]. Progressive macular hypomelanosis of the trunk Progressive macular hypomelanosis of the trunk is a common pigmentary disorder of the skin that is characterized by ill-defined nummular, hypopigmented, nonscaly macules and patches distributed on the trunk (Fig. 6). It occurs predominantly in young adults, mainly women. The disorder has been described in many parts of the world and is seen in all races [52]. The pathogenesis of progressive macular hypomelanosis of the trunk is unknown, although there seems to be a relation between the red follicular fluorescence, which is caused by the presence of porphyrin-producing Propionibacterium acnes in the infrainfundibular portion of follicles of sebaceous glands, and the hypopigmented macules. Porphyrins are responsible for the fluorescence induced by UV radiation as under Wood’s light [52]. The diagnosis of progressive macular hypomelanosis of the trunk is made by its clinical presentation. Patients with progressive macular hypopigmentation of the skin show pointed red
Fig. 6. Progressive macular hypomelanosis of the trunk presenting ill-defined nummular patches on the back of a young female adult.
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fluorescence in a follicular pattern inside the hypopigmented spots of lesional skin when observed under Wood’s light. Usually the healthy pigmented skin of the trunk does not show any fluorescence [52]. Histologic examination of hypopigmented lesions revealed only a decrease in the amount of melanin content in the epidermis compared with the neighboring healthy skin. No abnormalities were found in the dermis. Sometimes a mild perifolliculitis could be observed in the lesional skin. In the stratum corneum, no spores, hyphae, or bacteria were seen. Propionibacterium acnes could be isolated in biopsy specimens from lesional follicular skin [52]. Progressive macular hypopigmentation of the trunk is often mistaken for pityriasis versicolor and pityriasis alba [52]. Exceptionally, mycosis fungoides and sarcoidosis may present with diffuse hypopigmented skin lesions [53,54]. Some endocrinologic disorders, such as Addison’s disease, thyroid gland disorders, and hypopituitarism, are related to hypomelanosis [55]. Summary Lesions of acquired hypomelanotic skin disorders may appear in a localized or diffuse pattern. Diagnosis is mainly based on a detailed clinical examination. The use of Wood’s lamp distinguishes hypopigmentation from depigmentation of the involved skin. The absence or presence of associated inflammatory lesions may be helpful to further refine the diagnostic approach of the hypomelanotic lesions. Histologic examination is often not mandatory to establish the diagnosis. References [1] Mosher DB, Fitzpatrick TB, Ortonne JP, et al. Normal skin color and general considerations of pigmentary disorders. In: Freedberg IM, Eisen AZ, Wolff K, et al, editors. Fitzpatrick’s dermatology in general medicine. 5th edition. New York: McGraw-Hill; 1999. p. 936–44. [2] Asawanonda P, Taylor CR. Wood’s light in dermatology. Int J Dermatol 1999;38:801–7. [3] Paraskevas LR, Halpern AC, Marghoob AA. Utility of the wood’s light: five cases from a pigmented lesion clinic. Br J Dermatol 2005;152:1039–44. [4] Thoma W, Kra¨mer HJ, Maysert P. Pityriasis versicolor alba. J Eur Acad Dermatol Venerol 2005;19: 147–52. [5] Crespo-Erchiga V, Florencio VD. Malassezia yeasts and pityriasis versicolor. Curr Opin Infect Dis 2006; 19:139–47.
