23.8 Disorders of pigmentation 5677 Eugene Healy

23.8 Disorders of pigmentation 5677 Eugene Healy

ESSENTIALS Normal human skin colour results from the reflection of light from haemoglobin in blood, and carotenoids and melanin pigmenta- tion in skin. Melanin pigmentation is the major component for determining differences in skin colour between races. Increases and decreases in skin pigmentation (hyperpigmentation and hypopigmentation, respectively) can be localized or generalized, can result from a wide variety of physiological or pathological pro- cesses, including both genetic and acquired factors, and may reflect underlying systemic disease. Addison’s disease (primary adrenocortical hypofunction) can re- sult in diffuse hyperpigmentation, more pronounced in sun-​exposed areas, sites exposed to trauma (such as the elbows and knees), the creases of the palms and soles, surgical scars, the buccal and gingival mucosa, as well as the nipples and genital region. Numerous drugs can cause changes in pigmentation (e.g. amiodarone can cause a blue-​grey discolouration of the skin, whereas bleomycin can cause a flagellate pattern of hyperpigmentation). Vitiligo is characterized by white patches of variable size, but in some darker-​skinned people the margin or entire patch may be an inter- mediate colour of light brown (trichrome vitiligo). Patches may be gen- eralized or segmental in distribution, and the borders are often irregular. In the generalized form lesions are usually symmetrical, and the more frequently involved sites are around the orifices (eyes, nose, mouth), flexures (axillae, groins, genitals), and extensor surfaces (elbows, knees, digits). The isomorphic or Koebner phenomenon can occur, in which trauma to the skin can produce lesions at that site. The skin is usually normal otherwise, with no evidence of scaling or atrophy. Microbial diseases such as pityriasis versicolor, leprosy, and syph- ilis are important infectious causes of hypopigmentation. Irrespective of cause and associations with underlying systemic disease, disorders of pigmentation can cause considerable distress to sufferers due to the visible nature of this condition. Introduction Melanin is synthesized in intracellular organelles called melanosomes by the melanocyte, a dendritic cell situated in the basal layer of the epidermis and in the hair follicle. Melanocytes develop from melanoblasts which arise from the neural crest and migrate to the skin during embryogenesis where they differen- tiate into melanin-​producing cells. The amount of melanin in the epidermis relates to constitutive skin colour (i.e. genetically de- termined white, brown, or black skin) and facultative skin pigmen- tation (e.g. resulting from ultraviolet radiation-​induced tanning). There are two types of melanin, brown-​black eumelanin and red-​ yellow phaeomelanin, and the combination of these in different proportions results in a wide variety of skin and hair colours worldwide. The biochemical pathways responsible for the syn- thesis of the two melanin types involve the sequential manufacture of several melanin intermediates from the precursor amino acid tyrosine, and require certain melanogenic enzymes, including tyro- sinase, tyrosinase-​related protein 1, and dopachrome tautomerase (tyrosinase-​related protein 2) (Fig. 23.8.1). Melanin-​laden melanosomes are passed along the dendrites of the melanocyte, and into adjacent keratinocytes; approximately 36–​40 keratinocytes receive melanin from a single melanocyte, thus forming the epidermal melanin unit. In keratinocytes, especially in the basal layer of the epidermis, the melanin becomes packaged over the nucleus to protect the DNA against incident ultraviolet (UV) radiation. It is widely accepted that eumelanin is photoprotective, with greater quantities of eumelanin in darker-​skinned races. Although there has been some debate about the photoprotective versus phototoxic effects of phaeomelanin, the evidence suggests that phaeomelanin in the physiological situation also protects against DNA damage caused by repeated exposure to UV. Some variation in pigmentation exists within and between dif- ferent skin sites in most individuals, for example, the freckling (ephelides) of fair Celtic skin, and the lighter pigmentation on the palms and soles of black skin. Increases and decreases in skin pigmentation (hyperpigmentation and hypopigmentation, re- spectively) can result from a wide variety of physiological and patho- logical processes. The degree to which alterations in pigmentation are obvious to an independent observer, and the amount of con- cern that they cause affected individuals, is often influenced by the patient’s natural (constitutive) skin colour and the extent to which the altered pigmentation contrasts with this. However, even minor alterations in pigment can cause significant distress to patients, pos- sibly related to the fact that mild pigmentary changes can often be 23.8 Disorders of pigmentation Eugene Healy

section 23  Disorders of the skin 5678 detected relatively easily by individuals from the same racial group as the affected person. Normal skin pigmentation Skin and hair colour varies within and across populations, with vari- ations in hair colour greater in light-​skinned than more pigmented races. Despite the large differences in constitutive skin colour be- tween races, and despite the number of melanocytes varying at dif- ferent body sites (with greater numbers on the face and genitals), similar numbers of melanocytes are present at comparable sites in white, brown, and black skin, but the melanosomes are signifi- cantly larger in black skin. Greater amounts of total melanin, es- pecially eumelanin, are present in darker coloured skin but, in general, all normal human skin contains a mixture of eumelanin and phaeomelanin, with the overall ratio and amount of these two mel- anin types determining skin colour. A combination of genome-​wide association studies and research on biological processes in skin/​melanocytes has identified multiple genes which influence variation in normal human skin, hair, and eye colour. A single evolutionary alteration in the SLC24A5 gene (OMIM 609802)  (substitution of threonine for alanine at codon 111) is responsible for lighter skin pigmentation, and has become fixed in European populations. In addition, certain heterozygous variants of the melanocortin 1 receptor (MC1R) gene cause fair skin type in white populations, whereas compound heterozygous and homozygous MC1R variants lead to red hair. Other genes relevant to variation in skin, hair, and/​or eye pigmentation within and across populations include the agouti signalling protein (ASIP)(OMIM 600201), tyrosinase (TYR) (OMIM 606933), tyrosinase-​related pro- tein 1 (TYRP1) (OMIM 115501), solute carrier family 45, member 2 (SLC45A2, also known as membrane associated transporter protein, MATP) (OMIM 606202), KIT ligand (KITLG) (OMIM 184745), solute carrier family 24 (sodium/​potassium/​calcium exchanger), member 4 (SLC24A4) (OMIM 609840), interferon regulatory factor 4 (IRF4) (OMIM 601900), pink-​eyed dilution (OCA2) (OMIM 611409), and HECT domain and RCC1-​like domain 2 (HERC2) (OMIM 605837) genes. In general, cutaneous melanocytes are restricted to the hair follicles in non​human primates and mammals, and it is thought that the development of melanocytes in human skin evolved in Africa as a means of photoprotection, possibly to