Biology of hypopigmentation

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V O L U M E 19

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AUGUST 1988

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Continuing medical education Biology of hypopigmentation Jean L. Bolognia, M.D.,* and John M. Pawelek, Ph.D. New Haven, CT A review of the basics of pigment cell biology is followedby a discussion of the characteristics of several disorders of hypopigmentation.By determining such features as inheritance pattern, time of onset (congenital,childhood, adulthood), natural history (stable vs progressive),type of pigment loss (diffuse or circumscribed), distribution of lesions (generalizedvs localized), degree of pigment loss (incomplete or complete), number of melanocytes,if any, in biopsy specimensof affected areas, type of melanocytic dysfunction,and associated inflammation or infection, one can classify the disorders of hypopigmentation.The proposed pathophysiologyfor each disorder of hypomelanosisis presented. (J AM ACAODERMATOL1988;19:217-55.)

The diversity of color seen in the integument of vertebrates results in a large part from the type and distribution of melanin pigments. Melanin is responsible for five basic colors in human skin and hair: black, brownt red, yellow, and white (absence of melanin). There are several proposed functions for this cutaneous pigmentation. They include camouflage, heat absorption, and protection from ultraviolet light. The human pigmentary system is a complex set of dynamic cellular interactions that begins during embryogenesis and continues throughout the life of the individual. Within this system there are multiple sites for dysfunction, each one potentially resulting in a disorder of pigmentation. The disorders of hyperpigmentation were reviewed in the "Continuing Medical Educa-

The CME articles are made possible through an educational grant from Syntex Laboratories, Inc. From the Department of Dermatology, Yale University Sehco| of Medicine. Reprint requests to: Dr. Jean L. Belognia, Departmer~t of Dermatology, Yale University School of Medicine, 333 Cedar St,, New Haven, CT 06510.

tion" article by Fulk in January 1984. This article will review the disorders of hypopigmentation. PIGMENT CELL BIOLOGY Melanoeytes The melanocyte is the site of pigment production in the skin. Melanin is formed within melanosomes, membrane-bound organdies located in the cytoplasm of the melanocyte. Melanocytes are found predominantly in the basal layer of the epidermis as well as in the matrix of the hair follicle. In addition, pigment cells reside in the dermis, the mucous membranes, 1"3the leptomeninges,4 the retina and uveal tract of the eye, and the cochlea and vestibular labyrinth of the ear? Deposition of melanin in the retina occurs primarily during fetal development,but in the skin it is a continual process?,7 The vast majority of pigment ceils are derived from precursor cells in the embryonic neural crest? One exception is the pigmented layer of the retina--its ceils originate from the optic cup of the forebrain. A migration of melanoblasts from the neural crest to the integument has been observed in mammalian embryos? The rich supply of melano217

218 Bolognia and Pawelek

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Fig. 1. Melanocytes are found in basal layer of epidermis.They are characterized by clear cytoplasm (arrows). (Hematoxylin-eosin-stainedsection; X400,) cytes found in the dermis of human fetal skin presumably represents a similar pattern of migration, that is, from the neural crest to the epidermis. Ultrastructural studies have revealed melanosomecontaining cells in the fetal epidermis at a gestational age of 8 to 10 weeks. 1~Although this process of pigment cell migration is normally completed prior to birth, there can be residual dermal melanocytes. These can become clinically apparent, for example, as mongolian spots--the blue-black patches seen predominantly in the sacral area of oriental and black infants. An estimate of the melanocyte mass in an aduk human is 1.0 to 1.5 cm3.I~ Histologic analysis of the epidermis indicates that melanocytes comprise approximately 10% of the cells in the basal layer. In hematoxylin-eosin-stained sections, they have a clear appearance (a result of shrinkage of the cytoplasm during fixation) and a relatively small basophilic-staining nucleus (Fig. 1). Specialized staining techniques, such as (1) the FontanaMasson (reduction of ammoniated silver nitrate to free black silver by melanin) or (2) the dopa reaction (oxidation of 3,4-dihydroxyphenylalanine [dopa] to black dopa-melanin by tyrosinase-

containing cells [Fig. 2]), are often necessary to appreciate the highly dendritic quality of the melanocyte (Fig. 3)) 2 The Fontana-Masson stains melanin in formalin-fixed, paraffin-embedded tissue, whereas the dopa reaction for the detection of tyrosinase activity requires fresh tissue. The cytoplasm of both melanocytes and keratinocytes can exhibit positive staining by the Fontana-Masson method because both cell types can contain melanin (see below). The dopa stain is more specific for melanocytes, and it is usually done on an epidermal sheet following its chemical (2 N sodium bromide [NaBr]) separation from the dermis. This latter method provides an estimate of melanocyte density. In the human epidermis each melanocyte supplies melanin pigment to an average of 36 keratinocytes. This association has been termed the epidermal melanin unit. T M In order to transfer pigment from the melanocyte to the keratinocyte, the squamous cell must phagocytize the melanosome-laden dendritic tips of the melanocyte (Fig. 4). This active process has been observed in co-cultures of epidermal keratinocytes and melanocytes~5,~6 (Fig. 5). The transfer step is crucial

Volume 19 Number 2, Part 1 August 1988

because the pigmentation of one's skin is determined primarily by the amount of melanin transferred to the keratinocyte. If melanin is to contribute significantly to the color of the skin, it must be transferred to the keratinocyte. TM Several comparative studies have focused on the basis for the wide variation seen in human pigmentation. When dopa-stained epidermal sheets from the same anatomic region of black and white patients were examined, no differences were observed in the number of melanocytes per unit area of skin. 17'18 ALSO, no variation was seen in the distribution of melanocytes within the epidermal melanin units. The major difference was in the activity of individual melanocytes--in black skin they were larger, more dendritic, and a greater proportion contained melanin in comparison to white skin. 17,19A difference in melanocyte density was observed only when various regions of the body were compared/7, 2o For example, the lowest number of melanocytes per square millimeter of skin was found on the trunk and arm (1100-1250/ram 2) and the highest concentration was seen on the face (2900/mm2) xL (Fig. 6). The next section on the structure and function of melanosomes, the sites of melanin production, 21 should provide a basis for understanding the variation in melanocytic activity and resultant cutaneous pigmentation. Melanosomes

Melanosomes contain: (1) structural matrix proteins, (2) the enzyme tyrosinase, which catalyzes the initial step in the melanin biosynthetic pathway, and (3) several proteins of unknown structure and function. Tyrosinase is synthesized on ribosomes and accumulates in the Golgi-associated, smooth endoplasmic reticulum before it is incorporated into small membrane-bound vesicles 22,23(Fig. 7). Fusion of these vesicles to the structural proteins (derived separately from blebs of endoplasmic reticulum) results in the formation of a melanosome. The structural proteins form a lameUar matrix within the melanosome upon which melanin is deposited. Four representative stages in melanosome development have been described (Fig. 8)7,24: 1. Stage I melanosomes are spherical (0.3 gm diame-

Biology of hypopigmentation 219

Leu~odopachtome

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Fig. 2. Melanin biosynthetic pathway, s5 Tyrosinase is involved in three steps: conversion of tyrosine to dopa, dopa to dopaquinone, and 5,6-dihydroxyindole to indole-5,6-quinone. Dopachrome conversion factor converts dopachrome to 5,6-dihydroxyindole-2-carboxylic acid. (From Pawelek JM, Krrner AM. The biosynthesis of mammalian melanin. Am Sci 1982;70:136-45; published with permission.) ter) and may contain filaments with a distinct periodicity. 2. Stage II melanosomes are oval in shape and have numerous parallel longitudinal filaments with no melanin deposition. 3. Stage III melanosomes have a high level of tyrosinase activity and their internal structure is partially obscured by the deposition of melanin pigment. 4. In stage IV melanosomes there are very low levels of tyrosinase activity and melanin is deposited throughout the structure, rendering it electron-opaque. As melanosomes pass from the perinuclear area of the melanocyte to the dendrites, they progress from stage I to stage IV melanosomes (Fig. 7). There is evidence that 10 nm filaments are involved in this peripheral migration of organelles. 25 In the non-sun-exposed epidermis of fair-skinned whites, the melanocytes contain predominantly stage I and II melanosomes and an occasional melanosome is seen in adjacent keratinocytesS, 26T h e melanocytes of more darkly pigmented whites contain stage I, II, and III melanosomes and stage IV melanosomes can be seen in nearby keratinocytes. In both the melanocytes and the keratinocytes of black

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220 Bolognia and Pawelek

Fig. 3. Epidermal sheet exposed to L-dopa. Incubation with 2 N sodium bromide allows epidermis to separate from dermis as an intact sheet. Epidermis is then placed in a solution of 5 mM L-dopa for 3 to 5 hours at 37~ C. Melanocytes turn black because they contain the enzyme tyrosinase, which converts dopa to black dopa-melanin. (•

skin, the predominant form of melanosome is stage IV. In addition to the positive correlation that exists between the degree of cutaneous pigmentation and the extent of melanization of melanosomes, there is a relationship between skin color and melanosome size and packaging. In black skin, the length of the melanosomes ranges from 0.5 ~m to 0.8 /~m, whereas in white skin it ranges from 0.3 gm to 0.5 /zmY As a consequence of their larger size, the melanosomes in the keratinocytes of black skin are individually dispersed. 2s,29 In contrast, the smaller melanosomes in the keratinocytes of mongoloids and whites are aggregated into groups of two or three (melanosome complexes), and these aggregates are bound by the membrane of a phagolysosome. 3~The natural history of transferred melanosomes (except in hair) is a degradation of its proteins by lysosomal enzymes as the squamous cell differentiates. This process proceeds at a faster rate in the epidermal cells of whites, thereby explaining the presence of intact melanosomes in the superficial layers of non-sun-exposed black skin. 3t In conclusion, darkly pigmented skin has melanosomes that are more numerous, larger, singly dispersed, higher in melanin content, and

degraded more slowly than the melanosomes of lightly pigmented skin. 12,28

Melanin synthesis In the classic Mason-Raper pathway of melanin synthesis, tyrosinase, a copper-containing enzyme, converts tyrosine to dopa and oxidizes dopa to dopa quinone32'33 (Fig. 2). The possibility that the conversions of tyrosine to dopa and dopa to dopa quinone are under the control of two enzymes (peroxidase and dopa oxidase) rather than one (tyrosinase) has been raised. 3~,35However, several investigators have provided evidence that pigment cells contain only one enzyme, tyrosinase, which utilizes both tyrosine and dopa as substrates. ~6,37 The subsequent reactions that eventually lead to the formation of melanin (dopa quinone ~ leucodopachrome -~ dopachrome ~ 5,6-dihydroxyindole ~ indole-5,6-quinone ~ melanochrome melanin) were thought to proceed spontaneously via auto-oxidation and therefore without any form of regulatory control. More recently, however, it was shown that tyrosinase was directly involved in the conversion of 5,6-dihydroxyindole to melanin. 38 In addition, a new regulatory factor was identified: dopachrome conversion factor, which converts

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Biology of hypopigmentation 221

•lStratum granulosum

EPIDERMIS Stratum spinosum

Basal 9ayer DERMIS

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Fig. 4. Epidermal melanin unit. Mature melanosomes move into dendrites of melanocyte and keratinocytes phagocytize dendritic tips. As squamous cells differentiate, melanosomeswithin them are degraded by lysosomal enzymes.