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associated with the local expansion of a limited number of T cell clones. J Immunol 1999;162:1789–94. Barona MI, Arrunategui A, Falabella R, et al. An epidemiologic case-control study in a population with vitiligo. J Am Acad Dermatol 1997;36:282–3. de Vijlder HC, Westerhof W, Schreuder GM, et al. Difference in pathogenesis between vitiligo vulgaris and halo nevi associated with vitiligo is supported by an HLA association study. Pigment Cell Res 2004;17:270–4. Brochez L, Boone B, Naeyaert JM. Hypomelanoses associated with melanocytic neoplasia. In: Nordlund JJ, Boissy RE, Hearing VJ, et al, editors. The pigmentary system: physiology and pathophysiology. 2nd edition. Oxford (UK): Blackwell Publishing Ltd.; 2006. p. 705–24. Rodriguez-Cuevas S, Lopez-Chavira A, Zepeda del Rio G, et al. Prognostic significance of cutaneous depigmentation in Mexican patients with malignant melanoma. Arch Med Res 1998;29(2):155–8. Yee C, Thompson JA, Roche P, et al. Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of T cell-mediated vitiligo. J Exp Med 2000;192(11):1637–43. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 1998; 4(3):321–7. Becker JC, Guldberg P, Zeuthen J, et al. Accumulation of identical T cells in melanoma and vitiligo-like leukoderma. J Invest Dermatol 1999;113:1033–8. Wallace ML, Grichnik JM, Prieto VG, et al. Numbers and differentiation status of melanocytes in idiopathic guttate hypomelanosis. J Cutan Pathol 1998;25:375–9. Falabella R, Escobar CE, Carrascal E, et al. Leukoderma punctata. J Am Acad Dermatol 1988;18(3): 485–94. Park YK, Hann SK, Hong KT, et al. Generalized punctate leukoderma following UVB phototherapy in the psoriasis patients. Annals of Dermatology 1990;2:93–5. Park JH, Lee MH. Case of leukoderma punctata after topical PUVA treatment. Int J Dermatol 2004; 43(2):138–9. Westerhof W, Relyveld GN, Kingswijk MM, et al. Propionibacterium acnes and the pathogenesis of progressive macular hypomelanosis. Arch Dermatol 2004;140:210–4. Gu¨lekon A, O¨zsoy E, Gu¨rer MA, et al. Hypopigmented mycosis fungoides in an adolescent Turkish boy. Int J Dermatol 2005;44:795–6. Mashek H, Kalb R. Hypopigmentation of the extremities. Arch Dermatol 1998;134:743–8. Konkolova R. Acquired hypomelanoses. In: Lotti T, Hercogova´ J, editors. Vitiligo problems and solutions. New York: Marcel Dekker Inc.; 2004. p. 381–8.
Origin, Clinical Presentation, and Diagnosis of Hypomelanotic Skin Disorders Ilse Mollet, MD, MSc, Katia Ongenae, MD, PhD*, Jean-Marie Naeyaert, MD, PhD Department of Dermatology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
Hypomelanotic skin disorders are cutaneous pigmentary disorders characterized by a reduced melanin content in the skin that results in a lightening of the skin. Hypomelanoses can be congenital or acquired, and the hypopigmented or depigmented lesions may appear in a localized form or diffuse pattern. Establishing the correct diagnosis for hypomelanotic skin disorders requires a good history, a detailed physical examination, the use of special lighting techniques, such as Wood’s light, and sometimes a biopsy of the abnormally pigmented skin and the normally pigmented skin [1]. Wood’s lamp, first described in 1903, is an important diagnostic tool in dermatology, particularly in the examination of pigmentary disorders [2]. The Wood’s light is produced using a filter opaque to all light except for a band between 320 and 400 nm, in the ultraviolet (UV) range, with a peak at 365 nm. Melanin is responsible for absorbing most of the radiation to which the skin is exposed, especially that in the shorter wavelengths. Its natural tendency to absorb radiation in the UV range is exploited by the Wood’s light examination, because hypermelanotic skin lesions, which possess an increased concentration of epidermal melanin, appear darker by contrast to the surrounding normal skin, and hypomelanotic lesions, which possess decreased melanin, appear brighter [3]. For optimal use, the Wood’s lamp should be allowed to warm up for approximately 1 minute and the Wood’s light examination should be performed in a totally darkened room. It is also
* Corresponding author. E-mail address: [email protected] (K. Ongenae).
essential that the examiner adapt to the dark before examining the skin under Wood’s light illumination to see the contrasts clearly [2]. This article focuses on the origin, clinical presentation, and diagnosis of acquired hypomelanotic skin disorders. An algorithm for the diagnostic approach to these hypomelanoses is given in Fig. 1.