prevent the photodegradation of folate and/​or to avoid blistering sunburn leading to infection and death in childhood and early adulthood. As human populations moved out of Africa, the subsequent light- ening of skin secondary to genetic changes might have occurred to enable the UVB-​induced synthesis of vitamin D in skin, or resulted from the loss of selective pressure from UV radiation (i.e. the lack of a requirement for high-​level photoprotection in places with lower UV radiation exposure), or possibly because of other non​pigment related evolutionary advantages (e.g. MC1R is expressed in many somatic tissues, including musculoskeletal and nervous systems, during embryogenesis). UV radiation-​induced pigmentation/​tanning UV radiation is a frequent cause of increased skin pigmentation, with UVB and UVA both able to stimulate tanning (Fig. 23.8.2). In general, the history of sun exposure is obvious, and there is a sharp cut-​off in pigmentation between exposed and unexposed sites. The speed of development, colour, and intensity of the tan differs be- tween individuals, with people having a Celtic skin phenotype less likely to tan, or more likely to tan poorly following UV radiation exposure. Several molecular mechanisms have been proposed to underlie the tanning response, and signalling via the melanocortin 1 re- ceptor secondary to increased α-​melanocyte-​stimulating hormone (αMSH) is thought to be one important mechanism. Although 5,6-dihydroxy- indole-2- carboxylic acid Tyrosine DOPAquinone Eumelanin CysteinylDOPA 1,4-Benzothiazine intermediates Phaeomelanin Tyrosinase Tyrosinase or Tyrosinase-related protein 1 DOPAchrome tautomerase Glutathione or Cysteine CysteinylDOPA- quinones Ortho-quinonimine LeukoDOPAchrome (cycloDOPA) DOPA DOPAchrome 5,6-dihydroxy -indole Indole-5,6- quinone Indole-5,6-quinone- carboxylic acid Fig. 23.8.1  Melanin synthesis pathways in the melanosome. DOPA, 3,4-​dihydroxyphenylalanine.

23.8  Disorders of pigmentation 5679 repeated exposure to UV radiation causes melanin synthesis and an increase in the total amount of melanin in skin, the initial changes in skin colour during tanning may result from a redistribution of some melanin to a higher level in the epidermis. In a single individual, the degree of melanin synthesis and thus the degree of tanning is dependent on the dose of UV radiation (including UV radiation in- tensity and duration of exposure). Whereas the increased amount of melanin in tanned skin is considered to offer greater protection against UV radiation, photoprotection by other mechanisms (e.g. thickening of the stratum corneum) is also physiologically im- portant. It should be noted that there are indications that tanning might be a response to DNA damage, which alongside the other ef- fects of UV radiation in skin (including photoaging and skin cancer) has led to the viewpoint that ‘there is no such thing as a healthy tan’. Hyperpigmentation The causes of hyperpigmentation are given in Table 23.8.1. Endocrine causes of hyperpigmentation Several hormones can stimulate melanin synthesis in melano- cytes. These include proopiomelanocortin (POMC), a peptide synthesized in the pituitary (a precursor of adrenocorticotropic hormone, ACTH), αMSH (the first 13 amino acids of ACTH), and β-​melanocyte-​stimulating hormone (βMSH). In Addison’s disease (primary adrenocortical hypofunction) the lowered serum cortisol level means that there is a lack of negative feedback on the pituitary synthesis of ACTH and related POMC peptides. This results in dif- fuse hyperpigmentation that is more pronounced in sun-​exposed sites, and is similar to that observed following the exogenous admin- istration of ACTH, αMSH, and βMSH. Pigmentation is also more evident at sites exposed to trauma, such as the elbows and knees, as well as at the creases of the palms and soles, surgical scars, the buccal and gingival mucosa, the nipples, and genital region; however, the absence of hyperpigmentation does not exclude the diagnosis of Addison’s disease (see Chapter 13.5.1). Hyperpigmentation in an Addisonian pattern can occur in Cushing’s syndrome (raised serum cortisol), where it arises from excess adrenocorticotropic hormone secretion from a pituitary ad- enoma (termed Cushing’s disease), or ectopic adrenocorticotropic hormone secretion from a malignancy (e.g. bronchial small cell car- cinoma, pulmonary carcinoid tumours). Similarly, diffuse marked hyperpigmentation is seen in Nelson’s syndrome following bilateral adrenalectomy for pre-​existing Cushing’s disease, where high cir- culating adrenocorticotropic hormone levels from a pituitary ad- enoma are increased further as a result of the absence of negative feedback by cortisol from the adrenals. Generalized pigmentation of the skin can also be observed in patients with thyrotoxicosis caused by Graves’ disease. Hyperpigmentation is also common in pregnancy, with darkening of the linea alba to form the linea nigra, and pigmentation of the nipples, genital skin, and face; the hypermelanosis of the cheeks, chin, and forehead is termed melasma (see next) and is also seen in women taking oral contraceptives. Melasma Melasma, also known as chloasma, is a hyperpigmentary disorder affecting the face. It generally develops symmetrically as darker brown areas on the cheeks, upper lip, forehead, and chin, and is seen more frequently in women, but also affects men. It is more common in darker-​skinned white individuals who tan well and in people with brown skin colour, and is more apparent following sun exposure, sometimes fading during the winter months and relapsing during the summer. In some cases histology shows increased melanin in the epi- dermis, whereas in others the melanin is in dermal melanophages. The exact pathogenesis of melasma is unclear, but several factors seem important in aggravating the condition (e.g. pregnancy, oral contraceptives, and exposure to UV radiation). Theories that have been postulated to explain its aetiology include the melanogenic effects of oestrogens, locally produced αMSH, aberrant Wingless-​ related integration site (Wnt) pathway signalling, and altered se- creted frizzled-​related protein 2 (sFRP2) expression in lesional skin. Some authors have suggested that the disorder might arise as a re- sult of a photosensitivity reaction to some ingredient in cosmetic products. In addition, certain drugs (e.g. phenytoin) can induce a melasma-​like condition. Melasma might resolve after parturition or when contraceptives are discontinued, but in a proportion of cases it can last for several years. Adherence to adequate sun protection measures is impera- tive as part of any treatment strategy. Topical bleaching agents, such as those containing hydroquinone, can be helpful, but it is important that the concentration of hydroquinone is not greater than 2–​4%, as higher concentrations seem more likely to cause hyperpigmentation (ochronosis), or in some cases be toxic to melanocytes and cause per- manent depigmentation. Hydroquinone can also be combined with topical corticosteroids to reduce the occurrence of contact dermatitis and post-​inflammatory hyperpigmentation. Other therapeutic agents include tretinoin, azelaic acid, and 4% N-​acetyl-​4-​S-​cysteaminylphenol, and a triple combination approach of topical hydroquinone, tretinoin, and a corticosteroid can have beneficial effects. Fig. 23.8.2  Ultraviolet radiation-​induced tanning in a white individual.

