Disorders of Pigmentation Part 2

Dowling-degos disease


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 presents as symmetrical, reticulated hyperpigmentation of the groin, axilla, antecubital area, infra-mammary areas, and neck.42 The lesions begin as 1 to 3 mm mac-ules 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 of Dowling-Degos disease 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. In addition, the disease has been reported in a large kindred with reticulate acropigmenta-tion of Kitamura and acropigmentation of Dohi, suggesting an association between and overlap of these conditions.44 Histologically, thin, pigmented epithelial strands of downgrowth extend from the epidermis and follicular wall in a filiform pattern resembling adenoid seborrheic keratoses.42,45


In general, there is no effective treatment for Dowling-Degos disease. Adapalene and the erbium:YAG laser have 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. The de-pigmentation results from loss of cutaneous melanocytes. These lesions are cosmetically disfiguring and usually cause emotional trauma in both children and adults [see Figure 3].


Vitiligo affects 1% to 2% of the population. Onset may begin at any age, but peak incidence is in the second or third decade 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 racial and ethnic groups. Females are affected more often than males. The disease has a familial incidence of 25% to 30%. Genetic studies suggest a polygenic inheritance pattern.

HLA studies have reported increases in a variety of haplo-types of class I and class II antigens in patients with vitiligo. However, results vary significantly by race and ethnicity of the population studied. The reported HLA associations include increased frequencies of HLA A30, CW6, CW7, DR1, DR3, DR4, and DQW3.47

Etiology and Pathogenesis

The precise cause of vitiligo is unknown. Multiple theories have been proposed, including genetic, autoimmune, neural, biochemical, and viral mechanisms. Reviews addressing the etiology of vitiligo suggest that vitiligo is probably a heterogeneous disease encompassing multiple etiologies.47,48

An immune-mediated pathogenesis is the most popular theory. This theory is predicated on the increased frequency of a plethora of immunologic diseases in patients with vitiligo, including hypothyroidism (Hashimoto thyroiditis), Graves disease, pernicious anemia, diabetes mellitus, and alopecia areata.

Vitiligo is indicated by generalized patches of depigmentation of the trunk.

Figure 3 Vitiligo is indicated by generalized patches of depigmentation of the trunk.

Thyroid diseases are the most common associated diseases. Other disorders reported in association with vitiligo include Addi-son 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.47,48 Numerous studies have documented an increased frequency of organ-specific autoantibodies. Antithyroid, gastric antiparietal cell, and antinuclear antibodies are most commonly demonstrated. Patients with positive organ-specific autoantibodies unassociated with autoimmune disease have an increased risk of subsequent subclinical or overt autoimmune disease.

Antimelanocyte antibodies, often demonstrated in the sera of patients with vitiligo, induce the destruction of cultured melanocytes by complement-mediated lysis and antibody-dependent cellular cytotoxicity. The presence and titer of antime-lanocyte antibodies correlate with the severity and activity of vitiligo. These antibodies are directed against melanocyte cell surface antigens with molecular weights of 25, 35 to 40, 75, 90, and 150 kd. 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.

Cellular immune-mediated defects include diminished contact sensitization and quantitative and qualitative alterations in T cells and natural-killer cells. Skin-homing cytotoxic T cells have also been implicated in the destruction of melanocytes. Immunohisto-chemical 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 cy-tokine production and cellular infiltrates in vitiligo.47 Studies have documented alterations in cytokine production in patients with vitiligo. Studies of affected skin showed a significantly lower expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), basic fibroblast growth factor (bFGF), and stem cell factor.50 In contrast, expression of interleukin 6 (IL-6) and tumor necrosis factor-a (TNF-a ) was greater in lesional skin than in perilesional or normal skin. Another study reported increased expression of TNF-a, interferon gamma, and IL-10 in the lesional and adjacent skin of vitiligo patients.

Cytomegalovirus DNA has been demonstrated in the involved and uninvolved skin of patients with vitiligo. No viral DNA was detected in matched control subjects.52 These findings suggest that in some cases, vitiligo may be triggered by a viral infection.

