Chapter 75. Hypomelanoses and Hypermelanoses

Pigmentation disorders of the skin can either be hypomelanotic, hypermelanotic, or may present with a pattern of mixed hypo- and hypermelanosis. The diagnosis of these disorders can be quite challenging. An algorithmic approach based on clinical features and history of pigmentary disorders is used throughout this chapter and serves as a guide for the clinician’ diagnosis and treatment (eFigs. 75-0.1 and 75-0.2) (Table 75-1, eTable 75-1.1).

Generalized hypopigmentation, including the various defects, classified as “albinism” has been discussed in Chapters 73 and 74. Localized forms of hypomelanosis can be related to defects in melanocyte precursor migration and disordered pigment transfer between melanocytes and keratinocytes, and as a result of postinflammatory changes.

Congenital Hypomelanosis

Some genetic disorders with reduced skin and hair pigmentation are caused by impaired melanocyte migration/differentiation or melanosome abnormalities.1 Piebaldism, Waardenburg syndrome, and Tietze syndrome, characterized by a localized absence of melanocytes resulting in “white-patch” patterns, belong to the first group whereas oculocutaneous albinism (OCA), Griscelli syndrome (GS), Elejalde syndrome (ES), Chédiak–Higashi syndrome (CHS), and Hermansky–Pudlak syndrome (HPS) belong to the second group. OCA, CHS, and HPS are discussed in Chapter 73; GS and ES are discussed here. They are rare autosomal recessive disorders with abnormal biogenesis or transport of “lysosome-related organelles” (a group of specialized cytoplasmic organelles including melanosomes, platelet dense bodies, and lymphocyte lytic granules).2 GS, ES, and CHS are termed “silvery hair syndromes” because hair of these patients has a particular silver–gray hue.3

Griscelli Syndrome

Three types of GS [GS types I–III (GS1–3)] are known. The phenotype of the patients is characterized by various degrees of skin hypopigmentation and hair with a silvery shine (Fig. 75-1), usually lighter than in unaffected family members. Furthermore, neurological signs and symptoms and/or immunologic impairment with “accelerated phases” of uncontrolled lymphocyte and macrophage activation with lymphohistiocytic infiltration of the central nervous system (CNS) are associated.4 This lymphoproliferative syndrome is similar to that observed in, for example, virus-associated hemophagocytic syndrome.5

Briefly, patients with GS type I (GS1) are characterized by primary and severe neurological symptoms occurring early in life or even at birth without signs of an accelerated phase. These symptoms can include seizures, spasticity, psychomotor retardation, peripheral facial palsy, hemiparesis, encephalopathy, and hypotonia. CNS disorder is pertinent and never regresses with time.

Immunological and hematological manifestations are only observed in GS type II (GS2) and include: anemia, neutropenia, and lack of natural killer cell function, with development of an accelerated phase of the disease with fever, jaundice, hepatosplenomegaly, lymphadenopathy, pancytopenia, and generalized lymphohistiocytic infiltrates of various organs, including the CNS. Onset of the accelerated phase seems to be associated with viral or bacterial infections. When a remission occurs, recurrent accelerated phases with increasing severity will be observed.

Neurological problems may also occur in GS2 patients and are related to lymphocyte infiltration of the CNS. Associated symptoms are, for example, hyperreflexia, seizures, signs of intracranial hypertension (e.g., vomiting), hypertonia, nystagmus, and ataxia. Psychomotor development is normal at onset, and regression of CNS signs, at least in part, can be observed during remission, although some sequelae may be irreversible. Skin hypopigmentation and silvery-grey hair in Griscelli patients are not caused by deficient melanosome biogenesis but by impaired intramelanocytic melanosome transport. Murine models with autosomal recessive mutations on the dilute (d), ashen (ash), and leaden (ln) locus present a phenotype close to that of their human GS counterparts.6 These loci respectively encode three molecules, myosin Va, Rab27a, and melanophilin (Mlph) that act as a tripartite complex linking the melanosome to subcortical actin. When MYO5A (GS1), RAB27A (GS2), or MLPH (GS3) is mutated in human melanocytes, the tripartite complex fails to form and melanosomes can no longer be tethered near the plasma membrane for transfer to keratinocytes, leading to a pigmentary defect.7

The prognosis for patients with GS is generally bad. They usually die in the first or second decade of their life if accelerated phases are not treated adequately. As for GS2 therapy, allogeneic bone marrow transplantation has appeared to be successful in some cases, especially when carried out at an early age.8–11 Palliative therapy consists of suppressing the accelerated phases with immunosuppressive therapy (high-dose corticosteroids, cyclosporine) and chemotherapeutic agents (methotrexate, etoposide, cytosine arabinoside). For GS1 there is no therapy. Palliation consists of treating infections with antibiotics.12

The hematologic, immunologic, and neurologic findings in GS1–3 presumably relate to organelle transport difficulties in the respective organ systems.

Griscelli Syndrome Type I [Online Mendelian Inheritance in Man (OMIM #214450)]

Griscelli Syndrome Type II (OMIM #607624)

Griscelli Syndrome Type III (GS3)

Elejalde Syndrome (OMIM #256710)

ES, also referred to as neuroectodermal melanolysosomal disease, is another autosomal recessive pigment mutation with silvery hair, pigment abnormalities, and severe CNS dysfunction21,22 similar to those of GS1. ES patients do not manifest the hemophagocytic syndrome or immunological impairment associated with GS2.23,24

Certain patients with ES have clinical and histologic features suggestive of GS1, indicating that these are other cases of MYO5A mutations.25,26 Further work will be required to define the molecular basis of ES and to group all patients with these rare disorders correctly.

Acquired Localized Hypomelanosis

Pityriasis Versicolor

(See Chapter 189).

Pityriasis versicolor is characterized by slightly scaling macules that can either be hypopigmented, pink or salmon-colored, or hyperpigmented (Fig. 75-2); variants with red and black macules have also been described. The prevalence of pityriasis versicolor is very high in hot and humid climates.

This superficial mycosis is caused by Malassezia species of which M. globosa, M. sympodialis, and M. Furfur are most frequently identified in lesional scales. M. Furfur cultures produce a wide range of fluorochromes and pigments that appear to lead to depigmentation, high resistance to ultraviolet (UV)-induced tanning, and lack of inflammation observed in pityriasis versicolor.27 In approximately one out of three patients, a yellow–green fluorescence is visible using Wood's light. It should be differentiated from the nonscaling depigmented lesions of vitiligo that frequently affect hands and feet, whereas pityriasis versicolor is mainly located on the trunk. The slightly scaling patches of pityriasis alba (PA) usually occur on the face and limbs and are nonfluorescent. Many local and systemic antifungal preparations are effective but relapses often occur.28,29

Pigmentary Demarcation Lines

Originally described in Japanese patients as a line present on upper and lower extremities corresponding to a border of transition between the more deeply pigmented skin of the outer (dorsal) surfaces and the lighter inner (ventral) surfaces, the concept of pigmentary demarcation lines was expanded to include five specific patterns, labeled A–E, with A: upper anterolateral arms, across pectoral area (Fig. 75-3), B: posteromedial portion of lower limb, C: vertical hypopigmented line in pre- and parasternal area, D: posteromedial area of spine, and E: bilateral aspect of chest, marking from midthird of clavicle to periareolar skin. In a population survey of black and white patients it was determined that these lines appeared in early childhood. They are present in the majority of female black adults, with types A and B being most prevalent. Seventy-five percent of black adult males had at least one type of pigmentary demarcation line, with type C the most prevalent. Fifteen percent of white female adults had at least one line, and 14% of black women saw type B lines appearing during pregnancy.30 The lines of pigmentation are often called Futcher's lines in the United States.

The pathogenesis of pigmentary demarcation lines is uncertain. Some authors believe that these lines coincide with lines of Blaschko and are secondary to a form of pigmentary mosaicism. Others suggest that there is no true genetic difference but hypothesize that the difference between cells on the dark, posterior side versus the light, anterior side are due to the normal function of genes, such as the agouti locus.31

According to some reports, pigmentary demarcation lines do not follow lines of Blaschko but have a pattern similar to lines of Voigt, which separate dermatomes arising from nonconsecutive dorsal roots. The difference in melanogenesis would be explained by a strict territorial control by different homeobox genes during development.32

Pityriasis Alba

PA is a common benign condition mainly affecting the head and neck region of preadolescent children. Although the disease is more noticed in darker skin types, there is no predilection for either sex or skin type. The etiology and pathogenesis remain poorly understood. PA is widely understood to represent mild atopic dermatitis. Unprotected sun exposure, frequent bathing, and hot baths are strongly related to the development of PA. Lower serum levels of copper, a cofactor for tyrosinase, could also play a role in the pathogenesis of this condition.

PA may present as a pink patch with an elevated border, fading after several weeks into a paler spot covered with powdery white scale (Fig. 75-4). The lesions progress to nonscaly hypopigmented macules persisting for months or years. The three stages may occur simultaneously.

