Chapter 18 Disorders of pigmentation
2. How do you diagnose a pigmentation disorder?
The clinical history is the most important aspect of the investigation of a pigmentation disorder. It should focus on the time of onset (such as at birth, during childhood, or later in life) and a family history. Other facts to be determined include any associated illness or symptoms, drug ingestion, chemical exposure, occupation, and exposure to sunlight, artificial ultraviolet light, heat, or ionizing radiation. Finally, a careful review of systems should be performed, followed by a skin examination.
3. What are the important elements of a skin examination of a patient with a pigmentation disorder?
The entire skin surface should be evaluated with attention to the color, shape, and distribution of the lesion(s). Lesion color helps to place the disorder into a specific category to aid in narrowing the diagnostic possibilities. The shape of a lesion is sometimes diagnostic. Linear areas of depigmentation, often in areas of trauma, are suggestive for vitiligo, whereas ash-leaf–shaped hypopigmented macules suggest tuberous sclerosis. Distribution of pigmentary changes also helps in diagnosis. Symmetrical depigmentation on the arms, legs, and/or torso suggests vitiligo. Increased pigmentation of the oral mucosa, axillae, and palmar creases is associated with Addison’s disease.
4. What is a Wood’s lamp?
A hand-held black light. A Wood’s lamp emits light in a narrow spectrum of long-wave ultraviolet to short-wave visible light. Hypopigmented areas appear lighter, and depigmented areas appear pure white. Furthermore, epidermal hyperpigmentation is enhanced (appears darker), whereas dermal hyperpigmentation is not enhanced.
Leukoderma: partial or complete loss of skin pigmentation
5. Name some heritable forms of leukoderma.
• Albinism is a group of autosomal recessive disorders characterized by generalized depigmented or hypopigmented skin and decreased visual acuity and nystagmus secondary to alterations in the formation of melanin.
• Waardenburg’s syndrome is an autosomal dominant disorder associated with congenital deafness, heterochromic irides, amelanotic skin macules, white forelock, laterally displaced medial canthi, and widening of the nasal root.
6. Name the skin disorder that manifests with complete loss of skin pigmentation.
Vitiligo is a depigmenting disorder due to loss of epidermal melanocytes. There are both familial and nonfamilial forms, and the overall incidence is 1% in the United States. Vitiligo has been reported to be associated with autoimmune disorders, including thyroid disease and diabetes mellitus type 1. The pathogenesis is not totally understood. Curiously enough, patients have both circulating antimelanocyte antibodies and skin-homing melanocyte-specific cytotoxic T lymphocytes. How these two portions of the immune system interact to result in melanocyte destruction is not understood. Vitiligo affects all races and affects both sexes equally.
Halder RM, Chappell JL: Vitiligo update, Semin Cutan Med Surg 28:86–92, 2009.
7. Describe the clinical appearance of the skin lesions in vitiligo.
Typically, lesions of vitiligo are stark white with a well-demarcated border and no other skin changes. Sometimes, the border is hyperpigmented and rarely erythematous. Areas commonly affected are the periorbital, perioral, and anogenital areas, as well as the elbows, knees, axillae, inguinal folds, and forearms. Frequently, lesions of vitiligo develop symmetrically on the trunk and extremities (Fig. 18-1A). Vitiligo also causes depigmentation of hair (leukotrichia). Less commonly vitiligo is focal or segmental (Fig. 18-1B).
9. Do any factors influence the onset of vitiligo?
The patient presenting with vitiligo usually describes asymptomatic areas of skin that have rapidly lost all pigment. Rarely does the patient recall an associated illness, but skin trauma is commonly reported to cause vitiligo lesions. One caveat: Vitiligo occurs only in patients predisposed to the condition. Thus skin trauma will not induce vitiligo in nonpredisposed individuals.
10. Is vitiligo treatable?
Yes. Vitiligo repigments in small part from the border and mostly from the hair follicle. Localized vitiligo may be treated with high-potency topical steroids, topical tacrolimus and pimecrolimus, as well as topical calcipotriene. For more generalized vitiligo, narrow-band ultraviolet light B (UVB, 311 nm) is now the treatment of choice. It must be administered 2 to 3 times weekly for many months. All patients with vitiligo should use sunscreens to protect depigmented skin from sun damage.