section 23  Disorders of the skin 5680 Chemical and drug-​induced hyperpigmentation Increased skin pigmentation at localized skin sites can occur fol- lowing contact with certain chemicals in plants and perfumes when combined with UV radiation exposure. Phytophotodermatitis is an inflammatory and hyperpigmentary reaction at a skin site that has been in contact with a plant containing furocoumarins or psoralens, and subsequently been exposed to UV radiation. The inflamma- tion (consisting of erythema and sometimes blistering) and later pigmentation is often streaked, because of the accidental nature of the contact between the plant juices and the skin. Although less fre- quent, berloque dermatitis is a similar entity in which the offending agent is bergapten (5-​methoxypsoralen), found in bergamot oil, which is present in some perfumes. The hands can be affected by phytophotodematitis after squeezing or slicing fruit, as this allows exposure to psoralens present in the peel. Topical treatment with nitrogen mustards can cause localized hyperpigmentation through an unknown mechanism. Another cause of linear streaks of pigmentation secondary to exogenous agents is that of following systemic therapy with the anticancer drug bleomycin, which induces a flagellate derma- tosis. The site of the reaction and the streaky nature of the initial inflammation and later pigmentation might be caused partially by scratching of the skin by the patient during the bleomycin therapy. Generalized pigmentation or more localized pigmentation of the mucosae and/​or nails can be seen during treatment with a wide variety of drugs and therapeutic agents. In some situations the cause is generally obvious to the patient, for example, during photochemotherapy for psoriasis with psoralen and UVA (PUVA). In cases of generalized pigmentation secondary to systemic medi- cations the discolouration of the skin can vary from brown to slate grey, depending on the causative drug (Fig. 23.8.3). Medications re- sponsible for this type of pigmentation are listed in Table 23.8.1. For example, amiodarone can cause a generalized blue-​grey discolour- ation of the skin. Fixed drug eruptions are localized inflammatory reactions in skin, caused by various agents including antimicrobials, analgesics/​ non​steroidal anti-​inflammatories, sedatives, mucolytics, metals, and halides. The inflammatory reaction recurs at the same skin site on each occasion the offending agent is ingested, and seems to result from ‘drug-​reactive’ intraepidermal CD8 + T cells in the skin at the affected location. Multiple lesions can occur, but in most cases soli- tary lesions are observed. Upon resolution of the inflammation there remains, in many cases, a brownish discolouration caused by pig- mentary incontinence resulting from damage to the basal layer of the epidermis; deposition of the melanin in dermal macrophages causes persistence of the pigmentation for weeks to months. The skin site often becomes progressively darker as more melanin accumulates Table 23.8.1  Causes of skin hyperpigmentation Type Cause Localized Lentigo type Lentigo simplex, lentigo senilis, lentigo maligna, Peutz–​Jeghers syndrome, xeroderma pigmentosum, LEOPARD syndrome, Carney complex, PUVA lentigines Café-​au-​lait type Normal skin (fewer than six), neurofibromatosisa type 1 (von Recklinghausen’s disease), McCune–​Albright syndrome, Fanconi’s anaemia Naevoid type Junctional naevus, congenital melanocytic naevus, Becker’s naevus, naevus spilus, naevus of Ota, naevus of Ito, Mongolian blue spot, seborrhoeic keratosis (early stage) Drugs Fixed drug eruption (caused by various drugs, e.g. nonsteroidal anti-​inflammatories), minocycline, bleomycin-​induced flagellate dermatosis Melasma Pregnancy, oral contraceptives, idiopathic Infections Erythrasma, tinea (pityriasis) versicolor Inflammatory/​ postinflammatory Lichen planus, psoriasis, eczema, trauma (e.g. burns), acne vulgaris Miscellaneous Incontinentia pigmenti, urticaria pigmentosa, acanthosis nigricans, morphoea, erythema ab igne, poikiloderma, tattoo ink, primary localized cutaneous amyloidosis (macular amyloidosis, lichen amyloidosis) Generalized Endocrine Addison’s disease, Cushing’s disease, Nelson’s syndrome, ACTH-​ and αMSH-​secreting tumours, thyrotoxicosis Drugs Phenothiazines/​chlorpromazine, antimalarials (chloroquine, hydroxychloroquine, quinine), anticancer drugs (busulfan, cyclophosphamide, dactinomycin, doxorubicin, fluorouracil, hydroxycarbamide, methotrexate), miscellaneous (amiodarone, minocycline, phenytoin) Ultraviolet radiation Natural sunshine, artificial sources (broadband UVB, narrowband UVB, UVA, PUVA) Postinflammatory Lichen planus, psoriasis, eczema, and so on Nutritional deficiency Malabsorption, malnutrition Miscellaneous Haemochromatosis, scleroderma, porphyria cutanea tarda, liver disease, dyskeratosis congenita, Fanconi’s anaemia, confluent and reticulated papillomatosis ACTH, adrenocorticotropic hormone; αMSH, α-​melanocyte-​stimulating hormone; PUVA, psoralen and UVA; UV, ultraviolet. Note that the distinction between localized and generalized is not absolute, and that generalized pigmentation can be diffuse (e.g. on the trunk) or consist of localized pigmentation on several body sites. a Neurofibromatosis is described in Chapter 24.17.