Acquired localized hypomelanotic skin disorders Infectious disorders Pityriasis versicolor Pityriasis versicolor is a common benign recurrent superficial fungal disease that is caused by Malassezia species. These yeasts are part of the normal human skin flora and occur predominantly in seborrheic areas because of their lipid dependency [4]. Research has postulated that pityriasis versicolor occurs when the yeasts change from the saprophytic or yeast phase to the parasitic or mycelial phase. The cause of this change remains unclear [5,6]. Although the prevalence of pityriasis versicolor tends to be much higher in hot and humid climates compared with temperate regions, evidence points to the importance of endogenous host factors in the development of the disease. These factors may include the use of oral anticoagulants and the use of systemic corticosteroids or immunosuppressive drugs [5]. Pityriasis versicolor is most commonly found in adolescents and young adults when sebaceous gland activity is maximal. The disease is characterized by the appearance of round to oval, slightly scaling macules that are most commonly
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Fig. 1. Algorithm for the diagnostic approach of acquired hypomelanotic skin disorders. (Data from Lapeere H, Boone B, De Schepper S, et al. Hypomelanoses and hypermelanoses. In: Gilchrest BA, editor. Fitzpatrick’s dermatology in general medicine. 7th edition. In preparation.)
found on the trunk, chest, back, and shoulders (Fig. 2). Pityriasis versicolor is usually asymptomatic, although pruritus does occur in some cases [6]. These lesions may vary in color. The depigmented form of pityriasis versicolor, also called pityriasis versicolor alba, presents as white macules, whereas the hyperpigmented form of pityriasis versicolor is associated with pink, tan, brown, or black lesions. Recently, a variant with red maculae (pityriasis versicolor rubra) and another with black ones (pityriasis versicolor nigra) were described [5]. Pityriasis versicolor is diagnosed on the basis of its typical clinical appearance. The diagnosis always should be confirmed by microscopy. Direct examination of the scaling edge of a lesion is possible using a solution of potassium hydroxide at 10% to 20% and Parker ink in equal parts. This examination reveals the typical ‘‘spaghetti and meatballs’’ pattern, which reflects the presence of hyphae and blastospores. In general, it seems that the most common Malassezia species cultured from lesions of pityriasis versicolor are M globosa and M sympodialis [5,6]. In addition to microscopic examination, Wood’s light examination of
Fig. 2. Pityriasis versicolor presenting hypopigmented round to oval macules on the back and right shoulder of a young male adult.
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the patient may be used to confirm the diagnosis of pityriasis versicolor, but the yellow-green fluorescence of affected skin areas is visible in only approximately one third of the cases [6]. The characteristic pityriasiform scaling should clinically differentiate pityriasis versicolor from the nonscaling depigmented lesions of vitiligo. Vitiligo frequently affects hands and feet of a patient, whereas pityriasis versicolor predominates on the trunk. Pityriasis alba mainly affects the face and limbs and produces diffuse patches that are slightly scaling and nonfluorescent. Other differential diagnoses include tinea corporis, pityriasis rosea of Gibert, pityriasis rotunda, erythrasma, seborrheic dermatitis, confluent and reticulated papillomatosis of Gougerot and Carteaud, and secondary syphilis [6]. Other infectious diseases that may be associated with hypopigmented patches are treponematosis and onchocerciasis [7,8]. The development of hypopigmented skin lesions with altered sensitivity is a characteristic and diagnostic feature of leprosy [9]. Postinflammatory disorders Pityriasis alba Pityriasis alba is a common benign dermatosis usually seen in preadolescent children. It is characterized by the presence of pale white or pink irregular, slightly scaling plaques with well-defined borders that vary from 0.5 to 6 cm in diameter. It affects the head and neck region, trunk, and limbs. It is usually asymptomatic. Male subjects are thought to be affected more frequently, as are patients with darker skin color [10,11]. The etiology and pathogenesis of pityriasis alba are still poorly understood. Excessive and unprotected sun exposure, frequent bathing, hot baths, and cutaneous signs of atopy are strongly related to the development of pityriasis alba [10,11]. Most cases of pityriasis alba are diagnosed clinically [10,11]. Chemical and physical agents Exposure to chemical agents, such as monobenzylether of hydroquinone and hydroquinone, which destroy melanocytes, may result in hypopigmentation or depigmentation. The latter may be difficult to distinguish from vitiligo [12]. Physical agents, such as heat and cold and UV and laser light, may damage melanocytes and give rise to localized depigmentation [13].