Fig. 5. Phase contrast photomicrograph of a co-culture of guinea pig melanocytes and keratinocytes. Pigment is being transferred from the melanocyte (center) to the keratinocytes (underlyingmonolayer) via melanosomes. (Courtesy S. Klaus, M.D., Jerusalem, Israel.)

dopachrome to 5,6-dihydroxyindole-2-carboxylic acid. 39-41 Evidence has also been obtained that dopachrome conversion factor is an enzyme.42 When melanoma cells are exposed to melanotropin (see below), there is an increase in tyrosinase activity and melanin production. In the melanin biosynthetic pathway, tyrosinase plays an important regulatory role--its level of activity usually correlates with the degree of pigment production.43 In patients with tyrosinasenegative oculocutaneous albinism, this correlation is most evident. Several forms of tyrosinase have been described, and they differ primarily in their cellular localization and their patterns of glycosylation. 44 These latter posttranslational modifications are thought to occur within the cisternae of the Golgi apparatus prior to the enzyme's incorporation into the melanosome. Two major forms of melanin exist in humans: ( 1) phaeomelanin and (2) eumelanin. Eumelanin is a brown to black, high molecular weight heteropolymer whose monomers include 5,6-dihydroxyindole, 5,6-dihydroxyindole-2-earboxylic acid, and indole-5;6-quinone. 4s The exact chemical structure of melanin is not understood because it is difficult to solubilize this compound without altering its monomeric units. Eumelanin is contained within ellipsoid melanosomes and it is formed by the pathway illustrated in Fig. 2. Phaeomelanin is

yellow-red in color and is found within spherical melanosomes.46The pathway of phaeomelanin synthesis differs from that of eumelanin. It is thought that during phaeomelanin synthesis dopa quinone reacts with the thiol group of cysteine to form 5-S eysteinyl-dopa.45 This latter intermediate undergoes oxidation to form phaeomelanin.

Melanotropins Three forms of melanotropins (also known as melanocyte-stimulating hormones [MSH]) have been described: a, /3, and %47 They are small peptide hormones ranging in size from 12 to 18 amino acids. In vertebrates, they are products of the intermediate lobe of the pituitary gland. 48 The ability of MSH to cause an increase in skin pigmentation has been demonstrated in several animal models and in humans. 49,5~ The three melanotropins are cleavage products of a common precursor peptide, pro-opiomelanocortin.47 There exists a family of peptide hormones that is derived from the pro-opiomelanocortin precursor. It includes corticotropin (ACTH), corticotropin-like intermediate-lobe peptide, i3-lipotropin (/3-LPH) and/3-endorphin, as well as the melanotropins (Fig. 9). The processing of the pro-opiomelanocortin peptide depends on the tissue in which the gene is expressed, for example, A C T H and f3-LPH are the primary products of the anterior lobe of the

222

Journal of the American Academy of

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Dermatology

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Fig. 6. Regional distribution of epidermal melanocytes. Figures represent mean values per square millimeter + SEM. (From Rosdahl I, Rorsman H. J Invest Dermatol 1983;81:278-81; published with permission from Williams & Wilkins, Baltimore, MD.)

pituitary gland, while in the intermediate lobe A C T H is further processed to a-MSH. 5~ As a result, A C T H and o~-MSH contain homologous internal sequences. The hyperpigmentation that occurs in Addison's disease, Nelson's syndrome, and the ectopic A C T H syndrome may be the result of a hypersecretion of A C T H , ~-MSH, 13-LPH, or a combination of these peptides, sz, 53 Cloudman mouse melanoma cells have been used extensively in studies on the mechanism of action of MSH. 54,55Evidence has been obtained to support the following conclusions: (1) M S H binds to specific, high-afFinity receptors on the cell's surface predominantly during the (32 phase of the cell cycle5648; (2) formation of the hormone-receptor complex is followed by a stimulation of the adenylate cyclase system and a net increase in intracellular levels of cyclic adenosine monophosphate (cAMP)59,6~ (3) the increased levels of cAMP result in increased tyrosinase activity and melanin deposition, as well as in changes in mor-

Fig. 7. Schematic representation of melanosome formation within melanocyte. Tyrosinase (T) is synthesized on ribosomes of rough endoplasmic reticulum (RER) and transported through smooth endoplasmic reticulum (SER) to the Golgi apparatus. Posttranslational modifications such as glycosylation occur within the cisternae of the Golgi apparatus. Tyrosinase is then released within membrane-bound vesicles. Structural melanosomal proteins (MP) are also synthesized on the RER and they are incorporated into vesiclesat the SER. Fusion of the two types of vesicles results in formation of a melanosome. As melanosome matures and more melanin is deposited on the lamellar matrix, it passes into the dendrite of the melanocyte. There are receptors on the surface of pigment cells for melanocyte-stimulating hormone (MSH). (Courtesy J Varga, Ph.D., Bethesda, MD.)

phology and rates of proliferation61; and (4) these processes are mediated, at least in part, by cAMPdependent protein kinases.62,63 Effect of ultraviolet irradiation

The spectrum of ultraviolet (UV) irradiation has three major divisions: (i) ultraviolet C (200-290 nm), which does not reach the earth's surface because of the filtering effects of the ozone layer; (2) ultraviolet B (290 to 320 nm), also known as the sunburn or erythema spectrum; and (3) ultraviolet A (320 to 400 nm), referred to as long~ wavelength UV. After an exposure to solar irradi-

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Biology of hypopigmentation 223

Fig. 8. Electron photomicrographs of representative stages of melanosome development. A, Late stage I/early stage II melanosome (parallel longitudinal filaments; no melanin deposition); B, early stage III melanosome (small amounts of eumelanin deposited on lamellar matrix); C, late stage III melanosome (increased deposition of eumelanin, internal structure partially obscured); D, stage IV melanosome (fully melanized; electronopaque). (• (Melanosomes in cultured human melanocytes, courtesy R. Halaban, Ph.D.; photographs, courtesy G. Moellmann, Ph.D., and E. Kuklinska, New Haven, CT.)

POMC I

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Fig. 9. Schematic representation of the precursor peptide pro-opiomelanocortin (POMC) and its cleavage p r o d u c t s # Position of the three forms of melanotropin (c~-,/3-,and 3,-MSH) is shown. It illustrates the homologoussequences of: (1) corticotropin (ACTH) and a-MSH and (2)/3-1ipotropin (13-LPH),3,-lipotropin #-LPH), and 13-MSH. CLIP,Corticotropin-like intermediate lobe peptide. (From Nakanishi S, Inone A, Kita T, et al. Nature 1979; 278:423-7; copyright 9 Macmillan Magazines Limited.) ation, the human pigmentary system responds in two w a y s . 64 Immediate pigmentary darkening occurs within minutes of sun exposure, and at the conclusion of the exposure it fades within 6 to 8 hours. UVA and visible light are responsible for immediate pigmentary darkening, and the increase in pigmentation appears to be the result of an oxidation of preexisting melanin or its precursors rather than the synthesis of new pigment. There are conflicting data as to whether or not immediate

pigmentary darkening also involves a peripheral migration of melanosomal complexes within keratinocytes.65,66Delayed tanning is the second response of the skin, and it is due to both UVB and UVA irradiation. Delayed tanning is clinically apparent within 48 to 72 hours, and it is the result of new pigment production. After a single exposure to UV light, the number of melanocytes in the human skin does not change. However, their size and level of tyrosinase activity

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Table I. Sites of dysfunction in disorders of hypomelanosis Defect

Abnormal migration and differentiation of melanoblasts Tyrosinase activity Abnormal structure of melanosomes ~Melanization of melanosomes [Transfer (to keratinocytes) or r degradation (within melanocytes) of melanosomes

[

Disorder of hypomelanosis

Piebaldism; Waardenburg's syndrome;Woolf's syndrome Albinism, e.g., ty-neg, Ym Ash leaf spots; Chediak-Higashi syndrome Albinism, e.g., ty-pos; ash leaf spots; incontinentia pigmenti achrornians; tinea versicolor;idiopathic guttate hypomelanosis Nevus depigmentosus;pityriasis alba; postinflammatory hypopigrnentation;tinea versicolor; Chediak-Higashi syndrome.

do increase. 67 In skin that has undergone repeated exposures to UV irradiation, there is an increase in the number of melanocytes actively synthesizing melanin and an increase in the number of stage IV melanosomes transferred to keratinocytes.6s,69 These effects of UV light on the production of melanin are presumably related to the photoprotective properties of melanin. Melanin strongly absorbs both UV and visible light and is the major absorber of light in the skin. As a result, approximately five times as much UVB and UVA reaches the papillary dermis of whites as reaches that of blacks. 7~The high incidence of actinically induced squamous cell carcinomas in blacks with albinism living in equatorial Africa underscores the role of melanin in photoprotection,a PUVA (psoralens plus UVA) is another known stimulator of melanogenesis, in addition to MSH and UV irradiation. Exposure of the skin to PUVA can result in an increase in: (1) melanocyte size, (2) tyrosinase activity, (3) the number of functioning melanocytes, (4) transfer of melanosomes to keratinocytes, and (5) migration of melanocytes from hair follicles. 7z'74The formation of psoralen DNA photoadducts in the nuclei of melanocytes has been reported to increase the G2 phase of the cell cycle, the phase in which MSH receptors are most active. 7s In white skin, a single PUVA treatment with topical trimethylpsoralen altered the size and aggregation pattern of the melanosomes they were larger and singly dispersed, similar to the melanosomes in black skirl.76 Other reported stimuli of melanogenesis include estrogen, estrogen plus progesterone,77nitrogen mustard, 27and prostaglandins E2 and D2. 7s

DISORDERS OF HYPOMELANOSIS

In the following section we discuss several disorders of hypomelanosis, as well as their pathogenesis as it applies to the structure and function of the melanocyte. The diseases included in this section are vitiligo, Vogt-Koyanagi-Harada syndrome, chemical leukoderma, oeulocutaneous albinism, piebaldism (partial albinism), tuberous sclerosis, nevus depigmentosus, hypomelanosis of Ito, and idiopathic guttate hypomelanosis. We also review the association of hypopigmentation with cutaneous infections and inflammation. The assignment of particular disorders of hypopigmentation to blocked steps in melanin synthesis or transfer has been proposed by Ortonne et al. 79 Table I is a summary of the diseases discussed in this article, together with the presumed sites of dysfunction. VitiUgo

Vitiligo is a common acquired disorder that has an estimated incidence of 1% in our population,s~ Its mode of inheritance is thought to be either polygenic or autosomal dominant, with incomplete penetrance and variable expression81.82; there is a positive family history in at least 30% of cases. Approximately one half of the patients with vitiligo develop it before the age of 20.82It is characterized by a fairly symmetric pattern of circumscribed macules and patches of amelanosis. The areas of depigmentation are the result of a loss of melanocytes, and they can be made more clinically apparent by the illumination of a Wood's lamp (output of 340 to 400 nm; peak at 365 nm [long-wavelength UV]). s3 On occasion, the border

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Biology of hypopigmentation 225

Table II. Compounds known to produce chemical leukoderma ~7~,1~ Hydroquinone Monobenzyl ether of hydroquinone Monoethyl ether of hydroquinone Monomethyl ether of hydroquinone (hydroxyanisole) p-Isopropylcatechol p-Methylcatechol

p-tert-Butylcatechol p-tert-Butylphenol p-tert-Amylphenol Mercaptoamines N- (2-Mercaptoethyl)-dimethylamine hydroehloride 2-Mercaptoethylamine hydrochloride N,N',N"-Triethylenethiophosphoramide (thiotepa) of a depigrnented area may have an intermediate level of color (trichrome vitiligo), an erythematous halo (inflammatory vitiligo), or a rim of hyperpigmentation. The following areas are most commonly involved in vitiligo: (1) periorifical (around the mouth, nose, eyes, nipples, umbilicus, and anus), (2) flexor wrists, (3) extensor surfaces of extremities (elbow, knee, anterior tibial surface, and dorsa of hands and feet), (4) intertriginous zones (groin and axilla), and (5) oral mucosa. This pigmentary disorder exhibits the Koebner phenomenon; it usually begins in a peripheral location and can eventually involve the entire integument (generalized vitiligo). When the extent of depigmentation is unilateral and dermatomal-like in distribution, it is referred to as segmental or type B vitiligo (type A vitiligo is the common form of the disease described above) 84 (Fig. 10). A dysfunction of the sympathetic nerves within areas of segmental vitiligo has been described. There is evidence that the process of vitiligo can involve the choroid and the retinal pigment epithelium as well as the skin. In one series of patients with vitiligo, 30% had discrete areas of pigment loss in the fundus and 5% had an associated uveitis?5 The pigmentary changes in the choroid and retinal pigment epithelium, however, were usually clinically silent? 6 Vitiligo has also been observed in patients with other ocular disorders, including the Vogt-Koyanagi-Harada syndrome (see below), Alezzandrini's syndrome (unilateral degenerative retinitis, facial vitiligo, and poliosis), and sympathetic ophthalmia? 7 In addition, several autoim-

