ACP medicine, 3rd Edition
Disorders of Pigmentation
Pearl E. Grimes MD1
Clinical Associate Professor of Dermatology
1Division of Dermatology, University of California Los Angeles David Geffen School of Medicine; Director, Vitiligo and Pigmentation Institute of Southern California
The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Disorders of Hyperpigmentation
Melasma is a common acquired symmetrical hypermelanosis characterized by irregular light-brown to gray-brown macules involving the face. There is a predilection for the cheeks, forehead, upper lips, nose, and chin [see Figure 1]. Lesions may occasionally occur in other sun-exposed areas, including the forearms and back.1,2,3
Figure 1. Melasma is characterized by hyperpigmentation of the cheek, forehead, and upper lip.
Melasma is most commonly observed in females. Men constitute only 10% of cases and usually demonstrate the same clinicopathologic features as noted in women. The condition affects all racial and ethnic groups but is most prevalent in people with darker complexions (i.e., skin types IV through VI). It is also more common in geographical areas exposed to intense ultraviolet radiation (sunlight), such as tropical and subtropical regions.
Etiology and Pathogenesis
Although the precise cause of melasma is unknown, multiple contributing factors have been identified. These factors include genetic influences, intense ultraviolet radiation exposure, pregnancy, oral contraceptive use, hormone replacement therapy, cosmetics, and phototoxic and antiseizure medications.1
Endocrinologic studies of patients with melasma report varying results. A detailed study of nine women with melasma showed significantly increased levels of luteinizing hormone (LH) and low levels of estradiol, suggesting an increase in subclinical mild ovarian dysfunction. In contrast, a study of 26 women that assessed LH, follicle-stimulating hormone (FSH), and α-melanocyte-stimulating hormone (α-MSH) levels found no differences between patients and control subjects.3 Thyroid dysfunction and increased levels of 17β-estradiol have also been reported in patients with melasma.
Clinically, the light-brown patches are commonly evident on the malar, forehead, chin, nose, and upper lip areas of the face. Patients may exhibit a malar, centrofacial, or mandibular distribution. Histologically, an epidermal, epidermal-dermal, or dermal pattern of increased pigmentation occurs. Light microscopic and ultrastructural biopsies of both the involved and uninvolved facial skin of patients with melasma reveal enlarged, hyperactive basal melanocytes with prominent dendrites.4 Korean patients with melasma showed histologic evidence of increased solar damage in the involved areas, compared with uninvolved skin.5 A Wood light examination enhances the epidermal pattern of pigment deposition. Such epidermal lesions are most amenable to treatment.
Melasma must be distinguished from other conditions that cause facial hyperpigmentation, such as postinflammatory hyperpigmentation, drug-induced hyperpigmentation, discoid lupus erythematosus, lichen planus, and photosensitivity disorders.
Current treatments for melasma include broad-spectrum sunscreens, 2% (over-the-counter) and 4% (prescription) hydroquinone formulations, azelaic acid, kojic acid formulations, α-hydroxy acid products, retinoic acid, superficial chemical peels, and microdermabrasions.1,6,7 Laser therapy offers minimal long-term success and instead may worsen the condition. Of the topical agents, maximal efficacy has been reported with combination agents such as the triple-combination bleach containing hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01% (TriLuma).8 In addition, hydroquinone 4% combined with retinol in a microsponge formulation has demonstrated significant efficacy in patients with melasma.9 Intense pulsed-light therapy and fractional photothermolysis have demonstrated efficacy in some patients.10,11
In January 2001, hydroquinone was banned from cosmetic skin-lightening formulations in the European Union. In the United States, the Food and Drug Administration has raised the possibility that manufacturers of older hydroquinone preparations might be required to file new drug applications, effectively removing those preparations from the market. The FDA is concerned about potential side effects, such as exogenous ochronosis and theoretical risks of carcinogenicity.12 Most of the cases of exogenous ochronosis in the United States are due to 2% hydroquinone, while in Africa they are usually caused by higher concentrations13 or excessive quantities of the product. Concerns about carcinogenicity have been raised because hydroquinone is a derivative of benzene. Nevertheless, there has not been a single documented case of malignancy associated with topical application of hydroquinones.12,14 Carcinogenicity assays have not sufficiently demonstrated the carcinogenic potential of hydroquinone, and epidemiologic studies of workers exposed extensively to hydroquinones have not shown any negative systemic health effects.15 Similarly, developmental and reproductive studies in animals have not shown negative effects, and dermal toxicity studies in animals have failed to show any systemic toxicity.15 A study of women in Africa found no differences in pregnancy outcomes between users and nonusers of hydroquinone.16 Nevertheless, the FDA continues to scrutinize hydroquinone preparations closely.
Although current therapies improve melasma, none are curative. Hence, it is essential for patients to rigidly adhere to a regimen of daily sunscreen or other protection against the sun to control the progression of melasma.
An instrument for assessing quality of life—the Melasma Quality of Life scale (MELASQOL)—has been developed for patients with melasma.17The use of MELASQOL before and after treatment facilitates the tracking of therapeutic success.
Postinflammatory hyperpigmentation is an acquired increase in cutaneous pigmentation secondary to an inflammatory process [see Figure 2]. Excess pigment deposition may occur in the epidermis or in both epidermis and dermis.
Figure 2. Postinflammatory hyperpigmentation of the face may be secondary to acne vulgaris.
The condition occurs in all racial and ethnic groups; however, it has a higher incidence in people with darker complexions. In a diagnostic survey of 2,000 black patients seeking dermatologic care, the third most common diagnosis was pigmentary disorders, of which postinflammatory hyperpigmentation was the most prevalent.1
Etiology and Pathogenesis
Pigmentary changes may be a result of production of inflammatory mediators and altered cytokine production.18,19 In turn, this may lead to an increase in the number and size of epidermal melanocytes. Hyperpigmentation may also be a consequence of pigmentary incontinence, with deposition of pigment in the upper dermis. Postinflammatory hyperpigmentation is seen with a variety of inflammatory skin disorders, including acne, allergic reactions, drug eruptions, papulosquamous disorders, eczematoid disorders, and vesiculobullous conditions.20
Clinically, postinflammatory pigmentary changes may be localized, circumscribed, or generalized. Lesions range in color from brown to black to ashen gray and usually follow the distribution of the primary dermatosis.
Therapies for postinflammatory hyperpigmentation include over-the-counter and prescription hydroquinone preparations. Other treatments are azelaic acid, kojic acid, and retinoic acid [see Melasma, above]. Maximal results are achieved with hydroquinone formulations. A recent study reported significant efficacy of tazarotene 0.1% cream for treatment of postinflammatory hyperpigmentation caused by acne vulgaris.21
Drug-induced pigmentation represents 10% to 20% of all cases of acquired hyperpigmentation. Lesions may be localized or generalized. Medications can also cause hyperpigmentation of the oral mucosa and nails. Some improvement may occur after withdrawal of the offending agent; however, drug-induced hyperpigmentation can persist for many years.
The cause of drug-induced hyperpigmentation varies with the inciting agent. Potential mechanisms include accumulation of melanin after nonspecific inflammation, accumulation of the triggering drug, synthesis of special pigments under the direct influence of the drug, or deposition of iron after damage to blood vessels. Sun exposure exacerbates many types of drug-induced hyperpigmentation.22
Medications causing drug-induced hyperpigmentation include minocycline, oral contraceptives, estrogens, zidovudine, bleomycin, hydrochlorothiazide, phenytoin, amiodarone, tetracycline, busulfan, chlorpromazine, quinacrine, and imipramine.23,24,25,26
Heavy metals can also cause hyperpigmentation. Such preparations include arsenic, gold, silver, mercury, and bismuth.24
Treatment is often limited to sun avoidance or interruption of treatment with the offending drug. Laser therapy has shown benefit in some cases.22
Erythema Dyschromicum Perstans
Erythema dyschromicum perstans (EDP, or ashy dermatosis), first described in 1957, is an acquired benign condition characterized by slate-gray to violaceous macules.