Key Points: Racial Differences in Pigmentation
1. Pigmentation is determined by the type of melanin synthesized and the amount distributed to the surrounding keratinocytes.
2. Fair-skinned people produce a light brown form of melanin (pheomelanin), and distribute only small amounts to surrounding keratinocytes.
Key Points: Pigmentation Disorders
2. Fortunately, the most common pigmentation disorders are benign, self-limited, and reversible. For example, one of the most common develops following a cutaneous inflammatory reaction, when the skin is either more darkly pigmented (postinflammatory hyperpigmentation) or less pigmented (postinflammatory hypopigmentation) than surrounding normal skin.
Key Points: Sun-tanning
1. Sunlight stimulates human epidermal melanocytes to increase melanin synthesis and stimulates increased melanocyte transfer of melanosomes to keratinocytes. This melanocyte response to sunlight is called tanning.
2. The action spectrum of sunlight that causes tanning is the ultraviolet spectrum (wavelengths 290 to 400 nm).
3. Excess sunlight exposure causes abnormal melanocyte function, resulting in areas of melanocyte overproduction of melanin and increased melanocyte proliferation.
11. What is piebaldism?
Piebaldism is an uncommon autosomal dominant depigmentation disorder that is characterized by a white scalp forelock and hyperpigmented macules within areas of skin depigmentation. Piebaldism is due to mutations on the KIT protooncogene that is located on chromosome 4. A normal KIT receptor is required for normal development and migration of melanocytes. Melanocytes migrate during embryologic development in a dorsal-to-ventral direction; melanocytes in piebaldism fail to properly migrate to ventral skin surfaces, such as the forehead, abdomen, and volar arms and legs. For this reason, depigmented areas in piebaldism predominate on ventral skin surfaces. Patients are otherwise healthy. There is no treatment available for piebaldism.
12. What is albinism?
Albinism is a group of inherited disorders of the melanin pigment system. All forms are autosomal recessive. In oculocutaneous albinism type 1 (OCA1), there is a defect in the enzyme tyrosinase with an absence in melanin synthesis. Generally, albinism presents as depigmented or hypopigmented skin and hair, nystagmus, photophobia, and decreased visual acuity (Fig. 18-2). There are four different forms of oculocutaneous albinism. Some forms affect the skin, hair, and eyes (oculocutaneous albinism); other forms primarily affect the eyes (ocular albinism). There is no treatment available for albinism.
15. How do chemicals cause skin depigmentation or skin hypopigmentation?
Monobenzyl ether of hydroquinone (MBEH) and para–substituted phenols (PSP) cause skin depigmentation by destroying melanocytes. It is believed that both MBEH and PSP are taken up by melanocytes and metabolized into toxic products that kill the melanocytes. Hydroquinone, a commonly used skin-lightening agent, causes decreased melanin synthesis by competing with tyrosine and dihydroxyphenylalanine for the enzyme tyrosinase. With hydroquinone bound to its active site, tyrosinase is unable to synthesize melanin. Other chemicals, such as arsenic, mercaptoethyl amines, chloroquine, hydroxychloroquine, and corticosteroids, act to metabolically suppress melanocytes, resulting in decreased melanin synthesis and skin lightening. In most cases, the effects of these chemicals are reversible.
16. Can patients with nutritional disorders suffer from leukoderma?
Yes. Patients suffering from protein loss or deficiency diseases, including kwashiorkor, intestinal malabsorption, and nephrotic syndrome, often manifest with facial, truncal, and extremity hypopigmentation. The hypopigmentation is believed to be due to dysregulation of normal melanogenesis secondary to lack of amino acid precursors for melanin synthesis and for normal melanin polymer formation. Normal pigmentation returns following treatment of the nutritional disorder.