23.8  Disorders of pigmentation 5681 with each subsequent exposure to the drug. Discontinuation of the offending agent and its future avoidance is the treatment of choice. Urticaria pigmentosa Urticaria pigmentosa is the most common manifestation of a group of cutaneous mastocytosis disorders in which excess mast cells are present in the skin (Fig. 23.8.4). In the adult-​onset disease, which is usually lifelong, lesions often first appear in the 20–​40 year age group, and affect internal organs (e.g. bone marrow, liver) as well as the skin. By contrast, childhood-​onset disease typically arises in the first year of life, but can appear at any time in the first decade, and tends to clear spontaneously. The skin exhibits multiple brown or red-​brown macules and pap- ules on the trunk and limbs, which urticate on rubbing (Darier’s sign), causing oedema and redness typical of a weal and flare re- sponse. In one variant of the adult disease, known as telangiectasia macularis eruptiva perstans, the disorder is characterized by mul- tiple telangiectatic lesions on the skin. The lesions can be pruritic, and generalized flushing can occur as a result of mast cell degranula- tion. The cause of urticaria pigmentosa is unclear in most cases, but mutations in the KIT gene (OMIM 164920) have been identified in some affected individuals. Despite the lifelong aspect of the adult disease, the prognosis is generally good, although patients with mastocytosis are at increased risk of osteoporosis. The mainstay of treatment for mastocytosis is to avoid substances that trigger mast cell degranulation, and to sup- press the itch with antihistamines. Phototherapy (narrowband UVB or PUVA) can temporarily clear or improve the skin, but long-​term phototherapy can lead to skin cancer, and the skin lesions of urti- caria pigmentosa relapse when phototherapy is discontinued. Potent topical steroids can also clear the skin lesions, but the risk of steroid atrophy and systemic adrenocortical suppression limits their use. Assessment of bone mineral density, for example, by dual-​energy X-​ ray (DEXA) scan, is helpful for detecting concomitant osteoporosis. Incontinentia pigmenti Incontinentia pigmenti is a disorder with four recognized stages (vesiculobullous, verrucous, pigmented, and atrophic), although the lesions from the first three phases may overlap. The lesions, which are linear or grouped, tend to arise on the extremities (often on the flexor surface) and on the lateral parts of the trunk. The blistering phase, with erythematous areas and vesicles/​bullae, is seen at birth or usually within the first couple of months of life; it is thought that the disease can also begin and progress in utero. The warty lesions develop between two and six weeks of life, often on an erythema- tous base, in whorls or patches. Later, streaks and whorls of pig- mentation with an appearance suggestive of marble cake appear, and usually last for years. The pigmentation, which can appear re- ticulate and range from blue-​grey to brown, slowly resolves leaving atrophic hypopigmented reticulate areas, especially on the calves. Abnormalities of the teeth, nails, hair, eyes, and central nervous system can also occur. The X-​linked condition mainly affects females (more than 95% of cases), generally being prenatally lethal in males, although some cases have been reported in boys. The genetic alterations responsible for the disorder reside in the IKBKG (also known as NF-​κB essential modulator; NEMO) gene (OMIM 300248) on chromosome Xq28; most cases are accounted for by genomic rearrangement resulting in deletion of part of the IKBKG gene, rather than a single base muta- tion at this locus. IKBKG plays a role in the activation of NF-​κB, which functions as a transcription factor controlling inflammation, immunity, and apoptosis. In affected females, due to the random inactivation of an X chromosome (lyonization), cells expressing the abnormal IKBKG allele undergo apoptosis, and are replaced by cells with the active Fig. 23.8.3  Slate-​grey pigmentation, diffuse on the scalp and more pronounced at the nape of the neck, secondary to oral minocycline treatment for rosacea. Fig. 23.8.4  Multiple pigmented macules and papules on the trunk and upper limbs in a patient with urticaria pigmentosa.

section 23  Disorders of the skin 5682 IKBKG on the normal X chromosome. In affected males, this re- placement by cells with a normal IKBKG gene is not possible, re- sulting in intrauterine mortality, or death from infection during childhood. In females, treatment for the skin lesions is usually not required, but monitoring and treatment for other related problems is usually recommended, including ophthalmological monitoring for the first 3–​5 years of life. McCune–​Albright syndrome Also known as Albright’s syndrome, this condition consists of hyperpigmented (café-​au-​lait) patches, fibrous dysplasia of bones, and precocious puberty (the latter is more common in affected fe- males, but can also occur in males with McCune–​Albright syn- drome) (Fig. 23.8.5). The hyperpigmented patches vary in size, but are usually large with irregular/​jagged borders, and develop either at birth or more commonly during the first two years of life. The bone lesions, which often affect the long bones, tend to de- velop during the first decade of life and manifest as bone pains and fractures, and sometimes deformities. Cystic spaces are seen in the cortex of affected bones on radiography. Overgrowth of the skull can lead to problems with vision and hearing. Puberty begins be- fore 10 years of age in most females, and in the first 5 years of life in about half of all cases. Other endocrine problems are also en- countered, including hyperthyroidism, hyperparathyroidism, and Cushing’s syndrome. McCune–​Albright syndrome is caused by postzygotic somatic activating mutations in the stimulatory G protein gene (GNAS, also known as GNAS1; OMIM 139320), with the mutation frequently observed at codon 211, which normally codes for arginine in the wild-​type protein. Lifespan is usually normal, and therapies are dir- ected towards the treatment of complications. Fractures generally heal without sequelae. Localized pigmentation caused by dermal melanocytosis Localized dark pigmentation of the skin can arise from the for- mation of collections of melanocytes in the dermis during embry- onic development, possibly as a result of impaired migration of melanoblasts from the neural crest. The lesions are seen more fre- quently in oriental races, and have a blue or slate-​brown colour. The hyperpigmentation in naevus of Ota affects the skin on one side of the face in an area innervated by the ophthalmic and maxillary division of the trigeminal nerve, and can involve the eye (sclera, iris, retina). In naevus of Ito, the skin over the shoulder (innervated by the posterior supraclavicular and lateral brachial cutaneous nerves) is af- fected. The Mongolian blue spot, frequent on the lower back, occurs in most East Asian babies and is also common in black children. It usually fades during childhood; however, it might persist throughout life, whereas naevus of Ota and naevus of Ito are generally lifelong. Treatment with laser to destroy the dermal melanocytosis can im- prove cosmetic appearances in