The neural theory 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.

Several studies suggest that oxidative stress may be the initial event in the destruction of melanocytes.53,54 Defective recycling of tetrahydrobiopterin, increased production of hydrogen peroxide, and decreased catalase have been demonstrated in the skin of patients with vitiligo.55,56 In addition, lesional catecholamine biosynthesis and release are increased. Thus, abnormal release of catecholamines from autonomic nerve endings and oxidative stress 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.

A variety of environmentally ubiquitous compounds containing catechols, phenols, and sulfhydryls can induce hypopigmen-tation, depigmentation, or both. These compounds are most often encountered in industrial chemicals and cleaning agents. Possible mechanisms for altered pigment production by these compounds include melanocyte destruction via free radical formation, inhibition of tyrosinase activity, and interference with the production or transfer of melanosomes.


Clinical manifestations Vitiliginous lesions are typically asymptomatic depigmented macules without clinical 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 darker-complex-ioned persons. These lesions are characterized by zones of white, light-brown, and normal skin color. 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 in their families. Vit-iliginous lesions can remain stable or can slowly progress for years. In some instances, 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 the generalized or vulgaris, acral or acrofacial, localized, and segmented types. The generalized pattern is characterized by symmetrical macules or patches 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. Segmental vitiligo occurs in a dermatomal or quasidermatomal distribution; lesions rarely spread beyond the affected der-matome. This type 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. Vitili-go 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-complex-ioned races, especially Asians.

The syndrome has been divided into stages. The first, or meningeal, stage, is associated with headache, nausea, vomiting, fever, confusion, cranial nerve palsies, hemiparesis, and cerebro-spinal fluid pleocytosis. Usually, there are a few neurologic sequelae. In the second stage, ophthalmic and auditory changes predominate, including 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.

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.

Laboratory findings Histologically, the predominant finding in vitiligo is an absence of melanocytes in lesional skin. Light microscopy and ultrastructural studies have also revealed vac-uolar degeneration of basal and parabasal keratinocytes and revealed epidermal and dermal lymphohistiocytic cell infiltrates.

A patient with Vogt-Koyanagi-Harada syndrome shows periorbital depigmentation.

Figure 4 A patient with Vogt-Koyanagi-Harada syndrome shows periorbital depigmentation.

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; sedimentation rate; comprehensive metabolic panel, including liver function tests; and autoantibody tests (antinuclear antibody, thyroid peroxidase, and parietal cell antibodies).

Differential Diagnosis

Other disorders characterized by depigmentation may occasionally mimic vitiligo clinically. These include piebaldism, nevus depigmentosus, nevus anemicus, postinflammatory depigmen-tation or hypopigmentation, pityriasis alba, tinea versicolor, discoid lupus erythematosus, scleroderma, hypopigmented mycosis fungoides, and sarcoidosis. Therefore, in some instances, a skin biopsy may be necessary to substantiate a diagnosis of vitiligo.

Treatment Selection

Therapeutic objectives in vitiligo should include both stabilization of the disease and repigmentation of vitiliginous skin lesions. Repigmentation can be accomplished medically57-59 or, in patients with localized stable lesions, surgically.60 The choice of repigmentation therapies should be predicated on the age of the patient, extent of cutaneous surface involvement (severity), and activity or progression of the disease. The disease can be divided into four stages: limited (less than 10% involvement), moderate (10% to 25% involvement), moderately severe (26% to 50% involvement), and severe (greater than 50% involvement) [see Table 1].

Medical Treatment

Medical therapies for vitiligo include topical and systemic steroids, topical and systemic PUVA, narrow-band ultraviolet light therapy (UVB), excimer laser therapy, nutritional vitamin supplementation, immunomodulators, calcipotriol, phenylala-nine, and khellin.

Steroids 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 used safely for 2 to 3 months, then interrupted for 1 month or tapered to low-potency preparations. Patients must be closely monitored for topical steroid side effects, which include skin atrophy, telangiectasias, hypertrichosis, and acneiform eruptions. Since the introduction of topical immunomodulators (tacrolimus and pimecrolimus), topical steroids are used less often in vitiligo patients.