EDP is reported most commonly in dark-skinned persons. However, cases have been reported globally and in all skin types. The disease appears to have a relative equal frequency in males and females. EDP usually appears in adults, but isolated cases and small series have been reported in children.27
Etiology and Pathogenesis
The precise cause of EDP is unknown. Studies suggest that pollutants, hair dyes, chemicals, and drug exposure may play a role in the pathogenesis.28,29,30 Findings in light microscopic, ultrastructural, and immunofluorescent studies of EDP have been similar to those in studies of lichen planus, leading some investigators to postulate that EDP may be a variant of lichen planus. Other studies suggest that EDP is a distinct entity. Expression of intercellular adhesion molecule-I (ICAM-I) and major histocompatibility complex (MHC) class II molecules (i.e., human leukocyte antigen DR [HLA-DR]) has been reported.31 These findings suggest that aberrant cell-mediated immunity may be involved in the pathogenesis of EDP.
In an immunopathologic study of EDP in 43 patients, histologic features included vacuolization of the basement membrane zone and exocytosis of lymphocytes. Melanophages were present in all of the specimens. A perivascular dermal lymphocytic infiltrate was present in 86% of the patients. There was a predominance of CD8+ T cells in the dermis and HLA-DR+, ICAM-1+ keratinocytes in the epidermis. These findings suggest that response to antigenic stimulation may play a role in the development of EDP.32
Clinically, the macules of EDP are ashen and may have an erythematous, slightly raised border during the early stages of the disease. Erythematous macules have also been described during the early stages. Areas of erythema eventually resolve, leaving slate-gray areas of pigmentation. The lesions are usually symmetrically distributed and vary in size from small macules to very large patches. Common sites of involvement include the face, neck, trunk, and upper extremities. Mucous membrane, palms, soles, and nails are usually spared. Light microscopy shows slight epidermal atrophic changes, spongiosis, lymphocytic exocytosis, and basal vacuolopathy in the epidermis and lymphohistocytic, lichenoid dermal infiltrates. Later stages lack the epidermal changes and show increased deposition of dermal pigment.
Postinflammatory hyperpigmentation, pityriasis rosea, lichen planus, fixed drug eruption, Addison disease, pinta, syphilis, macular amyloidosis, hemochromatosis, and argyria must be distinguished from EDP.
In general, therapies for EDP have been minimally effective. Potential therapeutic agents include sunscreens, hydroquinone, bleaching creams, topical corticosteroids, griseofulvin, clofazamine, antibiotics, and antimalarials.
A lentigo is a well-circumscribed, brown to brown-black macule, usually less than 1 cm in size, that appears at birth or in early childhood. Lentigines occur in all skin types and may be found in any cutaneous surface, including the palms, soles, and mucous membranes. They do not darken with sun exposure. Lentigines can be localized and must be distinguished from freckles (ephelides). Clinical differentiating features include the later appearance of freckles (at 4 to 6 years of age) and their predominance on sun-exposed skin and increased frequency in redheads and fair-skinned persons. Freckles also tend to fade in winter and with advancing age. Lentigo must also be distinguished from junctional nevi, macules caused by postinflammatory pigmentation, and pigmented actinic keratoses.
Multiple lentigines have been reported in 18.5% of black newborns and 0.04 % of white newborns. Solar lentigines have been reported in 90% of whites older than 60 years.
Several types of lentigines are recognized, including lentigo simplex, solar lentigines, nevus spilus, lentigines induced by psoralens plus ultraviolet A light (PUVA), generalized lentiginosis, and syndrome-related lentiginosis.
Lentigo simplex lesions may occur as solitary localized macules or may be numerous and widespread. They often occur during the first decade of life and can be found on any cutaneous surface.
Solar (senile) lentigines, or so-called liver spots, are brown macules that appear late in adult life on chronically sun-exposed skin. The incidence of solar lentigines correlates with the tendency to freckle and two or more sunburns after 20 years of age.
The histopathology of lentiginoses shows elongated rete ridges, increased numbers of basal melanocytes, and increased basal melanization. In contrast, freckles result from hypermelanization of basal melanocytes without a concomitant increase in number.
Nevus spilus, or speckled lentiginosis nevus, is a congenital brown patch that develops dotted brown macules during childhood. Histologically, the brown patch has features of a lentigo, whereas the dotted brown macules most often reveal features of junctional nevi. Zosteriform patterns have also been described. Generalized lentiginosis is characterized by innumerable lentigines that are not associated with other abnormalities.
Familial lentiginosis syndromes cover a wide phenotypic spectrum, ranging from a benign inherited predisposition to develop cutaneous lentigines not associated with systemic disease to associations with several syndromes that carry an increased risk of the development of hamartomas, hyperplasias, and other neoplasms.33
Familial lentiginosis syndromes include LEOPARD syndrome (lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary artery stenosis, abnormal genitalia, retarded growth, deafness), Noonan syndrome, Carney complex, and Peutz-Jeghers syndrome. Cellular signaling pathways involved in lentiginoses syndromes include the Ras/Erk MAP kinase pathway in LEOPARD/Noonan syndrome; the protein kinase A (PKA) pathway in Carney complex (CNC); and the mammalian target of rapamycin (mTOR) pathway in Peutz-Jeghers syndrome.33,34
Lentigo must be distinguished from other flat, pigmented lesions, including freckles, junctional nevi, postinflammatory hyperpigmentation, and pigmented actinic keratoses. An important challenge facing clinicians is recognizing and distinguishing benign pigmented lesions from cutaneous melanoma. Physicians' diagnostic accuracy is sometimes less than perfect, which has prompted research into the use of noninvasive technology such as reflectance mode in vivo confocal scanning laser microscopy (CSLM).35
Therapies for lentigines include both topical and physical agents, including retinoids and hydroquinone bleaching agents. A topical solution containing mequinol 2% and tretinoin 0.01% (Solagé) has been shown to be effective and superior to hydroquinone 3%.36 Cryotherapy remains a mainstay for treatment of solar lentigo. Other physical modalities include intense pulsed light (IPL) and the Q-switched pigmented lasers.
Confluent and Reticulated Papillomatosis of Gougerot and Carteaud
The eruption of confluent and reticulated papillomatosis was initially described by Gougerot and Carteaud in 1927 and 1932. The condition consists of 2- to 5-mm hyperpigmented papules having a predilection for the sternal area and midline of the back and neck.
Confluent and reticulated papillomatosis has an equal frequency in males and females and shows no racial or ethnic predilections. The disease usually begins during the third decade of life. It occurs predominantly in young adults and teenagers.37
Etiology and Pathogenesis
The precise cause of confluent and reticulated papillomatosis is unknown. Endocrine disturbances, abnormal host response to Pityrosporum orbiculare, and genetically determined defects of keratinization have been suggested.38
Patients present with 2 to 5 mm hyperpigmented, slightly verrucoid papules having a predilection for the back, scapula, and inframammary areas. The papules become confluent near the midline and possess a reticulated pattern near the periphery. The lesions do not form a true scale but, rather, a mealy deposit that can easily be removed with the fingertips. Histologic studies show hyperkeratosis, decreased granular cell layers, papillomatosis, absence of sweat glands, and fragmentation of elastic fibers.
Other conditions that simulate confluent and reticulated papillomatosis are tinea versicolor and acanthosis nigricans.
Although a variety of treatments exist, studies have shown minocycline to be beneficial.39,40 Azithromycin has also been shown to be effective and may become the preferred treatment, because it has a more benign adverse effect profile than minocycline. Other effective antibacterial treatments include fusidic acid, clarithromycin, erythromycin, tetracycline, and cefdinir.41 Other treatments that have shown some efficacy include selenium sulfide shampoo, salicylic acid, vitamin A, retinoids, and PUVA.