naevus of Ota and naevus of Ito but lesions can recur. Ophthalmological review is recommended for naevus of Ota because of the risk of glaucoma in cases affecting the eye. Ocular melanoma has also been reported in some cases. Post-​inflammatory hyperpigmentation/​ hypopigmentation Inflammation resulting from a wide variety of causes can frequently lead to the development of dyspigmentation at that site. The con- dition is more common and more problematic in darker-​skinned subjects. The degree of dyspigmentation varies, and can follow in- flammation from exogenous stimuli (trauma, burns) as well as from inflammatory skin disorders (e.g. acne vulgaris, atopic eczema, li- chen planus, lupus erythematosus, morphoea/​systemic sclerosis, macular amyloid) (Fig. 23.8.6). In cases where the hyperpigmentation arises secondarily to damage to the epidermal basal cell layer (e.g. lichen planus and lupus erythematosus), there is pigmentary incontinence by the basal epidermal cells, and subsequent phagocytosis of the melanin by macrophages (in this situation also known as melanophages) in the dermis. The tendency is for these melanophages to remain in the dermis for a long period, thus the hyperpigmentation can take many months to resolve. Hyperpigmentation resulting from excess melanin in the epi- dermis can also occur as a result of inflammation, although hypo- pigmentation (possibly resulting from reduced melanin transfer to keratinocytes) is more frequent. Hypopigmentation frequently follows psoriasis, atopic eczema, discoid lupus erythematosus, sys- temic lupus erythematosus, and pityriasis versicolor. Fig. 23.8.5  Café-​au-​lait patches with jagged borders in a child with McCune–​Albright syndrome. Fig. 23.8.6  Post-​inflammatory hyperpigmentation on the trunk and upper limbs in a patient with psoriasis; the psoriasis has cleared in some areas (as a result of systemic antipsoriatic therapy) leaving the post-​ inflammatory hyperpigmentation.

23.8  Disorders of pigmentation 5683 Hypopigmentation The causes of hypopigmentation are given in Table 23.8.2. Vitiligo Vitiligo is a disorder with reduced pigmentation resulting from the death of melanocytes in the epidermis, with or without the concomi- tant death of melanocytes in the hair bulb. There are various theories as to the mechanism of melanocyte death, including damage to the cell from a variety of factors (e.g. reactive oxygen species), and/​or activation of the immune system (antibody and cell mediated) to recognize melanocyte-​specific antigens. The prevalence of vitiligo varies from about 0.38 to 1.78% in dif- ferent populations, and the disease can begin at any age, with ap- proximately 50% of cases affected before the age of 20 years. The condition is usually more problematic in darker-​skinned individ- uals, who may view it as a social stigma because of the combination of significant cosmetic impairment and the incorrect suspicion by others that the hypopigmentation may be a manifestation of leprosy. Males and females are equally affected. A family history is noted in up to one-​third of cases, and genetic factors are important in its sus- ceptibility/​pathogenesis, with many of the genetic loci associated with the disorder encoding immunoregulatory or melanocytic pro- teins. In general there is no obvious precipitating cause for most pa- tients presenting with vitiligo, but certain chemicals (hydroquinone derivatives, monobenzone, para-​tert-​butylcatechol) are toxic to melanocytes, and can cause vitiligo-​like depigmentation. The areas of hypopigmentation manifest as white patches of vari- able size (Fig. 23.8.7), but in some darker-​skinned individuals the margin or entire patch may be an intermediate colour of light brown (trichrome vitiligo). Patches may be generalized or segmental in dis- tribution, and the borders are irregular, similar to those of countries on a map. In the generalized form lesions are usually symmetrical, and the more frequently involved sites are around the orifices (eyes, nose, mouth), flexures (axillae, groins, genitals), and extensor sur- faces (elbows, knees, digits). The isomorphic or Koebner phenom- enon can occur, in which trauma to the skin can produce lesions at that site. The skin is usually normal otherwise, with no evidence of scaling or atrophy, but occasionally the lesions undergo an ini- tial inflammatory stage with raised erythematous (and sometimes hyperpigmented) borders. Although usually distinct clinically, microbial diseases such as pityriasis versicolor (Chapter 23.10), leprosy (Chapter 8.6.28), and syphilis (Chapter 8.6.37) are important infectious causes of hypo- pigmentation. For example, in leprosy, hypomelanosis is a feature of the tuberculoid and borderline tuberculoid types; in tuberculoid leprosy, light touch and, later, pinprick sensations are also impaired in the hypopigmented patch, there is often a lack of sweating, there might be loss of hair and an adjacent enlarged peripheral nerve might be palpable, which can be mistaken for an enlarged lymph node. There is an association between vitiligo and several autoimmune diseases, including hyperthyroidism and hypothyroidism, per- nicious anaemia, diabetes mellitus, and adrenal insufficiency (Addison’s disease). Vitiligo has also been reported in patients with several other disorders (psoriasis, alopecia areata, lichen planus, my- asthenia gravis, rheumatoid arthritis, and morphoea/​scleroderma), but the relevance of these diseases in a condition that is relatively common is unclear. Halo naevi can occur in patients with vitiligo, presumably as a result of an immunological response to melano- cytes cross-​reacting with the melanocytic naevus cells. Similarly, vitiligo can occur in individuals with melanoma, secondary to the antitumour immune response reacting against melanocytes at other skin sites. Although squamous cell carcinoma and basal cell car- cinoma of the skin have been reported occasionally in people with vitiligo, there is some evidence to suggest that the incidence of skin cancer may be lower in individuals with vitiligo; this may be because the skin is generally covered by clothing for cosmetic reasons, but Table 23.8.2  Causes of skin hypopigmentation Type Cause Localized Vitiligo Includes vitiligo vulgaris, vitiligo in patients with melanoma, and in Vogt–​Koyanagi–​Harada syndrome Naevus-​related Halo naevus, naevus depigmentosus, depigmentation within/​around a melanoma Postinflammatory Eczema (pityriasis alba), psoriasis (frequently post-​UV therapy), and so on Chemical/​drugs Hydroquinones, topical corticosteroids Congenital Piebaldism, Waardenburg’s syndrome, tuberous sclerosisa Infective Pityriasis (tinea) versicolor, leprosy, onchocerciasis, syphilis, yaws, pinta Scarring Trauma, surgical, discoid lupus erythematosus Miscellaneous Morphoea, lichen sclerosus, idiopathic guttate hypomelanosis, hypomelanosis of Ito Generalized Congenital Oculocutaneous albinism type I, oculocutaneous albinism type II, Prader–​Willi syndrome, Angelman syndrome, Chédiak–​Higashi syndrome, Hermansky–​ Pudlak syndrome, Griscelli syndrome Endocrine Hypopituitarism, hypogonadism (males) Vitiligo a Tuberous sclerosis is described in Chapter 24.17. Fig. 23.8.7  Loss of skin pigmentation on the dorsa of the hands in a subject with vitiligo.