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Lupus erythematosus Depigmentation is commonly seen in lupus erythematosus as a result of the destruction of the basal layer homing melanocytes. In discoid lupus erythematosus, the skin is atrophic and depigmented. In systemic lupus erythematosus, cutaneous depigmentation is often secondary to inflammatory skin lesions [14]. Scleroderma Hypopigmented lesions may be seen in morphea or localized scleroderma. Depigmented patches seeded with perifollicular hypopigmentation that mimic repigmenting vitiligo patches are also seen in scleroderma [15,16]. Lichen sclerosus Lichen sclerosus (LS) is a chronic skin disease predominantly found in the anogenital area. It may occur in patients of any age, sex, or race, but it is most commonly observed in white peri- and postmenopausal women [17–19]. In women, LS can affect the perineum, labia majora, labia minora, fourchette, and clitoris. Perianal involvement is characterized by the ‘‘figure of eight’’ shape. Vaginal involvement is not a feature of LS. Typical lesions of LS are milky white, atrophic papules that may coalesce into plaques. Follicular plugging is present in early lesions. Its atrophic form can lead to loss of the labia minora and entrapment of the clitoris [18]. In men, LS can affect the foreskin and glans but not the perianal region [18,19]. Patients who have LS may complain of pruritus, dysuria, dyspareunia, and a burning sensation. There is not always a correlation between disease severity and the severity of symptoms [18]. Extragenital lesions of LS are asymptomatic and occur most commonly on the neck and shoulders [18,19]. The true incidence of LS remains unknown, because many cases are left unreported [19]. Over the years, many terms have been used to describe this condition, such as lichen plan atrophique, kraurosis vulvae, hypoplastic dystrophy, weissflecken dermatose, balanitis xerotica obliterans, and lichen planus sclerosus et atrophicus. With time, the terminology has been redefined and the term ‘‘lichen sclerosus’’ has been adopted, excluding all other terms [18,19]. Although the cause of LS is still unknown, several mechanisms have been suggested to play a role in the pathogenesis of LS, including genetic, autoimmune, hormonal, infectious, and local factors. Studies of genetic factors in LS have focused on the role of the human leukocyte
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antigen (HLA). No significant association has been demonstrated between LS and HLA class I antigens. On the other hand, an important link between LS and HLA class II antigens has been found. Associated autoimmune diseases, particularly vitiligo, alopecia areata, thyroid disease, and diabetes, have been found in patients with LS, which suggests a possible autoimmune basis for the disease [18,19]. The highest incidence of LS is observed in prepubertal girls and postmenopausal women, who possess low estrogen levels. This finding leads to the hypothesis that sexual hormones might play a role in LS pathogenesis [19]. To date, no clear data have shown that LS is related to an infectious organism. The onset of LS has been recorded at sites of surgery, after repeated trauma, or as a result of irritation caused by sunburn and radiotherapy. The Koebner phenomenon also occurs in LS [18,19]. Three responsible mechanisms for the leukoderma in LS have been proposed: decreased melanin production, reduced transfer of melanosomes to keratinocytes, and melanocyte loss [20]. LS is associated with a 4% to 6% risk of progression to squamous cell carcinoma of the vulva, which makes long-term follow-up recommended in these patients [19]. Although diagnosis of LS can be suggested on its clinical evaluation, histologic confirmation should be sought [18]. The histologic aspects of LS depend on how long the disease has existed and changes that result from the act of scratching [19]. Typical LS cases show dermal sclerosis, vacuolar interface alterations, and a lymphocytic infiltrate underlying the sclerosis [21]. Vacuolar degeneration of the basal layer is usual, especially in earlier lesions [17]. Differential diagnosis includes lichen planus, vitiligo, psoriasis, and vulvar intraepithelial neoplasia [19].