Dowling-Degos disease, or reticulated pigmented anomaly of the flexures, is an autosomal dominant disorder with variable penetrance characterized by brownish-black macules of the flexures that develop in a reticulated pattern. It may be caused by an underlying defect in follicular epithelial proliferation.
Dowling-Degos disease manifests as symmetrical reticulated hyperpigmentation of the groin, axilla, antecubital area, inframammary areas, and neck.42 The lesions begin as 1- to 3-mm macules that gradually become confluent, assuming a reticulated lacelike pattern. In addition, perinasal and facial involvement is common. Pigmented pinhead-sized comedones are frequently observed in the affected areas, and perinasal, pitted acneiform scars can occur around the mouth.
Lesions begin in early adult life and are slowly progressive. The condition has been reported in association with reticulated acropigmentation of Kitamura and hidradenitis suppurativa,43 suggesting an underlying defect in follicular epithelial proliferation. Histologically, thin-pigmented epithelial strands of downgrowth extend from the epidermis and follicular wall in a filiform pattern resembling adenoid seborrheic keratoses. In a genome-wide linkage analysis of two German families, investigators mapped Dowling-Degos disease to chromosome 12q, with a cluster to screen for mutations. They identified loss-of-function mutations in the keratin 5 gene (KRT5) in all affected family members and in six unrelated patients with Dowling-Degos disease. The identification of loss-of-function mutations suggests a crucial role for keratins in the organization of cell adhesion, melanosome uptake, organelle transport, and nuclear anchorage.44
In general, there is no effective treatment for Dowling-Degos disease. Adapalene has been reported to offer some benefit.
Disorders of Hypopigmentation
Vitiligo is a common acquired, idiopathic skin disorder characterized by one or more patches of depigmented skin caused by loss of cutaneous melanocytes. These lesions are cosmetically disfiguring and usually cause severe emotional trauma in children as well as adults [see Figure 3].
Figure 3. Vitiligo is indicated by generalized patches of depigmentation of the trunk.
Vitiligo affects 1% to 2% of the population. Onset may begin at any age, but incidence peaks in the second to third decades of life. The disease shows no racial or ethnic predilection, but because of the stark contrast between depigmented and darker skin tones, it is more cosmetically disfiguring in darker-skinned racial and ethnic groups. Females are affected more often than males. The disease has a familial incidence of 25% to 30%.
Etiology and Pathogenesis
The precise cause of vitiligo is unknown. However, multiple theories have been proposed, including genetic, autoimmune, neural, biochemical, and viral mechanisms. Reviews addressing the etiology of vitiligo viewed in totality suggest that vitiligo is probably a heterogeneous disease encompassing multiple etiologies.45,46
Genetic studies of vitiligo suggest a polygenic inheritance pattern. Human leukocyte antigen (HLA) studies have reported increases in a variety of haplotypes of class I and class II antigens. Results vary significantly by race and ethnicity of the population studied, however. The reported HLA associations include increased frequencies of HLA A30, CW6, CW7, DR1, DR3, DR4, and DQW3.45
An immune-mediated pathogenesis is indeed the most popular theory. This theory is predicated on the plethora of immunologic diseases and immune phenomena reported in patients with vitiligo. Patients demonstrate an increased frequency of a variety of diseases, including hypothyroidism (e.g., Hashimoto thyroiditis, Graves disease), pernicious anemia, diabetes mellitus, and alopecia areata. Thyroid disease is the most common associated condition in patients with vitiligo. Other diseases reported in association with vitiligo include Addison disease, atopic dermatitis, asthma, lichen planus, morphea, lichen sclerosus et atrophicus, mucocutaneous candidiasis, biliary cirrhosis, myasthenia gravis, Down syndrome, AIDS, and cutaneous T cell lymphoma.
Humoral and cell-mediated immunologic defects are a common phenomenon in vitiligo.45,46 Numerous studies have documented an increased frequency of organ-specific autoantibodies. Antithyroid, antiµgastric parietal cell, and antinuclear antibodies are most commonly demonstrated. Patients with positive organ-specific autoantibodies that are not associated with autoimmune disease have an increased risk of subsequent subclinical or overt autoimmune disease.
Antibodies directed against melanocyte cell surface antigens are often demonstrated in the sera of patients with vitiligo. These antimelanocyte antibodies induce the destruction of melanocytes grown in culture by complement-mediated lysis and antibody-dependent cellular cytotoxicity. The presence and titer of antimelanocyte antibodies correlate with the severity and activity of vitiligo. Studies suggest that the antimelanocyte antibody may mediate the destruction of melanocytes in vitiligo. Tyrosinase antibodies have also been reported in patients with localized and generalized disease.47
Cellular immune-mediated defects include diminished contact sensitization and quantitative and qualitative alterations in T cells and natural-killer cells. Quantitative studies of Langerhans cells from involved and uninvolved skin are inconsistent. Immunohistochemical studies have demonstrated abnormal expression of MHC class II and ICAM-I by melanocytes in vitiligo, which may contribute to the aberrant cellular immune response. In addition, there is increased expression of the antiadhesive matrix component tenasin in perilesional and lesional vitiliginous skin. Increased tenasin expression may be a consequence of elevated cytokine production and cellular infiltrates in vitiligo.46
Cytotoxic T lymphocytes may play a significant role in the destruction of melanocytes that occurs in vitiligo.48,49 Activated cytotoxic T lymphocytes have been reported in abundance in the perilesional area of the vitiliginous skin, often in apposition to disappearing melanocytes.50 These infiltrating lymphocytes are predominantly cytotoxic CD8+ T cells that express skin homing receptors (i.e., cutaneous lymphocyte antigen). In addition, other studies have demonstrated the presence of increased numbers of circulating CD8+ cytotoxic T cells that are reactive to the melanosomal proteins MelanA/MART-1, gp100, and tyrosinase in HLA-A2-positive patients with vitiligo.50,51,52,53
Several investigations have also addressed the role of peripheral blood and lesional cytokine expression in the pathogenesis of vitiligo. Elevated levels of serum soluble interleukin-2 (IL-2) receptor, IL-6, and IL-8 and elevated lesional tissue levels of IL-2 have been reported in vitiligo patients.54,55,56 These findings correlate with an increased level of T cell activation. In biopsies of lesional, perilesional, and healthy skin, significantly lower levels of expression of granulocyte colony-stimulating factor (G-CSF), basic fibroblast growth factor, and stem cell factor were reported in vitiliginous skin, whereas the expression of IL-6 and tumor necrosis factor-α (TNF-α) were increased in lesional skin.57 G-CSF, basic fibroblast growth factor, and stem cell factor are paracrine cytokines secreted by keratinocytes. These paracrine cytokines stimulate melanogenesis and melanocyte proliferation, whereas IL-6 and TNF-α inhibit melanocyte proliferation and melanogenesis.58 Together, these findings suggest that keratinocyte function is also impaired in vitiliginous skin.
Increased expression of TNF-α and interferon gamma (IFN-γ) have been demonstrated in both the lesional and adjacent healthy skin of patients with vitiligo, as compared with the skin of matched control subjects. After 6 months of treatment with twice-daily application of tacrolimus, a topical immunomodulator, there was a significant depression in the level of TNF-α, which may be associated with repigmenatation of vitiliginous lesions.59
Cytomegalovirus DNA has been demonstrated in the involved and uninvolved skin of patients with vitiligo. No viral DNA was detected in matched control subjects.60 These findings suggest that in some cases, vitiligo may be triggered by a viral infection.
Neural involvement in vitiligo is supported by several clinical, biochemical, and ultrastructural observations. These observations include the occurrence of segmental vitiligo; the demonstration of lesional autonomic dysfunction, such as increased sweating; and the demonstration of nerve ending-melanocyte contact. The last observation is rare in normal skin. In addition, studies have demonstrated aberrant tetrahydrobiopterin and catecholamine biosynthesis and release in patients with vitiligo.46 It is therefore suggested that abnormal release of catecholamines from autonomic nerve endings may damage melanocytes by altering the free radical defense of the epidermis.