section 23  Disorders of the skin 5684 may also be due to elevated p53 expression in depigmented and normal skin in subjects with vitiligo. Vitiligo per se does not increase the risk of melanoma because the melanocytes necessary to give rise to melanoma are missing from the epidermis at the affected skin site. Furthermore, germline TYR polymorphisms which increase vitiligo susceptibility might promote immune responses against neoplastic as well as normal melanocytes, thus protecting against this tumour. Nevertheless, patients with vitiligo are advised to use good sun pro- tection measures (see Chapter 23.9) and there is evidence that treat- ment of vitiligo with UV radiation increases the risk of developing skin cancer in subjects with vitiligo. Vitiligo might last for many years, or it can repigment spontan- eously. When it does repigment, the pigment initially appears around hair follicles, and is thought to represent proliferation and migration of new melanocytes from precursors in the bulge region of the follicle. In general, therapies for vitiligo are limited, and the choice of treat- ment often depends on the constitutive skin colour of the patient. In people with lighter skin colour, advice on the use of sunscreens might be sufficient. Potent topical steroids and/​or UV radiation or topical calcineurin inhibitors can be employed with varying success, but UV radiation, if unsuccessful, can exaggerate the difference in colour be- tween normal and vitiliginous skin in darker-​skinned patients. In cases where there is stabilization of the vitiligo (i.e. lack of progres- sion of depigmentation) some authors consider surgical intervention with minigrafting of pigmented skin onto the affected sites. Cosmetic camouflage can be helpful in those cases that do not repigment spon- taneously, or those failing to respond to therapy. In addition, counsel- ling is important for those distressed by the condition. Endocrine causes of hypopigmentation Lighter pigmentation of skin can occur in endocrine disorders. Hypopituitarism often leads to a generalized skin pallor that is thought to result from a lack of proopiomelanocortin peptides, including αMSH and adrenocorticotropic hormone. Similarly, men who have hypogonadism (e.g. as a result of castration) have been reported to exhibit generalized skin pallor. The tanning response is impaired in these men, as it is in people with hypopituitarism. The administration of testosterone re-​establishes UV radiation-​induced tanning in hypogonadic men, whereas the administration of αMSH does likewise in cases of hypopituitarism. Depigmentation/​greying of hair The reduction and loss of pigment in hair, resulting in its greying (canities), is a normal ageing response in adults. The initial greying seems to result from a dilution of the pigment, secondary to a pro- gressive decline in the number and activity of melanocytes in some hairs, with the overall grey effect being the consequence of a mixture of hypopigmented/​white and normal-​coloured (blond, brown, and so on) hairs. Eventually the hair might appear white, as a result of most of the hairs lacking melanocytes. Canities affects most indi- viduals, frequently beginning in the fourth and fifth decades of life (senile canities), but can occur earlier in some people (premature canities). Rapid greying or whitening of the hair has been observed in some people as a result of diffuse alopecia areata causing generalized hair thinning on the scalp, with loss of pigmented hairs and retention of grey/​white depigmented hairs. In circumscribed alopecia areata, the hair loss might similarly be confined to pigmented hairs, with depigmented hairs surviving, or alternatively, during hair regrowth there may be earlier or selective regrowth of white hairs in the af- fected area. The presence of a localized patch of white hair, termed poliosis, can arise from a congenital or acquired defect; examples of the former include piebaldism and Waardenburg’s syndrome, whereas examples of the latter include alopecia areata and vitiligo. Piebaldism In this autosomal dominant condition, non​pigmented patches of skin are seen on the central forehead (often in a diamond or tri- angular shape and in association with a white forelock), as well as on the chest, abdomen, arms, and legs. The hypopigmented areas are present at birth, and do not vary throughout life, being caused by an absence of melanocytes in the affected skin. Islands of nor- mally pigmented skin are often seen in the hypomelanotic areas, and the hands, feet, and back are usually pigmented normally. Mutations in the KIT proto-​oncogene (OMIM 164920), and deletions within this locus on chromosome 4q are responsible. The consequently re- duced ability of the KIT ligand (stem cell factor) to signal via the KIT receptor on developing melanoblasts results in reduced survival of these cells during embryogenesis, thus causing the lack of mel- anocytes in affected skin sites. Deletion and mutation of SNAI2 (OMIM 602150), a zinc-​finger transcription factor gene that influ- ences SCF/​c-​kit signalling, can also result in piebaldism. Treatment for piebaldism is, in general, restricted to cosmetic camouflage, photoprotection with clothing and sunscreens, and in some cases skin grafting. Waardenburg’s syndrome Waardenburg’s syndrome, the severity of which varies widely, fea- tures the following abnormalities from birth: a white forelock, white eyebrows, premature greying of the hair, heterochromatic irides, and hypomelanotic macules on the skin, in combination with lateral dis- placement of the inner canthi/​dystopia canthorum, hypertrophy of the nasal bridge, and congenital neurosensory deafness in a propor- tion of cases. There are four subgroups, types I  to IV, with type II differing from type I by the absence of the lateral displacement of the inner canthi/​dystopia canthorum; type III (Klein–​Waardenburg syn- drome) being similar to type I, but with limb abnormalities; and type IV (Waardenburg–​Shah syndrome) being a combin- ation of Waardenburg’s syndrome and aganglionic megacolon (Hirschsprung’s disease). Types I  and III result from defects in the PAX3 gene (OMIM 606597), type II is caused by mutations in the microphthalmia-​ associated transcription factor (MITF; OMIM 156845), SOX10 (OMIM 602229), SLUG (SNAI2; OMIM 602150)  and KITLG (OMIM 184745) genes, whereas type IV is caused by alterations in the endothelin-​B receptor (EDNRB; OMIM 131244), endothelin 3 (EDB3; OMIM 131242), and SOX10 genes. In general, the pigmen- tation defects seem to occur as a result of effects on MITF signalling (caused by mutations in MITF or in genes that control MITF activity) or KIT ligand/​KIT signalling, which are important for neural crest and melanocyte development. However, in cases of Waardenburg’s syndrome type IV caused by EDNRB and EDB3 alterations, the megacolon and pigmentation abnormalities are caused by defective