Fig. 10. Segmental vitiligo. Depigmentation of skin and facial hairs in a unilateral and dermatomal-like distribution. When compared to adults with vitiligo, children had an increased incidence of segmented vitiligo?26 (Courtesy R. Hartman, M.D., Van Nuys, CA.) mune disorders have been associated with vitiligo, including hypothyroidism,88 Graves' disease,~9 pernicious anemia, 8~ Addison's disease, insulindependent diabetes mellitus,91 uveitis, 92 alopecia areata, 93chronic mucocutaneous candidiasis,94 and the polyglandular autoimmune syndromes (types I, II, and 111)95 (Fig. 11). Diseases of the thyroid gland are the most frequently associated disorders, and they can occur in up to 30% of patients with vitiligo. 88Although the reported incidence of pernicious anemia in patients with vitiligo has varied between 1% and 8%, 96,97 evidence of atrophic gastritis has been found in 15% to 20% of these patients. 97,98 In one series, more than 50% of the patients with vitiligo had at least one circulating autoantibody99; the most common were antithyroglobulin, antimicrosomal, and antiparietal cell antibodies. 1~176 The levels of circulating helper-inducer CD4-positive T lymphocytes have also been exam-

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Fig. 11. Vitiligo in a child with type 1 polyglandular autoimmune syndrome.95 She had hypoparathyroidism and chronic mucocutaneous candidiasis (note tongue involvement). (Courtesy R. Hartman, M.D., Van Nuys, CA.) Fig. 12. Contact dermatitis of face from application of monobenzylether of hydroquinone (MBEH). MBEH was being used as a depigmenting agent in this patient with vitiligo. Note that contact dermatitis is limited to uninvolved pigmented skin and spares vitiliginous skin, (Courtesy R. Hartman, M.D., Van Nuys, CA.) Fig. 13. Leukoderma in a patient with systemic scleroderma. Forehead and scalp had areas of depigmentation that spared perifollicular skin. There was no evidence of sclerosis in areas of leukoderma and no retention of pigment along course of superficial veins.

ined in these patients, but the results are conflicting)0Ho3 Histologic examination of the depigmented skin in vitiligo reveals no melanocytes, even with specialized stains or electron microscopy. TM In the border of active vitiligo lesions, one can see dopapositive melanocytes that are -two to four times

larger than the melanocytes of the normally pigmented skin. Ultrastructural studies have shown, however, the degeneration of both melanocytes and keratinocytes at the pigmented borders of vitiligo skin) ~ Three theories have been proposed to explain the destruction of melanocytes in vitiligo 106.

Volume 19 N u m b e r 2, Part 1 August 1988

Biology of hypopigmentation 227 NH2

~H2

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OH

Tyrosine

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Fig. 14. Halo nevus on trunk of a young adult. The central nevus has not changed in color or size. (Courtesy R. Hartman, M.D., Van Nuys, CA.)

oH Hydroquinone (HQ)

1. Autoimmune: It is associated with several autoimmune disorders and circulating antibodies against surface antigens of normal human melanocytes have been detected in patients with vitiligo or melanomaS~ these antibodies may represent a primary event or they may be secondary to a release of antigens from previously damaged melanocytes. 2. Neural: A neurochemical mediator from nearby nerve endings would be involved in the destruction of melanocytes; this provides an explanation for segmental vitiligo. 3. Self-destruction: The intermediates of melanin biosynthesis (e.g., dopa, dopachrome, and 5,6-dihydroxyindole; Fig. 2) are known to be selectively cytotoxic to pigment cells?~ 108.109Vitiligo would result from a disruption of the melanocyte's protective mechanisms against these compounds. This third hypothesis would explain the clinical observation that vitiligo occurs in areas of the body that are relatively hyperpigmented. 82 Repigmentation of areas of vitiligo is due primarily to a migration of melanocytes from the hair follicles. 74 This explains the poor rate of repigrnentation in skin that either has no hairs or has only white hairs. ~~ Although the process of repigmentation can occur spontaneously, it usually requires a stimulus such as P U V A to obtain a significant amount of repigmentation. The psoralens can be taken orally (8-methoxypsoralen [8-MOP], 0.3-0.6 mg/kg, or 4,5',8-trimethylpsoralen [TMP], 0.6-0.9 mg/kg), followed in 2 hours by U V A exposure, the source of which is either natural sunlight or high-intensity UVA-emitting bulbs. ~TM112 In order

CH~ CH3~ CJf-CH3

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OH p-TertiaryButylphenol

OH p-TertiaryBulylcatechol

OH MonobenzylElherol Hydroqulnone (MBEH)

Fig. 15. Chemical structures of two melanin precursors, tyrosine and dopa, and four compounds that can cause chemical leukoderma, hydroquinone, monobenzylether of hydroquinone, p-tert-butylphenol, and ptert-butylcatechol. These phenolic compounds have similar structures and similar cytotoxic effects on pigment cells. to avoid phototoxicity and possible Koebner phenomenon, the exposures should start at 5 to 10 minutes of summer sun or 1 to 2 joules/cm 2 followed by increments of 5 minutes or 0.5-1.0 joules/cm2. 96 In a large controlled study of oral psoralens (8-MOP, T M P , or psoralen in varying doses and combinations) plus sunIight thrice weekly for 2 to 3 years, the best results (complete repigmentation of the face in 45% of patients) were seen with low-dose 8-MOP (0.3 mg/kg) or a combination of 8-MOP (0.3 m g / k g ) and T M P (0.6 mg/kg). 1'3 Despite these findings, initial therapy is often begun with T M P because it is less phototoxic than 8-MOP. 1'4 Repigrnentation can require 150 or more P U V A treatments, and some areas, such as the fingertips, toes, palms, and soles,

228

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Bolognia and Pawelek

T a b l e III. Types of oculocutaneous albinism

Type

IA

Tyrosinasepositive (Ty-pos) II

AR'~

AR$

Tyrosinase negative (Ty-neg)

Allelic grouping Inheritance

Yellow mutant (Ym) tB AR

ChediakHigashi

HermanskyPndlak syndrome

syndrome

VI AR

AR

Clinical Hair Hair color

Skin Skin color

White throughout life

White, yeUow-tan; White at birth; darkens with yellow-red by age 6 mo

Pink to red

Pink-white to cream May be present and numerous

Pigmented Absent nevi and freckles Susceptibility + + + + to neoplasia Eye Eye color

+++

White at birth; Cream-gray to cream, slight tan light normal on exposed skin Present Present +

Blue in infancy, Blue, yellowdarkens with brown; age- and race-dependent age TransiUumina- No visible pigment Cartwheel effectw Adults---cartfion of iris or pupil and wheel effect lirnbus pigment Red reflex Present May be absent in Present dark-race adults

Fundal pigment Nystagmus Photophobia Visual acuity

Gray to blue

0

0 to + in adults

++++ + + to + + + ++4:.+ + + to + + + Most legally blind; Children, severe constant or defect; adults, worse with age same or better 20/200 to 20/ 20/60 to 20/ 400+ 400+

White, red, brown

0 to + in adults + to + + + + to + + May improve with age; 20/90 to 20/400

+++

Blond to dark brown; steel gray tint Pink to pinkwhite Present ++

Blue-gray to brown; race- and agedependent None to cartwheel effect

Blue to dark brown Cartwheel effect to normal Present in light Cau- Present, casians; less afnot in dark ter 5 adults years 0 to + in adults + to + + + 0 to + + + + to + + + + 20/70 to 20/400

Adapted from Witkop CJ, et al?~; publishedwith permissionfrom McGraw-HillBookCo., New York, NY. *Only syndromein which melanocytesare absent in the area of leukoderrna;not a true form of albinism. tCaucaslans 1/39,000; blacks 1/28,000 (in United States). :~Caucasians 1/37,000; blacks 1/15,000 (in United States). w effect--on transillumination, pigmentdepositionin iris results in a pattern of radial spokes.

0 to + + 0 to + + Normal to moderate decrease

Volume 19 Number 2, Part 1 August 1988

Cross syndrome

AR

Biology of hypopigmentation

Rufous

(red)

Brown albinism IV AR

albinism

V AR

Autosomal dominant ocuiocntaneous albinism VII AD

Minimal pigment IlI AR

229

Black locksalbinism-deafness syndrome* AR

White to light blond

Beige to light brown in Africans

Mahogany red to White to cream with White to light deep red reddish tint yellow

Snow white with pigmented locks

Pink to pinkwhite

Cream to light tan

Red-brown

White to cream

Pink-white

Present

May be present

May be present

May be present

Absent

Unknown

+ (similar to Low Caucasians in

Unknown

Unknown

White with melanized macules May be present in macular areas Unobserved (probably

++++)

Africa) Gray-blue

Hazel to light brown

Unknown; cataracts

Cartwheel effect Slight

Unknown; cata- Present in chilracts dren; may be absent in adults Unknown; cata- + to ++ in racts adults + + + to + + + + + to ++ Unknown + to ++ Blind 20/30 to 20/150

Red-brownto brown

Gray to blue

Gray to blue

Gray-blue

Translucent to pigment ring

No visible pigment

Unknown

Translucent to cartwheel effect Present in children

Present

Present in children and adults

+ to + + +

0 to+

0 to ++ 0 to ++ Normal to 20/100

++ to + + + + + to + + + 20/70 to 20/200

0 + + + to + + + + +++ to + + + + 20/160 to 20/200

0 ++++ ++++ 20/300 to 20/ 400+

continued

Journal of the American Academy of Dermatology

Bolognia and Pawelek

230

Table

III. Cont'd

Type Al~lie grouping Inheritance

Tyrosinase negative (Ty-neg) IA AR%

Tyrosinasepositive (Ty-pos) H

Yellow mutant (Ym)

AR~

AR

HermanskyPudlak syndrome VI AR

ChediakHigashi syndrome AR

Laboratory Hair bulbs Melanosomes in hair bulbs

Stages I and II only

Incubation of hair bulbs in L-tyrosine, or L-dopa pigmentation Detection of + heterozygote carrier by hair bulb tyrosinase activity Tyrosinase activity in: Homozygote Absent hair bulb

Heterozygote hair bulb Other

To early stage III

To stage III; pheomelanosornes

+

Variable*

-

+

To stage III; Giant and normal pheomelanostage IV somes; occasional macromelanosome

+ (slight)

-

+

Unknown

Moderate to high

Absent to low

Absent to moderate Unknown

Moderate Absent to low Prenatal diagnosis by skin biopsy2o5

Absent to low

Low to moderate

are particularly resistant to therapy? ~5 This m u s t be weighed against the social and psychologic impact of this disease on the particular patient. 11~ Topical psoralen therapy has also been successful, particularly in localized forms of vitiligo.~7, Hs However, it can produce painful phototoxic reactions as well as areas of hyperpigmentation at the borders of treated lesions. In order to decrease