Histologically, there is markedly reduced pigment in the epidermis of lesional skin, but no significant difference in melanocyte count was found between lesional and normal skin. Ultrastructurally, degenerative changes in melanocytes and a reduced number of melanosmes within keratinocytes were seen.33 Extensive PA often also involves the inferior torso in a symmetric pattern. The lack of a preceding inflammatory phase and spongiosis differentiate extensive PA from the classic form. This particular form of PA may overlap with progressive macular hypomelanosis (PMH), a condition mainly described in young female adults, characterized by relapsing hypopigmented, nonscaling patches involving the back, particularly after summer.34

Pigmenting PA is a variant associating classic PA with a superficial dermatophyte infection, almost always affecting the face. It is clinically characterized by a bluish hyperpigmentation, attributed to melanin deposits in the dermis surrounded by a hypopigmented scaly area. One-third of patients have concurrent classic PA.

Differential diagnosis includes any localized form of hypopigmentation, especially inflammatory skin conditions associated with postinflammatory hypopigmentation, such as psoriasis, but also with fungal infection, nevus depigmentosus, nevus anemicus, tuberous sclerosis, mycosis fungoides (MF), or vitiligo.

The disease is self-limited and treatment is often not completely successful. Topical steroids and emollients are helpful. Topical tretinoin has also been used with success, but may be irritating. Extensive PA and pigmenting PA have also responded to UV therapy and oral antifungals, respectively. Supportive measures such as decreasing sun exposure, use of sunscreens, and reducing frequency and temperature of baths should be recommended.

The pathogenesis of pigment loss is unclear.34–38

Sarcoidosis

(See Chapter 152).

Hypopigmentation is a rare manifestation of sarcoidosis. Hypopigmented macular lesions scattered over the trunk and extremities but also papular or nodular lesions may be present. The presence of noncaseating dermal granulomas, usually most evident in biopsies of indurated lesions, reinforce the diagnosis. A reduction in melanin content of the epidermis with preservation of melanocytes has been demonstrated.

The pathogenesis of pigment loss is unclear.39–41

Scleroderma

(See Chapter 157).

Hypopigmentation has been described as a pigmentary change in morphea (localized scleroderma) (Fig. 75-5) and scleroderma (progressive systemic sclerosis). Localized hypopigmentation and/or hyperpigmentation are seen in areas of localized sclerosis. Focal depigmentation with perifollicular hyperpigmentation (“salt and pepper pigmentation”) especially on upper trunk and extremities, mimicking vitiligo, is reported in up to 30% of patients with scleroderma. The coexistence of scleroderma/morphea and vitiligo has also been reported.42–44

Lupus Erythematosus

(See Chapter 155).

Pigment alterations are frequently seen in discoid lupus erythematosus. Hypopigmented patches result from interface dermatitis with destruction of the epidermal basal layer containing melanocytes. “Burned out” lesions are atrophic and depigmented and may be surrounded by hyperpigmentation. Cutaneous depigmentation is also reported in systemic lupus erythematosus, usually localized to inflammatory skin lesions. Biopsy specimens in depigmented skin feature degeneration of the basal layer with epidermal atrophy, a variable number of melanocytes, and pigmentary incontinence in the superficial dermis. The mechanism of hypopigmentation in lupus is not known but could be postinflammatory or cicatricial.

Vitiligo has also been reported in association with lupus erythematosus.45 A shared genetic predisposition may explain the association of these two autoimmune disorders.46

Mycosis Fungoides

(See Chapter 146).

MF, the most common type of cutaneous T-cell lymphoma, is clinically characterized by three cutaneous phases: (1) the patch phase, (2) the plaque phase, and (3) the tumor phase. Several pigmentary changes have been described in MF.

In poikiloderma vasculare atrophicans, a variant of the patch stage, mottled pigmentation, atrophy and telangiectasia of the involved skin are observed. A mix of hyper- and hypopigmentation may remain after regression of the skin lesions following treatment.

Hypopigmented MF is an uncommon variant of this lymphoma. It mainly develops before the fourth decade, predominantly in juvenile-onset cases and in dark-skinned individuals, without sex predilection. Irregular hypopigmented patches with variably distinct borders are preferentially located on trunk and extremities. Erythema, scaling, and infiltration may be present. A central area of normal pigmentation may be observed. These lesions may also be associated with the more typical lesions of the three cutaneous phases. The hypopigmentation develops without preceding skin changes and occasionally complete depigmentation is observed.

Histopathologically, hypopigmented MF is characterized by minimal dermal involvement, lack of epidermal atrophy, and moderate to marked exocytosis. Pigment incontinence and decrease or absence of melanin may be observed. Infiltrating lymphocytes often have a T-suppressor cell CD8+ phenotype, but a CD4+ phenotype has also been reported.

Electron microscopy may disclose degenerative changes in melanocytes. Melanocytes may be incompletely melanized or occasionally reduced in number. The number of melanosomes within keratinocytes is normal or decreased and melanin-containing macrophages can be observed in the papillary dermis. T-cell receptor gene rearrangement analysis may help to confirm the diagnosis but is often negative, as in early stage MF.

The pathogenesis of hypopigmented MF is not clear. At least in cases showing a CD8+ phenotype, hypopigmentation could be due to the melanocytotoxic effect of nonneoplastic CD8+ lymphocytes, as hypothesized in vitiligo.

Hypopigmented MF responds well to treatment, particularly psoralen and UVA light (PUVA) or narrowband UVB therapy. It has a relatively benign course, although recurrences are common. Hypopigmented MF should be distinguished from other causes of diffuse hypopigmentation, especially vitiligo, tinea versicolor, PA, or postinflammatory hypopigmentation.47–51

Infections

Treponematoses

(See Chapters 200 and 201).

Nonvenereal treponematoses are currently endemic in parts of Central and South America, Africa, Asia, and the Pacific Islands and can be severely disfiguring. Depigmentation is seen in several stages of yaws, bejel, and pinta. When the primary lesion of yaws disappears, a typical depigmented and pitted scar remains. In the tertiary stage of bejel, gummatous nodules develop in the skin and in other organs. Most skin lesions regress, leaving depigmented, noncontracted scars. Pinta is the only treponematosis that only affects the skin and causes pigmentary abnormalities in the first, second, and third stages of the disease. The sentinel lesion of pinta may heal at the end of the primary stage, leaving a macular dyschromia. The secondary stage is characterized by the appearance of the so-called pintids, which are initially red but often turn brown, slate-blue, gray, or black. This stage can last several years, leading to a mix of depigmentation and hyperpigmented lesions. Generalized pigmentary abnormalities develop during the tertiary stage. A symmetrical pattern of vitiligo-like lesions and brown, gray or blue and black lesions is seen over bony prominences (Fig. 75-6).52

Onchocerciasis

(See Chapter 207).

Several different skin manifestations can become apparent during the course of onchocerciasis. Onchocercal depigmentation or “leopard skin” is rarely associated with itch and is one of the most common skin manifestations of onchocerciasis. Hypopigmented patches with perifollicular spots of normally pigmented skin, typically occur symmetrically on the pretibial area of older people in endemic areas.53 (Fig. 75-7).

Post-Kala-Azar Dermal Leishmaniasis (PKDL)

(See Chapter 206).

Post-kala-azar dermal leishmaniasis develops in insufficiently treated kala-azar or visceral leishmaniasis, which is caused by Leishmani. donovani. Skin manifestations of PKDL are nodules and plaques, facial erythema, and hypopigmented macules. Nodules and plaques typically develop around the mouth and spread to the face, arms and chest, but the macules may occur more generalized over the whole body. Mild disease can resolve spontaneously, but severe forms require systemic treatment.54,55

Leprosy

(See Chapter 186).