The self-destruction hypothesis proposes that melanocytes may be destroyed by phenolic compounds formed during the synthesis of melanin. In vivo and in vitro studies have demonstrated the destruction of melanocytes by phenols and catechols. In addition, industrial workers who are exposed to catechols and phenols may experience depigmentation of areas of skin or leukoderma.
A variety of environmentally ubiquitous compounds containing catechols, phenols, and sulfhydryls can induce hypopigmentation, depigmentation, or both. These compounds are most often encountered in industrial chemicals and cleaning agents. Possible mechanisms for altered pigment production by the aforementioned chemicals include melanocyte destruction via free radical formation, inhibition of tyrosinase activity, and interference with the production or transfer of melanosomes.
Clinically, vitiliginous lesions are typically asymptomatic depigmented macules that are without signs of inflammation. However, inflammatory vitiligo with erythematous borders has been reported. Hypopigmented lesions may coexist with depigmented lesions. The patches are occasionally pruritic. Macules frequently begin on sun-exposed or perioral facial skin and either remain localized or disseminate to other cutaneous sites. Areas of depigmentation vary in size from a few millimeters to many centimeters, and their borders are usually distinct. Trichrome lesions are most often observed in persons of darker complexion. These lesions are characterized by zones of white, light brown, and normal skin color. This finding suggests that melanocyte loss begins in the hair follicle. Depigmented hairs are often present in lesional skin and do not preclude repigmentation of a lesion. In addition, there is a high incidence of premature graying of scalp hair in patients with vitiligo and their families. Vitiliginous lesions can remain stable or slowly progress for years. In some instances, however, patients undergo almost complete spontaneous depigmentation over a few years.
Vitiligo is subclassified into different types on the basis of the distribution of skin lesions. These subclassifications include generalized vitiligo (vitiligo vulgaris), acral (acrofacial) vitiligo, localized vitiligo, and the segmented types. The generalized pattern is characterized by symmetrical macules occurring in a random distribution. Acral or acrofacial vitiligo consists of depigmented macules confined to the extremities or to the face and extremities, respectively. A subcategory of the acrofacial type is the lip-tip variety, in which lesions are confined to the lips and the tips of the digits. The generalized and acrofacial varieties are the most common. Localized vitiligo occurs in a dermatomal or quasidermatomal distribution; lesions rarely spread beyond the affected dermatome. This variety is the less common variety of vitiligo and most often occurs along the distribution of the trigeminal nerve.
Melanocytes of the eye, ear, and leptomeninges may also be involved in vitiligo. Depigmented areas of the retinal pigment epithelium and choroid have been reported in 39% of patients studied. These lesions usually do not interfere with vision. Vitiligo is also a manifestation of the Vogt-Koyanagi-Harada syndrome, which is characterized by poliosis, chronic uveitis, alopecia, dysacusis, vitiligo, and signs of meningeal irritation. It usually begins in the third decade of life, and although no race is spared, the disease tends to be more severe in darker-complexioned races, especially Asians. The syndrome has been divided into three stages. The first, or meningeal, stage is associated with headache, nausea, vomiting, fever, confusion, cranial nerve palsies, hemiparesis, and cerebrospinal fluid pleocytosis. Usually, there are few neurologic sequelae. In the second stage, ophthalmic and auditory changes predominate; such changes include photophobia, ocular pain, visual loss, anterior or posterior uveitis, and sometimes retinal detachment, tinnitus, and dysacusis. Cutaneous lesions are dominant in the third, or convalescent, stage, occurring as the uveitis begins to subside. Common features are vitiligo, which frequently involves the eyelids and periorbital region [see Figure 4]; poliosis of the scalp, hair, eyelashes, and eyebrows; and diffuse or patchy alopecia.
Figure 4. A patient with Vogt-Koyanagi-Harada syndrome shows periorbital depigmentation.
Patients with malignant melanoma frequently experience a vitiligolike depigmentation surrounding melanoma lesions and at distant sites. The presence of depigmentation in melanoma patients portends a longer survival.
Histologically, the predominant finding of vitiligo lesions is an absence of melanocytes in lesional skin. Light microscopy and ultrastructural studies have also revealed vacuolar degeneration of basal and parabasal keratinocytes, as well as epidermal and dermal lymphohistiocytic cell infiltrates. Immunohistochemical staining has confirmed the presence of a predominantly T cell infiltrate in vitiliginous and adjacent skin.
In view of the association of vitiligo with myriad other autoimmune diseases, the routine baseline evaluation of a patient should include a thorough history and physical examination. Recommended laboratory tests include a complete blood count; erythrocyte sedimentation rate; comprehensive metabolic panel, including liver function tests; thyroid function tests; and autoantibody tests (i.e., antinuclear antibody, thyroid peroxidase, and parietal cell antibodies).
Other disorders characterized by depigmentation may occasionally mimic vitiligo clinically. These include piebaldism, nevus depigmentosus, nevus anemicus, postinflammatory depigmentation or hypopigmentation, pityriasis alba, tinea versicolor, discoid lupus erythematosus, scleroderma, hypopigmentated mycosis fungoides, and sarcoidosis. Therefore, in some instances, a skin biopsy may be necessary to substantiate a diagnosis of vitiligo.
Both medical and surgical approaches are used for repigmentation of vitiliginous lesions. Medical therapies include topical and systemic steroids, narrow-band ultraviolet B light (UVB), PUVA, vitamin supplementation, oral and topical phenylalanine, and immunomodulations.61,62,63 Surgical therapies are indicated only in patients with localized stable lesions and include autologous blister grafts, punch grafts, sheet grafts, and micropigmentation.64
Therapeutic measures should include efforts to stabilize or slow the progression of vitiligo, as well as appropriate use of therapies to induce repigmentation of vitiliginous lesions.
Repigmentation therapies should be predicated on the age of the patient, the extent of cutaneous surface involvement (severity), and the activity or progression of the disease. The disease can be divided into four stages: limited (< 10% involvement), moderate (10% to 25% involvement), moderately severe (26% to 50% involvement), and severe (greater than 50% involvement) [see Table 1].
Table 1 Therapeutic Approaches for Vitiligo
Mid- to high-potency steroids are indicated in patients with limited involvement. Low-potency topical steroids are usually ineffective. Topical mid- to high-potency steroids can be safely used for 2 to 3 months, then interrupted for 1 month or tapered to a low-potency preparation. Patients must be closely monitored for topical steroid side effects, which include skin atrophy, telangiectasias hypertrichosis, and acneiform eruptions.
Short courses of oral prednisone for 1 to 2 weeks or intramuscular triamcinolone acetonide injections, 40 mg/month for 2 to 3 months, are often extremely helpful in stabilizing rapidly progressive vitiligo. Prolonged use of systemic steroids is not indicated.
Historically, PUVA was considered the gold standard for repigmenting vitiliginous skin lesions; however, PUVA-induced repigmentation rates varied considerably.62,65 In addition, the adverse effects of PUVA can be substantial; such effects include phototoxicity and gastrointestinal irritation. PUVA requires ocular protection because of the risk of PUVA-induced cataracts.66
Narrow-band UVB phototherapy has emerged as the initial treatment of choice for patients with moderate to severe vitiligo.66 Narrow-band UVB involves the use of UV lamps with a peak emission around 311 nm.67 These shorter wavelengths provide higher energy fluences and induce less cutaneous erythema. Narrow-band UVB induces local immunosuppression, stimulates the production of melanocyte-stimulating hormone, and increases melanocyte proliferation and melanogenesis. The first major study of narrow-band UVB in patients with vitiligo compared the efficacy of narrow-band UVB to PUVA.68 Significantly enhanced repigmentation was achieved in patients treated with narrow-band UVB, as compared with those treated with PUVA. Adverse effects were minimal in patients treated with narrow-band UVB, whereas phototoxicity was observed in patients treated with PUVA. Subsequent studies have further confirmed the efficacy of narrow-band UVB phototherapy for vitiligo69,70,71 [see Figure 5].