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The depigmentation does not cross the midline and affects one segment of the integument. These types of vitiligo can be classified as localized vitiligo. Acrofacial vitiligo involves distal extremities and face, whereas vitiligo vulgaris (Fig. 3) is characterized by scattered macules over the entire body with a symmetrical distribution pattern. Both types are classified as generalized vitiligo [23,24]. The prevalence of vitiligo in the global population is estimated at approximately 0.5% to 1% [22]. The disease has no predilection for either sex or ethnic origin. Vitiligo usually begins in childhood or young adulthood and has an unpredictable but often progressive course, with phases of stability and spreading of lesions [25,26]. Segmental vitiligo usually affects younger people and has a rapid onset with a progression limited to months or a few years [27]. Various factors are suspected to affect the progression of vitiligo: emotional shock, sunburn, pregnancy, physical illness, and trauma. The latter is known as the Koebner phenomenon, which is defined as the development of macules at the site of trauma, such as cut, burn, or abrasion [23]. The diagnosis of vitiligo is mainly clinical. The current consensus on the histologic presentation in vitiligo is a complete absence of melanocytes in the amelanotic lesions. The perilesional area
Vitiligo Vitiligo is an acquired depigmenting disorder characterized by the progressive loss of melanocytes from the epidermis and epidermal appendages, which results in milky white macular lesions, usually on predilection sites such as extensor areas of extremities and hands or face [22]. According to the distribution of the lesions, several types of vitiligo have been distinguished. Focal vitiligo involves one or more maculae in one area but not clearly in a zosteriform or segmental distribution. Vitiligo segmentalis is characterized by one or more maculae in a quasidermatomal pattern.
Fig. 3. Vitiligo vulgaris involving the back of a woman.
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exhibits melanocyte and keratinocyte damage with an occasional perivascular mononuclear leukocyte infiltrate. In early lesions some persistent melanocytes may be found, giving a partial depigmentation (hypopigmentation) [28,29]. The etiopathogenesis of vitiligo is still not completely elucidated. One hypothesis considers vitiligo an autoimmune disease [30]. The association with autoimmune disorders and organspecific antibodies and the fact that nonsurgical repigmenting therapies have immunomodulating effects indirectly support the idea of an autoimmune pathogenesis of the disease. The exact immune mechanism involved in vitiligo remains unknown, however. A humoral immune reaction is implicated through the detection of circulating antibodies against melanosomal and other melanocyte autoantigens. The variety of detected antibodies and the lack of melanocyte specificity points to a secondary phenomenon after melanocyte destruction and disruption of the melanocyte/ keratinocyte unit. In vitro assays demonstrate the melanocytotoxic capacity of some antibodies, however. Recent research focuses on a melanocytespecific cytotoxic T-cell immune reaction in the destruction of melanocytes. Analyses on the inflammatory infiltrate accompanying the depigmentation and high frequencies of circulating melanocyte-specific cytotoxic T cells further suggest the involvement of melanocyte-specific T cells recruited from the circulation in the disappearance of melanocytes. The neural hypothesis suggests that melanocyte death is caused directly or indirectly by mediators such as neuropeptides, catecholamines, or their metabolites or by an overactive sympathic system [31]. The biochemical hypothesis bases melanocyte death on an intrinsic increased sensitivity to oxidative stress that arises from autocytotoxic intermediate metabolites of the melanin synthesis or from other sources (eg, catecholamines). Defective homeostasis of pterins and essential cofactors in the hydroxylation of phenylalanine to tyrosine together with an increased hydrogen peroxide concentration and decreased catalase levels may contribute to the depigmenting process [22]. Other possible etiologic factors, such as deficiency in unidentified melanocyte growth factors, intrinsic defect of structure and function of melanocytes, or genetic factors, are proposed to be involved in the depigmentation process. The convergence theory suggests that the different causal factors could contribute in variable
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proportions to the destruction of melanocytes [32,33]. Different pathogenic pathways could be involved in the various clinical types of vitiligo. The neural hypothesis is probably involved in segmental vitiligo, whereas the autoimmune hypothesis is commonly related with generalized or focal nondermatomal vitiligo. In vivo morphologic studies recently demonstrated detachment of living melanocytes (melanocytorrhagy) in normal skin of patients with generalized vitiligo after friction. Detachment, followed by transepidermal migration and eventually melanocyte death, is suspected to be responsible for depigmentation in the Koebner phenomenon [34]. A chronic ‘‘melanocytorrhagy’’ caused by defective adhesion or loss of dendricity has been proposed as primary defect in a pathogenetic model integrating other known theories in nonsegmental vitiligo. Loss of dendricity could be mediated by oxyradicals or increased catecholamines, exaggerating transepidermal loss induced by minor trauma, whereas autoimmune phenomena could be triggered by antigen release and aggravate melanocyte detachment [31]. Halo nevus A halo nevus is a pigmented nevus surrounded by a ring of depigmentation. The nevus usually undergoes progressive regression over a period of several months. Halo nevi are estimated to affect 1% of the population. The lesions usually develop in children and young adults and are preferentially located on the back. A halo nevus may remain solitary, but up to half of patients may develop multiple lesions that develop simultaneously or successively. Complete regression of the nevus leaves a round- to oval-shaped depigmented macule (Fig. 4) [35]. The area of depigmentation may remain stable for months to years, but a considerable percentage repigments spontaneously [36]. Histologically, a moderate to dense mononuclear infiltrate with lymphocytes and marcophages is observed in close association with nevus cells [37]. In the depigmenting halo, melanocytes show degenerative signs, such as vacuolization of the cytoplasm [38]. The pathophysiology of halo nevi is not well known. A cytotoxic cell-mediated immune response is suspected to be involved in the destruction of nevomelanocytes [39]. A local proliferation of T-cell clones, activated by common nevus antigens, has been found in different halo nevi of the same patient [40]. Halo nevi and vitiligo seem to have different
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Fig. 4. Halo nevi on the lower back: Typical halo nevus adjacent to a depigmented macula after complete regression of the nevus.
