Bonus images for this chapter can be found online at

http://www.expertconsult.com

36

Disturbances of Pigmentation

The visible pigmentation of the skin or hair is a combination

of the amount of melanin, type of melanin (eumelanin versus
pheomelanin), degree of vascularity, presence of carotene, and
thickness of the stratum corneum. Other materials can be
deposited abnormally in the skin, leading to pigmentation.
Eumelanin is the primary pigment producing brown coloration of the skin. Pheomelanin is yellow or red, and is also
produced solely in melanocytes. Melanin is formed from tyrosine, via the action of tyrosinase, in the melanosomes of
melanocytes. There are hundreds of genes expressed only in
melanosomes and apparently important in melanin production and delivery. Melanosomes are lysosome-related
organelles. Melanosome formation and the end result, pigmentation, require both the adequate manufacture of melanin
and the appropriate transport of melanosomes within the
melanocyte. The melanosomes are transferred from a melanocyte to a group of 36 keratinocytes called the epidermal
melanin unit, to which they provide melanin. The variations
in skin color between persons and races are related to the
degree of melanization of melanosomes, their number, and
their distribution in the epidermal melanin unit. Disorders of
loss or reduction of pigmentation may be related to loss of
melanocytes or the inability of melanocytes to produce melanin
or transport melanosomes correctly. Woods light examination
is often performed to evaluate lesions of hyper- or hypopigmentation. Hyperpigmented lesions that enhance with
Woods light usually have increased epidermal melanocyte
number or activity. If the lesions do not enhance, the
melanin is located in the dermis. Woods light will markedly
enhance depigmented lesions (complete loss of pigment),
but does not enhance lesions with partial pigment loss
(hypopigmentation).
Barral DC, Seabra MC: The melanosome as a model to study organelle
motility in mammals. Pigment Cell Res 2004; 17:111.
DellAngelica EC: Melanosome biogenesis: shedding light on the origin
of an obscure organelle. Trends Cell Biol 2003; 13:503.
Rees JL: Genetics of hair and skin color. Annu Rev Genet 2003; 37:67.
Setaluri V: The melanosome: dark pigment granule shines bright light
on vesicle biogenesis and more. J Invest Dermatol 2003; 121:650.

Pigmentary demarcation lines

Pigmentary demarcation boundaries of the skin can be classified into six groups, as follows:
1. Group A: Lines along the outer upper arms with variable
extension across the chest.
2. Group B: Lines along the posteromedial aspect of the
lower limb (Fig. 36-1).
3. Group C: Paired median or paramedian lines on the
chest, with midline abdominal extension.
4. Group D: Medial, over the spine.
5. Group E: Bilaterally symmetrical, obliquely oriented,
hypopigmented macules on the chest.
6. Group F: Facial pigmentary demarcation lines.

More than 70% of black patients have one or more lines; they
are much less common in white patients. Type B lines often
appear for the first time during pregnancy.
Pigmentary demarcation lines must be distinguished from
the much rarer condition, acquired dermal melanocytosis. This
primarily affects Asian and Hispanic women (male to female
ratio, 1:17). It often first appears during pregnancy or the
therapeutic use of estrogen/progesterone. Lesions present as
bluegray patches, with superimposed brown macules affecting the face, trunk, or extremities. Lesions do not enhance with
Woods light. They may be localized (following trauma) or
more diffuse. Biopsy shows melanocytes in the dermis, similar
to the findings in Mongolian spot, nevus of Ota, and nevus
of Ito.
Bonci A, Patrizi A: Pigmentary demarcation lines in pregnancy. Arch
Dermatol 2002; 138:127.
Rubin AI, et al: Acquired dermal melanocytosis: appearance during
pregnancy. J Am Acad Dermatol 2001; 45:609.
Ruiz-Villaverde R, et al: Pigmentary demarcation lines in a pregnant
Caucasian woman. Int J Dermatol 2004; 43:911.

Abnormal pigmentation
Hemosiderin hyperpigmentation
Pigmentation due to deposits of hemosiderin occurs in
purpura, hemochromatosis, hemorrhagic diseases, and stasis
dermatitis. Clinically, hemosiderin hyperpigmentation is distinguished from postinflammatory dermal melanosis by a
golden brown hue, as opposed to the brown or grayblue
pigmentation of epidermal and dermal melanin, respectively.
At times, a biopsy is required to distinguish melanin- from
hemosiderin-induced hyperpigmentation. Some medications
(including minocycline) deposit in the skin and complex with
both iron and melanin, making uniquely colored (usually
bluegray) deposits.

Postinflammatory hyperpigmentation
(postinflammatory pigmentary alterationPIPA)
Any natural or iatrogenic inflammatory condition can result
in hyper- or hypopigmentation. Postinflammatory dyspigmentation is more frequent in persons with Fitzpatrick skin
types IV, V, and VI, especially those of skin types IV and V. It
is equally common in males and females. Hyperpigmentation
may result from two mechanisms:
1. increased epidermal pigmentation via increased
melanocyte activity
2. dermal melanosis from melanocyte damage and melanin
dropout from the epidermis into the dermis.
Woods light examination will distinguish these two patterns
of postinflammatory hyperpigmentation. Lesions of hyperpigmentation tend to be tan to brown (Fig. 36-2), and may have

Grimes PE: Management of hyperpigmentation in darker racial ethnic

groups. Semin Cutan Med Surg 2009; 28:77.
Lacz NL, et al: Postinflammatory hyperpigmentation: a common but
troubling condition. Int J Dermatol 2004; 43:362.
Ortonne JP, et al: Latest insights into skin hyperpigmentation. J Invest
Dermatol Symposium Proceedings 2008; 13:10.

Melasma

enhance with Woods light. Tretinoin application may enhance

the effect of hydroquinone. Laser treatments and chemical
peels must be done with extreme caution, as increased pigmentation may result. For additional management approaches,
see the section on melasma below.

Melasma (chloasma)

Fig. 36-1 Pigmentary demarcation lines.

Fig. 36-2 Postinflammatory hyperpigmentation from varicella.

a gray hue (due to dermal melanin). Hypopigmented lesions

are prominently lighter than the surrounding area.
Histologically, there is melanin in the upper dermis and
around upper dermal vessels, located primarily in macrophages (melanophages). The pattern of the dermal melanosis
does not predict whether the lesion will be lighter or darker
as a result of the prior inflammatory processhence the tendency of pathologists to provide a diagnosis of postinflammatory pigmentary alteration in such cases. Postinflammatory
dyspigmentation is addressed initially by treating the underlying skin disease, if possible. The resolution of pityriasis alba
with mild topical steroids and moisturizers is an example of
resolution of postinflammatory hypopigmentation by treating
the cause. This should be the sole approach in hypopigmented
lesions after inflammation. For hyperpigmented lesions,
hydroquinone may be used in hyperpigmented cases that

Melasma is a very common disorder. It tends to affect

darker-complexioned individuals, especially East, West, and
Southeast Asians, Hispanics, and black persons who live in
areas of intense sun exposure and have Fitzpatrick skin types
IV and V. Subtle melasma, as identified by ultraviolet (UV)
light examination, may be seen in up to 30% of middle-aged
Asian females. Men are also affected, especially those from
Central America, who may have prevalence rates as high as
35%. Guatemalan men seem to be at greater risk than Mexican
men, and speaking a native tongue is also a risk factor, suggesting a genetic component associated with indigenous
heritage.
The pathogenesis of melasma is not known. However, many
observations strongly suggest that sun exposure is the primary
trigger. Melasma affects the face, a sun-exposed area, and
worsens in the summer. Melasma patients have lower MED
(minimal erythema dose) to UV light, and pigment more easily
with UV exposure. There is an association between the number
of melanocytic nevi and the development of vitiligo. The
number of nevi, in addition to being familial, is also related to
sun exposure. The prevalence of melasma increases with age
in both men and women. Solar elastosis is more marked in
areas of melasma, compared to unaffected facial skin. At the
cellular level, areas of melasma have higher levels of inducible
nitric oxide synthase and phosphorylated Akt, an element of
the nuclear factor kappa B (NF-B) pathway. The role of sunlight in inducing melasma may be to cause elevated levels of
nitric oxide via the NF-B pathway. Inducible nitric oxide
stimulates tyrosinase activity of melanocytes, increasing local
melanin production. This results in the clinically evident
hyperpigmentation in sun-exposed sites.
After sun exposure, the second most important triggers for
melasma are female hormones. Melasma is more common and
severe in women than men. It occurs frequently during pregnancy, with oral contraceptives use, or with hormone replacement therapy (HRT) at menopause. Discontinuing the use of
contraceptives or HRT rarely clears the pigmentation and it
may last for many years after the drugs are discontinued. In
contrast, melasma of pregnancy usually clears within a few
months of delivery. Melasma may be seen in other endocrinologic disorders, and with dilantin therapy.
Melasma is characterized by brown patches, typically on the
malar prominences and forehead. The forearms may also be
affected. There are three clinical patterns of facial vitiligo: centrofacial, malar, and mandibular. The centrofacial and malar
patterns comprise the majority of patients (Fig. 36-3), but most
patients have multiple types, making this classification not
very useful therapeutically. The pigmented patches are usually
quite sharply demarcated. While melasma has classically been
classified as epidermal- or dermal-based on the presence or
absence of Woods light enhancement, respectively, most cases
show both epidermal and dermal melanin. Dermal melanophages are a normal finding in sun-exposed Asian skin.
Independent of Woods light findings, a therapeutic trial of
847

ble, and the variable results may be in part technique-dependent.

Intense pulse light, fractional resurfacing, erbium:YAG resurfacing, 578nm copper bromide, and Q-switched Nd:YAG
have all been reported as effective. However, results are inconsistent, and complications may result.