If incubation with Hemorrhagic diath- Susceptibility to tyrosine and esis 2 ~ to platelet infection; giant cysteine---instorage defect; lysosomal-like creased red or ceroid-like deposgranules in yellow pigment; its in RE system, leukocytes; common in lung, and gastrolymphoreticular Amish 2~ intestinal tract malignancy (se~ text) (see text)

these side effects, the patient should use a UVAabsorbing sunscreen between treatments to prevent unintentional overexposure. Initial U V A exposures should be 0.12-0.25 joule/era 2, and the commerciaUy available psoralen solutions should be diluted, for example, 1% 8-MOP is diluted to 0.1% or 0 . 0 1%.114,119,120

Other forms of therapy for vitiligo include

Volume 19 Number 2, Part 1 August 1988

Cross syndrome

AR

Scanty; stage III; some stage IV

Biology of hypopigmentation

Brown albinism

Rufous (red) albinism

IV AR

V AR

To stage III; few IV

Unknown

Autosomal dominant oculocutaneous albinism VII

Minimal pigment Ill

AD

AR

Stage I to early stage III

Stage I and II

231

Black locksalbinism-deafness syndrome* AR

White hair and skin--no melanocytes; pigmented hair and skin--normal melanoeytes and melanosome8

+

+ (slight)

+

+

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Pigmented hairs + white hairs +

Absent

Unknown

Unknown

1 parent--normal 1 parent--low 1~ MicrophthalFound only in Seen in Africans mia; oligophre- Africans and and New nia; gingival New Gllineans Guineans2~ fibromatosis; to date athetosis

topical and intralesional corticosteroids, 84,121.122topical 5-ttuorouracil, 123,124cosmetic cover-ups, such as Dermablend and Covermark, and autografts. 1~5-1z7 Autografts are particularly useful in cases of segmental vitiligo because this form of the disease is usually stable and does not respond as well to psoralens, 128In children under the age of 12, topical steroids and topical psoralens are used more fre-

Profound sensorineural deafness

quently. In all cases it is necessary to protect the depigrnented skin from the harmful effects of U V irradiation through the use of a broad-spectrum sunscreen, preferably SPF-15. Sunscreens also reduce the contrast between depigmented and normally pigmented skin, which is especially important i n patients with skin type I or II who choose no treatment other than cover-ups.

232

Bolognia and Pawelek

Fig. 16. A Puerto Rican woman with HermanskyPudlak syndrome. Hermansky-Pudlak syndrome is a ty-pos form of OCA and this patient had brown eyes, red-brown hair, freckles, and pigmented nevi. In comparison to her first-degree relatives, she had an obvious pigmentary dilution. (Courtesy R. Langdon, M.D., New Haven, CT.) In severe widespread vitiligo in which the prospect of significant repigrnentation is dim, depigmentation of the entire skin surface can be accomplished with topical 20% monobenzyl ether of hydroquinone. ~29 The patient must be aware that the depigmentation from monobenzyl ether of hydroquinone can occur in areas other than the sites of application, is often irreversible, and complete depigmentation can require up to 10 to 12 months of therapy. It is interesting to note that this compound can cause an allergic contact dermatitis, but the reaction is limited to the uninvolved pigmented skin ~3~(Fig. 12). A diminished contact sensitivity response to dinitrochlorobenzene (DNCB) (efferent limb) has also been reported within the lesions of vitiligo, and one proposed etiology was a dysfunction of the Langerhans cells (afferent limb) in these areas. ~3~,m In patients with the clinical diagnosis of vitiligo, it is necessary to exclude an exposure to depigmenting chemicals such as phenols (see below). Vitiligolike leukodermas can also be seen in patients with scleroderma or malignant melanoma. In scleroderma, the leukoderma is said to resemble "repigmenting vitiligo," that is, perifollicular macules of pigmentation within areas of amelanosis (Fig. 13). 133This leukoderma tends to occur on extensor surfaces as well as the upper part of the trunk, and it can involve clinically normal skin. TM Dopastained epidermal sheets from these patients have

Journal of the American Academy of Dermatology

shown no functioning melanocytes in the areas of amelanosist35; ultrastructural studies have confirmed the absence of melanocytes, t36 The basis of this leukoderma is unknown--there is no evidence of inflammation in areas of involvement, but it can resolve if the underlying connective tissue disease becomes inactive. TM In contrast to idiopathic vitiligo, the depigrnentation in patients with melanoma often begins on the trunk and spreads centrifugally. 137 Biopsy specimens of the involved skin have revealed either a decreased number of large melanocytes or a total absence of melanocytes. 138'139 In two groups of patients with metastatic melanoma, the presence of this leukoderma was associated with prolonged survival. 137,139The possibility exists that the destruction of normal melanocytes results from an immune response against malignant melanocytes and that this immune response retards melanoma growth. The association of leukoderma and melanoma has also been reported in Sinclair miniature swines, but in these animals the leukoderma had no significant effect on the natural history of the tumors. 14~141 Halo nevi. In a halo nevocellular nevus (leukoderma aequisitum centrifugum or Sutton's nevus), a rim of depigmentation develops around a pigmented nevus (Fig. 14). The central nevus often tightens in color and may disappear, while the amelanotic halo may or may not repigrnent. Histologic examination of a halo nevus usually shows a bandlike infiltrate of mononuclear cells admixed with the nevus cells and a marked reduction or absence of melanocytes in the epidermis of the halo. 142 Occasionally either no infiltrate is found, despite a classic clinical presentation, or an infiltrate is seen in the absence of a halo. 143Antimelanoma antibodies, as well as lymphocytes cytotoxic to aUogeneic melanoma cells, have been described in patients with active halo nevi, 144,~45 lending support to an immunologic reaction against the pigment cells. Evidence of destructive changes in the nevus cells and epidermal melanocytes has also been reported. 146,147 Halo nevi are observed most commonly on the trunk of young, healthy adults, but they can also be seen in patients with (1) melanoma, 148,149 (2) vitiligo or a family history of vitiligo, ~~ and (3) the Vogt-Koyanagi-Harada syndrome. 1~~ There is some debate as to whether halo nevi and premature graying of the hair (before age 30) fall within the

Volume 19 Number 2, Part 1 August 1988

Biology of hypopigmentation 233

B,

A. R, eye

L, eye

decreased Lateral i f Genlculate

~X

o.n,cu,a,o

,,.

)

///',~T_y

~

\ ) "- _ ~ , \

Cortex

Fig. 17. Schematic drawing of retinal --~ geniculate --~ visual cortex pathways. 216,2~7A, In vertebrates with binocular vision, fibers from the temporal aspect of the retina remain ipsilateral and fibers from the nasal aspect of the retina decussate. This results in fusion of similar fields of vision. B, In albino mammals and in vertebrates with monocular vision, there are reduced or absent ipsilateral fibers. (From Witkop CJ, King RA, Creel DJ. Pigment Cell 1976;3:201-10; published with permissionfrom S. Karger AG, Basel.)

spectrum of vitiligo. 151'152 Halos of hypopigmentation have also been described in the following lesions: primary melanomas (some of which have regressed),14~.1s3metastatic melanomas,~54congenital nevi, blue nevi, 'ss histiocytomas)s6 basal cell carcinomas, 157 neurofibromas,'58 seborrheic keratoses, and involuting flat w a r t s J 59 Vogt-Koyanagi-Harada syndrome. Classical Vogt-Koyanagi syndrome consists of: (1) vitiligo, (2) poliosis--eyelashes, eyebrows, scalp and body hair; (3) alopecia---circumscribed more often than diffuse; (4) acute nontraumatic anterior uveitis-iritis, iridocyclitis, or cyclitis; and (5) tinnitus, hearing loss, and dysacusis (ear discomfort from certain sounds). Harada's disease is characterized primarily by: (1)posterior uveitis---choroiditis, (2) retinal detachment, and (3) aseptic meningitis.16~ However, an overlap in the manifestations of these two syndromes is frequently observed and they are routinely combined into one clinical entity. Signs of meningeal irritation often precede the uveitis and dysacusis, while depigmentation of the skin (60% of patients) and hair (80%-90% of patients) frequently appears as a third phase of the diseaseJ61 An increased incidence of the Vogt-KoyanagiHarada syndrome has been reported in orientals, blacks, and heavily pigmented whites. 162Lymphocytes from patients with Vogt-Koyanagi-Harada syndrome have been shown to undergo blast transformation when mixed with bovine uveal pigment,

and they exhibit cytotoxicity toward allogeneic melanoma cells in vitro. '63,'64It has been suggested that the clinical findings of uveitis, dysacusis, and aseptic meningitis result from the death of melanocytes in the uveal tract, inner ear, and leptomeninges, respectively)~~ Chemical leukoderma

The topical application of several compounds, including catechols and phenols such as hydroquinone and monobenzyl ether of hydroquinone, can result in a decrease or loss of cutaneous pigmentation. This effect was first noted on the hands and arms of factory workers who wore rubber gloves containing monobenzyl ether of hydroquinone as an antioxidant.'6s. 166There followed several reports of similar pigmentary changes in patients exposed to phenol-containing germicides, hydroquinone photographic developer, and a variety of monobenzyl ether of hydroquinone-treated rubber products. ,67.x68The chemical structure of these phenolic compounds is very similar to that of the melanin precursors, and their cytotoxic effects on pigment cells are also quite similar (Fig. 15). 1~ Following the reports of monobenzyl ether of hydroquinoneinduced leukoderma, it was used as a topical treatment for several disorders of hypermelanosis169 until it became clear that areas remote from the site of application could also undergo depigmentation and the depigmentation was permanent in a

234

Journal of the American Academyof Dermatology

Bolognia and Pawelek

Fig. 18. Areas of hypopigrnentation present since birth on legs of a patient with piebaldism. Involvement of mid portion of extremities is characteristic of this disorder. Maeules of hyperpigmentation and normal pigmentation are scattered within areas of leukederma.

significant number of patients. 17~Today the only clinical application for monobenzyl ether of hydroquinone is in the depigmentation of patients with widespread and unresponsive vitiligo. 129 Hydroquinone can also cause destruction of melanocytes, but its effects are limited to the area of application and the secondary hypopigrnentation is usually neither complete nor irreversible, especially when low concentrations (2% to 3%) are employedJ 71,J72It is currently used (often in combination with topical steroids and tretinoin) to treat several conditions, including melasma, lentigines, and postinflammatory hyperpigmentation.17z 173Prior to institution of therapy, lesions should be examined with a Wood's lamp to determine whether the increased pigment is in the epidermis (enhanced contrast) or the dermis (decreased contrast)Y 4 This provides valuable clinical information because hydroquinone is much more effective at reversing cutaneous hyperpigmentation when the excess melanin is located in the epidermis as opposed to the dermis, m The other side effects of hydroquinone include contact dermatitis, exogenous ochronosis, and pigmented colloid milium, t76'177 There are several possible explanations for the effects of monobenzyl ether of hydroquinone and related compounds on the pigmentary system. Quinones are capable of forming free radicals and reactive free radicals can oxidize lipid membranes.