Figure 5. Vitiligo (a) before and (b) after treatment with narrow-band ultraviolet B light.
The major advantages of narrow-band UVB include an established safety profile in both children and adults and a lack of systemic adverse effects. Unlike treatment with PUVA, narrow-band UVB does not require eye protection beyond treatment exposure time. Beyond isolated case reports and in contrast to the findings reported for psoriasis patients who have undergone this therapy, no studies have documented an increase in squamous cell carcinomas, basal cell cancers, or malignant melanomas in vitiligo patients treated with either PUVA or narrow-band UVB.62
A potential mechanism for the apparent low risk of skin cancers in patients with vitiligo is the overexpression of a functioning wild-type p53 protein, which has been demonstrated in both the depigmented and healthy pigmented epidermis of patients with vitiligo, as compared with healthy control subjects.72 However, long-term follow-up studies are needed to fully assess the risks of narrow-band UVB.
Targeted phototherapy systems have also demonstrated improved efficacy for the treatment of localized vitiligo. These units deliver high-intensity light only to the affected areas, while avoiding exposure of the healthy skin and lowering the cumulative UVB dose. Targeted light units include the xenon chloride excimer laser, broad-band UVB units, and combination broad-band UVB/UVA units.73,74,75
Abnormalities of both humoral and cell-mediated immunity have been documented in patients with vitiligo. Hence, a rational therapeutic approach involves the use of immunomodulatory drugs. The efficacy of isoprinosine, cyclosporine, levamisole, and anapsos has been reported in patients with vitiligo.61
Several studies have documented the efficacy and safety of topical calcineurin inhibitors (i.e., tacrolimus and pimecrolimus) for the treatment of vitiligo. These agents affect T cell and mast cell function by binding to cytoplasmic immunophilins and by inactivating calcineurin. Tacrolimus inhibits the synthesis and release of inflammatory cytokines and vasoactive mediators from basophils and mast cells.76 Calcineurin inhibitors offer several advantages in treating vitiligo. These agents are extremely well tolerated in children and adults and can be used for long periods without evidence of atrophy or telangiectasias, the common complications associated with long-term steroid use [see Figure 6]. This is a key advantage in treating a chronic disease such as vitiligo; however, long-term data on the use of these agents for the treatment of vitiligo are lacking.
Figure 6. Vitiligo (a) before and (b) after treatment with tacrolimus.
Calcipotriol is a synthetic analog of vitamin D3. Vitamin D3 binds to vitamin D receptors in the skin, affecting melanocyte and keratinocyte growth and differentiation. It also inhibits T cell activation.77 Melanocytes are thought to express 1-α-dihydroxyvitamin D3 receptors, which may have a role in stimulating melanogenesis. Some studies have shown that when used in combination with UV phototherapy, calcipotriol may be well tolerated and effective in treating both children and adults with vitiligo.78,79 In other controlled studies, however, minimal repigmentation was observed.80,81,82
Preliminary open-label studies have documented stabilization and repigmentation in vitiligo patients treated with high-dose vitamin supplementation, including ascorbic acid (1,000 mg daily), vitamin B12 (1,000 mg daily), and folic acid (1 to 5 mg daily).61
Depigmentation is a viable therapeutic alternative in patients with greater than 50% cutaneous depigmentation who have demonstrated recalcitrance to repigmentation or in patients with extensive vitiligo who have no desire to undergo repigmentation therapies. Monobenzylether of hydroquinone (MBEH, or monobenzone) has been used as a depigmenting agent for patients with extensive vitiligo since the 1950s. In general, MBEH causes permanent destruction of melanocytes and induces depigmentation locally and in areas remote from the sites of application. Hence, the use of MBEH for other disorders of pigmentation is contraindicated. The major side effects of MBEH therapy are dermatitis and pruritus, which usually respond to topical and systemic steroids. Other side effects include severe xerosis, alopecia, premature graying, and the suppression of lymphoproliferative responses.
Surgical treatment is appropriate for patients with localized, stable areas of vitiligo that have been recalcitrant to medical treatment. Such approaches are contraindicated in patients with keloids or hypertrophic scars. Techniques for surgical grafting include suction blister grafts, punch grafts, sheet grafts, pure melanocyte cultures, and cocultures of melanocytes and keratinocytes. These techniques are indeed beneficial for localized lesions.
Micropigmentation (i.e., cosmetic tattooing) is often associated with the induction of koebnerization. Hence, it should be used only for the treatment of mucous membrane lesions.
Patients with vitiligo should be screened yearly, in light of the potential development of associated autoimmune diseases.
Albinism is an uncommon complex congenital disorder characterized by hypopigmentation of the hair, eyes, and skin. Albinism is generally subclassified as oculocutaneous albinism (OCA) and ocular albinism (OA), in which reduction of melanin is limited to the eye.83
Oculocutaneous albinism has been reported by investigators in all mammalian orders and in all human ethnic groups. It is one of the most widely distributed genetic abnormalities in the animal kingdom. Human albinism has been noted throughout history. OCA is the most common inherited disorder of generalized hypopigmentation.
Etiology and Pathogenesis
Albinism may result from primary defects that are specific for the melanin synthetic pathway or from defects that are not specific for melanin synthesis. Mutations in six genes have been reported to cause OCA or OA.84,85 They include the tyrosinase gene (OCA1), the oculocutaneous albinism gene (OCA2), the tyrosinase-related protein 1 gene (OCA3), the HPS gene (Hermansky-Pudlak syndrome), the CHSgene (Chédiak-Higashi syndrome), and the OA1 gene (X-linked ocular albinism). In some cases, different mutations in the same gene can cause OCA or OA.
Clinically, the most severe disease is observed in OCA1A, oculocutaneous albinism resulting from mutations in the tyrosinase gene. It is characterized by absent tyrosinase activity, which results in complete absence of melanin in the eyes, skin, and hair. There is no improvement with age. Affected individuals have marked photophobia, nystagmus, and profound sun sensitivity because of an inability to tan.
OCA1B, or yellow albinism, is less severe. Tyrosinase activity is low or absent, and pigmentation of the hair and skin improves with age. In contrast to OCA1A, pigmented freckles and lentigines develop with age.
OCA1-MP, or minimal pigment oculocutaneous albinism, is characterized by white skin and hair at birth. Iris pigment is present at birth, or it appears during the first decade of life. All reported cases have been in white persons. The tyrosinase gene mutation produces a less active enzyme.
Temperature-sensitive oculocutaneous albinism (OCA1-TS) is characterized by white skin and hair and blue eyes at birth and the development of patterned pigmentation by puberty. Darker hair develops in cooler areas (extremities), and white hair is retained in warmer areas (axilla and scalp). The pattern results from a tyrosinase mutation that causes a temperature-sensitive enzyme.
OCA2, tyrosinase-positive oculocutaneous albinism, with normal tyrosinase activity, is the most common variety. The hair darkens with age, but the skin remains white. Pigmented nevi, lentigines, and freckles develop and are especially pronounced in sun-exposed areas. This type has recently been ascribed to mutation of the P gene, on chromosome 15q, which encodes the tyrosinase-transporting membrane protein.
OCA4 has a range of clinical presentations. Phenotypes vary from a complete absence of pigmentation to some pigmentation with brown hair and irides. Some patients show increasing pigmentation during the first decade of life.86 OCA4 is caused by mutations in the membrane-associated transporter protein gene (SLC45A2). SLC45A2 contains 12 putative transmembrane domains; it is expressed only in melanocytes. Tyrosinase processing and trafficking are disrupted before delivery to early melanosomes. The SLC45A2 gene seems to be transcriptionally modulated by microphthalmia-associated transcription factor (MITF), which is a melanocyte-specific transcription factor, by an indirect mechanism.