23.8  Disorders of pigmentation 5685 EDB3/​EDNRB signalling, which is necessary for the migration of neuron precursor cells to the gastrointestinal tract, and melanoblasts into skin. Similar to piebaldism, there is no simple effective treat- ment for the pigmentary defects in Waardenburg’s syndrome. Oculocutaneous albinism type I In this type of albinism (OCA1) there is a lifelong absence of mel- anin pigment in the skin, hair, and eyes such that, irrespective of race, the skin is pink, the hair white, the irides light-​coloured, and the red-​eye reflex prominent. There is an absence of pigmented naevi and freckling. Photophobia, visual impairment, and nystagmus are common. The condition is autosomal recessive, and the genetic defect re- sponsible for the condition lies in the tyrosinase (TYR; OMIM 606933)  gene. The tyrosinase enzyme is essential for normal melanogenesis, catalysing the production of DOPAquinone in the melanin synthetic pathway (Fig. 23.8.1). Although mutations in the coding region of the TYR gene can inhibit the enzymatic activity of tyrosinase, there is evidence that mutant tyrosinase might fail to traffic adequately to the melanosome, where it is required for mel- anin synthesis. There is no specific treatment for the lack of skin pigmentation in OCA1 (or OCA2), but advice at an early age on appropriate photoprotective clothing and sunscreens, and limiting sun exposure, are important to reduce the risk of skin cancer devel- opment in later life. Oculocutaneous albinism type II Oculocutaneous albinism type II (tyrosinase-​positive albinism; OCA2) is more common in black populations, whereas OCA1 is more frequent in whites. In OCA2 in whites there is absence of pig- ment in the skin, hair, and eyes, but pigmented naevi might be seen. In darker populations, the presence of some melanin pigmentation is seen, and blacks with this type of albinism tend to have yellow hair and pigmented freckles on their skin. Affected individuals might also have nystagmus and photophobia. The condition is autosomal recessive, and results from muta- tions in the pink-​eyed dilution gene (OCA2; OMIM 611409) and/​ or deletions of this locus on chromosome 15q. The exact function of the protein encoded by the OCA2 gene has been debated, but it is thought that OCA2 results from a failure of the gene product to control melanosomal pH, thus reducing tyrosinase activity, or from effects on posttranslational processing of tyrosinase or on transport of tyrosine into the melanosome. The fact that people with OCA2 in darker populations have yellow hair suggests that the net effect is an absence of eumelanin production, whereas some phaeomelanin can still be synthesized. In hotter climates, appropriate sun protection is necessary to limit the development of skin cancers, and regular monitoring of affected individuals is recommended to identify skin cancers at an early stage. Praeder–​Willi and Angelman syndromes Both these syndromes exhibit lighter pigmentation of the skin, hair, and retina, in association with developmental delay and behavioural abnormalities. In Prader–​Willi syndrome there is concomitant obesity, hypotonia, hypogonadism, and short stature. In Angelman syndrome there is hypotonia, ataxia, motor retardation, epilepsy, ab- sence of speech, and a characteristic facies. Cytogenetic and molecular investigations of Prader–​Willi syn- drome have demonstrated deletions in the paternal copy of chromo- some 15q (or maternal uniparental disomy, which gives rise to two copies of chromosome 15q, both of which are maternal in origin), whereas deletions of the maternal copy of this region (or paternal uniparental disomy) are observed in Angelman syndrome, suggesting that both disorders are caused by loss of function of imprinted genes on chromosome 15q as a result of epigenetic modi- fication. Alterations in the gene for the E6-​associated protein ubi- quitin-​protein ligase (UBE3A; OMIM 601623) have been detected in Angelman syndrome, whereas the deletions in Prader–​Willi syndrome affect the SNRPN (OMIM 182279)  and NDN (OMIM 602117) genes. Depigmentation in Prader–​Willi syndrome occurs predomin- antly in those cases with 15q deletions, rather than in patients with maternal uniparental disomy. Similarly, hypopigmentation is infre- quent in cases of Angelman syndrome with very small deletions, indicating that the affected gene in cases with hypopigmentation may be located further along the same chromosome. These observa- tions, coupled with the fact that the human OCA2 gene, mutations of which cause OCA2, is also located on chromosome 15q has led to the hypothesis that reduced expression of the OCA2 gene through haploinsufficiency is responsible for the hypopigmentation pheno- type in Prader–​Willi and Angelman syndromes. However, UBE3A can regulate transcription of the melanocortin 1 receptor (MC1R) gene, thus alterations in UBE3A may reduce signalling via MC1R leading to fairer skin in Angelman syndrome. Hermansky–​Pudlak syndrome The features of this rare autosomal recessive syndrome are oculocutaneous albinism, which can vary in the degree of hypo- pigmentation, in association with a bleeding diathesis caused by a platelet abnormality, and deposits of pigment in cells of the reticu- loendothelial system. Pulmonary fibrosis and granulomatous colitis can also occur. It is more common in Puerto Ricans, but has been reported worldwide. The underlying problem is a defect in lysosomal ceroid-​ lipofuscin storage affecting several organelles within cells, including melanosomes, lysosomes, and platelet dense granules, resulting in abnormal synthesis/​development of these organelles; platelet num- bers are normal, and the diagnosis is confirmed by a lack of platelet dense bodies on electron microscopy or examination of the numbers of CD69-​positive structures in platelets by super-​resolution micros- copy. Based on genetic heterogeneity there are at least ten subtypes of Hermansky–​Pudlak syndrome (HPS1, HPS2, and so on), which are caused by mutations in different genes; HPS1 on chromosome 10q (OMIM 604982), AP3B1 on 5q (causing HPS2; OMIM 603401), HPS3 on 3q (OMIM 606118), HPS4 on 22q (OMIM 606682), HPS5 on 11p (OMIM 607521), HPS6 on 10q (OMIM 607522), DTNBP1 on 6p (resulting in HPS7; OMIM 607145), and BLOC1S3 on 19q (causing HPS8; OMIM 609762), BLOC1S6 on 15q (resulting in HPS9; OMIM 604310) and recently AP3D1 on 19p (resulting in HSP10). Avoidance of aspirin-​containing products is warranted and platelet transfusion is the suggested treatment of choice for bleeding episodes. Treatment with desmopressin (1-​desamino-​8-​d-​arginine vasopressin; dDAVP) has been suggested to reduce the bleeding