Fig. 19. Ash leaf spot on leg of a child with tuberous sclerosis. Pigment within lesion was reduced but not absent. (Courtesy J. McGuire, M.D., New Haven, CT.) The destruction of cellular membranes can resuk in either cell death or a release of cellular antigens. When these antigens are released, they can activate circulating lymphocytes, which are then capable of reacting against other melanocytes. The pigment cell specificity of these toxic effects has been explained by the selective uptake and metabolism of phenols and catechols by tyrosinase. 178,45 A similar situation may exist in idiopathic vitiligo, except that the initial destruction would be secondary to the free radicals generated by melanin precursors. Lastly, there is an additional explanation for the depigmenting properties of hydroquinone: at relatively high concentrations in vitro, it inhibits tyrosinase activity and subsequent melanin formation. 179 Chemical leukoderma can mimic idiopathic vitiligo, both clinically and histologically. Therefore, an inquiry into possible chemical exposures should be done in patients with the diagnosis of vitiligo. Table II is a list of compounds that have been associated with cases of "occupational vitiligo." For a comprehensive fist of products that contain these chemicals, see reference 180. Oeuloeutaneous albinism

Oculocutaneous albinism is an inherited congenital disorder in which there is a generalized decrease or absence of pigment in the eyes, skin,

Volume 19 Number 2, Part 1 August 1988

Biology of hypopigmentation 235

Table IV. Diagnostic criteria for tuberous sclerosis*

Primary criteria (one required for diagnosis) Adenoma sebaceum (angiofibromas) Ungual fibroma (Koenen's tumor) Fibrous plaque on forehead or scalp* Retinal hamartoma Cortical tubers Subependymal glial nodules

Multiple renal angiomyolipomas

Secondary criteria (two required for presumptive diagnosis) Hypopigmented macules Shagreen patch Gingival fibromas Single peripapillary retinal hamartoma (indistinguishable from drusen) Seizures, including infantile spasms Wedge-shaped subcortical or cortical calcifications Multiple subcortical hypomyelinated lesions Multiple renal tumors or cysts Cardiac rhabdomyoma Pulmonary lymphangiomyomatosis First-degree relative with tuberous ,sclerosis

From Gomez MR, ed. Tuberous sclerosis, 2nd ed, New York: Raven Press, 1988; published with permission from Raven Press. *Recently included by Gomez. 24z254

and hair. Although these areas have a normal number of melanocytes, the ability of these cells to produce melanin is either reduced or absent. Tyrosinase-negative (ty-neg) oculocutaneous albinism is characterized by a complete lack of tyrosinase activity. However, in the other ten forms of ocutocutaneous albinism that have been identified to date, the primary biochemical defects are not well understood (Table III). Some of these patients have a decrease in tyrosinase activity, but the precise mechanism has not been established. In patients with ty-pos oculocutaneous albinism and normal levels of tyrosinase activity, there may be an abnormality in the regulation of more distal steps in the melanin pathway. 42 All forms of oculocutaneous albinism except one (autosomal dominant oculocutaneous albinism) are inherited as autosomal recessive traits. Two parents, both with oculocutaneous albinism, can have unaffected children if their forms of albinism are nonallelic or complementary. There have been reports of normally pigmented offspring in families in which one parent had ty-neg albinism (allelic group 1A) and the other parent had ty-pos albinism (allelic group II) (Table III). ~SzOnly the ty-neg (1A) and yellow mutant (Ym;1B) forms of oculocutaneous albinism are known to be allelic and therefore noncomplementary.

In order to establish the diagnosis and type of albinism, it is necessary to examine the skin, hair, eyes, and hair bulbs of the patient, as outlined in Table III. The primary clinical findings in oculocutaneous albinism include: (1) dilution in the color of hair, skin, and eye (iris and fundus), (2) nystagmus, (3) photophobia, and (4) decreased visual acuity. These clinical signs and symptoms vary inversely with the degree of pigmentation in the individual patient: The laboratory work-up can include: (1) an examination of hair bulb melanosomes by electron microscopy and (2) determination of pigment formation in anagen hair bulbs incubated in L-tyrosine or L-dopa. In the latter test, increased pigmentation is observed if the hair bulb contains active tyrosinase. 183 The complete absence of tyrosinase activity and pigment in ty-neg oculocutaneous albinism results in the most severe form of the disease. In contrast to the other forms of albinism, patients of all races with ty-neg oculocutaneous albinism have: (1) no increase in the pigmentation of skin, hair, or eyes with age, (2) no pigmented nevi, (3) no pigment formation when hair bulbs are incubated in etyrosine or L-dopa; and (4) no stage III nor stage IV melanosomes?~4 At birth, tyrosinase-positive infants (e.g., ty-pos, Ym, Hermansky-Pudlak syndrome) can resemble ty-neg infants with snow-

236 Bolognia and Pawelek

Iournal of the American Academy of Dermatology

Fig. 20. Nevus depigmentosuspresent since birth. This area of hypomelanosis followed Blaschko's lines (see Fig. 22) and did not cross the midline. (Courtesy J. McGuire, M.D., New Haven, CT.) white hair and pink-white skin, but as they age they usually acquire some pigmentation (Fig. 16). The degree and type of oculocutaneous pigmentation depend on the racial background of the patient and the particular subtype of ty-pos oculocutaneous albinism. By using a modification of the Pomerantz assay, King has developed a method of detecting carders of oculocutaneous albinism? s5,~86 In this assay, the level of tyrosinase activity is reflected in the production of tritiated water from tritiated tyrosine. Anagen hair bulbs served as the source of tyrosinase and reduced levels of this enzyme were found in ty-neg and Ym obligate heterozygotes when they were compared to controls (Table III). In contrast, an overlap was seen between the levels in the ty-pos or HermanskyPudlak heterozygotes and in those of the control group. In conclusion, the test is useful in the detection of carriers of either ty-neg or Ym oculocutaneous albinism. There are two forms of tyrosinase-positive oculocutaneous albinism having distinct clinical characteristics that aid in the clinical diagnosis. They are the Hermansky-Pudlak syndrome and the Chediak-Higashi syndrome. Patients with HermanskyPudlak syndrome have a bleeding diathesis secondary to a platelet storage pool defect. These platelets have decreased numbers of dense granules and decreased levels of substances normally stored in

Fig. 21. Streaks of hypopigmentationin a patient with hypomelanosis of Ito. Distribution of these lesions is along the lines of Blaschko (see Fig. 22). (Courtesy J. McGuire, M.D.; from Rudolph AM, Hoffman JIE. Pediatrics. 18th ed. Norwalk: 1987, Appleton & Lange; published with permission from Appleton & Lange, Norwalk, CT.)

them, for example, serotonin and adenosine diphosphate (ADP). 187 The aggregation patterns of these platelets in response to agents such as epinephrine and collagen are abnormal? 88Patients often give a history of epistaxis, easy bruising, or prolonged bleeding following tooth extraction or childbirth. There are also deposits of lipid and ceroidlike material in the macrophages of the bone marrow, lymph nodes, liver, spleen and lung, mucosa of the gastrointestinal tract, and renal tubular cells, 189'19~ In the lung these deposits can lead to interstitial fibrosis and restrictive pulmonary disease, and in the gastrointestinal tract they lead to granulomatous colitis. 1~1,~gzThe following findings are useful in diagnosing Hermansky-Pudlak syndrome: (1) ceroidlike deposits in bone marrow macrophages, circulating leukocytes, buccal mucosal cells, or the urinary sediment, which exhibit a yellow autofluorescenee~9~; (2) a prolonged bleeding time; (3)

Volume 19 Number 2, Part 1 August 1988

Fig. 22. Lines of Blaschko as described in 1901.327 They were based upon clinical observations of patterns of nevoid skin lesions such as linear and systematized epidermal nevi and linear nevus sebaceus. In addition to hypomelanosis of Ito, there are several other inherited disorders in which cutaneous lesions follow these lines, including incontinentia pigmenti (X-linked dominant), focal dermal hypoplasia (X-linked dominant), chondrodysplasia puncta (X-linked dominant), and carriers of Menkes' syndrome (X-linked recessive)27~Hypohidrotic areas in female carriers of X-linked hypohidrotic ectodermal dysplasia also follow these lines.3~8 an abnormal platelet aggregation curve (lack of the second irreversible wave); (4) decreased pulmonary diffusing capacity (DL~o); and (5) interstitial fibrosis on chest x-ray examination. Hermansky-Pudlak syndrome is most frequently observed in people from southern Holland and the Arecibo region of Puerto Rico. Patients with the Chediak-Higashi syndrome havel94: (1) recurrent pyogenic sinopulmonary and cutaneous infections; Staphylococcus aureus is the most common pathogen; (2) granulocytes with giant lysosomal granules that fail to discharge their contents into phagocytic vacuoles in a normal mannerS95; (3) peripheral neuropathy; (4) an accelerated phase with pancytopenia and lymphohistiocytic infiltrates of the lymph nodes, spleen, and liver; and (5) death at an early age, usually prior to age 20. Some of the patients also have a 'platelet storage pool defect with a secondary bleeding diathesis. ~96 In Chediak-Higashi syndrome, the

Biology of hypopigmentation 237

Fig. 23. Idiopathic guttate hypomelanosis. Extensor surface of legs is the most common location for this acquired disorder of hypomelanosis. (Courtesy R. Hartman, M.D., Van Nuys, CA.) abnormally large cytoplasmic granules, including lysosomes and melanosomes, are thought to be secondary to an ongoing fusion of organeUes. 197The macromelanosomes in the melanocytes pass with difficulty to surrounding keratinocytes and there is destruction of melanosomes within phagosomes in the melanocytes and keratinocytes of these patients. ~98 The combination of these events leads to a pigmentary dilution. The differential diagnosis of Chediak-Higashi syndrome includes the Griscelli syndrome, which is associated with (1) thrombocytopenia, (2) neutropenia, (3) recurrent pyogenic infections, (4) immunodeficiency--hypogammaglobulinemia, defective helper T cell function, and a lack of delayed skin hypersensitivity, (5) hepatosplenomegaly, and (6) silvery gray hair as well as areas of cutaneous hypopigmentation. ~99 The pigmentary changes seem to be secondary to a block in the transfer of melanosomes to keratinocytes, but there are no giant lysosomal or melanosomal granules in this disorder. The reduced cutaneous pigmentation of albinos results in photosensitivity, an accelerated photoaging of the skin, and an increased incidence of solar keratoses and squamous cell carcinomas. Preven-

238

Bolognia and Pawelek

tion of these complications involves avoidance of U V light, the use of sunscreens, and routine skin examinations. Genetic counseling and detailed ophthalmologic examination and follow-up also play an important role in the care of the patient with oeulocutaneous albinism. Those patients with Hermansky-Pudlak syndrome should be warned against the use of aspirin and other inhibitors of platelet adhesion, whereas the patients with Chediak-Higashi syndrome must be monitored frequently for infection and the accelerated phase of their disease. Oculocutaneous albinism must be distinguished from oculocutaneous albinoidism, which is an unusual autosomal dominant disorder. The patients with albinoidism are characterized by white, yellow, or red hair, pink-white skin, and blue irides, but they do not have photophobia, nystagmus, nor a significant reduction in visual acuity2 9~ Tietz2~~reported the association of albinoidism with deaf-mutism and hypoplasia of the eyebrows, but existence of such a syndrome has been questioned)~1 There are other instances of generalized pigmentary dilution of the skin and hair in which the classical eye findings of oculocutaneous albinism, such as nystagmus, are not found. These include phenylketonuria (see below), homocystinuria, 2~ kwashiorkor, pancreatitis with malabsorption, TM and Menkes' kinky hair syndrome.2~176 Patients with Menkes' disease have low serum levels of copper, the metal ion required for tyrosinase activity. Lastly, total vitiligo can easily be distinguished from oculocutaneous albinism by lack of melanocytes in depigrnented skin. 2~176 Ocular albinism. In addition to the various types of oculocutaneous albinism, there are several forms of ocular albinism in which the pigmentary disturbance involves primarily the eye. These patients have congenital nystagmus, photophobia, decreased visual acuity, strabismus (primarily exotropia), diaphanous irides, hypopigmented fundi, and foveal hypoplasia. The various types of ocular albinism include: (1) X-linked recessive NettleshipFails (see below), (2) autosomal recessive, 2~ (3) X-linked recessive Forsius-Eriksson (associated with color blindness), (4) X-linked recessive Winship (associated with late-onset sensorineural deafness and the presence of macromelanosomes [giant