Disturbances of Pigmentation

36

Fig. 36-3 Melasma of the cheek.

some form of hypopigmenting agent should be recommended

if the patient requests it.
A number of topical therapies are available. Exposure to
sunlight should be avoided and a complete sunblock with
broad-spectrum UVA coverage should be used daily.
Bleaching creams with hydroquinone are the gold standard
and are moderately efficacious; they contain from 2% (available over the counter) to 4% hydroquinone. Tretinoin cream
may be added to increase efficacy. While tretinoin alone may
reduce melasma, it may also increase pigmentation via its
irritant effect. The combination of hydroquinone and tretinoin, administered in conjunction with a topical steroid, has
been called Kligmans formula and is excellent. This is
available as a commercial product, Triluma, used once a day.
The efficacy of this product has been reported to be superior
to any combination of two of its ingredients, with a more
rapid and complete response with the triple combination.
Glycolic acid is at times added to hydroquinone to enhance its
efficacy. In some patients with melasma, 4% hydroquinone is
insufficient and higher doses of hydroquinone must be compounded. Satellite pigmentation and local ochronosis are
potential complications from use of these higher-concentration
preparations. Mequinol, azelaic acid, kojic acid, licorice
extract, ellagic acid, glucosamine, niacinamide, vitamin C,
vitamin E, phytosterol, glycyrrhetinic acid, pidobenzone 4%,
and arbutin are other therapies with efficacy. Many of these
agents are added to cosmetic products for skin lightening,
and may be combined, as they act on different steps of
melanogenesis.
Various surgical procedures, such as peels and light-based
treatments, have been proposed as effective for melasma. Most
patients who undergo surgical procedures have been previously treated with hydroquinone, and this therapy is frequently continued or is used in preparation for the surgical
treatment. Peels are usually given in a series. It is suggested
that repeated peels with glycolic acid, low-concentration TCA,
and salicylic acid, when combined with pretreatment with
hydroquinone, enhance the improvement obtained with
hydroquinone alone, but comparative trials are lacking. The
use of surgical modalities for the treatment of melasma should
be approached with caution. These products are all irritants
and these therapies may be complicated by hyperpigmentation, irritation, hypopigmentation, and even scarring, if not
used appropriately. Since these treatments are not standardized from one report to another, the literature is not compara848

Adalatkhah H, et al: Melasma and its association with different types of

nevi in women: a case-controlled study. BMC Dermatology 2008; 8:3.
Balkrishnan R, et al: Improved quality of life with effective treatment of
facial melasma: the pigment trial. J Drugs Dermatol 2004; 3:377.
Ertam I, et al: Efficiency of ellagic acid and arbutin in melasma: a
randomized, prospective, open-label study. J Dermatol 2008; 35:570.
Goldberg DJ, et al: Histologic and ultrastructural analysis of melasma
after fractional resurfacing. Lasers Surg Med 2008; 40:134.
Grimes PE: Management of hyperpigmentation in darker racial ethnic
groups. Semin Cutan Med Surg 2009; 28:77.
Guevara IL, Pandya AG: Safety and efficacy of 4% hydroquinone
combined with 10% glycolic acid, antioxidants, and sunscreen in the
treatment of melasma. Int J Dermatol 2003; 42:966.
Hantash BM, Jimenez F: A split-face, double-blind, randomized and
placebo-controlled pilot evaluation of a novel oligopeptide for the
treatment of recalcitrant melasma. J Drugs Dermatol 2009; 8:732.
Hernandez-Barrera R, et al: Solar elastosis and presence of mast cells
as key features in the pathogenesis of melasma. Clin Exp Dermatol
2008; 33:305.
Hurley ME, et al: Efficacy of glycolic acid peels in the treatment of
melasma. Arch Dermatol 2002; 138:1578.
Jo HY, et al: Co-localization of inducible nitric oxide synthase and
phosphorylated Akt in the lesional skins of patients with melasma. J
Dermatol 2009; 36:10.
Kim MJ, et al: Punctate leucoderma after melasma treatment using
1064-nm Q-switched Nd:YAG laser with low pulse energy. J Eur Acad
Dermatol Venereol 2009; 23:960.
Li YH, et al: Efficacy and safety of intense pulsed light in treatment of
melasma in Chinese patients. Dermatol Surg 2008; 34:693.
Nanda S, et al: Efficacy of hydroquinone (2%) versus tretinoin (0.025%)
as adjunct topical agents for chemical peeling in patients of melasma.
Dermatol Surg 2004; 30:385.
Ortonne JP, Bissett DL: Latest insights into skin hyperpigmentation. J
Investig Dermatol Symp Proc 2008; 13:10.
Pichardo R, et al: Prevalence of melasma and its association with
quality of life among adult male migrant Latino workers. Int J Dermatol
2009; 48:22.
Rendon M, et al: Successful treatment of moderate to severe melasma
with triple-combination cream and glycolic acid peels: a pilot study.
Cutis 2008; 82:372.
Rendon MI: Utilizing combination therapy to optimize melasma
outcomes. J Drugs Dermatol 2004; 3:S27.
Sarvjot V, et al: Melasma: a clinicopathological study of 43 cases.
Indian J Pathol Microbiol 2009; 52:357.
Scherdin U, et al: Skin-lightening effects of a new face care product in
patients with melasma. J Cosmet Dermatol 2008; 7:68.
Sharquie KE, et al: Topical 10% zinc sulfate solution for treatment of
melasma. Dermatol Surg 2008; 34:1346.
Varma S, Roberts DL: Melasma of the arms associated with hormone
replacement therapy. Br J Dermatol 1999; 141:592.
Wanitphakdeedecha R, et al: Treatment of melasma using variable
square pulse Er:YAG laser resurfacing. Dermatol Surg 2009; 35:475.
Zanieri F, et al: Melasma: successful treatment with pidobenzone 4%
(K5lipogel). Dermatol Ther 2008; 21:S18.

Pigmented anomalies of the extremities

This group of disorders is linked by the similar clinical features (reticulate pigmented macule) and characteristic
histologyadenoid pigmented proliferations of the rete ridges
of the interfollicular and infundibular follicular epidermis.
Patients may have features of several different syndromes,
making classification difficult. They probably represent at least
three distinct disorders, but since the genetic cause has not
been found for all these conditions, their uniqueness cannot
be proven. Interestingly, dermatopathia pigmentosa is due to
a mutation in the keratin 14 gene, and DowlingDegos disease

Dyschromatosis symmetrica hereditaria (DSH)

(reticulate acropigmentation of Dohi)
Originally described and still reported primarily in the
Japanese, acropigmentation of Dohi has been found to affect
individuals from Europe, India, and the Caribbean. It is also
referred to as dyschromatosis symmetrica hereditaria (DSH)
or symmetrical dyschromatosis of the extremities. It is inherited most commonly as an autosomal-dominant trait, although
autosomal-recessive kindreds have been reported. Patients
develop progressive hyperpigmented and hypopigmented
macules, often mixed in a reticulate pattern, concentrated on
the dorsal extremities, especially the dorsal hands and feet.
The lesions vary in size from pinpoint to pea-sized. Frecklelike macules can present on the face. Lesions appear in infancy
or early childhood and commonly stop spreading before adolescence. The pigmentary lesions last for life. The autosomaldominant form of DSH is due to a mutation in the DSRAD
gene, which encodes a double-stranded RNA-specific adenosine deaminase, an RNA editing enzyme. There is no association between the site of the mutation in this gene and the
clinical phenotype.
Alfadley A, et al: Reticulate acropigmentation of Dohi: a case report of
autosomal recessive inheritance. J Am Acad Dermatol 2000; 43:113.
Li M, et al: A novel mutation of the DSRAD gene in a Chinese family
with dyschromatosis symmetrica hereditaria. Clin Exp Dermatol 2004;
29:533.
Obieta MP: Familial reticulate acropigmentation of Dohi: a case report.
Dermatol Online J 2006; 12:16.
Oyama M, et al: Dyschromatosis symmetrica hereditaria (reticulate
acropigmentation of Dohi): report of a Japanese family with the
condition and a literature review of 185 cases. Br J Dermatol 1999;
140:491.
Suzuki N, et al: Mutation analysis of the ADAR1 gene in dyschromatosis
symmetrica hereditaria and genetic differentiation from both
dyschromatosis universalis hereditaria and acropigmentatio reticularis.
J Invest Dermatol 2005; 124:1186.

Dyschromatosis universalis hereditaria (DUH)

Dyschromatosis universalis hereditaria is a rare autosomal or
autosomal-recessive genodermatosis characterized by reticulate hyper- and hypopigmented macules in a generalized distribution (Fig. 36-4). Lesions appear in childhood, often in the
first few months of life. The palms, soles, and mucous membranes of the mouth and tongue may be diffusely pigmented,
with hypopigmented macules interspersed. Most DUH
patients do not show other symptoms and are otherwise well.
Uncommonly reported associations include ocular and auditory abnormalities, photosensitivity, developmental delay,
and short stature. In different kindreds the causal gene has
been reported on chromosome 6 or 12, making this syndrome
genetically distinct from DSH and DowlingDegos disease.
Al Hawasai K, et al: Dyschromatosis universalis hereditaria: report of a
case and review of the literature. Pediatr Dermatol 2002; 19:523.
Bukhari IA, et al: Dyschromatosis universalis hereditaria as an
autosomal recessive disease in five members of one family. J Eur
Acad Dermatol Venereol 2006; 20:628.
Kenani N, et al: Dyschromatosis universalis hereditaria: two cases.
Dermatol Online J 2008; 14:16.

Fig. 36-4 Dyschromatosis universalis hereditaria.

Nuber UA, et al: Dyschromatosis universalis hereditaria: familial case
and ultrastructural skin investigation. Am J Med Genet A 2004; 125:261.
Sethuraman G, et al: Dyschromatosis universalis hereditaria. Clin Exp
Dermatol 2002; 27:477.
Stuhrmann M, et al: Dyschromatosis universalis hereditaria: evidence for
autosomal recessive inheritance and identification of a new locus on
chromosome 12q21q23. Clin Genet 2008; 73:566.

Pigmented anomalies of the extremities

is due to a similar mutation in keratin 5. Keratin 5 and 14 are

a keratin pair highly expressed and required for structural
integrity of the basal cell layer. Also the rare EB subtype, EB
simplex with mottled pigmentation, is also due to a mutation
in keratin 14. These genetic clues can explain how slightly different syndromes can have similar phenotypes, since the
genetic defects are in proteins that interact in vivo.

Reticular pigmented anomaly of the flexures

(DowlingDegos disease)
Reticular pigmented anomaly of the flexures is a rare
autosomal-dominant pigmentary disorder; it is sometimes
called DowlingDegos disease or dark dot disease.
Pigmentation usually appears at puberty or in early adolescence, but may present later in adulthood. The skin lesions
primarily affect the axillae, neck, and inframammary/sternal
areas. In some cases, the dorsal hands are involved. The pigmentation is reticular; at the periphery, discrete, brownishblack macules surround the partly confluent central pigmented
area. In more mildly affected patients the pigmentation is
dappled. The pigmentation progresses very gradually. There
are frequently acneiform, pitted scars, sometimes pigmented,
about the mouth. Comedonal and cystic lesions have been
described on the flexures and in the axilla. Hidradenitis
suppurativa-like lesions in the groin and axilla may occur.
Patients may complain that the condition is worse during hot
weather. Squamous cell carcinoma of the buttocks or perianal
area has been described.
Histologically, in addition to the typical lentiginous adenoid
proliferations of the rete ridges, small horn cysts may be
present, so that the pattern resembles that of a reticulated
seborrheic keratosis. Comedones may be present. Erbium:YAG
laser has treated the pigmented lesions of the chest.
DowlingDegos disease is caused by mutations in the
keratin 5 gene. The reported mutations have been proposed as
altering function of the initiation codon, or premature termination of the keratin 5 polypeptide. Similar mutations occur in
GalliGalli disease, suggesting that the two conditions represent variants of the same disorder, rather than separate
diseases.