The presence of a hypopigmented lesion with reduced sensation is the hallmark of leprosy and is one of the diagnostic criteria (Fig. 75-8). Indeterminate leprosy, frequently the first manifestation of leprosy, is characterized by the presence of a few such lesions. Tuberculoid leprosy usually manifests as a limited number of well-defined, depressed, hairless lesions occur that appear hypopigmented in black patients and erythematous in white patients.56

Chemical and Pharmacologic Agents

The potential for chemicals to induce hypopigmentation was discovered in the first half of the twentieth century. Leukoderma was noticed in rubber workers exposed to the monobenzylether of hydroquinone (MBEH), a frequently used antioxidant in the rubber industry. Since then, depigmenting properties have been attributed to many chemicals and new therapeutic depigmenting agents have been developed.57

Occupational exposure to chemicals that have a destructive effect on melanocytes can result in chemical leukoderma. Agents such as para-tertiary butylphenol, para-tertiary butyl catechol, MBEH, and hydroquinone can cause permanent depigmentation. The depigmentation caused by chemicals is difficult to distinguish from idiopathic vitiligo. The former usually starts at the hands and forearms, presumptive sites of contact, but depigmentation at a distance is also possible (Fig. 75-9). Chemical leukoderma spreads by coalescence of small macules, whereas the sudden appearance of large patches with perifollicular sparing is more suggestive of vitiligo. Chemical leukoderma is very likely if several exposed workers develop depigmentation. However, not all exposed individuals develop leukoderma and it is hypothesized that the individual susceptibility is variable.57,58

Chemicals are also employed therapeutically or cosmetically to lighten skin color. There are three main mechanisms of action for bleaching agents. Some act before melanin is synthesized by inhibiting tyrosinase transcription and glycosylation. Other agents act during melanin synthesis by inhibiting enzymes such as tyrosinase or peroxidase or act as reducing agents or radical oxygen species scavengers. Finally, some agents act after melanin synthesis because they are responsible for tyrosinase degradation, inhibition of melanosome transfer, or acceleration of skin turnover, leading to depigmentation.59

MBEH was used as a lightening agent until its ability to cause total permanent and often confetti-like depigmentation became apparent. It should be used only to produce total depigmentation in patients with diffuse vitiligo. A formulation with 20% MBEH is usually prescribed for that purpose. Hydroquinone is one of the most popular depigmenting substances and is frequently used for the treatment of melasma in concentrations between 2% and 5%. Concentrations higher than 5% incur a risk of permanent depigmentation. Adverse effects are irritation, postinflammatory pigmentation, and exogenous ochronosis.57,59–61

Physical Agents

Heat, freezing, X-ray, ionizing radiation, UV irradiation, and laser light can cause hypopigmentation or permanent depigmentation by damaging melanocytes, leading to destruction or impaired function.62

Lichen Sclerosus

(See Chapter 65).

Lichen sclerosus typically presents as a pruritic erythematous patch in the early stage, evolving to a depigmented atrophic plaque with porcelain white appearance.

Mechanisms believed to play a role in this idiopathic leukoderma include decreased melanin production, blocked transfer of melanosomes to keratinocytes, and loss of melanocytes.

Melanoma-Associated Leukoderma

(See Chapter 124).

Regression in a primary melanoma lesion typically causes a depigmented scar-like area within the lesion.

Melanoma-associated hypo- or depigmentation, also known as leukoderma acquisitum centrifugum, can occur around the primary melanoma or metastases or at distant sites. The latter is often called vitiligo, although the resemblance is limited. Whereas vitiligo depigmentation is usually symmetric and spreads centripetally to the trunk, melanoma-associated hypo- or depigmentation tends to be extensive, patchy, and asymmetric. The lesions may be mottled (hypomelanotic) or milk white (amelanotic). In most cases, leukoderma appears simultaneously with the finding of metastases. Histologic examination of lesions shows a decrease or complete absence of melanocytes. Macromelanocytes with stubby dendrites can also be observed. Melanoma with associated leukoderma may be associated with a better survival rate than comparably advanced lesions without epidermal pigment loss. Strong evidence suggests that melanoma-associated leukoderma results from host immune reaction against the malignancy, involving humoral and cellular mechanisms. Both passive and active immunotherapeutic strategies used in the treatment of melanoma have been associated with leukoderma (Fig. 75-10).63,64

Acquired Diffuse Hypopigmentation

Nutritional disorders and endocrinopathies mainly cause hyperpigmentation. Diseases such as copper deficiency, vitamin B12 deficiency, kwashiorkor, Addison disease, hyperthyroidism, and diabetes can also be associated with hypopigmentation, but are discussed under Section “Hypermelanosis” because hyperpigmentation is their main feature.

Hypothyroidism

(See Chapter 151).

Hypothyroidism is frequently associated with cutaneous alterations. The skin is pale due to anemia and vasoconstriction. Yellowish discoloration of the palms, soles, and nasolabial folds is caused by an accumulation of carotene in the stratum corneum. The associated hypercarotinemia results from reduced capacity of the liver to convert β-carotene to vitamin A. Vitiligo has been associated with autoimmune hypothyroidism.65–67

Hypopituitarism

Panhypopituitarism results from a variety of conditions that compromise the anterior pituitary. As a consequence, release of pituitary-derived factors including melanocyte-stimulating hormone (MSH), thyroid-stimulation hormone, adrenocorticotrophic hormone, luteinizing hormone, follicle-stimulating hormone, growth hormone, and vasopressin is decreased. Due to the reduction of circulatory pituitary hormones, production of cortisol, thyroxine, estrogens, and testosterone in target organs is lowered.

Patients suffering from panhypopituitarism look pale due to anemia and decreased cutaneous blood flow. As well, generalized hypopigmentation results from decreased adrenocorticotrophic and MSH that stimulate epidermal melanogenesis.66

Hypogonadism

Castrated human males are characteristically pale and their genital skin is not hyperpigmented as in normal men. An impaired tanning response to UV radiation has been described. Administration of testosterone makes the skin turn darker and restores the tanning response.68

Selenium Deficiency

Loss of hair and skin pigmentation due to selenium deficiency has been described in children receiving long-term total parenteral nutrition. After selenium supplementation, skin and hair darken.69

Copper Deficiency

Acquired copper deficiency occurs in severely malnourished infants. Hypopigmentation of the hair is attributed to copper deficiency, presumably because tyrosinase is a copper-dependent enzyme, but as multiple nutritional deficiencies tend to coexist pathogenesis is difficult to confirm.70

Idiopathic Guttate Hypomelanosis

Idiopathic guttate hypomelanosis (IGH) is an acquired leukoderma, characterized by discrete, round, or oval porcelain-white macules of approximately 2–5-mm diameter, which increase in number with aging (Fig. 75-11). Any associated hairs often remain pigmented. Lesions are found in a photodistribution and tend to occur in chronically sun-damaged skin. They are often seen pretibially and on the forearms, although they may also arise on other sun-exposed areas, including the face, neck, and shoulders. IGH has been hypothesized to be UV-induced, although controversy exists. Some suggest that IGH may reflect the normal aging process.71

Histologically, IGH lesions are characterized by slight basket-weave hyperkeratosis with epidermal atrophy and flattening of the rete pegs. Lesions show a decrease in melanocytes and melanin content of the affected epidermis and pigment granules are irregularly distributed.

A variety of therapies with variable success are described, including cryotherapy, superficial dermabrasion, topical steroids, and topical retinoids.72,73

Leukoderma Punctata

Leukoderma punctata was first described by the development of multiple punctiform hypopigmented and achromic spots after several months of PUVA treatment.74 Later, similar cases were described after UVB therapy for psoriasis and after topical PUVA in one case of segmental vitiligo.75

Lesions are predominantly present on the extremities, upper back and chest. They are round or oval, sharply demarcated, and small (0.5–1.5 mm), without follicular distribution. Spontaneous reduction of the leukodermic lesions has been observed.74

It has been suggested that phototoxicity damage to keratinocytes and melanocytes is the etiologic factor. Leukoderma punctatum is suggested to be distinct from IGH on the basis of the clinical and histologic features. In IGH, lesions are larger and spontaneous resolution is not reported. Ultrastructurally, leukoderma punctata demonstrates slight-to-severe damage of keratinocytes and melanocytes not reported in IGH.

Canities

Hair graying or canities is a process of chronological aging and occurs regardless of gender or race.76 The age of onset, which appears to be hereditary, is usually in the fourth decade. The average age for whites is mid-30s, for Asians late 30s, and for Africans mid-40s. Premature canities (before 20s or 30s) can be associated with pernicious anemia, hyper/hypothyroidism, osteopenia, and several rare syndromes like progeria and pangeria (Werner syndrome). Graying usually appears at the temples first, then the vertex, and, finally, the occiput. Beard and body hair are affected later. Gray hairs seem to be thicker and longer than normally pigmented hairs. The perception of “gray hair” derives in large part from the admixture of pigmented and white hair, but individual hair follicles can indeed exhibit pigment dilution or suboptimal melanocyte–cortical keratinocyte interactions during the graying process.77–79 An acute episode of alopecia areata may result in a very sudden “overnight” graying (so-called canities subita) that is caused by the preferential loss of pigmented hair in this immune-mediated disorder.

Hemodialysis

Chronic hemodialysis patients frequently show disorders of skin pigmentation, primarily involving hyperpigmentation of sun-exposed body areas. Hypopigmentation of skin and hair is rather exceptional but occurs, possibly due to a disturbance of phenylalanine metabolism.

Progressive Macular Hypomelanosis

PMH is an entity that affects the trunk with nummular, hypopigmented nonscaly macules. It affects young adults, mainly women. Although described in people of mixed racial ancestry (known as Creole dyschromia),80 it is seen in all races. It can be mistaken for PA and pityriasis versicolor. Topical and systemic antifungal treatment and topical steroids are ineffective, but the disorder may resolve, sometimes temporarily, after sun exposure or phototherapy.