Journal of the American Academy of Dermatology

melanin granules that measure 3.5 to 5.0 gm in diameter] in normal skin,~~176 and (5) autosomal dominant (associated with congenital scnsorineural deafness and multiple cutaneous lentigines that on biopsy reveal macromelanosomes).190.2n The Nettleship-FaUs variant is the most common form of ocular 0Jbinism and is characterized by the presence of macromelanosomes in the melanocytes and keratinocytes of the skin and the pigment epitheliurn of the eye.212 When these male patients are compared to their unaffected siblings, a mild generalized cutaneous pigmentary dilution is seen in some cases. In addition, hypomelanotic macules and patches have been reported in several individuals with this form of ocular albinism. 21~,2~3Female carriers of Nettleship-Falls ocular albinism can be identified by the presence of: (1) pigmentary mosaicism of the peripheral aspect of the retina secondary to the Lyon phenomenon (random inactivation of the X chromosome), (2) partially translucent irides, and (3) macromelanosomes in the epidermis and dermis. The finding of macromelanosomes in the biopsy specimens of normal skin often plays a critical role in the diagnosis of Ncttleship-Falls ocular albinism, especially in the case of darkly pigmented individuals who can have pigmented fundi and no transillumination of the iris.m It also distinguishes Nettleship-Falls ocular albinism from both autosomal recessive and Forsius-Eriksson ocular albinism, the two forms of ocular albinism that are not associated with macromelanosomes.2OS,2~4 Optic traets in albinism. Patients with oculocutaneous and ocular albinism have several characteristic visual disturbances. They have congenital nystagmus and monocular, rather than the normal binocular, vision. The monocular vision is thought to be secondary to abnormalities in the optic pathways connecting the retina and the geniculate nuclei (Fig. 17, A). In vertebrates with laterally placed eyes and monocular vision, all of the optic axons decussate at the optic chiasm. In vertebrates with binocular vision, there is an increase in the number of fibers from the temporal retina that remain ipsilateral. This allows impulses from corresponding points in the two retinas (e.g., right temporal and left nasal) to project to the same area

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of the brain. 215 In the majority of animals and humans with albinism, there is a decrease or absence of these homolateral fibers216,2t7 (Fig. 17, B). When visually evoked potentials are recorded over the right and left occipital areas of scalp in albinos, there is a marked difference between the two hemispheres following monocular, but not binocular, stimulation. ~16The basis for the abnormal neural pathways is presumed to be a lack of pigment in the optic stalk during crucial steps in embryologic development.2~8 Similar abnormal pathways have been found in patients with other disorders of hypopigmentation, for example, the Prader-Willi syndrome, which is associated with obesity, hypogonadism, mental retardation, strabismus, and hypopigmentation in 50% of patients? t9 There is also evidence suggesting that albinos have abnormalities in the organization of the lateral geniculate nuclei,22~the geniculocortical tracts, and the auditory pathways of the brainstem. TM Patients with albinism experience photophobia as a result of excess light scatter in the hypopigmerited fundus. They also experience decreased visual acuity as the consequence of a hypoplastic fovea. It has been suggested that the normal hyperpigmentation of the foveal area may act as an inducer of differentiation in this area of the sensory retina during embryogenesis.213 The nystagrnus seen in these patients is presumably secondary to poor visual resolution that results from foveal hypoplasia215 as well as abnormal development of the abducens nucleus.TM Strabismus, both esotropia and exotropia, is a common finding in human albinos and may be a consequence of misdirected oculomotor reflexes.2~s

Phenylketonuria The majority of patients with phenylketonuria have an oculoeutaneous pigmentary dilution (blonde hair, fair skin, and blue eyes) in addition to mental retardation, seizures, hyperreflexia, dermatitis, and, rarely, scleroderma-like skin lesions,z~2a4 In this autosomal recessive disorder, the hepatic enzyme L-phenylalanine hydroxylase, which converts L-phenylalanine to L-tyrosine, is deficient. As a result, there are elevated levels of phenylalanine

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and its metabolites, such as phenylpymvic acid, in the serum and urine. One proposed mechanism for the hypopigrnentation is the competitive inhibition of tyrosinase by the excess L-phenylalanine.22~,226 Another proposal is a decrease in L-tyrosine, the first intermediate in the melanin biosynthetic pathway (Fig. 2). 43 Hair color darkening has been reported in several patients after they were placed on a low phenylalanine diet or given excess dietary tyrosine (1 g m / k g / d a y ) Y ,zz~ We propose a third possibility, that phenylalanine hydroxylase is directly involved in melanin production. This is based on the observation that phenylalanine hydroxylase is expressed in melanotic but not in amelanotie mouse melanoma cells in culture. 229

Piebaldism Piebaldism, also referred to as partial albinism, is a congenital disorder characterized by discrete patches of leukoderma. It is inherited in an autosomal dominant pattern and the common areas of cutaneous involvement include the scalp beneath the midfrontal white forelock, the forehead, mid regions of the upper and lower extremities, and the ventral aspect of the trunk. There is a characteristic sparing of the middorsal portion of the trunk. Within the symmetric areas of hypomelanosis, there are normally pigmented and hyperpigrnented macules of various sizes (Fig. 18). Hyperpigmented macules are also seen on normally pigmented skin. In contrast to vitiligo, the lesions in piebaldism are present at birth and the extent of involvement does not change significantly with age. Occasionally there can be darkening of affected skin following UV exposure.23~A biopsy specimen of areas without pigment reveals either a complete absence of melanocytes as is seen in vitiligo or a small number of morphologically abnormal melanoeytes with spherical, granular melanosomes.TM In both vitiligo and piebaldism, the clear cells in the basal layer are Langerhans cells. Because piebaldism is a stable leukoderma, autologous grafts or transplants of autologous cultured melanocytes can be used to repigment the areas of hypomelanosis.230, 231a Two mechanisms have been proposed to explain the skin findings in piebaldism: (1) a defect in the migration of melanoblasts from the neural crest to

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the ventral aspect of the skin during development and (2) a failure of melanoblasts to survive or differentiate into melanocytes once they reach the ventral aspect of the skin. 23z There is evidence of abnormalities in the neural crest and its melanoblasts in several strains of mice with white spotting (intrinsic defects), while other strains contain areas of skin in which the environment is hostile to melanoblasts (extrinsic defects). 23~ Piebaldism is primarily a cutaneous disorder, but it has been associated with Hirschsprung's disease (congenital megacolon secondary to underdevelopment of Auerbach's plexus). This association has been described in both mice and humans, and it points to an abnormality in the embryonic migration of two neural crest-derived elements, melanocytes and myenteric ganglion cells.234,235There have also been case reports of associated mental retardation and cerebellar ataxia. :36 In two of the patients with mental retardation, interstitial deletions of chromosome 4 were seen. 237,~8 The overlap of piebaldism with Waardenburg's and Woolf's syndromes will be described in the next section. Waardenburg's syndrome. Waardenburg's syndrome is an autosomal dominant disorder that has variable expression and is characterized by: (1) lateral displacement of the inner canthi in the presence of a normal interpupiUary distance (99% of patients in Waardenburg's original series; 77% of patients in later series), (2) broad nasal root (78%), (3) confluent eyebrows due to hypertrichosis of their medial portions (45%), (4) iris heterochromia, partial or total (25%), (5) congenital sensorineural hearing loss, unilateral or bilateral (20%), and (6) a white forelock (at least 17%). 2~ It should be noted that the more recent series have included patients with bilateral pale blue (isohypochromic) eyes, and this may account for the difference in the reported incidence of dystopia canthorum. In addition, the white forelock disappears in some patients as they age, and this certainly affects its reported incidence. Premature graying of the hair has also been observed, and an estimated 12% of patients have lesions of piebaldism in addition to the white forelock.TM In white cats, there is an association between iris heterochromia and deafness; when the inner ears of

these animals were examined, no pigment was seen. 239As stated previously, active melanocytes are normally present in the inner ear and they may serve a function during the development of this organ. An alternative explanation for the congenital hearing loss is the failure of nerve cells to migrate properly from the neural crest to the inner ear. ~ Examination of the inner ear of a patient with Waardenburg's syndrome did reveal an absent organ of Corti and atrophy of the spiral ganglion in the presence of an intact auditory pathway. A defect in the neural crest or in the migration of its components could result in both the pigmentary changes and the deafness seen in these patients. Unfortunately, there is no unifying concept or developmental mechanism to explain aU of the findings in Waardenburg's syndrome. There are two additional disorders in which patients have deafness in association with circumscribed hypomelanosis. Woolf's syndrome was originally described in two American Indian brothers who had congenital sensorineural deafness and piebaldism. TM They did not have any of the other manifestations of Waardenburg's syndrome such as dystopia canthorum, broad nasal root, or hypertrichosis of the eyebrows. Because of this association, patients with piebaldism should have routine auditory testing performed. Ziprkowski et al. 242,243 described 14 members of one family who inherited congenital deafness as an X-linked recessive trait. They also had white hair, iris heterochromia, and geographic areas of hypopigrnentation and hyperpigmentation, with a resemblance to leopard skin. Except for areas of gluteal and scrotal skin, the hyperpigmentation was not present at birth. In contrast to piebaldism, the number of melanocytes was normal in involved areas and the activity of these melanocytes correlated with the degree of pigmentation. Tuberous sclerosis

Tuberous sclerosis is a phakomatosis characterized by the classic triad of epilepsy, mental retardation, and adenoma sebaceum (multiple angiofibromas). It is an autosomal dominant disorder, but in at least one half of the patients it results from spontaneous mutation.244.245There is evidence that

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the gene for tuberous sclerosis is on chromosome 9, but the basic defect is unknown.TM The earliest cutaneous sign of this syndrome is the ash leaf spot, which is usually present at birth (Fig. 19)? 47 Examination of the skin with a Wood's lamp aids in the detection of this circumscribed leukoderma, especially in fair-skinned infants. In patients with tuberous sclerosis, the reported incidence of ash leaf spots varies from 50%248to 98%. 249In one study approximately 90% of these dull white macules were on the trunk or lower extremities?49 The number of lesions can vary from 1 to 100, although one half of patients have 5 or less,249 and the size ean vary from 1 mm to 12 cm, with the majority in the range of 1 to 3 cm. 25~The more common shapes are oval, polygonal, and ash leaf or lance-ovate (tapered at one end and round at the other) and the less common are dermatomal and confetti-like. In contrast to vitiligo, the ash leaf spots are stable in size and shape and the pigment within them is reduced but not absent. Occasionally there are lesions that have perifollicular pigmentation?s~ Electron micrographs of hypopigmented skin have shown a normal number of melanocytes, a decreased number of melanosomes in melanocytes, and abnormally small melanosomes that are poorly melanized.TM As a reflection of their small size, the melanosomes in black patients formed complexes within the keratinocytes of lesional skin, rather than being singly dispersed. The reduction in melanosomal size has not been observed as consistently as a decrease in the number of pigmented melanosomesY2 The basic abnormality in ash leaf spots appears to be an arrest in the maturation of melanosomes. Additional cutaneous signs of tuberous sclerosis include poliosis, connective tissue nevi (shagreen patches), caf6 au lait spots, fibromas, most commonly ungual and gingival, soft fibromas of the neck and axillae, and fibrous plaques of the forehead.253-255 The differential diagnosis of ash leaf spots includes nevus depigmentosus, nevus anemicus, and vitiligo. Patches of vitiligo are amelanotic rather than hypomelanotic because of the loss of melanocytes, and the areas of involvement tend to change with time. In addition, vitiligo commonly involves the face, hands, and feet, whereas ash leaf