section 23  Disorders of the skin 5686 tendency in some cases, but was not shown to reduce the bleeding time in most cases in an open-​label trial, hence it has been suggested that responses to dDAVP should be determined on an individual basis. Avoidance of exposure to cigarette smoke, early treatment of lung infections, and pneumococcal/​influenza vaccination are advo- cated to limit additional lung pathology. Lung transplantation has been employed in some cases for treatment of pulmonary fibrosis, and infliximab has been reported as a useful treatment for the granulomatous colitis. Chédiak–​Higashi syndrome This uncommon disorder consists of reduced pigmentation of the skin, hair, and eyes, with atypical inclusions in several cell types, including leucocytes, bone marrow, spleen, liver, kidney, some endo- crine glands, and the mucosa of the gastrointestinal tract. Decreased retinal pigmentation, photophobia, and nystagmus may also occur. Abnormally large melanosomes are present in melanocytes, and are retained in the melanocyte rather than being transported to the asso- ciated keratinocytes in the skin, accounting for the reduced pigmen- tation. The giant granules in leucocytes similarly affect their function, and markedly increase susceptibility to bacterial (staphylococcal and streptococcal) and viral infections, often resulting in death during the first decade of life. In those who survive for longer, lymphadenop- athy and hepatosplenomegaly develop (called the accelerated phase), with the patient ultimately dying from lymphoma. Some of these pa- tients may develop neurological problems. The disorder is autosomal recessive, resulting from mutations in the lysosomal trafficking regulator gene on chromosome 1q (LYST; OMIM 606897). It is thought that the genetic abnormality causes fu- sion of the secretory lysosomes in neutrophils, cytotoxic T lympho- cytes, and natural killer cells, inhibiting the secretion of proteases by these cells. This is also thought to be the case with melanosomes, where a failure to fuse to the plasma membrane of the dendrites in- hibits melanosome transfer to surrounding keratinocytes. In add- ition, some of the clinical problems in Chédiak–​Higashi syndrome may be caused by an inability to repair lesions in the plasma mem- brane (which seem to occur in all eukaryotic cells), because of the reduced ability of lysosomes to fuse with and therefore repair the cell membrane. There is limited effective therapy for the underlying problem, and treatment is based on the complications that arise (e.g. antibiotics for infections); however, haematopoietic stem cell trans- plantation has been reported as helpful in restoring haematological and immunological function in this condition. 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Melanocortin-​1-​receptor gene and sun sensi- tivity in individuals without red hair. Lancet, 355, 1072–​3. Hermansky F, Pudlak P (1959). Albinism associated with hemor- rhagic diathesis and unusual pigmented reticular cells in the bone marrow:  report of two cases with histochemical studies. Blood, 14, 162–​9. Huynh C, et al. (2004). Defective lysosomal exocytosis and plasma membrane repair in Chédiak-​Higashi/​beige cells. Proc Natl Acad Sci USA, 101, 16795–​800. Jin Y, et al. (2010). Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. N Engl J Med, 362, 1686–​97. Jin Y, et al. (2012). Genome-​wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat Genet, 44, 676–​80. Kantor B, et al. (2004). Establishing the epigenetic status of the Prader–​ Willi/​Angelman imprinting center in the gametes and embryo. Hum Mol Genet, 13, 2767–​79. Kemp EH, et al. (2002). The melanin-​concentrating hormone receptor 1, a novel target of autoantibody responses in vitiligo. J Clin Invest, 109, 923–​30. Lamason RL, et al. (2005). SLC24A5, a putative cation exchanger, af- fects pigmentation in zebrafish and humans. Science, 310, 1782–​6. Lee HO, Levorse JM, Shin MK (2003). The endothelin receptor-​B is required for the migration of neural crest-​derived melanocyte and enteric neuron precursors. Dev Biol, 259, 162–​75. Lerner AB, McGuire JS (1961). Effects of alpha-​ and beta-​melano- cyte stimulating hormones on the skin colour of man. Nature, 189, 176–​9. Longley BJ, et al. (1996). Somatic c-​KIT activating mutation in urti- caria pigmentosa and aggressive mastocytosis:  establishment of clonality in a human mast cell neoplasm. Nat Genet, 12, 312–​14. Miller R, Ashkar FS, Jacobi J (1970). Hyperpigmentation in thyrotoxi- cosis. J Am Med Assoc, 213, 299. Nelson DH, Meakin JW, Thorn GW (1960). ACTH-​producing pitu- itary tumors following adrenalectomy for Cushing’s syndrome. Ann Intern Med, 52, 560–​9. Nishimura EK, et al. (2002). Dominant role of the niche in melanocyte stem-​cell fate determination. Nature, 416, 854–​60. Ogg GS, et al. (1998). High frequency of skin-​homing melanocyte-​spe- cific cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med, 188, 1203–​8. Paradisi A, et al. (2014). Markedly reduced incidence of melanoma and nonmelanoma skin cancer in a nonconcurrent cohort of 10,040 pa- tients with vitiligo. J Am Acad Dermatol, 71, 1110–​6. Rinchik EM, et al. (1993). A gene for the mouse pink-​eyed dilution locus and for human type II oculocutaneous albinism. Nature, 361, 72–​6. Robinson S, et al. (2010). Protection against UVR involves MC1R-​me- diated non-​pigmentary and pigmentary mechanisms in vivo. J Invest Dermatol, 130, 1904–​13. Sánchez-​Martín M, et al. (2003). Deletion of the SLUG (SNAI2) gene results in human piebaldism. 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