Acquired Diffuse Hypopigmentation with Vascular Causes

Anemia

The color of the skin is determined by several chromophores, usually predominantly melanin pigment, but the hemoglobin content of the skin also contributes to the skin color. The pale skin color observed in anemia is due to decreased levels of circulating oxyhemoglobin and is proportional to the severity of the anemia.

Bier Spots

Bier spots are small, irregular apparently hypopigmented areas, usually on arms and legs in young adults, resulting in a reticulated appearance. The surrounding skin is erythematous and blanches with pressure causing the “hypopigmented” macules to disappear. The condition is a vascular anomaly with vasoconstriction in the pale areas and venodilatation in erythematous skin.81,82

Woronoff's Ring

(See Chapter 18).

Woronoff's ring represents a blanched halo surrounding a psoriatic lesion. It is observed after UV treatment or topical steroid treatment, but may also occur in untreated psoriasis. The pathogenesis is not clear. A decreased melanin content has been found in both psoriatic and halo epidermis suggesting a true hypomelanosis. A local decreased prostaglandin synthesis with decreased vasodilatation or a diffusion of anti-inflammatory mediators from the psoriatic lesion to the halo is also postulated.

Cutaneous Edema

Cutaneous edema produces an appearance of leukoderma that is not true hypomelanosis. Decreased absorption of light, reduced capillary blood flow, and increased dermal thickness may contribute to the pale appearance of the skin.

Congenital Diffuse Hypermelanosis

Congenital Diffuse Nonfigured Hypermelanosis

Descriptions of the rare and poorly understood conditions, arterial dissection with lentigines, and progressive familial hyperpigmentation are provided within.

Arterial Dissection with Lentiginosis

Progressive Familial Hyperpigmentation

Congenital Diffuse Linear Hypermelanosis

Linear and Whorled Nevoid Hypermelanosis

Linear and whorled nevoid hypermelanosis (LWNH) is characterized by hyperpigmented macules in streaky configuration along the lines of Blaschko without preceding inflammation or atrophy.89 Similar cases have been described under different descriptive names (zosteriform hyperpigmentation, zosteriform lentiginous nevus, zebra-like hyperpigmentation). Lesions are typically located on the trunk and limbs and do not cross the midline. Face, palms, soles, eyes, and mucous membranes are spared. Kalter et al described LWNH as having onset within a few weeks of age and progression during the initial years of life.89 The pigmentation can fade gradually with increasing age. Several cases have been reported with both hyper- and hypopigmentations. Pigmentary mosaicism is a useful term to encompass all these different phenotypes.90

The presence of mosaicism has been confirmed in a few cases (mosaic trisomy 7, 14, 18, 20, and X-chromosomal mosaicism) by chromosomal analysis on lymphatic cultures or dermal fibroblasts.91

LWNH may be differentiated from incontinentia pigmenti (IP) and epidermal nevus.89

Extracutaneous abnormalities have been observed in a number of LWNH cases, including developmental and growth retardation, facial and body asymmetry, ventricular septal defect, and pseudohermaphroditism.

Histologic examination reveals increased pigmentation of the basal layer and prominence or vacuolization of melanocytes. Pigment incontinence is usually but not always absent.92

Incontinentia Pigmenti

IP, also known as Bloch–Sulzberger syndrome, was first described by Garrod et al in 1906. It is an X-linked, dominantly inherited disorder, reported primarily in females, and believed to be embryonic lethal in the majority of males. In most cases, IP is due to a mutation in the gene NEMO [nuclear factor κB (NF-κB) essential modulator] on the X chromosome at Xq28.93–96 In IP females, inactivation of one of the two X chromosomes through a process termed lyonization occurs during embryogenesis. Epidermal cells expressing the defective NEMO gene give rise to typical skin lesions along the lines of Blaschko, reflecting the embryonic migration path of the affected keratinocytes. Lesions usually proceed through four cutaneous stages, sometimes with some overlap: (1) vesicular stage (from birth or shortly thereafter), (2) verrucous stage (between 2 and 8 weeks of age), (3) hyperpigmented stage (several months of age into adulthood), followed by (4) hypopigmentation stage (from infancy through adulthood) (Fig. 75-12). A significant percentage of IP patients have ocular, dental, skeletal, and CNS anomalies.97

The cutaneous lesions in the first stage represent the population of NEMO-deficient cells that fail to activate NF-κB, leading to apoptosis, as NF-κB normally protects against tumor necrosis factor-induced apoptosis. The number of NEMO-deficient cells decreases secondary to apoptosis and is replaced by cells expressing the normal allele. Subsequently, the inflammatory and vesicular stage ends. The hyperproliferation in the second stage is likely due to compensatory proliferation of normal NEMO keratinocytes. Hyperpigmentation in the third stage results from incontinence of melanin pigment from the destroyed epidermis into the dermis.

The hyperpigmentation appears in streaks and whorls along the lines of Blaschko and is usually most pronounced on the trunk, but can also appear on the extremities. The degree of hyperpigmentation varies among individuals. Histologically, the areas of pigmentation show many melanin-laden melanophages, extensive deposits of melanin in the basal cell layer and dermis. There is vacuolization and degeneration in the epidermal basal cell layer. Usually, the hyperpigmentation fades gradually after several years and the skin can become hypopigmented (stage 4), which represents postinflammatory dermal scarring. The hypopigmentation stage is characterized by linear, atrophic, hairless scars following the Blaschko's lines.

Histologically, the number of melanocytes seems to be normal, although a reduced number of melanocytes also has been reported. The epidermis is thinner and there is an absence or reduction of skin appendages in the dermis that may contribute to the impression of hypopigmentation.98

A beneficial effect of topical steroids and topical tacrolimus in the vesicular stage has been described.99,100

Congenital Diffuse Reticular Hypermelanosis

Dyskeratosis Congenita

Dyskeratosis congenital (DKC) or Zinnser–Engmann–Cole syndrome is characterized by reticulate skin pigmentation, nail atrophy, leukoplakia, and bone marrow failure. Bone marrow failure and malignancy develop in the second and third decades. In all characterized cases of DKC, the causative mutations are present in components of the telomerase complex. Rapidly dividing somatic cells express low but detectable levels of telomerase activity that slows the otherwise progressive telomere shortening that occurs with each cycle of DNA replication and eventually leads to cellular senescence (permanent loss of proliferative capacity). It is now thought that DKC is due to defective telomere maintenance, limiting the proliferative capacity of hematopoietic and epithelial cells. Increased melanin synthesis is now recognized to occur in senescent melanocytes, likely accounting for the pigmentary phenotype of DKC; and critically short telomeres may force cells into “replicative crisis,” at which time activation of an alternative “ALT” mechanism for lengthening telomeres in the absence of telomerase may lead to development of malignancies. The finding of shortened telomeres in DKC was indeed the first evidence of the role of telomeres in cell biology (cellular aging).101

X-linked DKC is caused by mutations in the DKC1 gene located at Xq28, encoding for dyskerin. Females carrying one mutated allele are protected by expression of normal telomerase on the unaffected allele. In autosomal dominant DKC the majority of cases are due to mutations in TERC, the RNA component of the telomerase complex. TERT (telomerase reverse transcriptase) is affected much less often in autosomal dominant DKC. The autosomal dominant form has the better prognosis, presumably because some telomerase activity is preserved, due to the presence of an unaffected allele.

In the autosomal recessive form of DKC, mutations in telomerase-associated proteins such as NOP10, NHP2, and TINF2 are involved.102–104 Skin biopsy of hyperpigmented skin shows nonspecific changes, including epidermal atrophy, a chronic inflammatory infiltrate with numerous melanophages in the upper dermis. DKC may be confused with Fanconi's syndrome, characterized by short stature, hypoplastic or aplastic thumbs, and a reduced number of carpal bones. Here, there is a patchy hyperpigmentation of the trunk, neck, groin, and axillary region that manifests itself earlier than in DKC, i.e., in the first few years of life.

For a discussion of Naegeli–Franceschetti–Jadassohn syndrome, dermatopathia pigmentosa reticularis, Dowling–Degos disease, Galli–Galli disease, Kitamura reticular acropigmentation, Haber's syndrome, and Partington syndrome, see below.