pathogenetic mechanisms. A recent case control study indicated that halo nevi are infrequent in symmetrical and unilateral vitiligo [41]. Differences in HLA association suggest that vitiligo vulgaris and halo nevi associated with vitiligo have distinct pathogenetic mechanisms [42]. Melanoma-associated leukoderma Three different types of hypomelanosis may occur in patients with melanoma: leukoderma within the primary tumor or its metastases due to regression, leukoderma acquisitum centrifugum around the primary tumor or its metastases, and vitiligo-like depigmentation remote from the tumor or its metastases. The latter is also called melanoma-associated leukoderma [43]. Clinically, melanoma-associated leukoderma is a diffuse patchy vitiligo-like macular hypomelanosis or depigmentation that often develops at sites distant to the location of the primary melanoma. In classic vitiligo, depigmentation is symmetrical, usually starts on hands, face, and feet, and spreads centripetally to the trunk. In melanoma-associated leukoderma, depigmentation is asymmetrical, starts more commonly on the trunk, and spreads centrifugally toward the neck, face, and extremities. The leukoderma may be hypomelanotic and mottled or amelanotic and milk white. The time of onset of the leukoderma and the finding of metastases in melanoma patients may be fairly close [43]. Patients with melanoma-associated leukoderma may have a better survival rate than patients with melanoma without leukoderma [43,44]. Diagnosis of melanoma-associated leukoderma is mainly clinical. Wood’s lamp examination enhances the numerous discrete, white macules and
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patches. Histologic examination of the hypopigmented skin shows a decrease or a complete absence of melanocytes. Hypertrophic macromelanocytes with stubby dendrites may be present [43]. Growing evidence suggests that melanomaassociated, vitiligo-like leukoderma results from an immune reaction against shared antigenic determinants on normal and malignant melanocytes. Although humoral immune responses are commonly found in patients with melanoma, increasing evidence points toward an important role for cellular immune responses [43,45]. The association between vitiligo-like leukoderma, which results from destruction of normal melanocytes, and melanoma regression, which results from destruction of cancer cells, in patients who have melanoma suggests that targets of immunotherapy involved in melanoma regression comprise normal melanocytic differentiation antigens [46]. Vitiligo-like lesions have been observed in melanoma patients after successful immunotherapy with tumor-infiltrating T lymphocytes specific for tyrosinase and gp100, two melanocytic differentiation antigens [45]. Research also has demonstrated that T cells involved in the destruction of neoplastic melanocytes are identical clones of those that accumulate in melanoma-associated leukoderma [47].