The secondary varieties of albinism, in which the primary defect is not specific for the melanin synthetic pathway, include Hermansky-Pudlak syndrome,87 Chédiak-Higashi syndrome, Cross-McKusick-Breen syndrome, Prader-Willi syndrome, and Angelman syndrome. The autosomal recessive Hermansky-Pudlak syndrome is characterized by low to absent tyrosinase activity. The HPS gene has been mapped to chromosome 10q.88,89 There are eight known human HPS subtypes, each of which can lead to a particular clinical HPS subtype. In the mouse model, there are 15 HPS genes, only five of which have known functions (AP3B1, AP3D1, VPS33A, RABGGTA, and Slc7a11); four of these have roles in regulating membrane vesicle and protein trafficking.90
In patients with HPS, skin and hair color varies from white to light brown. Freckles and lentigines develop with age. Iris pigment correlates with hair and skin pigmentation. Affected individuals experience a hemorrhagic diathesis secondary to a platelet storage pool deficiency. They lack storage granules—that is, sites of storage of serotonin, calcium, and adenine nucleotides. Ceroidlike deposits are present in macrophages of the bone marrow, lungs, liver, spleen, and gastrointestinal tract. Patients bruise easily and are subject to epistaxis and gingival bleeding. Pulmonary fibrosis and granulomatous colitis develop as a consequence of the ceroid deposits.
HPS is very common in Puerto Rico, with a frequency of approximately 1:1,800. Two HPS genes and mutations have been identified in Puerto Rico, a 16-base pair (bp) duplication in HPS1 and a 3.904 bp deletion in HPS3. These findings provide insights into the genetics of albinism and HPS in Puerto Rico and provide the basis for genetic screening for these disorders in this minority population.91
Chédiak-Higashi syndrome consists of hypopigmentation, recurrent sinopulmonary bacterial infections, peripheral neuropathy, and giant lysosomal granules and leads to death at an early age as a result of lymphoreticular malignancies. The CHS gene locus is on chromosome 1q.61
Cross-McKusick-Breen syndrome includes hypopigmentation, microphthalmia, nystagmus, and severe mental and physical retardation.
Prader-Willi syndrome is a developmental syndrome characterized by mental retardation, neonatal hypotonia, and poor feeding followed by hyperphagia and obesity later in life. Short stature, hypogonadism, and inappropriate emotional behavior constitute the syndrome. Fifty percent of patients have a deletion on the long arm of chromosome 15. Patients have ocular abnormalities and skin and hair hypopigmentation consistent with oculocutaneous albinism.
Mutation of the P gene has been reported in Angelman syndrome and is also characterized by mental retardation, abnormal behavior, and hypopigmentation. The pattern of hypopigmentation is similar to that in Prader-Willi syndrome. In addition, Angelman syndrome is associated with a deletion on chromosome 15. However, in contrast to Prader-Willi syndrome, the deletion occurs on the maternal chromosome.
The management of patients with albinism should include genetic counseling and patient education regarding the use of sunscreens and clothing for protection against ultraviolet radiation? induced damage. Magnifying lenses are beneficial for ocular symptoms.
The long-term consequences of albinism are solar keratoses and basal and squamous cell carcinomas. Malignant melanoma is uncommon.
Piebaldism is a rare autosomal dominant congenital disorder of pigmentation. It is a stable leukoderma and is characterized by patches of white skin and white hair. The affected areas are principally the frontal scalp, forehead, ventral chest, abdomen, and extremities. A white forelock occurs in 80% to 90% of patients.
Although rare, piebaldism occurs in all ethnic groups worldwide. Its estimated occurrence is one in 100,000 persons. It is found with equal frequency in males and females.
Etiology and Pathogenesis
Molecular genetics studies have shown that piebaldism results from frameshift and splice junction mutations of the KIT gene, located on chromosome segment 4q12. Mutations occur in the highly conserved tyrosinase kinase domain of c-Kit. Reduced KIT function arrests the migration of melanocytes into affected hair follicles and epidermis during embryonal development.92,93 Mice transgenic for the KIT Val620Ala mutation, which in humans has been associated with progressive piebaldism, exhibit dominant white spotting but show no evidence of progressive depigmentation. These results are consistent with the previous hypothesis that progressive piebaldism might result from digenic inheritance of the KIT(V620A) mutation that causes piebaldism plus a second, unknown locus that causes progressive depigmentation.94
In general, patients with piebaldism are healthy and do not have associated systemic abnormalities. However, the disorder occasionally has been associated with heterochromia irides, mental retardation, osteopathia striata, Woolf syndrome, and Hirschsprung disease.
Cutaneous depigmentation is the only manifestation of piebaldism in 10% to 20% of cases. Amelanotic macules are usually present on the ventral surface of the thorax and abdomen and extend to the back but spare the midline. Characteristic lesions of the extremities extend from midarm to wrist and occur on the midleg [see Figure 7]. White patches of the mucous membranes have also been reported. Hyperpigmented macules may appear within the areas of depigmentation.
Figure 7. A patient with piebaldism has the classic midextremity areas of depigmentation with islands of hyperpigmentation.
Light and electron microscopic studies of the white macules have typically revealed an absence of melanocytes. However, melanocytes have been demonstrated in the white forelock and amelanotic skin of three patients studied.
Piebaldism is sometimes confused with vitiligo, but in piebaldism the leukodermic patches are both congenital and relatively static in shape and size.
The lesions are usually stable throughout life, although some patients have reported spontaneous repigmentation. In general, therapeutic approaches, including psoralen photochemotherapy and grafting, are unsatisfactory. Autologous melanocyte grafting procedures may offer some benefit for localized or limited areas of involvement. In one study, autologous cultured epidermal sheets were used to reproducibly repigment large piebald lesions prepared by removal of the achromic epidermis with an erbium:YAG laser.95
Idiopathic Guttate Hypomelanosis
Idiopathic guttate hypomelanosis (IGH) is a common asymptomatic disorder characterized by hypopigmentation and depigmented polygonal macules ranging from approximately 2 mm to 8 mm in diameter.
IGH appears to be a very common, benign dermatosis. It occurs in all races with a frequency ranging from 46% to 70%. It is, however, more prevalent in darker-skinned racial and ethnic groups. Macules may begin to appear during the third or fourth decade of life and gradually increase in number thereafter.
Etiology and Pathogenesis
The precise pathogenesis has not been established for IGH. Long-term sun exposure, trauma, genetic influences, and aging, with a gradual loss of melanocytes, have been implicated in the pathogenesis of this disorder.96
The lesions of IGH are macules that are punctate to polygonal in shape, 2 to 8 mm in size, and hypopigmented to depigmented; they are most commonly observed on the lower extremities. There is no atrophy or change in the overlying skin. Histologic evaluation of lesions reveals hyperkeratosis, epidermal atrophy, and diseased epidermal melanin. Melanocytes may be normal or decreased.
IGH must be differentiated from other hypopigmentary disorders, such as vitiligo, scleroderma, leukodermic guttate parapsoriasis, tinea versicolor, hypopigmentated sarcoidosis, pityriasis alba, chemical depigmentation, and postinflammatory hypopigmentation.
No definitive treatment is currently available. Patients often need reassurance regarding the benign nature of these lesions. For patients concerned about the cosmetic appearance of lesions, camouflage, intralesional steroids, and topical photochemotherapy have been used.