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 for stabilizing rapidly progressive vitiligo. However, prolonged use of systemic steroids is not indicated.57-59

Photochemotherapy Until recently, topical and systemic PUVA therapies were the mainstay for repigmenting vitiliginous lesions.57,58 However, in the past several years, these therapies have been overshadowed by new ones, including narrow-band UVB phototherapy, lasers, and topical immunomodulators.

Topical photochemotherapy can be administered in the office or outside the office in combination with sunlight. The choice of topical PUVA is predicated on the severity of vitiligo, patient lifestyle, and convenience for the patient.

Table 1 Therapeutic Approaches for Vitiligo

Stages I and II disease*

Topical steroids

Topical photochemotherapy


In-office PUVA

Bath photochemotherapy


UVB phototherapy

Narrow band

Broad band

Excimer laser

Topical immunomodulators




Topical khellin/UVA



Tar emulsions

Vitamin supplementation

Autologous melanocyte grafting (stable lesions)

Oral photochemotherapy

Systemic steroids (oral, I.M.) (for


Bath photochemotherapy

UVB phototherapy

Narrow band

Stages III and IV disease*

Broad band

Oral khellin/UVA








Nitrogen mustard

Depigmentation (severe, recalcitrant lesions)

*Stage I, < 10% involvement; stage II, 10%-25% involvement; stage III, 26%-50% involvement; stage IV, > 50% involvement.

PUVA—psoralens plus ultraviolet A UV—ultraviolet UVA—ultraviolet A UVB—ultraviolet B

Topical in-office PUVA is appropriate for patients with less than 20% cutaneous surface involvement. A thin coat of 0.01% to 0.1% methoxsalen ointment is applied to affected areas 30 minutes before UVA exposure. Treatments are weekly or twice weekly. For patients with less than 10% involvement, an alternative approach involves the use of 0.001% methoxsalen ointment applied 30 minutes before sunlight exposure. Patients are allowed to expose the affected areas for 10 minutes, gradually increasing exposure time to 30 minutes. Treatments are daily or every other day.

Oral photochemotherapy is indicated in patients with greater than 20% to 25% cutaneous surface involvement. The standard dose of 8-methoxypsoralen (8-MOP) is usually 0.3 to 0.4 mg/kg ingested 1.5 hours before UVA exposure. The treatments are administered twice weekly. Broad-spectrum sunscreen protection is essential after PUVA treatments. In addition, because of the ocular pharmacokinetics of 8-MOP, protective UVA sunglasses should be worn indoors and outdoors for 18 to 24 hours after ingestion of 8-MOP.

Contraindications to oral PUVA treatment include liver disease and photosensitivity disorders. Side effects include headaches, nausea, vomiting, xerosis, pruritus, photoaging, diffuse hyperpigmentation, and hypertrichosis. Compared with topical PUVA, the major advantages of oral PUVA include its effectiveness in controlling the progression of active disease and its lower frequency of blistering reactions. Oral PUVA therapy has been associated with an increase in nonmelanoma and melanoma skin cancer in patients with psoriasis. However, similar documentation has not been reported in patients with vitiligo.

Factors that portend enhanced PUVA-induced repigmenta-tion include young age (children), patient motivation, maintenance of adequate lesional phototoxicity, and location of lesions. Maximal repigmentation occurs on the face and neck, and minimal responses occur in the hands and feet. Overall, mean repig-mentation of 60% to 65% of the affected areas can be achieved.58

Narrow-band UVB Recent studies have reported the benefits of narrow-band UVB phototherapy (NB-UVB).61 NB-UVB treatment was shown to be as effective as topical PUVA, with fewer side effects. In a study of NB-UVB phototherapy versus oral PUVA, 56% of the UVB group had greater than 25% repig-mentation, compared with 63% of the oral PUVA group. The difference was not statistically significant. Because of its efficacy and safety profile, NB-UVB has emerged as the therapy of choice for patients with moderate to severe disease.