Naegeli–Franceschetti–Jadassohn Syndrome

Dermatopathia Pigmentosa Reticularis

Dowling–Degos Disease

Galli–Galli Disease

Kitamura Reticular Acropigmentation

Haber's Syndrome

Congenital Circumscribed Hypermelanosis

Congenital Circumscribed Hypermelanosis with Dermal Melanocytosis

Dermal melanocytoses or dermal dendritic melanocytic proliferations are characterized by the presence of melanin-producing dendritic melanocytes in the dermis. They include the nevus of Ito, nevus of Ota, and Mongolian spot and dermal melanocyte hamartoma (Table 75-1). Associated vascular malformation has been described in phakomatosis pigmentovascularis (Port-wine stain type, Klippel–Trenaunay or Sturge–Weber syndrome).111

Nevus of Ota

Ota's nevus (nevus fuscocaeruleus ophthalmomaxillaris) was first described by Ota in 1939.112 It is characterized by blue–black or gray–brown dermal melanocytic pigmentation and typically occurs in areas innervated by the first and second branches of the trigeminal nerve. Mucosal pigmentation may occur involving conjunctiva, sclera, and tympanic membrane (oculodermal melanocytosis), (Fig. 75-13) or other sites. It is most frequently seen in the Asian population, has a female predominance, and is usually congenital, although appearance in early childhood or at puberty has been described. Nevus of Ota is now subclassified as mild (type 1), moderate (type 2), intensive (type 3), and bilateral (type 4). Bilateral cases should be differentiated from Hori nevus, which is acquired, does not manifest mucosal involvement and is less pigmented (see Table 75-1).113

Malignant melanoma may rarely develop in a nevus of Ota. This necessitates careful follow-up of the lesion, especially if it occurs in Caucasian patients, in whom malignant degeneration seems to be more frequent. Malignant melanocytic tumors in association with nevus of Ota have been shown to arise in the chorioidea, brain, orbit, iris, ciliary body, and optic nerve.114,115 In addition, association with ipsilateral glaucoma and intracranial melanocytosis has been described.116

Nevus of Ito

Nevus of Ito is a congenital dermal melanocytosis first described by Ito in 1954 as nevus fuscocaeruleus acromiodeltoideus.117 It can be considered as a variant of nevus of Ota but with involvement of the acromioclavicular and deltoideal region. Clinical, demographical, and histological characteristics are similar to nevus of Ota and both lesions can occur simultaneously (see Table 75-1).

Mongolian Spots

Mongolian spots are congenital, benign hyperpigmentations preferentially occurring in the African, Asian, and Hispanic population and only rarely seen in Caucasians.118 They occur in both sexes but with a slight male predominance,119 usually in the sacral area. (Fig. 75-14) They can also be found in the gluteal and lumbar region and on the thorax, abdomen, arms, legs, and shoulders. In most cases Mongolian spots spontaneously regress during childhood, but persistence into adulthood has been described.120 Histologically, these macules consist of spindle-shaped melanocytes in the lower dermis that have failed to migrate to the dermal–epidermal junction during fetal life. Several cases are described with extensive Mongolian spots involving large areas of the trunk and extremities, associated with inborn errors of metabolism such as GM1 gangliosidosis and mucopolysaccharidosis.121,122 Laser treatment in childhood or adolescence can give favorable results with sacral Mongolians spots being more laser-resistant than extrasacral ones.

Dermal Melanocyte Hamartoma

Dermal melanocyte hamartoma is a distinctive form of congenital dermal melanocytosis first described by Burkhart et al in 1981.123 Gray–blue pigmentation, caused by melanocytes residing in the dermis, occurs in a dermatomal pattern.

Congenital Circumscribed Hypermelanosis with Lentiginosis

Familial Lentiginosis Syndromes

Familial lentiginosis syndromes are characterized by the presence of lentigine-circumscribed brown macules (usually < 5 mm in diameter), which display an increased number of melanocytes in the epidermis (epidermal melanocytic hypermelanosis) and an increased incidence of cardiovascular, endocrine, or gastrointestinal neoplasias. They include Carney complex, Peutz–Jeghers syndrome (PJS), LEOPARD syndrome (LS) (lentigines, electrocardiogram conduction defects, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness), arterial dissection and lentiginosis, Laugier–Hunziker disease, familial benign lentiginosis, Bannayan–Ruvalcaba–Riley syndrome (BRSS), centrofacial lentiginosis, and segmental and agminated lentiginosis.124 (See Fig. 75-16.) Genetic loci and gene mutations have been identified for Carney complex, PJS, and BRRS.

Peutz–Jeghers Syndrome

PJS is an autosomal dominant cancer predisposition syndrome first described by Peutz (1921) and Jeghers (1949).125 Mucocutaneous pigmentation and intestinal hamartomatous polyposis are hallmarks of the disease. (See Fig. 75-15.) The pigmentary lesions resemble those of Carney complex, with small hyperpigmented macules typically appearing in childhood (not present at birth) on the lips and buccal mucosa, but they may also involve the eyelids, hands, and feet.124

The most common malignancies associated with PJS are gastrointestinal (small intestine, colorectal, stomach, pancreas). In addition, nongastrointestinal neoplasms such as breast, cervix, and endocrine tumors (thyroid, testicular, ovarian) have been described. More than half of all cases of PJS can be attributed to a mutation in the serine/threonine kinase 11 (STK 11 or LKB 1) gene,126 which is therefore thought to act as a tumor-suppressor gene. Close surveillance of PJS patients from a young age is warranted.

LEOPARD Syndrome

LS is an autosomal dominant genodermatosis124 The characteristic lentigines usually develop during childhood and in the first months of life. Clinical diagnosis is primarily based on the typical facial features and the presence of hypertrophic cardiomyopathy and/or café-au-lait macules (CALMs). The disorder is caused by mutations in the PTPN11 gene, coding for the protein tyrosine phosphatase SHP-2 and situated on chromosome 12. LS is allelic to Noonan syndrome and shares several clinical features (Fig. 75-16).127 Recently missense mutations in the RAF1 gene were found in two LS patients in whom no PTPN11 mutations could be discovered.128

For Carney complex, BRSS, and centrofacial lentiginosis.

Carney Complex

Bannayan–Riley–Ruvalcaba Syndrome

Centrofacial Lentiginosis

Congenital Circumscribed Hypermelanosis with Café-Au-Lait Macules

CALMs consist of sharply bordered hyperpigmented patches of skin, varying in size from 0.5 cm to more than 20.0 cm. They are often present at birth or appear in the early months of life. Between 0.3% and 18% of all newborns display isolated CALMs.137 Histologically, isolated CALMs show a normal number of melanocytes but increased epidermal melanin (epidermal melanotic hypermelanosis). Multiple CALMs are well-known markers for several multisystem disorders.

Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) was first recognized by Friedrich von Recklinghausen in 1882 and is therefore also called von Recklinghausen's disease (see Chapter 141 for detailed discussions).

NF1 is an autosomal dominant disease caused by a mutation in the NF1 gene, situated on chromosome 17q11.2 and encoding the neurofibromin protein. Neurofibromin takes part in several signaling pathways and exhibits multiple isoforms through alternative splicing mechanisms. The most important neurofibromin function involves downregulation of the Ras signal transduction pathway and it is, therefore, considered a tumor-suppressor gene.124,138

NF1 has been considered as a neurocristopathy and is characterized by a number of cutaneous and noncutaneous pigment cell-related manifestations such as CALMs, intertriginous freckling, and iris Lisch nodules.138,139 In 1987, the US National Institutes of Health Consensus Development Conference established clinical diagnostic criteria for NF1 (see Chapter 141). The presence of six or more CALMs greater than 5 mm in greatest diameter in prepubertal individuals or greater than 15 mm after puberty is one of the hallmarks of the disease. NF1-associated CALMs, contrary to isolated CALMs, contain a significantly increased number of melanocytes in the epidermis.140 Intertriginous freckles, pathognomic for NF1, also display increased numbers of epidermal melanocytes, which differentiates them from ordinary freckles (ephelides). (See eFig. 75-16.1.)

Mccune–Albright Syndrome

McCune–Albright syndrome (MAS) was first described by McCune (1936) and Albright (1937) as a triad of poly/monostotic fibrous dysplasia, CALMs, and hyperfunctioning endocrinopathies, including precocious puberty, hyperthyroidism, hypercortisolism, hypersomatotropism, and hypophosphatemic rickets.141,142 The CALMs are fewer in number and have more irregular borders than those seen in NF1. They are classically demarcated at the midline. MAS is caused by a postzygotic activating mutation of the α subunit of the cAMP-regulating Gs protein. Consequently, a mosaic distribution of MAS cells bears the constitutively active adenylate cyclase.143

For Bloom, Watson, and Silver–Russel syndromes, see below.

Bloom Syndrome

Watson Syndrome

Silver–Russell Syndrome

Nevus Spilus

Acquired Diffuse Nonfigured Hypermelanosis

Endocrinopathies

Addison's Disease

(See Chapter 151).

Addison's disease is a clinical syndrome characterized by salt-wasting and skin hyperpigmentation, associated with adrenal deficiency with inadequate secretion of corticosteroid and androgenic hormones, leading to compensatory overproduction of adrenocorticotropic hormone (ACTH) secretion by the pituitary gland.157

In the developed world, Addison's disease is usually autoimmune in etiology.

Hyperpigmentation is the most striking cutaneous sign of patients with chronic Addison's disease and is the consequence of ACTH binding to the melanocortin-1 receptor (see Chapter 72). The hyperpigmentation is diffuse and occurs preferentially on sun-exposed areas (face, neck, hands), on sites of trauma, scars, or chronic pressure (knees, spine, knuckles, elbows, shoulders), in the palmar creases, and on nipples, areolae, axillae, perineum, and genitalia.157

Cushing's Syndrome

(See Chapter 151).