GalliGalli disease
GalliGalli disease is now recognized as a variant of Dowling
Degos disease, also caused by mutations in the keratin 5 gene.
The skin lesions are 12mm, slightly keratotic, red to dark
brown papules, which are focally confluent in a reticulate
pattern (Fig. 36-5). The skin lesions favor skinfolds but other
skin sites may also be involved. The neck, axillae, upper
849

Disturbances of Pigmentation

36

Fig. 36-5 GalliGalli disease.

extremities, dorsal hands, trunk, groin, and even the scrotum

and lower extremities may be affected. Histologically, there is
prominent digitate downgrowth of the rete ridges, identical to
that seen in DowlingDegos disease. The characteristic histologic feature is a suprabasilar cleft and suprapapillary thinning of the epidermis. There is no dyskeratosis, as is seen in
Grovers disease.
Braun-Falco M, et al: GalliGalli disease: an unrecognized entity or an
acantholytic variant of DowlingDegos disease? J Am Acad Dermatol
2001; 45:760.
El Shabrawi-Caelen L, et al: The expanding spectrum of GalliGalli
disease. J Am Acad Dermatol 2007; 56:S86.
Gilchrist H, et al: GalliGalli disease: a case report with review of the
literature. J Am Acad Dermatol 2008; 58:299.
Hanneken S, et al: Systematic mutation screening of KRTS supports the
hypothesis that Galli-Galli disease is a variant of Dowling-Degos
disease. Br J Dermatol 2010; 163:197.
Kossard S, Krivanek J: DowlingDegos diseasea heat aggravated
variant. Australas J Dermatol 2001; 42:214.
Loo WJ, et al: Hidradenitis suppurativa, DowlingDegos and multiple
epidermal cysts: a new follicular occlusion triad. Clin Exp Dermatol
2004; 29:622.
Muller CS, et al: Changing a conceptcontroversy on the confusing
spectrum of the reticulate pigmented disorders of the skin. J Cutan
Pathol 2009; 36:44.
Sprecher E, et al: GalliGalli disease is an acantholytic variant of
DowlingDegos disease. Br J Dermatol 2007; 156:572.
Wu YH, Lin YC: Generalized DowlingDegos disease. J Am Acad
Dermatol 2007; 57:327.

Reticulate acropigmentation of Kitamura

Reticulate acropigmentation of Kitamura is a rare autosomaldominant disease, which initially was recognized in Japan, but
now has been seen in many countries, usually in persons of
color. The characteristic presentation is pigmented, angulated,
irregular, freckle-like lesions with atrophy, arranged in a reticulate pattern on the dorsal feet and hands. Lesions start in the
first to second decade, gradually progress, and slowly darken
over time. The axillae and groin may be affected, as can the
skin of the trunk and more proximal extremities. Linear irregular breaks in the dermatoglyphics of the palms are characteristic and help to distinguish this disorder from the other
reticulate flexural anomalies.
Kocaturk E, et al: Reticulate acropigmentation of Kitamura: report of a
familial case. Dermatol Online J 2008; 14:7.

Dermatopathia pigmentosa reticularis

Dermatopathia pigmentosa reticularis (DPR) is an autosomaldominant disorder characterized by the triad of generalized
reticulate hyperpigmentation (Fig. 36-6), noncicatricial alopecia, and onychodystrophy. Additional associations include
loss of dermatoglyphics, hypo- or hyperhidrosis, pigmented
850

Fig. 36-6 Dermatopathia pigmentosa reticularis.

Fig. 36-7 Transient neonatal pustulosis.

lesions of the oral mucosa, palmoplantar hyperkeratosis, and

nonscarring blisters on the dorsa of the hands and feet. Wiry
scalp hair and digital fibromatosis have also been reported.
Dental anomalies are not a feature of DPR. Some members
of families affected by NaegeliFranceschettiJadassohn syndrome (NFJS) have clinical features identical to DPR. Both
NFJS and DPR are due to mutations in the E1/V1 encoding
region of the keratin 14 gene, which would lead to premature
termination at the translation initiation site of keratin 14. NFJS
and DPR are now best considered variants of the same genetic
disorder. EB simplex with mottled pigmentation also has a
mutation in keratin 14, explaining the presence of blistering in
DPR and mottled pigmentation in this unique form of EB.
Brar BK, et al: Dermatopathia pigmentosa reticularis. Pediatr Dermatol
2007; 24:566.
Goh BK, et al: A case of dermatopathia pigmentosa reticularis with wiry
scalp hair and digital fibromatosis resulting from a recurrent KRT14
mutation. Clin Exp Dermatol 2009; 34:340.
Lugassy J, et al: NaegeliFranceschettiJadassohn syndrome and
dermatopathia pigmentosa reticularis: two allelic ectodermal
dysplasias caused by dominant mutations in KRT14. Am J Hum Genet
2006; 79:724.
Tunca M, et al: Early-onset gastric carcinoma in a man with
dermatopathia pigmentosa reticularis. Int J Dermatol 2008; 47:641.

Transient neonatal pustular melanosis

Also called transient neonatal pustulosis, this disorder is
present at birth. Newborns present with 13mm flaccid, superficial fragile pustules (Fig. 36-7). Some of the pustules may
have already resolved in utero, leaving pigmented macules.

Van Praag MC, et al: Diagnosis and treatment of pustular disorders in

the neonate. Pediatr Dermatol 1997; 14:131.

PeutzJeghers syndrome
PeutzJeghers syndrome (PJS) is characterized by hyperpigmented macules on the lips and oral mucosa, and polyposis
of the small intestine. The dark brown or black macules appear
typically on the lips, especially the lower lip, in infancy or
early childhood (Fig. 36-8). Similar lesions may appear on the
buccal mucosa, tongue, gingiva, and genital mucosa; macules
may also occur around the mouth, on the central face, and on
the backs of the hands, especially the fingers, toes, and tops of
the feet. More than two-thirds of patients have lesions on the
hands and feet, and 95% have perioral lesions. Skin lesions
grow in size and number until puberty, after which they begin
to regress. Similar pigmentation may be seen in the bowel.
The associated polyposis involves the small intestine by
preference (64%), but hamartomatous polyps may also occur
in the stomach (49%), colon (49%), and rectum (32%). The
polyposis of the small intestine may cause repeated bouts of
abdominal pain and vomiting. Bleeding is common; intussusception is frequent (47%).
Patients with PJS have a 15-fold greater lifetime cancer risk
(8593%) than the general population. The greatest risk is for
gastrointestinal malignancy of the colon (39% of patients),
stomach (29% of patients), and small intestine (13% of patients).
Cancers begin to appear around age 30 years. Cancers occur
in both the gastrointestinal tract and extraintestinal sites.
Pancreas (36%), breast (can be bilateral, 54%), ovary (21%),
lung, cervix, uterus, and thyroid carcinomas may develop.
SertoliLeydig cell stromal tumors occur in 9% of PJS males,

and sex cord tumors with annular tubules can occur in female
PJS patients. Patients with PJS lacking an STK11/LKB1 mutation have a 40% risk of cholangiocarcinoma.
The syndrome is transmitted as a simple mendelian dominant trait. Between 50 and 70% of families with PJS have a
germline mutation of the STK11/LKB1 tumor suppressor gene
on chromosome 19p13. The gene product is a serinethreonine
kinase involved in signal transduction in the mTOR pathway.
Patients have one inactive copy of this gene. Patients with
truncation of the gene rather than a missense mutation are
more severely affected, suggesting a phenotype/genotype
correlation.
LaugierHunziker syndrome and CronkhiteCanada syndrome should be considered in the differential diagnosis.
LaugierHunziker syndrome presents with mucosal pigmentation and pigmented nail streaks. Cronkhite-Canada syndrome consists of melanotic macules on the fingers and
gastrointestinal polyposis. Also there is generalized, uniform
darkening of the skin, extensive alopecia, and onychodystrophy. The polyps that occur are usually benign adenomas and
may involve the entire gastrointestinal tract. A protein-losing
enteropathy may develop and is associated with the degree
of intestinal polyposis. Onset is typically after age 30 in this
sporadically occurring, generally benign condition. Hypogeusia
is the dominant initial symptom, followed by diarrhea and
ectodermal changes. Seventy-five percent of all cases have
been reported from Japan. Zinc therapy may improve the
hypogeusia and other symptoms.

Riehl melanosis

Lesions affect the chin, neck, forehead, back, and buttocks, but
can occur anywhere. In dark-skinned infants, pigmented
macules may persist for weeks or months after the pustules
have healed, whereas in affected lighter-skinned neonates,
dyspigmentation less commonly occurs. The condition is
observed in 4.4% of black and 0.6% of white newborns.
Histologically, there are intracorneal or subcorneal aggregates predominantly of neutrophils, but eosinophils may also
be found. Dermal inflammation is composed of a mixture
of neutrophils and eosinophils. The differential diagnosis
includes erythema toxicum neonatorum, neonatal acne, and
acropustulosis of infancy.

Barnard J: Screening and surveillance recommendations for pediatric

gastrointestinal polyposis syndromes. J Pediatr Gastroenterol Nutr
2009; 48:S75.
Baudendistel TE, et al: Clinical problem-solving. The leading
diagnosisa 23-year-old black woman presented to the emergency
department with diffuse, colicky abdominal pain of 1 hours duration. N
Engl J Med 2007; 357:2389.
Campos-Munoz L, et al: Dermoscopy of PeutzJeghers syndrome. J Eur
Acad Dermatol Venereol 2009; 23:730.
Cureton E, Kim S: Images in clinical medicine. PeutzJeghers syndrome.
N Engl J Med 2007; 357:e9.
Flutter L, Mulik R: PeutzJegher syndrome. Arch Dis Child 2008;
93:163.
Heymann WR: PeutzJeghers syndrome. J Am Acad Dermatol 2007;
57:513.
Hezel AF, Bardeesy N: LKB1; linking cell structure and tumor
suppression. Oncogene 2008; 27:6908.
Katajisto P, et al: LKB1 signaling in mesenchymal cells required for
suppression of gastrointestinal polyposis. Nat Genet 2008; 40:455.
Kilic-Okman T, et al: Breast cancer, ovarian gonadoblastoma and
cervical cancer in a patient with PeutzJeghers syndrome. Arch
Gynecol Obstet 2008; 278:75.
Lynch HT, et al: Hereditary colorectal cancer syndromes: molecular
genetics, genetic counseling, diagnosis and management. Fam
Cancer 2008; 7:27.
Santos P, et al: Perioral pigmentation: what is your diagnosis? Dermatol
Online J 2008; 14:16.
Saranrittichai S: PeutzJeghers syndrome and colon cancer in a
10-year-old girl: implications for when and how to start screening?
Asian Pac J Cancer Prev 2008; 9:159.
Velez A, et al: Two novel LKB1 mutations in Colombian PeutzJeghers
syndrome patients. Clin Genet 2009; 75:304.
Wong SS, et al: PeutzJeghers syndrome associated with primary
malignant melanoma of the rectum. Br J Dermatol 1996; 135:439.
Yoo JH, et al: A novel de novo mutation in the serine-threonine kinase
STK11 gene in a Korean patient with PeutzJeghers syndrome. BMC
Med Genet 2008; 9:44.

Riehl melanosis
Fig. 36-8 PeutzJeghers syndrome, macular pigmentation of the
lower lip.

Riehl melanosis describes the pigmentation that occurs following photoallergic contact dermatitis, usually from fragrances
and essential oils in cosmetics. This term is no longer used.
851

Disturbances of Pigmentation

36

Miyoshi K, et al: Riehls melanosis-like eruption associated with

Sjgrens syndrome. J Dermatol 1997; 24:784.
Seike M, et al: Coexistence of Riehls melanosis and lichen planus. J
Dermatol 2003; 30:132.
Serrano G, et al: Riehls melanosis. J Am Acad Dermatol 1989;
21:1057.

Tar melanosis (melanodermatitis

toxica lichenoides)
Tar melanosis is an occupational dermatosis that occurs among
tar handlers after several years exposure. Severe widespread
itching develops and is soon followed by the appearance of
reticular pigmentation, telangiectases, and a shiny appearance
of the skin. In addition, there is a hyperhidrotic tendency.
Small, dark, lichenoid, follicular papules become profuse on
the extremities, particularly the forearms. Bullae are sometimes observed. This represents a photosensitivity or phototoxicity induced by tar. This condition is rarely observed with
current occupational protections.
Lebwohl M, et al: Tar melanosis. Mt Sinai J Med 1995; 62:412.