- Grimes PE: Melasma: etiologic and therapeutic considerations. Arch Dermatol 131:1453, 1996
- O'Brien TJ, Dyall-Smith D, Hall AP: Melasma of the forearms. Australas J Dermatol 38:35, 1997
- Boissy RE, Nordlund JJ: Molecular basis of congenital hyperpigmentary disorders in humans: a review. Pigment Cell Res 10:12, 1997
- Grimes PE, Yamada N, Bhawan J: Light microscopic, immunohistochemical, and ultrastructural alterations in patients with melasma. Am J Dermatopath 27:96, 2005
- Kang S, Krueger GG, Tanghett EA, et al: A multicenter, randomized, double-blind trial of tazarotene 0.1% cream in the treatment of photodamage. J Am Acad Dermatol 52:268, 2005
- Pramphongsant T: Treatment of melasma: a review with personal experience. Int J Dermatol 37:897, 1998
- Grimes PE: The safety and efficacy of salicylic acid peels in darker-racial ethnic groups. Dermatol Surg 25:19, 1999
- Grimes PE, Kelly PA, Torok H, et al: Community-based trial of a triple combination agent for the treatment of facial melasma. Cutis 77:177, 2006
- Grimes PE: A microsponge formulation of hydroquinone and retinol 0.5% in the treatment of melasma and postinflammatory hyperpigmentation. Cutis 74:362, 2004
- Wang CC, Hui CY, Sue YM, et al: Intense pulsed light for the treatment of refractory melasma in Asian persons. Dermatol Surg 30:1196, 2004
- Rokshar CK, Fitzpatrick RE: The treatment of melasma with fractional photothermolysis: a pilot study. Dermatol Surg 31:1645, 2005
- Westerhof W, Kooyers TJ: Hydroquinone and its analogues in dermatology: a potential health risk. J Cosmet Dermatol 4:55, 2005
- Zawar VP, Mhaskar ST: Exogenous ochronosis following hydroquinone for melasma. J Cosmet Dermatol 3:234, 2004
- Nordlund JJ, Grimes PE, Ortonne JP: The safety of hydroquinone. J Eur Acad Dermatol Venereol 20:781, 2006
- O'donoghue JL: Hydroquinone and its analogues in dermatology: a risk-benefit viewpoint. J Cosmet Dermatol 5:196, 2006
- Mahe A, Perret JL, Ly F, et al: The cosmetic use of skin-lightening products during pregnancy in Dakar, Senegal: a common and potentially hazardous practice. Trans R Soc Trop Med Hyg 101:183, 2007
- Balkrishnan R, McMichael AJ, Camacho FT, et al: Development and validation of a health-related quality of life instrument for women with melasma. Br J Dermatol 149:572, 2003
- McKenzie R, Sauder DN: The role of keratinocyte cytokines in inflammation and immunity. J Invest Dermatol 95:1055, 1990
- Kinbauer R, Kock A, Neuner P, et al: Regulation of epidermal cell interleukin production by UV light and corticosteroids. J Invest Dermatol 96:484, 1991
- Ruiz-Maldonado R, Orozco-Covarrubias ML: Postinflammatory hypopigmentation and hyperpigmentation. Semin Cutan Med Surg 16:36, 1997
- Grimes PE, Callendar V: Tazarotene cream for postinflammatory hyperpigmentation and acne vulgaris in darker skin: a double-blind, randomized, vehicle-controlled study. Cutis 77:45, 2006
- Dereure O: Drug-induced skin pigmentation: epidemiology, diagnosis, and treatment. Am J Clin Dermatol 2:253, 2001
- Metelita AI, Nguyen GK, Lin AN: Imipramine-induced facial pigmentation: case report and review of the literature. J Cutan Med Surg 9:341, 2005
- Granskin R, Sober AJ: Drug and heavy metal-induced hyperpigmentation. J Am Acad Dermatol 5:1, 1981
- Lerner EA, Sober AJ: Chemical and pharmacologic agents that cause hyperpigmentation or hypopigmentation of the skin. Dermatol Clin 6:327, 1988
- Miseg ME, Ghawan J, Stefanato CM: Imipramine-induced hyperpigmentation: four cases and a review of the literature. J Am Acad Dermatol 40:159, 1999
- Torrelo A, Zaballos P, Colmenero I, et al: Erythema dyschromicum perstans in children: a report of 14 cases. J Eur Acad Dermatol Venereol 19:422, 2005
- Combemale P, Faisant M, Guennoc B, et al: Erythema dyschromicum perstans: report of a new case and review of the literature. J Dermatol 25:747, 1992
- Dominguez-Soto L, Hojya-Tomoka T, Vega-Memye E, et al: Pigmentary problems in the tropics. Dermatol Clin 12:777, 1994
- Penagos H, Jimenez V, Fallas V, et al: Chlorethalanil: a possible cause of erythema dyschromicum perstans (ashy dermatitis). Contact Dermatitis 35:214, 1996
- Baranda L, Torres-Alvarez B, Cortes-Franco R, et al: Involvement of cell adhesion and activation molecules in the pathogenesis of erythema dyschromicum perstans (ashy dermatitis). Arch Dermatol 133:32, 1997
- Vasquez-Ochoa LA, Isaza-Guzman DM, Orozco-Mora B, et al: Immunopathologic study of erythema dyschromicum perstans (ashy dermatosis). Int J Dermatol 45:937, 2006
- Bauer AJ, Stratakis CA: The lentiginoses: cutaneous markers of systemic disease and window to new aspects of tumourigenesis. J Med Genet 42:801, 2005
- Stratigos AJ, Katsambas AD: Optimal management of recalcitrant disorders of hyperpigmentation in dark-skinned patients. Am J Clin Dermatol 5:161, 2004
- Langley RG, Burton E, Walsh N, et al: In vivo confocal scanning laser microscopy of benign lentigines: comparison to conventional histology and in vivo characteristics of lentigo maligna. J Am Acad Dermatol 55:88, 2006
- Jarratt M: Mequinol 2%/tretinoin 0.1% solution: an effective and safe alternative to hyroquinone 3% in the treatment of solar lentigines. Cutis 74:319, 2004
- Davis MD, Weenig RH, Camilleri RJ: Confluent and reticulate papillomatosis (Gougerot-Carteaud syndrome): a minocycline-responsive dermatosis without evidence for yeast in pathogenesis: a study of 39 patients and a proposal of diagnostic criteria. Br J Dermatol 154: 287, 2006
- Lee MP, Stiller SA, McClain JL, et al: Confluent and reticulated papillomatosis: response to high-dose oral isotretinoin therapy and reassessment of epidemiologic data. J Am Acad Dermatol 31:327, 1994
- Purg L, de Moragas JM: Confluent and reticulated papillomatosis of Gougerot and Carteaud: minocycline deserves trial before etritinate. Arch Dermatol 131:109, 1995
- Angeli-Besson C, Koeppel MC, Jacquet P, et al: Confluent and reticulated papillomatosis (Gougerot-Carteaud) treated with tetracyclines. Int J Dermatol 34:567, 1995
- Scheinfeld N: Confluent and reticulated papillomatosis: a review of the literature. Am J Clin Dermatol 7:305, 2006
- Kim YC, Davis MD, Schanbacher CF, et al: Dowling-Degos disease (reticulate pigmented anomaly of the flexures): a clinical and histopathologic study of six cases. J Am Acad Dermatol 40:462, 1999
- Lestringant GG, Masouye I, Frossard PM, et al: Co-existence of leukoderma with features of Dowling-Degos disease: reticulate acropigmentation of Kitamura's spectrum in five unrelated patients. Dermatology 105:337, 1997
- Betz RC, Planko L, Eigelshoven S, et al: Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet 78:510, 2006
- Kovacs SO: Vitiligo. J Am Acad Dermatol 38:647, 1998
- Boissy R, Le Poole C: Vitiligo. Semin Cutan Med Surg 16:3, 1997
- Baharav E, Merimski O, Shoenfeld Y, et al: Tyrosinase as an autoantigen in patients with vitiligo. Clin Exp Immunol 105:84, 1996