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spots usually spare these areas. Nevus anemicus is a localized vascular abnormality that presents as an area of pale skin. It lacks a flare response to rubbing or heat and the number and function of the melanocytes within a nevus anemicus are normal. Also, the border of the lesion can be obscured by diascopy, and it becomes inapparent under the illumination of a Wood's lamp. In nevus depigmentosus there is a decrease in the transfer of melanosomes to keratinocytes, but the size and melanin content of the melanosomes are normalY t If the hypomelanotic macules are lance-ovate in shape or there are three or more such lesions, the diagnosis of tuberous sclerosis must be ruled out. 247'249 If there is a combination of hypopigmented macules and seizures, the diagnostic criteria for tuberous sclerosis have been met (Table IV). 25~In addition to a thorough cutaneous examination with a Wood's lamp, the work-up can include an examination of the retina for phakomas (astrocytic hamartomas), an electroencephalogram, cranial computed tomography (periventricular calcifications) or magnetic resonance imaging (hamartomas), renal or cardiac ultrasound (angiolipomas, cysts, rhabdomyomas), x-ray examination of long bones, hands, and feet (sclerosis, pseudocysts, periosteal new bone), and an examination of family members. 245,256.257 Nevus depigmentosus Nevus depigmentosus is a stable, well-circumscribed hypomelanosis. It is present at birth, although it may not be readily apparent, especially in fair-skinned individuals. In most patients there is a single lesion on the trunk or proximal portion of the extremities (Fig. 20). Three clinical patterns have been described25k (1) isolated (circular or rectangular), (2) dermatomal, and (3) systematized (whorls or streaks predominantly in a unilateral pattern)? ~8The lesions are uniformly hypomelanotic but not amelanotic, and they become more apparent with a Wood's lamp examination. Biopsy specimens of nevus depigmentosus have revealed either a normal number or a decreased number of melanocytes, depending on the series of patients.251,259 The size and melanization of the melanosomes are normal. A defect in the transfer of

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melanosomes from melanocytes to keratinocytes has been reported. TM One explanation for this finding is the aggregation and degradation of melanosomes within autophagosomes of the melanocytes?6~ The proposed mechanism for nevus depigrnentosus is nonspecific--a developmental defect that affects pigment cell function. Evidence for a neurocutaneous disorder is limited to a few reports of associated seizures and mental retardation. TM Unilateral hypertrophy of the extremities on the same side as the nevus depigmentosus has also been described. 2~z The differential diagnosis of nevus depigmentosus includes segmental vitiligo, nevus anemicus, ash leaf spot, and hypomelanosis of Ito. Segmental vitiligo is a relatively stable leukoderma, as is nevus depigrnentosus, but it is acquired and the skin is amelanotic. There is an absence of melanocytes in the biopsy specimens of depigmented skin, and under Wood's lamp illumination it is chalk-white in color. Nevus anemicus is a circumscribed area of skin lightening, but it has several distinguishing characteristics that are outlined above in the differential diagnosis of ash leaf spots. Ash leaf spots are seen in association with other signs of tuberous sclerosis, and electron micrographs of involved skin show small numbers of poorly melanized melanosomes within melanocytesY 1 Hypomelanosis of Ito (described in detail in the following section) is an autosomal dominant neurocutaneous syndrome characterized by ocular, musculoskeletal, and central nervous system abnormalities, as well as streaks and sworls of hypopigmentation. The cutaneous changes are congenital in approximately 45% of patients and the extent of involvement is not stable---early in the course of the disease it can progress and later it can regress. 26~,~64

Hypomelanosis of Ito (ineontinentia pigmenti aehromians) Patients with hypomelanosis of Ito have an array of sworls, streaks, and patches of hypopigrnentation that can mimic the pattern of a marble cake (Fig. 21). 263 On the trunk there is a tendency for the streaks to run parallel to one ar~other along the lines of Blaschko (Fig. 22), 265,266 The pigmentary pattern is reminiscent of that seen in the third

Journal of the American Academy of Dermatology phase of incontinentia pigmenti, except that the affected areas are hypomelanotic rather than hypermelanotic.2~7 The trunk and the extremities are the most common areas of involvement, and the distribution can be unilateral or bilateral. 263 As in other disorders of hypomelanosis, examination of fair-skinned individuals with a Wood's lamp aids in diagnosis. ~68In approximately 75% of the reported cases, the hypopigmented streaks were present at birth or they appeared during the first year of life.TM Initially there may be a progression in the extent of cutaneous involvement, but later in the course of the disease fading of lesions and repigmentation can o c c u r . 263, 264, 269, 270 Most evidence points to an autosomal dominant pattern of inheritance in hypomelanosis of Ito, 27~ but the ratio of female to male cases has been 2.5:1. TM Patients with this disorder often have abnormalities of the musculoskeletal system with resultant asymmetry, disorders of the central nervous system, primarily seizures and mental retardation, and disorders of the eyes, primarily strabismus and hypertelorism.264,269,271 Other associations include diffuse alopecia, transverse ridging of the nails, and dental anomalies.264,249In addition to the one case of a balanced translocation (chromosomes 2 and 8),272 both diploid/triploid mixoploidy and chromosomal mosaicism have been reported in patients with hypomelanosis of ]~to.265'273 Chromosomal analyses were performed in two of these patients because the deformities of their digits (expanded terminal phalanges and wide gaps between the first and second toes) were similar to those described previously in diploid/triploid mosaics. ~65 An explanation for the association of chromosomal mosaicism and a pigmentary disorder that follows the lines of Blaschko is the proliferation and migration of two clones of primordial melanocytes with different pigment potential.270.273.274In X-linked dominant disorders such as incontinentia pigmenti and focal dermal hypoplasia, random inactivation of the X chromosome (lyonization) would result in a similar pigmentary pattern. 275 A biopsy specimen of affected skin in hypomelanosis of Ito has revealed either a normal number TM or a decreased number of melanocytes.276'277 The

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more consistent finding is a decrease in the number of pigmented melanosomcsY~278 There are a few reports of a decrease in the size of the melanosomes.~34.276Intracellular vacuolization of both keratinocytes and melanocytes has been observed,2w,279 but, in contrast to incontinentia pigmenti, there was no evidence of inflammation, dyskeratotic keratinocytes, liquefaetive degeneration of the basal layer, or dermal pigment in either hypopigmented or normal skin. 263,269.279 There are other major differences between incontinentia pigmenti and hypomelanosis of Ito. Incontinentia pigmenti is inherited in an X-linked dominant fashion, it is usually lethal in hemizygous males, and a biopsy specimen of the hyperpigmented skin reveals deposits of melanin in the dermis and within dermal macrophages (pigmentary incontinence).28~In addition, an inflammatory vesiculobullous phase (stage 1) and a verrucous phase (stage 2) do not precede the lesions in hypomelanosis of Ito, as they often do in incontinentia pigmenti. However, an estimated 14% of patients with incontinentia pigmenti have linear streaks of hypopigmentation, most commonly on the extremities. 28~283There have been several examples in which these hypopigmented streaks were the sole manifestation of incontinentia pigmenti in obligate carriers?8~,283 The other area of overlap between hypomelanosis of Ito and incontinentia pigmenti is their association with ectodermal and mesodermal defects primarily involving eyes, teeth, musculoskeletal and central nervous systems. Nevus depigmentosus is the major consideration in the differential diagnosis of hypomelanosis of Ito. Nevus depigmentosus is a stable congenital leukoderma that is rarely associated with other abnormalities.263,284It is not inherited, the ratio of female to male cases is equal, and a biopsy specimen of involved skin can reveal a defect in transfer of melanosomes from melanocytes to keratinocytes. TM Patients with focal dermal hypoplasia (Goltz syndrome) can also have splashes and streaks of hypopigrnentation,285,284but this disorder is thought to be X-linked dominant and is usually lethal in males. It is characterized by multiple, often linear, areas of dermal atrophy that are often accompanied by hamartomas or herniations of

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subcutaneous fat? 86 Additional manifestations of this syndrome include periorificial papillomas, telangiectases, areas of aplasia cutis, linear or reticular hyperpigmentation, nail dystrophy, and focal alopecia, as well as defects of the musculoskeletal system, eyes, and teeth. Lastly, there was a single case report of a black female patient with sworls and streaks of hypopigmentation who was the sister of a patient with Menkes' kinky hair syndrome?~ Presumably she was a carrier of the X-linked recessive trait and the pattern was due to lyonization. The differential diagnosis of hypomelanosis of Ito is limited to those pigmentary disorders that follow Blaschko's fines. They can be the result of a somatic mutation or a clonal proliferation of two functionally different populations of cells due to either mosaicism or lyonizationY5

Idiopathic guttate hypomelanosis Idiopathic guttate hypomelanosis is an acquired leukoderma characterized by multiple well-circumscribed macules usually measuring 2 to 8 mm in diameter (Fig. 23). The lesions are off-white or porcelain-white in color and there is no associated scale or atrophy. The outline of the macules can be circular or angulated, the latter often following the skin lines. Idiopathic guttate hypomelanosis is a fairly common disorder, and the lesions tend to increase in number with age387 In one series of 452 patients, it was seen in only 2% of the patients between the ages of 20 and 30, but in 80% of the patients over the age of 70. 2ss The extensor surfaces of the arms and legs are the most common locations for this leukoderma. The predilection of idiopathic guttate hypomelanosis for sun-exposed areas has led to the suggestion that sunlight is a causative factor3 s7 However, lesions are also found in unexposed areas of the body and in all racesman alternative suggestion is that idiopathic guttate hypomelanosis is the result of an age-related "somatic" mutation of melanocytes.289 A biopsy specimen of a hypopigmented macule shows a decrease in the melanin content of the basal layer and a decreased number of dopapositive melanocytes39~ There is a sharp demarcation between the normal epidermis and the hypopigmented epidermis,29~and this is reflected in the

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clinical appearance. Ultrastructural studies have shown a partial loss of melanocytes as well as a decrease in the melanogenic activity of many of the remaining melanocytes.289,29~ Some investigators have also reported epidermal atrophy and flattenhag of the fete ridges,29l,295 but these changes may be related to aging. The differential diagnosis of idiopathic guttate hypomelanosis includes the confetti-like lesions of tuberous sclerosis, vitiligo, lichen sclerosis et atrophieus, postinflammatory hypopigrnentation, and tinea versicolor. Both idiopathic guttate hypomelanosis and lichen sclerosis et atrophicus are characterized by a sharp demarcation between normal and involved skin, but there is associated epidermal atrophy, follicular plugging, hydropic degeneration, and homogenization of the papillary dermis in lichen sclerosis et atrophicus. Biopsy of a lesion will distinguish the two entities. When there are hypopigmented macules on the arms or trunk, tinea versicolor can be distinguished by its associated scale and potassium hydroxide (KOH) examination of this scale. Once established, the lesions of idiopathic guttate hypomelanosis are stationary 293 and there have been no reports of spontaneous repigmentation. 29~ In one series of 15 patients, treatment with intralesional triamcinolone, alone or in combination with autologous minigrafts, resulted in significant repigmentation (>50%) in at least one half of the cases.TM There was also one report of partial repigmentation of idiopathic guttate hypomelanosis with PUVA therapy, but the effect was temporary.* Sunscreens help prevent the enhancement of preexisting tesions that can occur when the surrounding normal skin tans.