Familial progressive hyperpigmentation

Familial progressive hyperpigmentation (FPH) is characterized by patches of hyperpigmentation, present at birth, which
increase in size and number with age. Later, hyperpigmentation appears in the conjunctivae and the buccal mucosa.
Eventually, a large portion of the skin and mucous membranes
becomes involved. Inheritance is in an autosomal-dominant
pattern with variable penetrance. A focus in a small village in
Germany has recently been reported. FPH is differentiated
from other hyperpigmentations mainly by the presence of
bizarre, sharply marginated patterns of hyperpigmented skin.
A gain-of-function mutation in c-KIT has been described in an
affected kindred.
Betts CM, et al: Progressive hyperpigmentation: case report with a
clinical, histological, and ultrastructural investigation. Dermatology
1994; 189:384.
Wang ZQ, et al: Gain-of-function mutation of KIT ligand on melanin
synthesis causes familial progressive hyperpigmentation. Am J Hum
Genet 2009; 84:672.
Zanardo L, et al: Progressive hyperpigmentation and generalized
lentiginosis without associated systemic symptoms: a rare hereditary
pigmentation disorder in south-east Germany. Acta Derm Venereol
2004; 84:57.

Periorbital hyperpigmentation
Dark circles around the eyes are not uncommon, often familial,
and frequently found in individuals with dark pigmentation
or Mediterranean ancestry. Atopic patients may also exhibit
periorbital pigmentation (allergic shiners). There are probably
multiple pathogenic factors involved, including epidermal
hypermelanosis, dermal melanosis, increased vasculature, and
normal anatomic variants. Since there are multiple etiologies,
treatment is often ineffective.

Metallic discolorations
Pigmentation may develop from the deposit of fine metallic
particles in the skin. The metal may be carried to the skin by
the bloodstream or may permeate into it from surface applications. Discolorations from medications containing silver and
gold are discussed in Chapter 6.
852

Arsenic
Acute arsenic poisoning is associated with flushing on day 1
of exposure, and facial edema on days 25. A morbilliform
eruption appears on days 46. Hepatic dysfunction occurs
simultaneously with the appearance of an eruption of discrete
redbrown, erythematous papules in the intertriginous areas
(areas of friction) of the lower abdomen, buttocks, and lateral
upper chest. It regresses after 23 weeks, at times accompanied
by acral desquamation. Three months after exposure, Mees
lines, total leukonychia, Beaus lines, and onychodystrophy
may be seen. Periungual pigmentation occurs in up to half of
acutely poisoned patients at 3 months.
Arsenic is an elemental metal that is ubiquitous, existing in
nature as metalloids, alloys, and a variety of chemical compounds. These various forms of arsenic may be deposited into
water, soil, and vegetation, producing serious health risks. In
West Bengal, India, an estimated 200000 people have arsenicinduced skin disorders and more than 1 million Indians are
drinking arsenic-laced water from contaminated wells.
Arsenic-contaminated water sources are a worldwide health
concern also affecting countries such as Japan, Chile, Taiwan,
and Mongolia. It is not known what are safe levels of arsenic
in drinking water.
Industries using arsenical compounds place their workers at
risk of exposure. Use of arsenic pesticides and exposure to
sodium arsenite, used as a veterinary pesticide exposing
sheep-dip workers, has resulted in chronic arsenism. In the US
arsenic is used for pesticides, rodenticides, herbicides, insecticides, desiccants, feed additives, and wood preservatives.
Pressure-treated lumber, particularly the marine-treated
plywood, exposes carpenters and shipbuilders. The largest
risk from wood products, however, occurs when pretreated
wood is burned and the arsenic fumes are inhaled. Electroplating
silver may also require arsenic. Another potential source of
exposure during the 1960s was American tobacco, resulting
mostly from the use of arsenic-containing insecticides.
The most common form of arsenic exposure worldwide is
chronic, from contaminated wells and ground water. In areas
of exposure, even young children can demonstrate cutaneous
stigmata. Skin lesions occur only when arsenic concentrations
are 200g/L or more. Two characteristic forms of skin disease
occur. Cutaneous hyperpigmentation is the most common and
earliest side effect. The hyperpigmentation is usually diffuse,
most prominent on the trunk. Patchy hyperpigmentation may
be accentuated in the inguinal folds, on the areolae, and on
palmar creases. This can simulate Addisons disease. Areas of
hypopigmentation may be scattered in the hyperpigmented
areas, giving a raindrop appearance. Focal melanotic
macules may also be present. The pigmentation may resolve
or persist indefinitely. Punctate keratoses on the palms and
soles are characteristic. Diffuse palmoplantar keratoderma
may rarely occur. Blackfoot diseasearsenic-induced peripheral vascular disease that can lead to vasospasm and peripheral gangreneand a severe peripheral neuropathy can also
occur with chronic arsenic ingestion. Risk factors for development of clinically evident arsenic-induced disease include:
concentration of arsenic contamination in exposure source
(usually water), and malnutrition/low body mass index (BMI).
There is significant variation in prevalence of skin disease
from arsenic exposure in different racial groups and different
individuals. There is evidence that polymorphisms in arsenicmetabolizing (methylation) pathways, specifically converting
monomethylarsonic acid to dimethylarsinic acid, may explain
these risk differences. Arsenic exposure is also associated
with a significant reduction in circulating helper T cells,
perhaps contributing to increased cancer risk. One study
identified polymorphisms in the XPD gene as a risk factor

Ahsan T, et al: Chronic arsenic poisoning. J Pak Med Assoc 2009;

59:105.
Chakraborti D, et al: Status of groundwater arsenic contamination in the
state of West Bengal, India: a 20-year study report. Mol Nutr Food Res
2009; 53:542.
Elmariah SB, et al: Invasive squamous-cell carcinoma and arsenical
keratoses. Dermatol Online J 2008; 14:24.
Li X, et al: Arsenic methylation capacity and its correlation with skin
lesions induced by contaminated drinking water consumption in
residents of chronic arsenicosis area. Environ Toxicol 2009 Sep 18
(Epub ahead of print).
Liao WT, et al: Differential effects of arsenic on cutaneous and systemic
immunity: focusing on CD4+ cell apoptosis in patients with arsenicinduced Bowens disease. Carcinogenesis 2009; 30:1064.
Lin GF, et al: Association of XPD/ERCC2 G23591A and A35931C
polymorphisms with skin lesion prevalence in a multiethnic, arseniasishyperendemic village exposed to indoor combustion of high arsenic
coal. Arch Toxicol 2009 Oct 16 (Epub ahead of print).
Pilsner JR, et al: Folate deficiency, hyperhomocysteinemia, low urinary
creatinine, and hypomethylation of leukocyte DNA are risk factors for
arsenic-induced skin lesions. Environ Health Perspect 2009; 117:254.
Rahman MM, et al: Chronic exposure of arsenic via drinking water and
its adverse health impacts on humans. Environ Geochem Health 2009;
31:189.
Ratnaike RN: Acute and chronic arsenic toxicity. Postgrad Med J 2003;
79:391.
Rossman TG, et al: Evidence that arsenite acts as a cocarcinogen in
skin cancer. Toxicol Appl Pharmacol 2004; 198:394.
Schuhmacher-Wolz U, et al: Oral exposure to inorganic arsenic:
evaluation of its carcinogenic and non-carcinogenic effects. Crit Rev
Toxicol 2009; 39:271.
Sengupta SR, et al: Pathogenesis, clinical features and pathology of
chronic arsenicosis. Indian J Dermatol Venereol Leprol 2008; 74:559.
Smith AH, Steinmaus CM: Health effects of arsenic and chromium in
drinking water: recent human findings. Annu Rev Public Health 2009;
30:107.
Tomi NS, et al: A silver man. Lancet 2004; 363:532.
Valenzuela OL, et al: Association of AS3MT polymorphisms and the risk
of premalignant arsenic skin lesions. Toxicol Appl Pharmacol 2009;
239:200.
Waalkes MP, et al: Arsenic exposure in utero exacerbates skin cancer
response in adulthood with contemporaneous distortion of tumor stem
cell dynamics. Cancer Res 2008; 68:8278.
Watson K, Creamer D: Arsenic-induced keratoses and Bowens disease.
Clin Exp Dermatol 2004; 29:46.
Xia Y, et al: Well water arsenic exposure, arsenic induced skin-lesions
and self-reported morbidity in Inner Mongolia. Int J Environ Res Public
Health 2009; 6:1010.

Lead
Chronic lead poisoning can produce a lead hue, with lividity
and pallor, and a deposit of lead in the gums may occur: the
lead line (Fig. 36-9).

Iron
In the past, soluble iron compounds were used in the treatment of allergic contact and other dermatitides. In eroded

Metallic discolorations

for arsenic-induced skin lesions. Histologically, the arsenical

keratosis on the palms and soles shows hyperkeratosis, para
keratosis, acanthosis, and papillomatosis. Approximately
67% of hyperkeratotic skin lesions will demonstrate basilar
atypia, and about 1% will show cancer. Arsenic exposure leads
to the development of nonmelanoma skin cancers. Bowens
disease represents the majority of arsenic-induced skin cancers
and may appear on sun-exposed or sun-protected skin. Basal
cell carcinomas are frequent, are usually multiple, are most
common on the trunk, and can be in sun-protected sites.
Squamous cell carcinoma may also occur. Acitretin may
improve arsenical keratoses. Arsenic exposure results in
increased risk for lung, liver, and renal carcinoma.
Fig. 36-9 Lead line.

areas, iron was sometimes deposited in the skin, like a tattoo.

The use of Monsel solution can produce similar tattooing, so
aluminum chloride is now preferred. If Monsel is used to
minimize tattooing, it is best applied with a cotton-tipped
applicator barely moistened with the solution, then rolled
across a wound that has just been blotted dry.