NB-UVB phototherapy offers several advantages over oral psoralen photochemotherapy, including ease of treatment, lack of need for posttreatment ocular protection, lack of the side effects (e.g., nausea, headaches, and gastritis) associated with oral methoxsalen, and minimal phototoxic reactions. Furthermore, NB-UVB phototherapy can be used to treat young children who have extensive, progressive vitiligo. Disadvantages include the need for more treatments for maximal efficacy (three times weekly for NB-UVB, compared with twice weekly for PUVA) and the lack of data concerning the possible long-term carcinogenic effects of NB-UVB phototherapy.

Dermatologists continue to treat patients with PUVA, and it remains the gold standard despite its inherent difficulties. Patients whose vitiligo does not respond to NB-UVB phototherapy are often switched to oral PUVA.

Repigmentation occurs gradually and requires many treatments: 16 to 24 treatments are usually needed for new pigment to become evident. In general, maximal repigmentation involves 6 to 12 months of NB-UVB or PUVA therapy.

Laser therapy The excimer laser (308 nm UVB), recently approved by the FDA for treatment of psoriasis, also shows promise as a therapy for vitiligo.62,63 This laser can be used as monotherapy or in combination with other modalities. Laser therapy targets the lesional area and theoretically reduces UV exposure. In addition, because the laser provides a focused, high-intensity dose of NB-UVB, treatment duration, in theory, may be reduced. Long-term, controlled studies are needed to further define the efficacy, risks, and benefits of the excimer laser for treatment of vitiligo.

Pseudocatalase The beneficial effects of pseudocatalase and calcium applied twice daily and UVB exposure twice weekly have also been reported. The rationale for this therapy is derived from previous studies that demonstrated aberrant catalase and calcium homeostasis in patients.

Vitamins Preliminary open-label studies have documented stabilization and repigmentation in vitiligo patients treated with high-dose vitamin supplementation, including daily doses of ascorbic acid (1,000 mg), vitamin B12 (1,000 ^g), and folic acid (1 to 5 mg).57

Topical immunomodulators Abnormalities of both humoral and cell-mediated immunity have been well documented in patients with vitiligo,47-52 which explains the apparent efficacy of several immunomodulators for this disease. Preliminary investigations have reported repigmentation of vitiliginous lesions with isoprinosine, levamisole, suplatast tosilate, and cyclosporine.

Tacrolimus ointment is a novel topical immunomodulatory drug for treatment of adult and pediatric atopic dermatitis. Tacrolimus exerts its therapeutic effect via inhibition of the production of proinflammatory cytokines. Moderate to excellent repigmentation was reported in five of six patients treated with tacrolimus. Patients ranged in age from 6 to 32 years. Repigmen-tation responses did not correlate with disease duration.58, 65

Calcipotriol Several studies have documented the efficacy of calcipotriol for repigmentation of vitiligo. Used in combination with UV exposure, calcipotriol was well tolerated and effective in both children and adults.58 Melanocytes are thought to express 1a,25-dihydroxyvitamin D3 receptors, which may play a role in stimulating melanogenesis.

Depigmentation Since the 1950s, monobenzylether of hy-droquinone (MBEH, or monobenzene) has been used as a depig-menting agent for patients with extensive vitiligo. In general, MBEH causes permanent destruction of melanocytes and induces depigmentation locally and remotely from the sites of application. Hence, the use of MBEH for other disorders of pigmentation is contraindicated.

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 repigmenta-tion therapies.55,58 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 suppression of lymphoprolif-erative responses.

Surgical Treatment

Surgical treatment is appropriate for patients with localized, stable areas of vitiligo that have been recalcitrant to medical treat-ment.60 Such approaches are contraindicated in patients with keloids or hypertrophic scars. Techniques for surgical grafting include suction blister grafts, punch grafts, sheet grafts, pure melan-ocyte cultures, and cocultures of melanocytes and keratinocytes. These techniques are indeed beneficial for localized lesions.

Micropigmentation is often associated with the induction of koebnerization; therefore, its use should be limited to treatment of mucous membrane lesions.

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