Cushing syndrome is characterized by clinical signs and symptoms due to chronic glucocorticoid excess.

Various degrees of hyperpigmentation can be seen, usually most severe in patients with the ectopic ACTH syndrome. As in Addison disease, hyperpigmentation is generalized, but most prominent in sun-exposed areas such as face, neck, and dorsal hands, as well as in areas subject to chronic mild trauma or pressure (shoulders, midriff, waist, elbows, knuckles, spine, knees) and on mucosal surfaces.158,159

Nelson's Syndrome

Nelson's syndrome comprises an enlarging pituitary tumor associated with elevated fasting plasma ACTH levels, hyperpigmentation, and neuro-ophthalmological symptoms in patients with Cushing's disease after bilateral adrenalectomy and inadequate hormonal replacement.160

Pheochromocytoma

Pheochromocytoma is a tumor derived from chromaffin cells of the adrenal medulla with associated excessive production of catecholamines. Pallor of the face due to vasoconstriction may be observed. In contrast, addisonian-like hyperpigmentation has been reported and is probably due to ectopic ACTH and MSH production by the tumor. Pigmentation rapidly fades after surgical treatment.161

Carcinoid Syndrome

Diffuse hyperpigmentation due to MSH-producing tumors, such as gastric or thymic carcinoid tumors, have been described in carcinoid syndrome. Carcinoid syndrome can also be accompanied by a pellagra-like rash occurring on light-exposed skin. The rash is secondary to a tryptophan deficiency, as a large amount of dietary tryptophan is diverted to serotonin by the tumor.

Hyperthyroidism

(See Chapter 151).

Thyrotoxicosis has multiple causes. The most common cause is Grave's disease, characterized by circulating antibodies against thyroid-stimulating hormone receptors.

The occurrence of hyperpigmentation in thyrotoxic patients has been estimated from 2% to as high as 40% in large series. The increased cutaneous pigmentation can be localized or generalized and is more common in dark-skinned people. The distribution of hyperpigmentation is often similar to that in Addison's disease with pigment deposition in the creases of the palms and soles. However, several features distinct from that of Addison's disease have been noted. Involvement of the mucous membranes is uncommon and pigmentation of the nipples and genital skin is less striking. Hyperpigmentation associated with thyrotoxicosis is thought to be due to an increased release of pituitary ACTH, compensating for accelerated cortisol degradation. The response of hyperpigmentation to therapy for the hyperthyroidism is reported to be poor.162–164 Autoimmune Grave's disease has been reported in association with vitiligo.

Melasma

Melasma is a common hypermelanosis that typically occurs on sun-exposed areas in the face. The pathogenesis is poorly understood, but genetic and hormonal influences in combination with UV radiation are important. Specific precipitants include birth-control pills, estrogen replacement therapy, mild ovarian or thyroid dysfunction, ovarian tumors, cosmetics, nutrition, phototoxic and photoallergic medications, phototoxic drugs, and medication for epilepsy.

Melasma is rarely reported before puberty and is far more common in women, especially those of reproductive age and often begins or is exacerbated during pregnancy, explaining the common appellation “mask of pregnancy.” People with darker skin types are more frequently affected. The lesions are brownish macules with irregular borders and symmetric, photodistribution usually on the face (Fig. 75-17), often coalescing in a reticular pattern. Sun exposure intensifies the lesions. There are three major patterns of distribution of the lesions: (1) centrofacial (63%: forehead, nose, chin, and upper lip), (2) malar (21%: nose and cheeks), and (3) mandibular (16%: ramus mandibulae). The anterior chest and dorsal forearms may also be affected.

From its appearance under Wood's lamp, melasma is classically classified into epidermal, dermal, and mixed. (Epidermal pigmentation is accentuated under Wood's lamp, whereas dermal pigmentation is less apparent.)

Sun protection is central to management. Epidermal pigmentation is known to be more responsive to topical treatment than dermal pigmentation. Hypopigmenting agents such as hydroquinone, tretinoin, azelaic acid, rucinol, and kojic acid are helpful when used for prolonged periods. The so-called Kligman formula is a popular combination of hydroquinone, tretinoin, and a mild topical corticoid. Chemical peels and laser therapy may be helpful in the treatment of melasma, but can also result in further unwanted hyperpigmentation. Sometimes, melasma slowly disappears after discontinuation of the hormonal stimulus and/or careful sun avoidance.165–167

Pregnancy

During pregnancy increased pigmentation occurs in 90% of women and is most prominent in darker skin types. Preexisting pigmented lesions such as nevi and ephelides become darker. Also, recent scars often darken. In normally pigmented areas, such as nipples, areolae, and genitalia, the pigmentation becomes more intense. The linea alba, the median line on the anterior abdominal wall, often becomes hyperpigmented during pregnancy and is then called linea nigra. In a small proportion of pregnant women, hyperpigmentation occurs in the axillae or the inner upper thighs. Melasma or “mask of pregnancy” (see Section “Melasma”) occurs in more than 50% of pregnant women (see Chapter 108).168,169

Acanthosis Nigricans

Acanthosis nigricans is discussed in Chapters 151 and 153.

Diabetes

(See Chapter 151.)

A higher vitiligo prevalence has been reported in patients with diabetes type I and II compared to the general population. Diabetic dermopathy is characterized by asymptomatic, irregular, light brown, depressed patches on the anterior lower legs,65 but the pathogenesis is not known.

Nutritional Conditions

(See Chapter 130).

Pigmentary changes can be secondary to nutritional conditions such as kwashiorkor, vitamin B12 deficiency, folic acid deficiency, or pellagra. The skin changes are reversible on correction of the nutritional deficiency.

Kwashiorkor

Vitamin B12 Deficiency

Folic Acid Deficiency

Pellagra

Metabolic Conditions

Porphyria Cutanea Tarda

(See Chapter 132.)

Porphyria cutanea tarda is a metabolic disorder that has been associated with diffuse brown hypermelanosis accentuated in sun-exposed areas. In females, a melasma-like hyperpigmentation of the face can be observed.

Hemochromatosis

Hereditary hemochromatosis is an autosomal recessive disorder associated with increased intestinal absorption of iron and deposition of excessive amounts of iron in the liver, pancreas, and other organs, including the skin. In the past, hemochromatosis was usually diagnosed at an advanced stage by the classic triad of hyperpigmentation, diabetes mellitus (“bronze diabetes”), and hepatic cirrhosis. Darkening of the skin was present in 70% of the patients due to two different mechanisms: (1) hemosiderin deposition causing a diffuse, slate-gray coloring and (2) increased epidermal melanin production. Because hemochromatosis is now usually diagnosed early, hyperpigmentation is less frequently observed. The pigmentation is usually generalized, but may be more pronounced in sun-exposed areas, genitalia, and scars. Skin bronzing is reversible by phlebitic therapy.178–180

Hepatolenticular Degeneration or Wilson's Disease

Lysosomal Storage Disease

Tumoral Conditions

Mast Cell Disorders and Melanoma

Mast cell disorders and melanoma can lead to hyperpigmentation and are discussed in Chapters 149 and 124, respectively. Diffuse, generalized melanosis associated with advanced metastatic melanoma is a rare, although well-documented, event. It is characterized by a slate bluish-gray to brown discoloration of the skin (Fig. 75-18). Histology reveals melanin particles and melanin-containing histiocytes and dendritic cells in the dermis and subcutaneous fat. No melanoma cells can be detected in the skin, and there is no increase in epidermal melanin pigment or number of melanocytes. Melanosomes circulating in the blood have been detected, supporting the hypothesis that diffuse melanosis may result from tumor lysis183 with release of their organelles into the circulation and subsequent deposition in the skin.

Physical Agents

Ultraviolet Radiation

(See Chapter 90.)

A major acute effect of UV radiation on normal human skin is tanning.

Ionizing Radiation

(See Chapter 240.) Exposure of skin to ionizing radiation during accidents, such as in Chernobyl, or after local fractionated radiotherapy can give rise to a cutaneous radiation syndrome characterized by fibrosis, keratosis, telangiectasias, and sharply demarcated lentiginous hyperpigmentation, resembling UV-induced lentigines (radiation dermatitis). Small hypopigmented spots can be intermingled with zones of hyperpigmentation. Skin biopsy shows altered melanin content in melanocytes and basal keratinocytes, corresponding to the clinical appearance. Electron beam therapy has been reported to induce tan-like transient hyperpigmentation and transverse melanonychia.184–189

Thermal Radiation

In superficial thermal burn injuries, when the melanocyte-bearing basal epidermis has not been destroyed, various degrees of hyperpigmentation result, depending on the skin color and time after the injury. Thermal injury resulting from laser therapy with intense, high-dose visible light also can give rise to hyperpigmentation, especially in dark-skinned patients. Cryotherapy, tissue destruction by application of cold, commonly causes (sometimes permanent) hypopigmentation in combination with peripheral hyperpigmentation in treated skin due to melanocyte injury.190–193

Trauma

Friction melanosis in an acquired pigmentary disorder due to repeated rubbing of the skin 194

Toxin- and Medication-Induced Hyperpigmentation

Hyperpigmentation caused by toxic agents or medication accounts for 10%–20% of all cases of acquired hyperpigmentations. CNS drugs, antineoplastic agents, anti-infectious drugs, antihypertensive medications, and hormones are most commonly responsible (eTable 75-1.1).