Hemochromatosis
Hemochromatosis is a disorder caused by mutations in at least
five different genes involved in iron absorption. It is very
common in the white European population, where the majority of the mutations are at two genetic loci, C282Y and H63D,
allowing for widespread genetic screening. At least four different phenotypes are described. Many of the patients with the
most common genetic defects do not develop any disease
(perhaps 25% of men and 6% of women). Men are affected
more frequently and at an earlier age (usually between 30 and
50 years). With widespread genetic testing, the age of diagnosis has been decreased, and the number of asymptomatic
affected females has dramatically increased. The characteristic
cutaneous manifestation is gray to brown mucocutaneous
hyperpigmentation. This is enhanced in sun-exposed areas of
the forearms, dorsal hands, and face, as well as in the inguinal
area. The mucous membranes are pigmented in up to 20% of
patients. The percentage of affected males with pigmentation
is around 30% and in women fewer than 10% of diagnosed
patients have skin changes. Other skin changes that can be
seen include koilonychia and localized ichthyosis. Alopecia is
common and pruritus can occur. Porphyria cutanea tarda may
be present due to inhibition of uroporphyrinogen decarboxylase in the liver by iron overload. In patients with chronic
venous insufficiency, the risk of lower leg ulceration is
increased six-fold in those also carrying the C282Y mutation,
leading some to suggest that this test should be ordered in
at-risk patients at the initial stages of venous insufficiency.
Biopsy of affected hyperpigmented skin shows dermal iron
deposition, but the visible pigmentation is actually increased
epidermal melanin in the basal cell layer.
The most seriously affected organ is the liver. Hepatomegaly
and elevated liver function tests are signs of hepatic iron overload. Cirrhosis and hepatocellular carcinoma may develop,
but are now uncommon with early diagnosis and treatment.
The endocrine system is also affected, with diabetes mellitus,
impotence, and amenorrhea being most common. Arthropathy
is seen in about 50% of women and 40% of men. Cardiac
abnormalities include heart failure and arrhythmias.
Consuming alcohol and smoking, as well as coexistent hepatitis C infection, all make it more likely that persons with
genetic predisposition will develop clinical disease.
853

Disturbances of Pigmentation

36

Laboratory evaluation should be pursued in persons with

appropriate clinical findings suggesting the diagnosis of
hemochromatosis. Levels of plasma iron and the serum ironbinding protein are elevated. The transferrin saturation (TS =
serum iron/total iron-binding capacity) is a useful screening
measure. A score of 45 or less is normal, except in premenopausal women when greater than 35 may be considered abnormal. High serum ferritin levels are also present. Genotyping
is now performed in persons with a TS greater than 45 and an
elevated ferritin, and confirms the diagnosis. Liver biopsy is
reserved for persons with elevated liver function tests, a ferritin greater than 1000, or age over 40.
Four different genes cause autosomal-recessive hemochromatosis and one causes autosomal-dominant disease. The
most common autosomal-recessive form is due to a mutation
in the HFE gene, most frequently C282Y, and less commonly
H63D. The incidence of homozygosity for C282Y is 5 in 1000
persons of northern European descent, making it ten times
more common than cystic fibrosis. Compound heterozygotes
(C282Y/H63D) also develop disease. Two autosomal-recessive
forms of juvenile hereditary hemochromatosis are described,
due to mutations in the Hemojuvelin and Hepcidin genes,
respectively. Mutations in the transferrin receptor 2 gene lead
to a form of autosomal-recessive adult-onset hemochromatosis. Ferroportin mutation leads to an adult-onset form of
autosomal-dominant hemochromatosis.
All forms of hemochromatosis are treated with phlebotomy
until satisfactory iron levels are attained. Vitamin C supplementation must be avoided, as it can worsen the disease.
Raw seafood should be avoided because Vibrio vulnificus
infection may occur. Phlebotomy can prevent cirrhosis.
Once cirrhosis is present, phlebotomy does not prevent the
development of hepatocellular carcinoma, which occurs in
30% of patients.
Limdi JK, Crampton JR: Hereditary haemochromatosis. Q J Med 2004;
97:315.
Pietrangelo A: Hereditary hemochromatosisa new look at an old
disease. N Engl J Med 2004; 350:2383.
Scotet V, et al: Impact of HFE genetic testing on clinical presentation of
hereditary hemochromatosis: new epidemiological data. BMC Med
Genet 2005; 6:24.
Zamboni P, et al: Hemochromatosis C282Y gene mutation increases the
risk of venous leg ulceration. J Vasc Surg 2005; 42:309.

Titanium
A titanium-containing ointment caused yellowish papules on
the penis in a patient. Titanium screws used for orthopedic
procedures, if they come in close proximity to the skin, can
cause cutaneous blueblack hyperpigmentation.
Akimoto M, et al: Metallosis of the skin mimicking malignant skin tumor.
Br J Dermatol 2003; 149:653.
Dupre A, et al: Titanium pigmentation. Arch Dermatol 1985; 121:656.

Canthaxanthin
The orangered pigment, canthaxanthin, is present in many
plants (notably algae and mushrooms) and in bacteria, crustaceans, sea trout, and feathers. When ingested for the purpose
of simulating a tan, its deposition in the panniculus imparts a
golden orange hue to the skin. Stools become brick red and
the plasma orange, and golden deposits appear in the retina.
Its use is not recommended, since it may be associated with
liver and retinal damage.
Lober CW: Canthaxanthin: the tanning pill. J Am Acad Dermatol 1985;
13:660.

854

Fig. 36-10 Idiopathic guttate hypomelanosis.

Idiopathic guttate hypomelanosis

(leukopathia symmetrica progressiva)
Idiopathic guttate hypomelanosis is a very common acquired
disorder that affects women more frequently than men. It
usually occurs after age 40 and its prevalence increases with
age. The lesions occur chiefly on the shins (Fig. 36-10) and
forearms, suggesting that sun exposure plays a role.
Widespread lesions have occurred in patients receiving UVB
therapy. Individual lesions are small (25mm on average),
hypopigmented macules. They usually number between 10
and 30, but numerous lesions may occur. Lesions spare the
trunk and face. The lesions are irregularly shaped and very
sharply defined, like depigmented ephelides. Histologically,
there is epidermal atrophy and reduced numbers of hypo
active melanocytes. Cryotherapy can improve the appearance
of the lesions.
Arrunategui A, et al: HLA-DQ3 is associated with idiopathic guttate
hypomelanosis, whereas HLA-DR8 is not, in a group of renal
transplant patients. Int J Dermatol 2002; 41:744.
Kaya TI, et al: Idiopathic guttate hypomelanosis: idiopathic or ultraviolet
induced? Photodermatol Photoimmunol Photomed 2005; 21:270.

Vitiligo
Vitiligo usually begins in childhood or young adulthood, with
a peak onset between 10 and 30 years. About half of cases
begin before the age of 20. The prevalence ranges from 0.5%
to 1%. Although females are disproportionately represented
among patients seeking care, it is not known whether they are
actually more commonly affected or simply are more likely to
seek medical care. Vitiligo has developed in recipients of bone
marrow transplant or lymphocyte infusions from patients
with vitiligo.

Clinical features
Vitiligo is an acquired pigmentary anomaly of the skin manifested by depigmented white patches surrounded by a normal

Vitiligo
Fig. 36-11 Localized vitiligo.

Fig. 36-13 Penile vitiligo.

Fig. 36-12 Vitiligo, generalized.

or a hyperpigmented border. There may be intermediate tan

zones or lesions halfway between the normal skin color and
depigmentationso-called trichrome vitiligo. Bluegray
hyperpigmented macules representing melanin incontinence
may be present focally. The hairs in the vitiliginous areas
usually become white also. Very rarely, the patches may have
a red, inflammatory border. The patches are of various sizes
and configurations, but the margins are usually smooth, except
in the case of segmental vitiligo.
Six types have been described, according to the extent and
distribution of the involved areas: localized (Fig. 36-11); or
focal (single or a few macules in one anatomic area, often the
trigeminal area, especially in children); segmental; generalized
(common symmetric); universal (Fig. 36-12); acrofacial; and
mucosal. The generalized pattern is most common. Involvement
is symmetrical. The most commonly affected sites are the face,
upper part of the chest, dorsal aspects of the hands, axillae,
and groin. There is a tendency for the skin around orifices to
be affected: namely, the eyes, nose, mouth, ears, nipples,
umbilicus, penis, vulva, and anus. Lesions appear at areas of
trauma, so vitiligo favors the elbows and knees. Universal
vitiligo applies to cases where the entire body surface is
depigmented. The acrofacial type affects the distal fingers
and facial orifices (lips and tips). Focal vitiligo may affect one
nondermatomal site (such as the glans penis) (Fig. 36-13), or

asymmetrically affects a single region. It is to be distinguished

from the segmental form of vitiligo, which is treatmentresistant, has an earlier onset, and is less frequently associated
with other autoimmune phenomena. It represents 5% of adult
vitiligo and 20% of childhood vitiligo. Segmental vitiligo often
has a dermatomal or quasi-dermatomal distribution.
In patients with vitiligo, local loss of pigment may occur
around nevi and melanomas, the so-called halo phenomenon.
Vitiligo-like leukoderma occurs in about 1% of melanoma
patients. In those with previously diagnosed melanoma, this
suggests metastatic disease. Paradoxically, however, as the
reaction indicates an autoimmune response against melanocytes, patients who develop it have a better prognosis than
patients without leukoderma. Lesions of vitiligo are hypersensitive to UV light and burn readily when exposed to the sun.
With repeated sun exposure, lesions of vitiligo can tolerate
additional UV exposure (photoadaptation), allowing for
increasing doses of therapeutic UV phototherapy.
Ocular abnormalities are increased in patients with vitiligo,
including iritis and retinal pigmentary abnormalities. Patients
have no visual complaints. Eight percent of patients with idio
pathic uveitis have vitiligo or poliosis. The conditions most
frequently associated with vitiligo are other autoimmune
diseases. These include type 1 diabetes mellitus, pernicious
anemia, Hashimoto thyroiditis, Graves disease, Addisons
disease, and alopecia areata, which in total affect 32% of
family members of patients with vitiligo. If a family history
of autoimmune disease is obtained, the vitiligo patient
(except those with segmental vitiligo) should be tested for
serum antithyroglobulin and antithyroid peroxidase antibodies, since autoimmune thyroid disease is the most common
autoimmune disease to be present in vitiligo patients.
Additional screening should be directed by signs and symptoms. Vitiligo occurs in 13% of patients with the autoimmune
polyendocrinopathycandidiasisectodermal
dystrophy
(APECED) syndrome, caused by mutations in the autoimmune
regulator gene (AIRE). Polymorphisms in the AIRE gene are
found more commonly in vitiligo patients than controls.
Although familial aggregation of vitiligo is seenup to 30%
of vitiligo patients have an affected relativeit is not inherited
as an autosomal-dominant or recessive trait, but rather seems
to have a multifactorial genetic basis. In addition to the auto
immune pathogenic hypothesis, which is most likely, oxidant/
antioxidant and neural theories have been proposed. Several
of these mechanisms may simultaneously be pathogenic in
vitiligo.
855

Disturbances of Pigmentation

36

The psychologic effect of vitiligo should not be underestimated. Patients are frequently anxious or depressed because
of the appearance of their skin and the way it affects their
social interactions. This is true for both children and adults.
Young adults with childhood vitiligo have persistent healthrelated quality of life impairment. Referring the patient to a
mental health professional or the National Vitiligo Foundation
(www.nvfi.org) may be helpful in this situation.

Histopathology
There is a complete absence of melanocytes. Usually, there is
no inflammatory infiltrate, but lichenoid or spongiotic inflammation may be detected at the edge of a substantial number
of vitiligo lesions. This explains the scaling or hyperpigmentation sometimes observed around lesions of vitiligo.

Differential diagnosis
Vitiligo must be differentiated from morphea and lichen sclerosus, both of which are hypopigmented but associated with
a change in the skin texture. Pityriasis alba has a fine scale, is
slightly papular, and is poorly defined. Tinea versicolor favors
the center back and chest, and has a fine scale; yeast and
hyphal forms are demonstrable with potassium hydroxide
(KOH) examination. The tertiary stage of pinta might easily
lead to diagnostic confusion, but a travel history and serologic
testing will help elucidate the diagnosis. Chemical leukoderma
(see below) may closely resemble vitiligo.