- Ongenae K, Van Geel N, Naeyaert JM: Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res 16:90, 2003
- Gauthier Y, Andre MC, Taieb A: A critical appraisal of vitiligo etiologic theories: is melanocyte loss a melanocytorrhagy? Pigment Cell Res 16:322, 2003
- Ogg GS, Rod Dunbar P, Romero P, et al: High frequency of skin-homing melanocytes-specific cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med 188:1203, 1998
- Lang KS, Caroli CC, Muhm A, et al: HLA-A2 rstricted, melanocytes-specific CD8 (+) T lymphocytes detected in vitiligo patients are related to disease activity and are predominantly directed against melanA/Mart1. J Invest Dermatol 116:981, 2001
- Palmero B, Campanelli R, Garbelli S, et al: Specific cytotoxic T lymphocyte responses against Melan-A/MART1, tyrosinase and gp 100 in vitiligo by the use of major histocompatibility complex/peptide tetramers: the role of cellular immunity in the etiophathogenesis of vitiligo. J Invest Dermatol 117:326, 2001
- Mandelcorn-Monsoon RL, Shear NH, Yau E, et al: Cytotoxic T lymphocyte reactivity to gp 100, MelanA/MART-1, and tyrosinase, in HLA-A2-positive vitiligo patients. J Invest Dermatol 121:550, 2003
- Yu HS, Chang KL, Yu CL, et al: Alterations in IL-6, IL-8, GM-CSF, TNF-E1, and IFN-E3 release by peripheral mononuculear cells in patients with active vitiligo. J Invest Dermatol 108:527, 1997
- Honda Y, Okubo Y, Koga M: Relationship between levels of soluble interleukin-2 receptors and the types of activity of vitiligo. J Dermatol 24:561, 1997
- Caixa T, Hongwen F, Xiran L: Levels of soluble interleukin-2 receptor in the sera and skin tissue fluids of patients with vitiligo. J Dermatol Sci 21:59, 1999
- Moretti S, Spallanzani A, Amato L, et al: New insights into the pathogenesis of vitiligo: imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res 15:87, 2002
- Imokawa G: Autocrine and paracrine regulation of melanocytes in human skin and in pigmentary disorders. Pigment Cell Res 17:96, 2004
- Hamzavi I, Jain H, McLean D, et al: Parametric modeling of narrow-band UVB phototherapy for vitiligo using a novel quantitative tool. Arch Dermatol 140:677, 2004
- Grimes PE, Sevall S, Vojdani A: Cytomegalovirus DNA identified in skin biopsy specimens of patients with vitiligo. J Am Acad Dermatol 35:21, 1996
- Grimes PE: Therapies for vitiligo. Drug Therapy in Dermatology. Millikan L, Ed. New York, Marcel Dekker (in press)
- Grimes PE: Psoralen photochemotherapy for vitiligo. Clin Dermatol 15:921, 1997
- Jimbow K: Vitiligo: therapeutic advances. Dermatol Clin 16:399, 1998
- Falabella R: Surgical therapies for vitiligo. Clin Dermatol 15:927, 1997
- Kwok YK, Anstey AV, Hawk JL: Psoralen photochemotherapy (PUVA) is only moderately effective in widespread vitiligo: a 10-year retrospective study. Clin Exp Dermatol 27:104, 2002
- Njoo MD, Spuls PI, Bos JD, et al: Nonsurgical repigmentation therapies in vitiligo: meta-analysis of the literature. Arch Dermatol 134:1532, 1998
- Parrish JA, Jaenicke KF: Action spectrum for phototherapy of psoriasis. J Invest Dermatol 76:359, 1981
- Westerhof W, Nievweboer-Krobotova L: Treatment of vitiligo with UV-B radiations topical psoralen plus UV-A. Arch Dermatol 133:1525, 1997
- Njoo MD, Bos JD, Westerhof W: Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB radiation therapy. J Am Acad Dermatol 42:245, 2000
- Tjioe MJ, Gerritsen MJD, Juhlin L, et al: Treatment of vitiligo vulgaris with narrow band UVB (311nm) for one year and the effect of addition of folic acid and vitamin B12. Acta Derm Venereol 82:369, 2002
- Natta R, Somsak T, Wisuttida T, et al: Narrowband ultraviolet B radiation therapy for recalcitrant vitiligo in Asians. J Am Acad Dermatol 49:473, 2003
- Schallreuter KU, Behrens-Williams S, Khaliq TP, et al: Increased epidermal functioning wild-type p53 expression in vitiligo. Exp Dermatol 12:268, 2003
- Spencer JM, Nossa R, Ajmeri J: Treatment of vitiligo with the 308-nm excimer laser: a pilot study. J Am Acad Dermatol 46:727, 2002
- Taneja A, Trehan M, Taylor C: 308-nm excimer laser for the treatment of localized vitiligo. Int J Dermatol 42:658, 2003
- Leone G, Iacovelli P, Para Vidalin A, et al: Monochromatic excimer light 308nm in the treatment of vitiligo: a pilot study. J Eur Acad Dermatol Venereol 17:531, 2003
- Tharp MD: Calcineurin inhibitors. Dermatol Ther 15:325, 2002
- Dusso AS, Thadhani R, Slatopolsky E: Vitamin D receptor and analogs. Semin Nephrol 24:10, 2004
- Parsad D, Saini R, Verma N: Combination of PUVAsol and topical calcipotriol in vitiligo. Dermatology 197:167, 1998
- Ermis O, Alpsoy E, Cetin L, et al: Is the efficacy of psoralen plus ultraviolet A therapy for vitiligo enhanced by concurrent topical calcipotriol? A placebo-controlled double-blind study. Br J Dermatol 145:472, 2001
- Baysal V, Yildirim M, Erel A, et al: Is the combination of calcipotriol and PUVA effective in vitiligo? J Eur Acad Dermatol Venereol 17:299, 2003
- Parsad D, Saini R, Nagpal R: Calcipotriol in vitiligo: a preliminary study. Pediatr Dermatol 16:317, 1999
- Chiaverini C, Passeron T, Ortonne JP: Treatment of vitiligo by topical calcipotriol. J Eur Acad Dermatol Venereol 16:137, 2002
- Lyle WM, Sangsker JO, Williams TD: Albinism: an update and review of the literature. J Am Optom Assoc 68:623, 1997
- Oetting WS, King RA: Molecular basis of albinism: mutations and polymorphism or pigmentation genes associated with albinism. Hum Mutat 13:99, 1999
- Orlow SJ: Albinism: an update. Sem Cut Med Surg 16:24, 1997
- Katsuhiko I, Tamio S, Shiro I, et al: Oculocutaneous albinism type 4: six novel mutations in the membrane-associated transporter protein gene and their phenotypes. Pigment Cell Res 19:451, 2006
- Shotelersak V, Gahl WA: Hermansky-Pudlak syndrome: models for intracellular vesicle formulation. Molec Gen Metab 65:85, 1998
- Taylor SI, Arioglu E: Syndromes associated with insulin resistance and acanthosis nigricans. J Basic Clin Physiol Pharmacol 9:419, 1998
- Schwartz RA: Acanthosis nigricans. J Am Acad Dermatol 31:18, 1994
- Wei ML: Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Res 19:19, 2006
- Santiago Borrero PJ: Genetic testing for oculocutaneous albinism type 1 and 2 and Hermansky-Pudiak syndrome type 1 and 3 in Puerto Rico. J Invest Drmatol 126:85, 2006
- Spritz RA: Piebaldism, Waardenburg syndrome, and related disorders of melanocyte development. Semin Cutan Med Surg 16:15, 1997
- Spritz RA, Hearing VJ Jr: Genetic disorders of pigmentation. Adv Hum Genet 22:1, 1994
- Spritz RA: “Out, damned spot!” J Invest Dermatol 126:949, 2006
- Guerra L, Primaver G, Raskovic, et al: Permanent repigmentation of piebaldism by erbium:YAG laser and autologous cultured epidermis. Br J Dermatol 150:715, 2004
- Falabella R: Idiopathic guttate hypomelanosis (review). Dermatol Clin 6:241, 1988
Editors: Dale, David C.; Federman, Daniel D.