In the majority of cases of medication-induced hyperpigmentation, the underlying pathogenetic mechanism involves one of the following.

Hyperpigmentation can be due to deposition of melanin in the dermis, usually in macrophages. Sometimes this melanin is complexed to the drug [drug-pigment complex (e.g., hydroxychloroquine)]. Accumulation of melanin can occur after cutaneous inflammation (postinflammatory) and/or DNA damage (e.g., carmustine). This type of hyperpigmentation is often increased by UV exposure and is usually more pronounced in sun-exposed areas.

Some substances (e.g., carotene, heavy metals) are directly deposited in the skin. Sometimes this type of pigmentation is also accentuated in sun-exposed areas as UV can induce a transformation in the deposited drugs, which may then become more visible.

In other cases, the dyschromia is caused by nonmelanin pigments synthesized or produced under the direct or indirect influence of the drug.

Clinical features vary with characteristic sites, patterns, and shades of discoloration. The forms associated with melanin accumulation are often worsened by sun exposure. Sometimes, the manifestation is more or less specific for the responsible drug, although the mechanism is often poorly understood. For example, a linear, sometimes flagellate hyperpigmentation can be observed in patients taking bleomycin or zidovudine. A diffuse hyperpigmentation on the palms and soles may be present in patients taking cyclophosphamide or doxorubicin. Bleomycin and doxorubicin may produce localized hyperpigmentation around small joints. Estrogen-related hormonal substances and phenytoin-like medication may cause melasma-like pigmentation. Nail unit involvement can be observed with some medications, most frequently chemotherapeutic agents, zidovudine, psoralens, minocycline, antimalarials, and gold. Mucosal hyperpigmentation has been reported with cyclophosphamide, doxorubicin, zidovudine, minocycline, and some heavy metals.

Amiodarone can produce blue–gray pigmentation in sun-exposed areas due to accumulation of a lipid-like substance in macrophages. Some of these patients display photosensitivity (Fig. 75-19). (Hydroxy) chloroquine may give rise to a yellow–brown to bluish-gray pigmentation on the face, neck, lower extremities, and forearms after several years of intake, due to deposition of a drug–melanin complex in the dermis (eFig. 75-19.1). The nail unit and hard palate may also be involved. Exogenous ochronosis has been reported after chronic hydroquinone use (see Section “Ochronosis”).

Chlorpromazine and related phenothiazines can produce a bluish-gray pigmentation, especially in sun-exposed areas, and pigmentation of the conjunctivae. Minocycline can induce skin hyperpigmentation, as well as pigmentation of the nails, sclerae, oral mucosa, thyroid, bones, and teeth. Skin hyperpigmentation may present as a blue–black discoloration, especially at sites of inflammation, but also in noninflamed sites, especially the anterior legs. In some patients, there is a dull brown discoloration, especially in sun-exposed areas. Argyria patients present with a generalized grayish-blue pigmentation; the nails and the sclerae may also be involved.

Treatment of toxin- and medication-induced hyperpigmentation involves discontinuation of the responsible agent, if possible. In a small subset of patients, the hyperpigmentation persists even after discontinuation, particularly the bluish or gray pigmentation characteristic of dermal deposition. Sun protection should be advised, especially in forms entailing melanin accumulation. Laser treatment has been reported to be successful in some cases (e.g., amiodarone).195

Ochronosis

Endogenous Ochronosis/Alkaptonuria

Endogenous ochronosis/alkaptonuria is discussed in Chapter 131.

Exogenous Ochronosis

Exogenous ochronosis results from the use of certain medications, which form a homogentistic acid polymer-like substance during their metabolism. It presents as asymptomatic hyperpigmentation of the face, sides and back of the neck, back, and extensor sites of the extremities (Fig. 75-20). Histopathologically, there is a collection of yellowish-brown (ochronotic) globules in the papillary dermis. There is no articular, renal, or cardiovascular involvement. It has been most frequently reported in association with hydroquinone (bleaching creams), usually in skin phototype VI patients, although it has been described in other skin types. Exogenous ochronosis has also been noticed after the use of antimalarials and products containing resorcinol, phenol, mercury, and picric acid. Treatment is rarely helpful, but the offending drug should be stopped to prevent progression.196

For POEMS syndrome and Cronkhite–Canada syndrome, and zidovudine-induced hyperpigmentation see below. The hyperpigmentation associated with the following disorders is discussed briefly below and/or the other indicated chapters: systemic sclerosis (Chapter 157), pinta (Chapter 201), onchocerciasis (Chapter 207), phytophotodermatitis (Chapter 90), flagellate pigmentation due to bleomycin (Chapter 227).

POEMS Syndrome

Cronkhite–Canada Syndrome

Systemic Sclerosis

(See Chapter 157.)

Different types of abnormal pigmentation have been described in systemic sclerosis. A diffuse, generalized hyperpigmentation similar to Addison's disease but with normal levels of MSH can be observed in severe systemic sclerosis.

Focal depigmentation with perifollicular hyperpigmentation may occur, especially on friction sites (e.g., shins, elbows, and dorsum of the hands). There can be localized hyper- and hypopigmentation.

A streaky hyperpigmentation over blood vessels on a background of depigmentation has been reported. Diffuse reticulated hyperpigmentation accentuated on the trunk has been reported in one case.43

Infections

(See Chapter 201.)

Erythematous, scaling papules termed pintids develop during the secondary stage of pinta. These initially red lesions can turn brown, slate-blue, black, or grayish.52

Chronic papular onchodermatitis is one of the skin manifestations of onchocerciasis. It is characterized by a severely pruritic maculopapular rash with hyperpigmented macules, most often occurring on shoulders, buttocks, and extremities (see Chapter 207).53

Acquired Circumscribed Hypermelanosis

Phytophotodermatitis

Contact with plants containing phototoxic agents such as psoralens, with subsequent UV exposure, may lead to phytophotodermatitis, which is followed by patterned hyperpigmentation.

Flagellate Pigmentation Due to Bleomycin

(See Chapter 227.)

Flagellate Mushroom Dermatitis

Flagellate mushroom dermatitis is characterized by linear grouped, erythematous, and intensely pruritic papules, a clinical pattern very similar to bleomycin-induced flagellate dermatitis. It is caused by eating raw or insufficiently boiled shiitake mushrooms (Lentinus edodes) and is not elicited by topical contact or ingestion of well-boiled shiitake. The pathogenesis is not yet known, but it is hypothesized that a thermolabile polysaccharide is responsible.199–201

Zidovudine-Induced Hyperpigmentation

Hypermelanosis—Acquired Diffuse Patterned or Reticular

Erythema Ab Igne

Erythema ab igne is caused by a chronic exposure to moderate heat. The reticular erythema can be accompanied by epidermal atrophy, scaling, and hyperpigmentation. It was seen in the past in people who frequently sat in front of open fires or stoves for warmth, but it occurs less often since the introduction of central heating. Nevertheless, it is still seen after local application of heating pads, hot water bottles, or heating blankets. Modern appliances that have been reported to elicit erythema ab igne are furniture with built-in heaters, car heaters, and laptop computers (Fig. 75-21).204–206

Prurigo Pigmentosa

Approximately 200 cases of prurigo pigmentosa have been published in the international literature since it was first described in 1971 by Nagashima. Prurigo pigmentosa presents itself as intensely pruritic erythematous papules, papulovesicles, and vesicles that involute in several days. The lesions develop symmetrically on the back, chest, neck, and lumbosacral region. The papulovesicular lesions heal spontaneously, leaving a nonpruritic reticular hyperpigmentation (see eFig. 75-21.1). The disease has a fluctuating course with exacerbations and recurrences. It is twice as frequent in females as in males. The eruption and pruritus respond well to minocycline and dapsone but the pigmentation does not and must resolve spontaneously. Environmental and metabolic factors have been suggested as causative agents but the pathogenesis remains unknown.207