Treatment
Vitiligo can be a frustrating condition to treat. Spontaneous
repigmentation occurs in no more than 1525% of cases.
Response is typically slow, and response rates are low in some
anatomic areas. Since vitiligo is common, many studies have
been published regarding therapeutic options. However, they
are often of poor quality, or have markedly different results
when performed at different centers. Persons of different
Fitzpatrick phototypes may have different rates of response
when facial vitiligo is treated. In addition, some forms of treatment, such as phototherapy, may actually worsen the appearance of the vitiligo initially by pigmenting surrounding skin,
accentuating the depigmented areas. This is particularly true
in persons of lower Fitzpatrick phototypes (I and II). The anatomic location of the lesion predicts the likelihood of response,
independent of the modality used for therapy. Facial vitiligo
has an excellent prognosis, with many patients achieving cosmetically significant improvement. The dorsal hands and feet,
by contrast, respond to most forms of treatment only about
1020% of the time. Truncal vitiligo demonstrates an inter
mediate response.
The major problem for the vitiligo patient is appearance.
With regard to vitiligo in persons of low Fitzpatrick phototypes (I and II), non-treatment is an option. These patients are
treated with sun protection, supplemented with cosmetic camouflage as required. The newer self-tanning creams are useful
for light-skinned and olive-complexioned patients with acral
lesions. Phototherapy may more dramatically increase the risk
of skin cancer in those with lower Fitzpatrick phototypes, suggesting that alternative approaches should be considered. In
addition, mucosal vitiligo (of the lips), and periungual and
dorsal hand vitiligo currently have essentially no reproducibly
effective form of medical therapy. Camouflage is, therefore, an
important therapeutic modality for the vitiligo patient.
Dihydroxyacetone is a brown dye that stains the skin. In lower
concentrations it can be used in lower phototypes, as it is a
856

golden or tan color (self-tanning products). In high concentrations it is dark brown and can be used in patients with type V
and VI phototypes to camouflage their lesions. As it is a stain,
it does not rub off, but needs to be reapplied because it is
sloughed off from the epidermis (every 510 days). Covermark,
Dermablend, Dermacolor, Keromask, Veil Cover, and
PerfectCover are trademarks that specialize in cosmetic products for patients with dyspigmentations, including vitiligo.
These products can be amazingly effective in making the vitiliginous skin blend completely into the normal surrounding
skin. However, it is technically difficult for patients to match
their skin color without instruction. In the beginning, vitiligo
patients using these products will benefit by consulting an
aesthetician trained in medical camouflage. Once applied,
the products tend to rub off. Application of Cavilon No
Sting Barrier Film as a spray over the camouflage cosmetic
may prevent the product from rubbing off during daily
activities.
Topical treatment is appropriate for limited skin areas (<10
20% body surface area [BSA]). Occlusion of all forms of topical
therapy may enhance efficacy. Topical potent to superpotent
steroids are used for a 2-month trial. Up to 80% of patients
with facial vitiligo will achieve >90% repigmentation. This
usually occurs diffusely, not perifollicularly, as occurs on
the trunk. On the trunk only 40% of patients achieve >90%
repigmentation. Treatment should be limited to 46 months
and the patient must be monitored for acne, atrophy, and
telangiectasias.
Topical pimecrolimus cream and tacrolimus ointment 0.1%
have been particularly efficacious in treating facial vitiligo. In
some series they have been as effective as superpotent topical
steroids and avoid the complications of atrophy and acne
induced by topical steroids. Patients who initiate treatment in
the summer have a higher rate of response. Continual application may be required, as patients who discontinue treatment
may suffer the appearance of new lesions. With topical therapies, new areas of vitiligo appear in untreated areas, suggesting there is no systemic effect. Topical pimecrolimus may
enhance the efficacy of narrow-band UVB (NBUVB) in repigmenting facial, but not non-facial vitiligo. Topical calcipotriene
and other vitamin D analogs have had variable results. Alone
these agents lack efficacy. When they are used in combination
with other treatments, some studies have demonstrated additive benefit and others no benefit. Therefore, these agents
cannot be recommended.
NBUVB twice weekly has become the preferred form of
phototherapy to treat vitiligo. It avoids the need for prolonged
eye protection and the occasional psoralen-induced nausea.
About half of patients will achieve more than 75% repigmentation of the face, trunk, proximal arms, and legs. Hand and foot
lesions repigment in less than 25% of patients. Children may
have slightly higher response rates than adults. In patients
with >20% BSA involvement, only about 5% will show complete repigmentation with phototherapy. Long courses of
treatment may be required. PUVA therapy can also be used to
treat vitiligo, but is less effective than NBUVB. Repigmentation
from phototherapy may begin after 1525 treatments; however,
significant improvement may take as many as 100200 treatments (624 months). On average, maximum improvement is
seen after about 9 months of therapy. If follicular repigmentation has not appeared after 3 months, phototherapy treatments
should be discontinued. Known photosensitivity, porphyria,
and systemic lupus erythematosus are contraindications to
phototherapy.
Topical application of 8-methoxypsoralen at a concentration
of 0.010.1%, followed by UVA exposure, may lead to repigmentation. Topical PUVA is used for focal or limited lesions.
Inadvertent burns with blistering are frequent complications

Total depigmentation
If more than 5080% of the body surface area is affected by
vitiligo, the patient can consider depigmentation. This form of
treatment should be considered permanent and the goal is
total depigmentation. Limited areas (such as those exposed
daily) may be treated, but satellite and distant depigmentation
may occur, so the action of the medication cannot be limited
to the applied area. Monobenzone (monobenzyl ether of
hydroquinone) 20% is applied twice a day for 36 months to
residual pigmented areas. Up to 10 months may be required
to complete the treatment. About 1 in 6 patients treated experiences acute dermatitis, usually confined to the still-pigmented
areas, but this rarely limits treatment. Once the patient achieves
a uniform depigmented appearance, he/she is very satisfied.
Topical 20% 4-methoxyphenol cream (mequinol, monomethyl
ether of hydroquinone) can also be used for depigmentation.
The Q-switched laser selectively destroys melanocytes and can
also achieve depigmentation. It can be combined with a topical
depigmenting agent for added efficacy.

Chemical leukoderma (occupational vitiligo)

Chemical leukoderma is an acquired, depigmented dermatosis caused by repeated exposure to chemicals. It is frequently
misdiagnosed as vitiligo. Patients with vitiligo or a family
history of vitiligo are at much greater risk of developing chemical leukoderma. The diagnostic criteria are:

1. acquired vitiligo-like depigmented lesions

2. history of repeated exposure to a specific chemical
compound
3. patterned vitiligo-like macules conforming to site of
exposure
4. confetti macules.
The majority of cases are caused by exposure to aromatic or
aliphatic derivatives of phenols and catechols, including
paratertiary butylphenol (adhesive in shoes), amylphenol,
butylcatechol, and alkyl phenols. However, sulfhydryls, mercurials, arsenics, cinnamic aldehyde, p-phenylenediamine,
chloroquine, and azelaic acid have also been incriminated.
Some of these compounds have a structure similar to tyrosine
and may be converted by tyrosine-related protein-1 to compounds toxic to the melanocyte. This process is considered to
be different from depigmentation following allergic contact
dermatitis. The clinical pattern may be very similar to idiopathic vitiligo, but lesions tend to be concentrated in areas of
repeated contact with the incriminated substance. The first
recognized cases of occupational vitiligo occurred in individuals who worked in rubber garments or wore gloves that contained monobenzyl ether of hydroquinone. This compound
may still contaminate some rubber products. Phenolic antiseptic detergents used in hospitals and in industrial cleaners have
caused chemical leukoderma in janitorial and housekeeping
employees. Adhesives and glues containing incriminated
chemicals may be found in shoes, wristbands, adhesive tape,
and rubber products used in brassieres, girdles, panties, or
condoms. Self-sticking bindis (the cosmetic used by many
Indian women on the forehead) have been reported to induce
leukoderma from the adhesive material. Also, electrocardiograph electrodes may cause similar round hypopigmented
spots at the site of contact.
The most common location for chemical leukoderma is the
face (40% of cases), followed by the hands and feet. The scalp
is rarely affected. Hair dye (at the rim of the scalp but not on
the scalp), deodorant (axilla), detergent, adhesives (face,
bindis), rubber sandals (feet), black socks and shoes (feet), and
rubber condoms (penis) are the exposures associated with
lesions in various anatomic regions. Pruritus occurs in more
than 20% of patients (a rare complaint in vitiligo patients). The
clinical lesions are sharply marginated macules and patches,
often with confetti or pea-sized macules seen at the periphery.
This clinical pattern is atypical for idiopathic vitiligo and
should suggest the diagnosis of chemical leukoderma. More
than 25% of patients have lesions outside the area of contact
with the incriminated chemical. In about 10% of patients, new
vitiliginous lesions will continue to develop, even after exposure to the chemical is stopped. Treatment is avoidance and
measures used for idiopathic vitiligo (see above). Chemical
leukoderma in a person without vitiligo has a good prognosis,
with repigmentation in up to 75% of cases. If a person with
vitiligo develops a chemical leukoderma, repigmentation only
occurs in 20% of cases. Histologically, the vitiliginous areas of
a chemical leukoderma show an absence of melanocytes identical to lesions of true vitiligo.

Chemical leukoderma

during treatment in the US, even when the patient is treated

by professionals. For this reason, topical PUVA has been very
difficult for the patient to carry out at home. Topical PUVA,
however, is widely used in India with success, suggesting that,
in the right hands, this treatment can be effective.
Excimer laser phototherapy can be as effective as NBUVB,
and the response is more rapid. It can be used on limited areas,
avoiding whole-body UV exposure. While 25% of treated
patches repigment completely, treatment-resistant areas
(elbows, knees, wrists, dorsal hands and feet) have only a 2%
rate of at least 75% repigmentation. The addition of topical
steroid treatment to excimer laser may enhance efficacy.
In certain situations, the use of systemic immunosuppressives may be appropriate in the treatment of vitiligo. This is
usually in the setting of very rapidly progressive disease, with
the goal of reducing the total amount of pigment loss. Systemic
corticosteroids are usually used and are tapered over several
months. Twice weekly dexamethasone, at a dose of 10mg, is
one such regimen. Once the disease is arrested, the patient can
be converted to phototherapy. The long-term use of systemic
immunosuppressives is not recommended. They initially may
control the disease, but with chronic use, unacceptable toxicity
often develops.
Surgical treatments can be applied to limited lesions if the
above methods do not prove beneficial, but these are timeconsuming. They are recommended primarily in patients with
treatment-resistant vitiligo. Patients must have stable disease
(no new lesions, or expansion of lesions for 1 year). Surgical
procedures are not effective in patients who exhibit Koebner
phenomenon or have active vitiligo. Given its expense, surgical treatment should be reserved for exposed skin sites covering less than 23% of BSA. Minigrafting, transplantation of
autologous epidermal cell suspension, and ultra thin epidermal grafts have all been used. UV phototherapy is often given
following the surgical procedure.
Systemic immunosuppressives, specifically high-dose
corticosteroids, can arrest rapidly progressive vitiligo.
However, they cannot be used long-term due to toxicity,
so another form of therapy must be sought once the vitiligo
has been arrested.

Akimoto S, et al: Multiple actinic keratoses and squamous cell

carcinomas on the sun-exposed areas of widespread vitiligo. Br J
Dermatol 2000; 142:824.
Alajlan A, et al: Transfer of vitiligo after allogeneic bone marrow
transplantation. J Am Acad Dermatol 2002; 46:606.
Attili VR, Attili SK: Lichenoid inflammation in vitiligoa clinical
and histopathologic review of 210 cases. Int J Dermatol 2008;
47:663.
Au WY, et al: Generalized vitiligo after lymphocyte infusion for relapsed
leukaemia. Br J Dermatol 2001; 145:1015.
Austin M: Fighting and living with vitiligo. J Am Acad Dermatol 2004;
51:S7.