Pityriasis alba Pityriasis alba is a very common disorder characterized by scaly hypopigmented patches with indistinct borders. The lesions usually measure 0.5 to 3 cm in diameter, and they can have slightly raised edges as weU as mild erythema. TM This condition is aggravated by factors that dry the skin, but it is generally asymptomatic except for occasional mild pruritus. 29~Pitydasis alba is seen pre*MeDaniel WE, Richfield DF. Maeular hypopigmentation on the legs of women. Dermatol Dig 1965;4:59-69.

dominantly in children, ages 3 to 16, and the most common locations are the face and neck.2~ It can also involve the arms and shoulders and occasionally there is a widespread eruption that includes the lower aspect of the trunk and extremities. 29s,296The extensive form of pityriasis alba is seen primarily in young adults with no history of atopy; it tends to have less scale, a longer course, and no associated erythema. 29~,297 As with other disorders of hypopigmentation, pityriasis alba is more noticeable in dark-skinned individuals.298 There are severn explanations for the hypopigmentation observed in this disorder: (1) a block in the transfer of melanosomes from melanocytes to keratinocytes as a result of edema and inflammation, ~9(2) screening of UV light by the associated hyperkeratosis and parakeratosis, 295 (3) reduced numbers of functional melanocytes and melanosomes (based upon cases of extensive pityriasis alba), 29~and (4) a reduced capacity of hypermetabolic epidermal cells to take in melanin granules. 299 There is no evidence suggesting a role for bacteria or fungi in the pathogenesis of pityriasis alba as was implicated in the original descriptions of this disorder.294.295 A biopsy specimen of a hypopigmented macule has revealed a decrease in the epidermal pigment in addition to the changes of a nonspecific dermatitis (mild hyperkeratosis, parakeratosis, a perivascular round cell infiltrate, edema; and occasional exocytosis.~95 The differential diagnosis includes tinea versicolor and the causes of postinflammatory hypopigmentation (see below). Topical treatments for pityriasis alba include emollients, steroids such as hydrocortisone ointment, half-strength Whitfield's ointment, and tar. 294,:95.298Unfortunately the response to therapy is variable. In six cases of extensive pityriasis alba unresponsive to topical therapy, five cleared after 1 month of P U V A treatments. 297

Inflammatory disorders There are a few inflammatory disorders that can occasionally have hypomelanotic lesions throughout the course of the disease. Included in this group are alopecia mucinosa,300,301 pityriasis lichenoides chronica,3~176 cutaneous T cell lymphoma, 3~176 and sarcoidosis. 3~ In the cases of alopecia

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mucinosa, the head and neck were the predominant sites of involvement, whereas in pityriasis lichenoides chronica, the eruptions were usually more widespread and involved the arms, thighs, and axillary folds?~ A due to the diagnosis of pityriasis lichenoides chronica in some cases was the presence of a few interspersed brown-red, scaly papules. 3~ In these disorders, biopsy specimens of the hypopigmented lesions revealed changes in melanocyte function in addition to the characteristic pattern of inflammation. For example, ultrastructural studies in hypopigrnented cutaneous T cell lymphoma revealed degenerative changes in the melanocytes and disordered melanogenesis with spherical melanosomes?~ In one series of cutaneous T cell lymphoma patients there was reversal of the hypomelanosis following topical application of BCNU or mechlorethamine?~ It is possible that these alkylating agents suppressed the associated inflammation or that they enhanced the melanogenic activity of the pigment ceils, the latter being a known side effect of both 1,3-bis-(2-chloroethyl)-l-nitrosourea (BCNU) and mechlorethamine. The hypomelanosis seen in patients with sarcoidosis can be in the form of nodules within areas of hypopigmentation or macular areas of hypopigmentation.306.307Biopsy specimens of the infiltrated lesions have consistently revealed sarcoidal granulomas, whereas the majority, but not all, of the biopsy specimens from the macular areas contained granulomas in the dermis. Melanocyte counts are equal in involved and uninvolved skin,3~ yet electron micrographs have shown degenerative changes in the melanocytes that resulted in depressed melanogenesis?~ The hypopigrnentation seen in cutaneous sarcoidosis could be secondary to a factor released from the granulomas?~ This hypothetical factor might also be responsible for the hypomelanosis seen in other granulomatous diseases such as tuberculoid leprosy. After 8 months of topical PUVA therapy, one patient did experience satisfactory repigmentation of her facial lesions.3~ However, topical steroids, oral steroids, and antimalarials have been generally unsuccessful in reversing this form of cutaneous sarcoidosis. There are a number of cutaneous disorders that

Biology of hypopigmentation 245

are easier to recognize because the hypopigmentation is seen within the characteristic inflammatory skin lesion, during either its active phase or its resolving phase. Disorders associated with postinflammatory hypopigmentation include psoriasis, atopic dermatitis, eczematous dermatitis, discoid lupus erythematosus, pityriasis lichenoides chronica, guttate parapsoriasis, lichen striatus, and lichen sclerosis et atrophicus. Rarely, it is seen following lichen planus rather than the characteristic postinflammatory hyperpigmentation.31~ In eczema and psoriasis, there is a block in the transfer of melataosomes from melanocytes to keratinocytes.134 Edema secondary to inflammation plays a role in the block in eczematous disorders, whereas the increased proliferation rate of psoriatic keratinocytes shortens their contact time with melanocytes. In the disorders characterized by hydropic degeneration of the basa! layer and a lichenoid infiltrate, there is presumably an attack and destruction of melanocytes.

Infectious diseases

The following cutaneous infections are known to cause hypomelanotic or amelanotic skin lesions: tinea versicolor, leprosy, secondary syphilis, onchocerciasis, late pinta, and tertiary yaws. Tinea versicolor is due to invasion of the stratum corneum by Pityrosporum orbiculare, a lipophilic yeast. It is a common disorder frequently found on the upper part of the trunk and neck of young adults, although it can also involve the face, scalp, extremities, and lower part of the trunk? ~ The infection begins as either hypopigmented or hyperpigrnented macules that eventually coalesce into patches with scalloped edges. The hypopigmented lesions tan poorly and therefore they often become more apparent after exposure to UV light. There is an associated scale that is easily accentuated by scratching the lesions, and KOH examination of this scale is diagnostic--short, thick hyphae and round spores. The hypopigmented areas of tinea versicolor are characterized by a normal number of melanocytes whose dendrites are filled with small, sparsely melanized melanosomes.3'2,3t3 In addition, the number of melanosomes is reduced in many of the adjacent keratinocytes. Therefore, there is evidence

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for an abnormal maturation of melanosomes as well as a partial block in their transfer to keratinocytes. 31z An explanation for the poorly melanized melanosomes in tinea versicolor is the formation of C9 and C l l dicarboxylic acids, such as azelaic acid, by the Pityrosporum organisms. These diearboxylic acids are produced by cultures of the lipophilic yeast, and they are known to inhibit tyrosinase activity in vitro. 3~4After treatment of the tinea versicolor with selenium sulfide or imidazoles, the scaling resolves but it may take months for the hypopigmentation to clear. In patients with long-standing onchocerciasis, there can be areas of depigmentation in the pretibial region, the groin, and over bony prominences of the pelvic girdle. 315 In advanced cases, the areas of involvement resemble "leopard skin." This disease is endemic in tropical Africa and Latin America, and the vectors of Onchocerca volvulus are a few species of blackfly (Simulium). The diagnosis can be made by finding microfilariae in either bloodless skin snips or in the anterior chamber of the eye. In hyperendemic areas between 5% and 15% of the patients with positive skin snips have macules of amelanosis. 3L5'n6 Preceding the leukoderma many patients will have pruritus, excoriations, and lichenification (onchodermatitis) on the back, buttocks, and thighs) 's A biopsy specimen of the dermatitie skin shows degranulation of eosinophils, deposition of major basic protein on the cuticle of microfilariae, and degeneration of microfiladae2 tT,318Additional stigmata of onchocerciasis include skin atrophy, onchocercomas (nodules of adult worms), sclerosing lymphadenopathy of the groin and axilla, adenolymphoceles ("hanging groin"), punctate keratitis, and retinal degeneration)t~,3~6,3,9 All of these manifestations, including the dermatitis, are found more frequently in patients with the leukoderma. 3~5 In contrast to the ocular pathology, the Mazzotti reaction, and the pruritus, there is currently no evidence suggesting a role for immediate hypersensitivity immune responses in the pathogenesis of the leukoderma) ~s One proposed mechanism for this depigmentation is a toxin liberated by the microfilariae, living adult worms, or disintegrating adult worms n5 After excision of onchocercomas, one

third of the patients will have repigmentation of involved areas within 12 months. 316However, relative rates of repigrnentation following treatment with diethylcarbamazine, suramin, or ivermectin are not available. Attempts at repigmentation with topical or oral psoralens have not been particularly successful.3~s,32o Hypopigmentation is commonly observed in the tuberculoid and indeterminate forms of leprosy, while it is seen only occasionally in the borderline or early lepromatous forms of the disease. Tuberculoid leprosy is characterized by a few asymmetric patches of hypomdanosis that have associated anesthesia, anhidrosis, and alopecia. Enlargement of l~ripheral nerves is also found in this form of leprosy. A biopsy specimen of infiltrated areas, in particular the elevated borders, reveals granulomas in the dermis and along nerve bundles, in addition to a lack of organisms. In indeterminate leprosy there are a few hypopigmented macules that are hypoesthetic. The inflammatory infiltrate is nonspecific and there are few, if any, organisms. In areas of involvement the number of active melanocytes is usually decreased.TM The remaining pigment cells may appear normal322or they may show signs of decreased function and atrophy. 323 Proposed mechanisms for the pigment loss include: (1) decreased vascular supply,TM (2) release of factor(s) from the inflammatory cells, 322 and (3) depletion of 3,4-dihydroxyphenylalanine (DOPA), a melanin precursor, by the Mycobacterium leprae.3~ These bacteria possess an o-diphenyl oxidase that can convert DOPA to quinones, and, in vitro, M. leprae interfere with the production of pigment by melanocytes. There is currently little evidence supporting the first theory, and the lack of a correlation between the degree of hypopigmentation and the number of organisms is against the last proposal. TM Repigmentation follows treatment of the infection with dapsone. SUMMARY In summary, there are multiple disorders of hypopigmentation that one can further classify after determining features such as (1) inheritance pattern, (2) age of onset (congenital, childhood, or adulthood), (3) natural history (stable vs progres-

Volume 19 Number 2, Part 1 August 1988 sive), (4) type of pigment loss (diffuse or circumscribed), (5) distribution of lesions (generalized vs localized), (6) degree of pigment loss (incomplete or complete), (7) number of melanocytes, if any, in biopsy specimens o f affected areas, (8) type of melanocyte dysfunction, and (9) associated inflammation or infection. Insight into the pathogenesis of these hypomelanoses requires a working knowledge of pigment cell biology.

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316. Edungbola LD, Asaolu SO. Parasitologic survey of onehocerciasis (river blindness) in Babana district, Kwara state, Nigeria. A m J Trop Med Hyg 1984;33:114754. 317. Connor DH, George GH, Gibson DW. Pathologic changes of human onchocerciasis: implications for future research. Rev Infect Dis 1985;7:809-19. 318. Ottesen EA. Immediate hypersensitivity responses in the immunopathogenesis of human onchocerciasis. Rev Infect Dis 1985;7:796-801. 319. Lariviere M, Vingtain P, Aziz M, et al. Double blind study of ivermectin and diethylcarbamazine in African onchocerciasis patients with ocular involvement. Lancet 1985;2:174-7. 320. Browne SG. Onchocerciasis and the skin. S Afr Med J 1976;50:301-4. 321. Nayer A, Job CK. A study of epidermal melanocytes in hypopigmented patches of leprosy. Indian J Med Res 1970;58:187-93. 322. Breathnach AS, Birbeek MS, Everall JD. Observations

Biology of hypopigmentation

323. 324. 325. 326. 327. 328.

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