Acquired Circumscribed Hypermelanosis

Nevus of Hori

Nevus of Hori was first described in 1984 as acquired, bilateral nevus of Ota-like macules termed ABNOM.208 It consists of blue–brown to slate-gray mottled hyperpigmentation on the face with predilection for the malar regions. Similar to nevus of Ota, it typically affects the Asian population and has a female predominance. However, the lack of ocular and mucosal membrane involvement and the acquired bilateral character distinguish the entities. Histologically, melanocytes with stage III or IV melanosomes reside in the upper and middle layers of the dermis. Sun exposure and hormonal changes during pregnancy have been described as triggering factors.209 Hori described three possible mechanisms for the pathogenesis of ABNOM: (1) “dropping” of epidermal melanocytes into the dermis, (2) migration of melanocytes from hair bulbs, and (3) reactivation of preexisting latent or immature dermal melanocytes.208 The latter has been suggested as being the most probable mechanism with UV-radiation and sex hormones as activating factors. In some cases, ABNOM can occur simultaneously with other pigmentary abnormalities such as melasma, freckles, solar lentigines, and nevus of Ota.113,209

Combination treatments of pigment-specific laser (Q-switched lasers) with chemical peels and topical bleaching agents have been used with variable results.210

Becker's Nevus (Becker Hamartoma, Becker Melanosis)

This acquired hyperpigmented epidermal nevus was first described in 1949 (Fig. 75-22). It preferentially occurs in the scapular region, although it has been described in any area of the body, and classically after an intense sun exposure. The lesion is androgen-dependent and becomes more prominent in adolescence, especially in the male population. Hypertrichosis in the lesion is often associated. Associated anomalies, such as ipsilateral breast hypoplasia, musculoskeletal abnormalities (scoliosis, ipsilateral limb hypoplasia, etc.), maxillofacial abnormalities, and additional cutaneous hypoplasias, occur in the rare Becker's nevus syndrome. Microscopic examination demonstrates normal numbers of melanocytes, but increased levels of melanin in the basal epidermal layer (epidermal melanotic hypermelanosis). The epidermis is acanthotic with variable hyperkeratosis and elongation of the rete ridges. In the dermis, the number of arrector pili muscles is increased, making it difficult to differentiate from the related smooth muscle hamartoma. Good therapeutic results have been reported using a long-pulsed alexandrite laser.215

Becker's nevus is suggested to follow a paradominant inheritance pattern, which means it (almost) always occurs sporadically. The rare familial cases that have been described (especially in Becker's nevus syndrome) can be explained by a somatic mutation during embryogenesis, resulting in loss of heterozygosity and formation of a mutant cell population. This hypothesis is supported by the identification of chromosomal mosaicism in fibroblasts derived from a Becker's nevus.216–218

Ephelides

Ephelides or freckles are small light brown macules appearing in sun-exposed skin of fair-skinned individuals, often those with red or blond hair and Celtic ancestry. They are more pronounced during spring and summer and fade during the winter period. They appear in early childhood and often regress later in life. Histopathologic examination shows a normal to reduced number of sometimes hypertrophic melanocytes but increased melanin in the basal epidermal layer.

Postinflammatory Hyperpigmentation

Postinflammatory hyperpigmentation (PIH) is a common condition caused by numerous preceding cutaneous insults such as drug and phototoxic reactions, infections, physical injury or trauma, allergic reactions, and inflammatory diseases. Clinically, PIH consists of a macular hyperpigmentation at the site of inflammation (Fig. 75-23).179 It is far more common and persistent in darker skin types (Fitzpatrick types III–VI) and can be characterized by epidermal as well as dermal melanotic hypermelanosis. A Wood's lamp examination can determine depth of the hyperpigmentation (see Section “Melasma”). Histologic features include pigment incontinence with accumulation of melanophages and increased melanin in dermal or epidermal layers.219 Management of PIH remains difficult,220–222 although epidermal PIH often shows slow spontaneous fading.

Familial Periorbital Hyperpigmentation

Increased pigmentation of the upper and lower eyelids has been described in a number of families. Histologically, increased basal pigmentation and dermal melanophages are seen. However, inflammation does not appear to precede the hyperpigmentation.223

Partial Unilateral Lentiginosis

Partial unilateral lentiginosis (PUL) is also known as unilateral lentigines, lentiginous mosaicism, zosteriform lentiginous nevus, segmental lentiginosis, and agminated lentiginosis.

Inherited-Pattern Lentiginosis in Blacks

Acquiered Brachial Cutaneous Dyschromatosis

Riehl Melanosis

Riehl melanosis, also known as female facial melanosis, is mostly seen in middle-aged women, especially in darker skin types, such as Mexicans and Asians (see eFig. 75-23.1).

It is characterized by a rapid onset of a reticular gray–brown to almost black hyperpigmentation.

The face (especially the forehead, zygomatic area, and temples) and the neck are principally involved, but the hands, forearms, and trunk can also be affected. Inflammatory findings such as erythema and pruritus are usually absent.

The main histopathologic feature is liquefactive degeneration of the basal layer of the epidermis, resulting in pigment incontinence in the dermis. The pathogenesis is not understood.226,227

The hyperpigmentation has been postulated to be induced by repeated contact with threshold doses of a contact sensitizer such as fragrances, some pigments, and bactericides used in cosmetics and optical whiteners, but is poorly documented in most cases.

Cutaneous Amyloidosis

Macular amyloidosis presents as brown to gray–brown macules, mainly on the back (see Chapter 133).

Laugier–Hunziker Syndrome

Atrophoderma of Pasini–Pierini

(See Chapter 67).

The cutaneous lesions of atrophoderma of Pasini–Pierini can be described as single or multiple gray to violaceous-brown atrophic patches from 1 cm to more than 10 cm in diameter with slight depression with a characteristic “cliff drop” border.

Fixed Drug Eruption

Fixed drug eruption can cause hyperpigmentation (see Chapter 41).

Erythema Dyschromicum Perstans

Erythema dyschromicum perstans, also known as ashy dermatosis, dermatosis cenicienta, and erythema chronicum figuratum melanodermicum, was first described by Ramirez in 1957. Patients with this eruption were labeled as los cenicientos, the ashy ones.229

The disease is characterized by hyperpigmented macules and patches of variable shape and size with an ashen-gray to brown–blue color. They may have a thin, raised erythematous border in the early stage that later can be absent or, mainly in darker skin types, evolve into a hypopigmented border that accentuates the hyperpigmentation. The eruption can also be polymorphic, presenting simultaneously hypo- and hyperpigmented macules. Lesions occur primarily on the face, the neck, the trunk, and the proximal part of the arms. The lesions are usually asymptomatic, although slight pruritus can be present. There is a slow progression of the lesion over several years, usually without spontaneous regression.

Erythema dyschromicum perstans is mainly observed in intermediate skin types. It is a disease of young adults, although there are small series reporting the disease in prepubertal children. There is no clear sexual predilection.230

Histologic examination of the inflammatory border may demonstrate lichenoid dermatitis with vacuolization of the basal cell layer, occasional colloid bodies, and increased epidermal melanin. The dermal changes are edema of the papillary dermis, a moderate or mild lymphohistiocytic infiltrate, and dermal melanophages. The pathogenesis of erythema dyschromicum perstans is unclear and likely influenced by many factors. An HLA-DR-associated susceptibility to develop erythema dyschromicum perstans has been described in a Mexican population.231

In inactive lesions, there is no vacuolization of the basal cell layer, a diminished dermal infiltrate, and an increased number of dermal melanophages. There is no effective treatment.229,230

Idiopathic Eruptive Macular Hyperpigmentation

Idiopathic eruptive macular hyperpigmentation is an uncommon disorder of pigmentation characterized, as the name suggests, by an eruption of asymptomatic, brown macules (5 mm to several cm in diameter) involving the trunk, neck, and proximal extremities in children and adolescents. No previous drug exposure has been implicated, and the lesions disappear gradually over several months to years.

Histopathologically, there is hyperpigmentation of the basal layer of the epidermis and prominent dermal melanophages. The number of mast cells is normal.232

Dyschromatosis Hereditaria Universalis

Dyschromatosis hereditaria universalis is an autosomal dominant disorder that usually presents in infancy or early childhood in Asian families and is characterized by pinpoint to pea-sized hypo- and hyperpigmented macules, distributed in a reticulated pattern over the trunk, abdomen, and limbs, usually sparing the face and palmoplantar surfaces.233

Reticulate Acropigmentation of Dohi

Reticulate acropigmentation of Dohi is a localized form of dyschromatosis universalis hereditaria, also called dyschromatosis symmetrica hereditaria. It is characterized by small, symmetric hyper-, and hypopigmented macules on the dorsal hands and feet, and is mainly seen in young children in South American and Asian families.

Westerhof Syndrome

Westerhof syndrome, described in three generations of one family, displays congenital hypo- and hypermelanotic macules. There is also small stature and mental retardation.234

Vagabond Leukoderma

Vagabond leukoderma is a condition found in persons living in poor hygienic conditions. Many abuse alcohol, live on an inadequate diet, and are infested with lice and/or scabies. Diffuse light-brown hyperpigmentation is present at the shoulder and waist girdle, and the neck and back are dotted with depigmented macules. The condition improves on institutions of a healthier lifestyle and likely represents a coexistence of many of the disorders.235