17. What disorders should the clinician consider in a patient with hypopigmented macules and patches?
19. What is nevus depigmentosus?
Nevus depigmentosus consists of single or multiple hypopigmented macules or patches that grow proportionally with the patient. The trunk is the most commonly affected body area. However, nevus depigmentosus has been reported to occur on the extremities, buttocks, and face, and may be localized, segmental, or, less often, systematized. Most lesions present by age 3 years with the remainder (about 7%) presenting later in childhood. Lesion morphology varies from circumscribed irregular, oval, or round macules or patches to a unilateral band or streak with a “splashed paint” appearance arranged along one or more Blaschko line. Lesional skin has normal melanocyte number but reduced numbers of melanosomes in melanocytes and surrounding keratinocytes. The etiopathogenesis has not been fully established.
20. How does nevus depigmentosus compare to hypomelanosis of Ito?
Some experts believe nevus depigmentosus to be a less severe form of hypomelanosis of Ito. The skin lesions of hypomelanosis of Ito very closely resemble those of nevus depigmentosus. However, hypomelanosis of Ito lesions are larger and more widespread. Moreover, 15% to 25% of hypomelanosis of Ito patients suffer from disorders of the central nervous system, eyes, hair, teeth, and musculoskeletal system. There is no single molecular mechanism underlying hypomelanosis of Ito. Some authorities believe that hypomelanosis of Ito should be referred to as linear and whorled nevoid hypomelanosis.
22. Describe the pigmentation changes seen with the treponematoses.
• Secondary syphilis: Hypopigmented macules can be found on the neck, shoulders, upper chest, and axillae in patients with secondary syphilis (due to Treponema pallidum). The hypopigmented neck lesions have been termed the “necklace of Venus.”
• Pinta: Pinta is a chronic nonvenereal disease caused by T. carateum that is endemic in Central and South America. The primary lesion, at the site of inoculation, is a hypopigmented patch or plaque on the arm, leg, or torso. Secondary pinta lesions (pintides) are at first erythematous, then become hyper- and hypopigmented. Later in the disease, pinta lesions become more uniformly hypopigmented.
• Yaws: Yaws is a nonvenereal disease caused by T. pallidum subspecies pertenue that is common in children in impoverished, very warm, tropical areas of Africa. It may also be seen in Southeast Asia, the Pacific Islands, and tropical America. The primary lesion heals as an atrophic hypopigmented scar. Secondary yaws often heals without dyspigmentation, but the gummatous tertiary yaws lesions localized to the lower extremities, volar wrists, and dorsal hands are depigmented.
23. What cutaneous lesions are seen with Hansen’s disease?
Hansen’s disease, or leprosy, is a chronic infectious disease caused by Mycobacterium leprae. M. leprae infects the skin and peripheral nerves and in some patients may produce anesthetic, hypopigmented patches, plaques, or nodules. Patients with indeterminate and tuberculoid leprosy have one or few lesions, whereas patients with lepromatous leprosy have many lesions. Lesions may repigment following antibiotic cure.
24. Why is lesional skin of tinea versicolor frequently hypopigmented?
Tinea (pityriasis) versicolor is caused by overgrowth of the normal skin flora of several species of yeast in the genus Malassezia (Pityrosporum) including M. globosa, M. sympodialis, M. furfur, M. obtusa, and M. slooffiae. In its pathogenic hyphal form, Malassezia secretes an enzyme that breaks down epidermal unsaturated fatty acids to azelaic acid, which inhibits melanocyte tyrosinase. Tinea versicolor is common in tropical and temperate climates and is found in all races and age groups. The typical lesion is a scaly, slightly erythematous macule or patch located on the proximal anterior and posterior torso (Fig. 18-3). Tinea versicolor may be either hypopigmented or hyperpigmented.
Melanoderma: abnormal darkening of the skin
25. What are lentigines? What heritable disorders manifest these?
Lentigines are brown to dark brown, 1- to 5-mm macules that may occur on any cutaneous surface. They resemble freckles, but on biopsy, these lesions have increased numbers of melanocytes and increased melanocyte and basal keratinocyte pigmentation.
A benign condition characterized by the rapid development of hundreds of lentigines widespread over the skin surface in adolescents or young adults has been described. However, the presence of multiple lentigines at a young age is suggestive of autosomal dominant disorders, especially Moynahan’s syndrome or Peutz-Jeghers syndrome (Fig. 18-4).