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Basak PY, et al: The role of helper and regulatory T cells in the
pathogenesis of vitiligo. J Am Acad Dermatol 2009; 60:256.
Chen YF, et al: Treatment of vitiligo by transplantation of cultured pure
melanocyte suspension: analysis of 120 cases. J Am Acad Dermatol
2004; 51:68.
Cockayne SE, et al: Vitiligo treated with topical corticosteroids: children
with head and neck involvement respond well. J Am Acad Dermatol
2002; 46:964.
Esfandiarpour I, et al: The efficacy of pimecrolimus 1% cream plus
narrow-band ultraviolet B in the treatment of vitiligo: a double-blind
placebo-controlled clinical trial. J Dermatolog Treat 2009; 20:14.
Falabella R, Barona MI: Update on skin repigmentation therapies in
vitiligo. Pigment Cell Melanoma Res 2009; 22:42.
Fenton JS, et al: Vitiligo: nonsurgical treatment options and the
evidence behind their use. J Drugs Dermatol 2008; 7:705.
Gawkrodger DJ, et al: Guideline for the diagnosis and management of
vitiligo. Br J Dermatol 2008; 159:1051.
Ghosh S, Mukhopadhyay S: Chemical leucoderma: a clinico-aetiological
study of 864 cases in the perspective of a developing country. Br J
Dermatol 2009; 160:40.
Godse KV: Comparison of two diluents of 1% methoxsalen in the
treatment of vitiligo. Indian J Dermatol Venerol Leprol 2008; 74:298.
Grimes PE: White patches and bruised souls: advances in the
pathogenesis and treatment of vitiligo. J Am Acad Dermatol 2004;
51:S5.
Grimes PE, et al: Topical tacrolimus therapy for vitiligo: therapeutic
responses and skin messenger RNA expression of proinflammatory
cytokines. J Am Acad Dermatol 2004; 51:52.
Halder RM, Chappell JL: Vitiligo update. Semin Cutan Med Surg 2009;
28:86.
Hartmann A, et al: Occlusive treatment enhances efficacy of tacrolimus
0.1% ointment in adult patients with vitiligo: results of a placebocontrolled 12-month prospective study. Acta Derm Venereol 2008;
88:474.
Hexsel CL, et al: A clinical trial and molecular study of photoadaptation
in vitiligo. Br J Dermatol 2009; 160:534.
Hsu S: Camouflaging vitiligo with dihydroxyacetone. Dermatol Online J
2008; 14:23.
Lepe V, et al: A double-blind randomized trial of 0.1% tacrolimus vs
0.05% clobetasol for the treatment of childhood vitiligo. Arch Dermatol
2003; 139:581.
Linthorst Homan MW, et al: Impact of childhood vitiligo on adult life. Br J
Dermatol 2008; 159:915.
Martin-Garcia RF, et al: Chloroquine-induced, vitiligo-like
depigmentation. J Am Acad Dermatol 2003; 48:981.
Mulekar SV, et al: Treatment of vitiligo on difficult-to-treat sites using
autologous noncultured cellular grafting. Dermatol Surg 2009; 35:66.
Natta R, et al: Narrowband ultraviolet B radiation therapy for recalcitrant
vitiligo in Asians. J Am Acad Dermatol 2003; 49:473.
Nicolaidou E, et al: Narrowband ultraviolet B phototherapy and 308-nm
excimer laser in the treatment of vitiligo: a review. J Am Acad Dermatol
2009; 60:470.
Njoo MD, et al: Treatment of generalized vitiligo in children with
narrow-band (TL-01) UVB radiation therapy. J Am Acad Dermatol
2000; 42:245.
Njoo MD, et al: Depigmentation therapy in vitiligo universalis with topical
4-methoxyphenol and the Q-switched ruby laser. J Am Acad Dermatol
2000; 42:760.
Nordlund JJ, et al: Dermatitis produced by applications of
monobenzone in patients with active vitiligo. Arch Dermatol 1985;
121:1141.
Olssom MJ: What are the needs for transplantation treatment in vitiligo,
and how good is it? Arch Dermatol 2004; 140:1273.
Passeron T, et al: Topical tacrolimus and the 308-nm excimer laser: a
synergistic combination for the treatment of vitiligo. Arch Dermatol
2004; 140:1065.
Radakovic-Fijan S, et al: Oral dexamethasone pulse treatment for vitiligo.
J Am Acad Dermatol 2001; 44:814.
Sassi F, et al: Randomized controlled trial comparing the effectiveness
of 308-nm excimer laser alone or in combination with topical
hydrocortisone 17-butyrate cream in the treatment of vitiligo of the face
and neck. Br J Dermatol 2008; 159:1186.
Silverberg NB, et al: Tacrolimus ointment promotes repigmentation of
vitiligo in children: a review of 57 cases. J Am Acad Dermatol 2004;
51:760.

Suga Y, et al: Medical pearl: DHA application for camouflaging

segmental vitiligo and piebald lesions. J Am Acad Dermatol 2002;
47:436.
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260:160.
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22:90.
Tazi-Ahnini R, et al: The autoimmune regulator gene (AIRE) is strongly
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van Geel N, et al: Double-blind placebo-controlled study of autologous
transplanted epidermal cell suspensions for repigmenting vitiligo. Arch
Dermatol 2004; 140:1203.

VogtKoyanagiHarada syndrome
VogtKoyanagiHarada syndrome (VKHS) is a disease
complex affecting the eyes, skin, auditory system, and central
nervous system (CNS). It affects primarily pigmented races
and is rare in white persons. It is more common in females,
and affects all ages. The disease occurs in four phases. First
is the prodromal phase or meningoencephalitic phase, with
fever, malaise, headache, nausea, and vomiting. The CNS
involvement can include meningismus, headaches, mental
status changes, cerebrospinal fluid pleocytosis, tinnitus, and
dysacusis. Recovery is usually complete. The second stage, the
uveitic phase, is characterized by anterior and/or posterior
uveitis and inflammation of many other parts of the eye. The
third or convalescent phase begins 3 weeks to 3 months after
the uveitis appears, usually as it begins to improve. This stage
is characterized by frontal non-cicatricial alopecia, vitiligo, and
poliosis of scalp, eyebrows, eyelashes, and hairs of the axillae.
The skin lesions must begin after the ocular symptoms to be
considered diagnostic. The fourth phase is one of recurrent
attacks of uveitis. Most ocular complications occur as a result
of this stage of the disease, and include permanent decreased
visual acuity, cataracts, and glaucoma.
VKHS is a cell-mediated autoimmune disease with the
autoantigen(s) felt to be solely expressed in melanin-containing
cells. The target antigens may be the tyrosinase family proteins, as immunization of mice with several of these proteins
can induce a syndrome similar to VKHS. Supporting this
hypothesis are the rare observations that vitiligo, erythroderma, interferon therapy for hepatitis C, and melanoma can
all be associated with the appearance of VKHS. Aggressive
immunosuppressive therapy with systemic steroids and
immunomodulatory medications (cyclosporine, azathioprine,
mycophenolate, tacrolimus, infliximab) may preserve ocular
function and prevent ocular complications. Th17 CD4+ cells
stimulated by high levels of interleukin (IL)-23 and secreting
IL-17 are present in VKHS patients with active uveitis. IL-23
is important in the production and maintenance of auto
immune diseases, and IL-17 is one of the most important
effector cytokines in autoimmune diseases. At least four
patients with psoriasis and VKHS have been reported.
Aisenbrey S, et al: VogtKoyanagiHarada syndrome associated with
cutaneous malignant melanoma: an 11-year follow-up. Graefes Arch
Clin Exp Ophthalmol 2003; 241:996.
Andreoli CM, Foster CS: VogtKoyanagiHarada disease. Int Ophthalmol
Clin 2006; 46:111.
Chi W, et al: IL-23 promotes CD4+ T cells to produce IL-17 in Vogt
KoyanagiHarada disease. J Allergy Clin Immunol 2007; 119:1218.
Kluger N, et al: VogtKoyanagiHarada syndrome associated with
psoriasis and autoimmune thyroid disease. Acta Derm Venerol 2008;
88:397.
Liu X, et al: Inhibitory effect of cyclosporin A and corticosteroids
on the production of IFN-gamma and IL-17 by T cells in
VogtKoyanagiHarada syndrome. Clin Immunol 2009; 131:333.

Alezzandrini syndrome
Alezzandrini syndrome is a very rare condition characterized
by a unilateral degenerative retinitis, followed after several
months by ipsilateral vitiligo on the face and ipsilateral poliosis. Deafness may also be present.
Hoffman MD, Dudley C: Suspected Alezzandrinis syndrome in a diabetic
patient with unilateral retinal detachment and ipsilateral vitiligo and
poliosis. J Am Acad Dermatol 1992; 26:496.

Leukoderma
Postinflammatory leukoderma may result from many inflammatory dermatoses, such as pityriasis rosea, psoriasis, herpes
zoster, secondary syphilis, and morphea. Sarcoidosis, tinea
versicolor, mycosis fungoides, scleroderma, and pityriasis
lichenoides chronica may all present with hypopigmented
lesions (only rarely are these actually depigmented), as may
Hansens disease. Burns, scars, postdermabrasion, and intra
lesional steroid injections with depigmentation are other
examples of leukoderma.
Friedman SJ, et al: Perilesional linear atrophy and hypopigmentation
after intralesional corticosteroid therapy. J Am Acad Dermatol 1988;
19:537.

Oculocutaneous albinism
Oculocutaneous albinism (OCA) is an autosomal-recessively
inherited trait with reduction or absence of melanin in skin,
hair, and eyes. Eye problems are frequently present, including
moderate to severe impairment of visual acuity, nystagmus,
strabismus, and photophobia. The cutaneous phenotype of the
various forms of albinism is broad, but the ocular phenotype
is reasonably constant in most forms. Genetic disorders of
pigment cells can now be defined as caused by:
1. disruption of melanoblast migration to target tissues
during development (Waardenburg syndrome and
piebaldism)
2. disruption of melanin synthesis (oculocutaneous
albinism)
3. disruption of melanosome formation (ChdiakHigashi
and HermanskyPudlak syndromes)
4. disruption of melanosome transport and melanin transfer
to keratinocytes (Griscelli syndrome).
The most serious sequelae of albinism are gross visual dis
turbances and the increased risk for the development of skin
cancer. A number of syndromes associated with albinism can
also cause premature mortality due to impairment of the functioning of other involved organs and systems.

Disorders of melanin synthesis

The four genetic forms of non-syndromal OCA are all caused
by disruption of melanin synthesis and all autosomal-recessive
disorders. Their prevalence varies widely around the world,
but is estimated to be about 1 in 17000. That means that about
1 in 70 persons carries a gene for OCA. Given the phenotypic
overlap of the various forms of OCA, genetic testing is recommended to establish the diagnosis. Since both parents are obligate carriers and two-thirds of healthy siblings are at risk for
being carriers, genetic counseling is recommended. Carriers
are asymptomatic. All persons with OCA and their parents
should be educated regarding aggressive sun protection with
sunscreens, appropriate clothing, and sun avoidance. Vitamin
D supplementation may be required. As adults, patients
should be examined for skin lesions suspicious for melanoma
and nonmelanoma skin cancer.