Acquired diffuse hypomelanotic skin disorders Idiopathic guttate hypomelanosis Idiopathic guttate hypomelanosis is a common acquired pigmentary disorder characterized by sharply defined white macules of approximately 2 to 6 mm in diameter that are most commonly located on the legs and forearms. The disease particularly affects middle-aged and elderly persons. Idiopathic guttate hypomelanosis develops equally in both sexes and no race is exempt [48]. The pathogenesis of idiopathic guttate hypomelanosis is uncertain. Because most idiopathic guttate hypomelanosis lesions occur in sunexposed skin, a possible etiologic role of chronic exposure to UV radiation could be of some importance. It has been suggested that idiopathic guttate hypomelanosis may represent an effect of the normal ageing process. The pathologic hallmark of idiopathic guttate hypomelanosis seems to be an absolute reduction in the number of melanocytes. Several mechanisms might be responsible for melanocyte loss in idiopathic guttate hypomelanosis. It may be due to a disturbance in
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the production of melanocyte growth factors by keratinocytes, or it may be due to direct cytotoxicity, as from chronic exposure to UV radiation [48]. Diagnosis is made clinical and can be confirmed by Wood’s light examination. Histologically, Idiopathic guttate hypomelanosis lesions are characterized by slight basket-weave hyperkeratosis with epidermal atrophy and loss of the ridge pattern. Hypopigmented macules show a decrease in melanocytes and melanin content within the basal layers of the epidermis [48]. Leukoderma punctata In 1988, Falabella and colleagues [49] first described leukoderma punctata as an entity with multiple punctate hypopigmented and achromic spots that developed after psoralen plus ultraviolet A (PUVA) treatment. Similar findings were described after UVB therapy in psoriasis patients and after topical PUVA in a patient with segmental vitiligo [50,51]. The typical skin lesions were usually numerous, distinct, sharply demarcated, round, or oval macules varying in diameter from 0.5 to 1.5 mm. They were predominantly present on the upper and lower extremities, upper back and chest, and occasionally the face (Fig. 5) [49].
Fig. 5. Leukoderma punctata with numerous round or oval hypopigmented macules on the lower leg of a woman.
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It has been postulated that the most likely cause of leukoderma punctata is UV phototoxicity [49,50]. Ultrastructural studies by Falabella and colleagues [49] showed varying degrees of cellular damage within keratinocytes and in melanocytes. Histologic findings revealed decreased numbers but not an absence of functional melanocytes and melanin granules [51]. The appearance of new punctate hypopigmented and achromic spots in a long-term PUVA treated patient in combination with characteristic histologic and ultrastructural findings may suggest the diagnosis [49]. Progressive macular hypomelanosis of the trunk Progressive macular hypomelanosis of the trunk is a common pigmentary disorder of the skin that is characterized by ill-defined nummular, hypopigmented, nonscaly macules and patches distributed on the trunk (Fig. 6). It occurs predominantly in young adults, mainly women. The disorder has been described in many parts of the world and is seen in all races [52]. The pathogenesis of progressive macular hypomelanosis of the trunk is unknown, although there seems to be a relation between the red follicular fluorescence, which is caused by the presence of porphyrin-producing Propionibacterium acnes in the infrainfundibular portion of follicles of sebaceous glands, and the hypopigmented macules. Porphyrins are responsible for the fluorescence induced by UV radiation as under Wood’s light [52]. The diagnosis of progressive macular hypomelanosis of the trunk is made by its clinical presentation. Patients with progressive macular hypopigmentation of the skin show pointed red
Fig. 6. Progressive macular hypomelanosis of the trunk presenting ill-defined nummular patches on the back of a young female adult.
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fluorescence in a follicular pattern inside the hypopigmented spots of lesional skin when observed under Wood’s light. Usually the healthy pigmented skin of the trunk does not show any fluorescence [52]. Histologic examination of hypopigmented lesions revealed only a decrease in the amount of melanin content in the epidermis compared with the neighboring healthy skin. No abnormalities were found in the dermis. Sometimes a mild perifolliculitis could be observed in the lesional skin. In the stratum corneum, no spores, hyphae, or bacteria were seen. Propionibacterium acnes could be isolated in biopsy specimens from lesional follicular skin [52]. Progressive macular hypopigmentation of the trunk is often mistaken for pityriasis versicolor and pityriasis alba [52]. Exceptionally, mycosis fungoides and sarcoidosis may present with diffuse hypopigmented skin lesions [53,54]. Some endocrinologic disorders, such as Addison’s disease, thyroid gland disorders, and hypopituitarism, are related to hypomelanosis [55]. Summary Lesions of acquired hypomelanotic skin disorders may appear in a localized or diffuse pattern. Diagnosis is mainly based on a detailed clinical examination. The use of Wood’s lamp distinguishes hypopigmentation from depigmentation of the involved skin. The absence or presence of associated inflammatory lesions may be helpful to further refine the diagnostic approach of the hypomelanotic lesions. Histologic examination is often not mandatory to establish the diagnosis. References [1] Mosher DB, Fitzpatrick TB, Ortonne JP, et al. Normal skin color and general considerations of pigmentary disorders. In: Freedberg IM, Eisen AZ, Wolff K, et al, editors. Fitzpatrick’s dermatology in general medicine. 5th edition. New York: McGraw-Hill; 1999. p. 936–44. [2] Asawanonda P, Taylor CR. Wood’s light in dermatology. Int J Dermatol 1999;38:801–7. [3] Paraskevas LR, Halpern AC, Marghoob AA. Utility of the wood’s light: five cases from a pigmented lesion clinic. Br J Dermatol 2005;152:1039–44. [4] Thoma W, Kra¨mer HJ, Maysert P. Pityriasis versicolor alba. J Eur Acad Dermatol Venerol 2005;19: 147–52. [5] Crespo-Erchiga V, Florencio VD. Malassezia yeasts and pityriasis versicolor. Curr Opin Infect Dis 2006; 19:139–47.