26. Why is it important to identify patients with Peutz-Jeghers syndrome?
Patients with Peutz-Jeghers syndrome have widespread cutaneous lentigines that involve the arms, legs, torso, digits, lips, buccal mucosa, palate, tongue, and eyelids. In addition, they suffer from gastrointestinal (GI) polyps, usually in the small bowel, which, by the second decade of life, can become symptomatic with diarrhea, hemorrhage, obstruction, or intussusception. Malignant degeneration of GI polyps has been reported, with carcinomas developing most commonly in the large intestine but also in the small intestine and stomach.
27. Describe the clinical manifestations of Moynahan’s syndrome.
Patients with Moynahan’s syndrome have hundreds of lentigines on the face, trunk, and extremities. Less commonly they may also demonstrate café-au-lait macules (Fig. 18-5). The mnemonic LEOPARD has been applied to the clinical symptoms associated with this syndrome:
28. Are there pigmentation disorders associated with neurofibromatosis?
Yes. Common pigmented lesions of neurofibromatosis 1 (NF1, von Recklinghausen’s disease) are café-au-lait macules (CALM) and inguinal and axillary freckling. CALM are, as the name would imply, flat, tan to light brown lesions located anywhere on the body; these range from a few millimeters to several centimeters in diameter. Greater than 90% of CALM of NF1 are present at birth or appear within the first year of life. CALM are relatively common, and a patient must have six or more for the diagnosis of NF1 to be considered. If six or more are present, the absolute number of CALM does not correlate with the development of other systemic problems associated with NF1. NF1 is a relatively common autosomal dominant disorder that occurs in 1:3000 live births.
29. Do any other disorders manifest with CALM?
Yes. In 1937, Albright reported a syndrome consisting of osteitis fibrosa disseminata, endocrine dysfunction with precocious puberty in females, and CALM. The CALM of Albright’s syndrome differ from those of NF1 by being larger and occurring predominantly on the forehead, posterior neck, sacrum, and buttocks. CALM of Albright’s syndrome tend to be unilateral and do not cross the midline, whereas CALM of NF1 exist in a random, generalized pattern. CALM of Albright’s syndrome appear at or soon after birth.
30. What is Becker’s melanosis?
Becker’s melanosis (also known as Becker’s pigmented hairy hamartoma or Becker’s nevus) is a benign pigmented lesion that develops in the second or third decade of life with a male:female ratio of 5:1. There is no predominance of race, and one large study reported a prevalence of 0.52% in males between ages 17 and 26 years. Greater than 80% of lesions occur on the trunk, appearing as a tan to dark brown patch with an irregular border ranging in size from 100 to 500 cm2. Excess hair growth has been reported in 56% of cases. With onset in the teen years and young adulthood, Becker’s melanosis is easily differentiated from a congenital nevus and CALM of Albright’s syndrome, which are present at birth. Once fully developed, Becker’s melanosis remains stable for the life of the patient.
32. Do any natural factors stimulate human epidermal pigmentation?
Yes. The following factors have been reported to enhance melanocyte growth and pigmentation:
33. What drugs are used to stimulate skin pigmentation? How do they work?
The psoralens or furocoumarins, potent photosensitizing drugs, have been used for thousands of years to stimulate skin pigmentation. The most commonly used agent in dermatology for skin photosensitization is 8-methoxypsoralen (8-MOP). The exact mechanism of skin photosensitization is not known, but 8-MOP is preferentially taken up by epidermal cells, where it binds to cell membranes and is concentrated within cell nuclei. Upon photoactivation, 8-MOP causes alteration in cell membrane signaling and forms covalent bonds with DNA that lead to the formation of psoralen-DNA adducts. Together, the altered cell membrane signaling and psoralen-DNA adducts incite a cascade of events that stimulate melanocyte melanin synthesis and melanin transfer to keratinocytes, resulting in increased skin pigmentation.
34. Can other drugs cause increased skin pigmentation?
Yes. Arsenicals, busulfan, 5-fluorouracil, cyclophosphamide, topical nitrogen mustard (mechlorethamine), and bleomycin most commonly cause increased skin pigmentation. The mechanisms by which these drugs cause hyperpigmentation are unknown, but it is possible that the drug or a metabolite either directly stimulates epidermal melanocytes to increase melanin synthesis or indirectly stimulates metabolic pathways that cause increased epidermal melanization.
Litt J, editor: Litt’s drug eruption reference manual, ed 15, New York, 2009, Informa Healthcare.
35. Can endocrine and metabolic disorders cause altered skin pigmentation?
Yes. Addison’s disease is the prototype disorder with diffuse hypermelanosis associated with pigment accentuation in mucous membranes, skin folds, palmar creases, and pressure points (elbows, knees, knuckles, and coccyx). Adrenocorticotropic hormone (ACTH) or melanocyte-stimulating hormone (MSH)–producing tumors can cause increased skin pigmentation. Similarly, systemic administration of ACTH and MSH may cause skin hyperpigmentation. Pregnancy and estrogen therapy can cause hyperpigmentation, usually of the nipples and anogenital skin. Additionally, a masklike hyperpigmentation, called melasma, can develop on the forehead, temples, cheeks, nose, and upper lip in pregnant women and women receiving estrogen therapy.
39. Differentiate a nevus of Ota from a nevus of Ito.
Nevus of Ota (oculodermal melanocytosis) is an acquired disorder of dermal melanocytosis with an age of onset in early childhood or young adulthood. Less than 1% of Asiatic individuals are affected, and non-Asiatic races are affected even less frequently. Females are affected five times more frequently than males, with color hues ranging from dark brown, to purplish-brown, to blue-black. In its most common form, it involves the periorbital skin of one eye, although bilateral forms can occur, and pigmentation can extend to involve the temple, forehead, periorbital cheek, nose areas, and ocular structures (Fig. 18-6).
Table 18-2. Classification of Dermal Hyperpigmentation
| INCREASED MELANOCYTE NUMBER | INCREASED MELANIN | NONMELANIN PIGMENTS |
|---|---|---|
| Genetic | ||
| Mongolian spot Nevus of Ota Nevus of Ito |
− − − |
− − − |
| Chemical or Drug | ||
| − − − − − − − − − |
Fixed drug eruption − − − − − − − − |
Silver Mercury Bismuth Gold Antimalarials Phenothiazines Minocycline Amiodarone |
| Endocrine or Metabolic | ||
| − − |
Chronic nutritional deficiency Melasma |
− Ochronosis |
| Physical | ||
| − | Erythema ab igne | − |
| Inflammation and Infection | ||
| − | Macular amyloidosis | − |
| − | Erythema dyschromicum perstans | − |
| − | Postinflammatory hyperpigmentation | − |
40. What types of hyperpigmentation are due to dermal melanin deposition?
41. How does erythema ab igne occur?
Erythema ab igne is a skin reaction to thermal injury. Chronic heating pad use is a common cause of this disorder. Usually, the affected area has a netlike pattern of blue-gray discoloration, sometimes with associated erythema and scale. Patients often complain that the affected area burns, stings, or itches. Treatment requires discontinuing heating pad use. Skin dyspigmentation slowly resolves over several months to a year, although permanent dermal scarring and hyperpigmentation can result.
42. Are there any metabolic disorders associated with nonmelanin skin dyspigmentation?
Yes. Ochronosis (alkaptonuria) is a rare autosomal recessive inherited deficiency of homogentisic acid oxidase that results in accumulation of homogentisic acid in connective tissue, where it causes a dark brown to bluish-gray dyspigmentation. Commonly affected skin areas include the pinna, tip of the nose, sclera, extensor tendons of the hands, fingernails, and tympanic membranes. Less commonly, blue macules develop on the central face, axillae, and genitalia.
43. What pigmentation disorders are associated with heavy-metal deposition in the dermis?
Silver, mercury, bismuth, arsenic, and gold can cause brown to blue-gray discoloration due to metal deposition in the dermis. Silver, mercury, and bismuth toxicity result in blue-gray discoloration of the skin, nails, and mucosa. Silver toxicity (argyria) is most prominent in sun-exposed areas. Chrysoderma is an uncommon brown skin pigmentation that develops following parenteral gold administration and is most prominent in sun-exposed areas.