et al [6] Gupta AK, Batra R, Bluhm R, et al. Skin diseases associated with Malassezia species. J Am Acad Dermatol 2004;51:785–98. [7] Farnsworth N, Rosen T. Endemic treponematosis: review and update. Clin Dermatol 2006;24(3): 181–90. [8] Enk CD. Onchocerciasis: river blindness. Clin Dermatol 2006;24(3):176–80. [9] Ramos-e-Silva M, Rebello PF. Leprosy: recognition and treatment. Am J Clin Dermatol 2001;2(4): 203–11. [10] Blessmann Weber M, Sponchiado de A´villa LG, Albaneze R, et al. Pityriasis alba: a study of pathogenic factors. J Eur Acad Dermatol Venerol 2002; 16:463–8. [11] Lin RL, Janniger CK. Pityriasis alba. Cutis 2005; 76(1):21–4. [12] Lerner EA, Sober AJ. Chemical and pharmacologic agents that cause hyperpigmentation or hypopigmentation of the skin. Dermatol Clin 1988;6(2): 327–37. [13] Lacour JP. Physical agents causing hypomelanoses. In: Nordlund JJ, Boissy RE, Hearing VJ, et al, editors. The pigmentary system: physiology and pathophysiology. 2nd edition. Oxford (UK): Blackwell Publishing Ltd.; 2006. p. 683–5. [14] Kuhn A, Gensch K, Stander S, et al. Cutaneous lupus erythematosus. Part 1. Clinical manipulations and classification. Hautarzt 2006;57:251–68 [in German]. [15] Bonifati C, Impara G, Morrone A, et al. Simultaneous occurrence of linear scleroderma and homolateral segmental vitiligo. J Eur Acad Dermatol Venerol 2006;20:63–5. [16] Ee HL, Tan SH. Reticulate hyperpigmented scleroderma: a new pigmentary manifestation. Clin Exp Dermatol 2005;30:131–3. [17] Meffert JJ, Davis BM, Grimwood RE. Lichen sclerosus. J Am Acad Dermatol 1995;32(3):393–416. [18] Funaro D. Lichen sclerosus: a review and practical approach. Dermatol Ther 2004;17:28–37. [19] Val I, Almeida G. An overview of lichen sclerosus. Clin Obstet Gynecol 2005;48(4):808–17. [20] Carlson JA, Grabowski R, Mu XC, et al. Possible mechanisms of hypopigmentation in lichen sclerosus. Am J Dermatopathol 2002;24(2):97–107. [21] Carlson JA, Lamb P, Malfetano J, et al. Clinicopathologic comparison of vulvar and extragenital lichen sclerosus: histologic variants, evolving lesions, and etiology of 141 cases. Mod Pathol 1998;11(9): 844–54. [22] Njoo MD, Westerhof W. Vitiligo: pathogenesis and treatment. Am J Clin Dermatol 2001;2:167–81. [23] Hann SK, Nordlund JJ. Clinical features of generalized vitiligo. In: Hann SK, Nordlund JJ, editors. Vitiligo: a monograph on the basic and clinical science. Oxford (UK): Blackwell Science; 2000. p. 35–48. [24] Ortonne JP, Mosher DB, Fitzpatrick TB. Vitiligo. In: Ortonne JP, Mosher DB, Fitzpatrick TB, editors. Vitiligo and other hypomelanoses of hair and skin.
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