Oculocutaneous albinism

Niccoli L, et al: Efficacy of infliximab therapy in two patients with

refractory VogtKoyanagiHarada disease. Br J Ophthalmol 2009;
93:1553.
Paredes I, et al: Immunomodulatory therapy for VogtKoyanagiHarada
patients as first-line therapy. Ocul Immunol Inflamm 2006; 14:87.
Rao NA, et al: VogtKoyanagiHarada disease diagnostic criteria. Int
Ophthalmol 2007; 27:195.
Rathinam SR, et al: VogtKoyanagiHarada syndrome after cutaneous
injury. Ophthalmology 1999; 106:635.
Sylvestre DL, et al: VogtKoyanagiHarada disease associated with
interferon alpha-2b/ribavirin combination therapy. J Viral Hep 2003;
10:467.
Tsuruta D, et al: Inflammatory vitiligo in VogtKoyanagiHarada disease.
J Am Acad Dermatol 2001; 44:129.
Wong SS, et al: VogtKoyanagiHarada disease: extensive vitiligo with
prodromal generalized erythroderma. Dermatology 1999; 198:65.

Oculocutaneous albinism 1
OCA1 results from mutations in the tyrosinase gene and
accounts for approximately 40% of OCA worldwide. It is the
most severe form of albinism, and is the most common type
of albinism in Japanese, non-Hispanic Caucasians, and a
mixed race European population, with a prevalence of about
1 in 40000. Affected patients are homozygous for the mutant
gene or are compound heterozygotes for different mutations
in the tyrosinase gene (TYR). OCA1 is divided into two forms:
OCA1A and OCA1B. At birth these are indistinguishable.
OCA1A is the most severe form, with complete absence of
tyrosinase activity and complete absence of melanin in the skin
and eyes. Visual acuity is decreased to 20/400. The hair, eyelashes, and eyebrows are white, and the skin is white and does
not tan. Irises are light blue to pink and fully translucent.
Amelanotic nevi may be present. In OCA1B, tyrosinase activity is greatly reduced but not absent. Affected patients may
show an increase in skin, hair, and eye color beginning at age
13 years, and can tan. Iris color may also darken over time.
OCA1B was originally called yellow mutant albinism.
Temperature-sensitive OCA (OCA1-TS) is considered a variant
of OCA1B; it results from mutations in the tyrosinase gene that
produce an enzyme with limited activity below 35C (95F)
and no activity above this temperature. Affected patients have
white hair, skin, and eyes at birth. At puberty, dark hair develops in cooler acral areas. Visual acuity is not as severely
affected in OCA1B.

Oculocutaneous albinism 2
OCA2 has a prevalence of 1 in 36000 in white Europeans, but
as much as 1 in 4000 in some parts of Africa. It is the most
common form of OCA, accounting for approximately 50% of
OCA worldwide. OCA2 was formerly called tyrosinasepositive albinism, or brown OCA. Inheritance is autosomalrecessive and results from mutations in the OCA2 gene,
formerly known as the P gene. The OCA2 gene encodes an
integral melanosomal protein that is important for normal
biogenesis of melanosomes and for normal processing and
transport of melanosomal proteins such as tyrosinase and
tyrosinase-related protein 1 (TYRP1). The cutaneous phenotype of OCA2 patients is broad, ranging from nearly normal
pigmentation to virtually no pigment. Newborns have pigmented hair. Nevi and ephelides are common. Pink irises are
usually not seen. Visual defects are not as severe as in OCA1.
Pigmentation increases with age and visual acuity improves
from infancy to adolescence. PraderWilli and Angelman syndromes are caused by deletions in the chromosomal region
contiguous to and sometimes including the OCA2 gene. One
percent of patients with these syndromes also have OCA2.
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36

Oculocutaneous albinism 3

HermanskyPudlak syndrome

OCA3 is caused by mutations in the TYRP1 gene. TRYP1

protein is an enzyme in the melanin biosynthesis pathway that
oxidizes dihydroxyindole carboxylic acid (DHICA) monomers
into melanin. Mutations in this enzyme result in delayed maturation and early degradation of tyrosine. This form of OCA
has been most commonly found in African patients and was
called rufous or red OCA. It has also been seen in a large
Pakistani family and a Caucasian patient. Patients have red
hair and reddish-brown skin. Visual abnormalities may not be
detectable.

HermanskyPudlak syndrome (HPS) is an autosomal-recessive

disorder consisting of oculocutaneous albinism, a hemorrhagic diathesis secondary to the absence of dense bodies
in platelets, and accumulation of a ceroid-like material in the
reticuloendothelial system, visceral organs, oral mucosa, and
urine. Patients with this disorder have a history of easy bruisability, epistaxis, gingival bleeding, hemoptysis, and bleeding
after various surgical procedures and childbirth. Major bleeding occurs in 40% of HPS patients. The hypopigmentation is
due to impaired melanosome formation, trafficking, or transfer to keratinocytes.
Currently, eight human genes (HPS18) have been identified,
which, when independently mutated, lead to a clinical picture
consistent with HPS. It is anticipated that more HPS genes will
be identified in humans, since in mice there are at least 14
non-allelic genes that, when singly defective, give rise to HPS.
While the HPS subtypes 18 all share the clinical signs and
symptoms noted above, a few subtypes either lack some of or
have additional unique features that serve to distinguish them
from the other HPS subtypes. Seven of the eight genes causing
HPS (not HPS2) are parts of distinct complexes that are called
biogenesis of lysosome-related organelle complexes, or BLOCs.
Mutations in any member of a BLOC tend to create a similar
clinical phenotype. There are three known BLOCs, and mutations in most of the BLOC subunits cause a variant of HPS.
The most common subtype is HPS1, which, together with
HPS4, comprises 50% of the known worldwide cases of HPS.
One in 21 Puerto Ricans has a mutation (usually a 16-base pair
[bp] duplication) in the HPS1 gene. HPS accounts for 80% of
albinos in Puerto Rico, and 1 in 1800 Puerto Ricans in the northwest region of the country has HPS. HPS1 and HPS4 are clinically very similar, since they together form the BLOC3 complex
(Fig. 36-14). These are the two most severe forms of HPS.
Skin pigmentation can vary from total lack to lighter hair and
skin coloring than in other members of the family. Ocular
changes similar to those of OCA can occur, including iris trans
illumination, hypopigmented retina, visual impairment, horizontal nystagmus, and strabismus. Atypical nevi, acanthosis
nigricans-like lesions in the axillae and neck, and trichomegaly
also occur. Solar damage, as evidenced by solar lentigines,
actinic keratoses, and nonmelanoma skin cancers, occurs in
80% of patients with the 16-bp duplication in HPS1. Interstitial
pulmonary fibrosis, inflammatory bowel disease, renal failure,
and cardiomyopathy are late complications, and can cause
premature mortality between the ages of 20 and 50 years.
Sixty percent of patients with HPS have pulmonary symptoms,
starting at a mean age of 35 years. Pirfenidone, an antifibrotic

Oculocutaneous albinism 4
OCA4 is due to mutations in the MATP gene encoding a
membrane-associated transporter protein, predicted to span
the membrane 12 times and to function as a transporter.
Patients are hypopigmented to a variable degree, and are
phenotypically identical to patients with OCA2. Visual acuity
is decreased and nystagmus is found in many but not all
patients. This has also been reported in a Turkish patient, as
well as German, Japanese, and Korean OCA patients.

Disorders of melanosome formation

These are multisystem syndromes that are associated with
albinism. These syndromes are caused by genes that function
in intracellular organelle formation and movement in a variety
of specialized cell types, such as melanocytes, neurons,
immune cells, monocytes, platelets, and type II epithelial cells
in lungs. The silver hair of some of these syndromes may
demonstrate pigment clumping, allowing the diagnosis to be
suspected.

ChdiakHigashi syndrome
ChdiakHigashi syndrome (CHS) is a progressively degenerative, fatal disease characterized by partial oculocutaneous
albinism (decreased skin, eye, and hair pigment), giant intracellular granules, pigment clumping in hair shafts, and a
bleeding diathesis due to absent or reduced platelet-dense
bodies. It presents in childhood, usually with life-threatening
infections of the skin and lungs. Common pathogens are
Staphylococcus aureus, streptococcus, Gram-negative organisms, Candida, and Aspergillus. Immunoglobulins, antibody
production, and phagocytosis are normal, but neutropenia is
common and leukocytes display impaired migration. Natural
killer cells are decreased in function. The hair of these patients
is blond and sparse. The ocular albinism is accompanied by
nystagmus and photophobia. In darker-skinned races, affected
patients are lighter-skinned than their parents and siblings,
and may have speckled hyper- and hypopigmentation.
CHS results from mutations in the SHS1 gene, the exact
biological function of which is unknown. The gene must be
important in lysosome and lysosome-related organelle trafficking or size regulation. Melanosomes are giant, and platelets, eosinophils, basophils, and monocytes have giant
intracellular granules that are azurophilic.
In 85% of cases a lymphohistiocytosis syndrome occurs,
referred to as the accelerated phase. It is fatal and caused by
the unfettered proliferation of lymphocytes creating a
lymphoma-like situation with fever, anemia, neutropenia,
hepatosplenomegaly, and lymphadenopathy. Liver function
tests and serum ferritin may be elevated. Bone marrow transplantation (BMT) prior to the onset of this phase may be lifesaving, and also prevents the infections. Unfortunately, even
with BMT, if CHS patients survive into adulthood they develop
progressive neurological involvement.
860

Fig. 36-14 HermanskyPudlak syndrome, freckling of the V of the

neck and a basal cell carcinoma in a Puerto Rican man.

Disorders of melanocyte transport

Griscelli syndrome
Griscelli syndrome (GS) is a rare autosomal-recessive disorder
with mild skin and hair hypopigmentation, immunological
impairment, lymphohistiocytosis, or defects in the central
nervous system. Patients do not have a bleeding tendency.
There are three forms of GS. GS1 is caused by mutations in the
MYO5A gene encoding the actin-associated myosin Va motor
protein. Patients have primary neurological dysfunction but
no immunological disease. They have silver hair. GS1 and
Elejalde syndrome are felt to be the same disease. GS2 is due
to mutations in the RAB27A gene. Patients have silver hair,
infections, and lymphohistiocytosis. Leukocytes infiltrating
the brain can cause secondary neurological disease, but
patients have no primary neural defects. GS3 is cause by mutations in Melanophilin and results only in cutaneous hypopigmentation. The three genes responsible for GS all form a
protein complex essential for the capture and local movement
of melanosomes in the actin-rich periphery of melanocytes.
Al-Khenaizan S: Hyperpigmentation in ChdiakHigashi syndrome. J
Am Acad Dermatol 2003; 49(5 Suppl):S244.
Emanuel PO, et al: Griscelli syndrome. Skinmed 2007; 6:147.
Gronskov K, et al: Oculocutaneous albinism. Orphanet J Rare Dis 2007;
2:43.
Huizing M, et al: Disorders of lysosome-related organelle biogenesis:
clinical and molecular genetics. Annu Rev Genomics Hum Genet
2008; 9:359.
Lazarchick J, et al: ChdiakHigashi syndrome. Blood 2005; 10:4162.
Tager AM, et al: Case records of the Massachusetts General Hospital.
Case 32-2009: a 27-year-old man with progressive dyspnea. N Engl J
Med 2009; 361:1585.
Toro J, et al: Dermatologic manifestations of HermanskyPudlak
syndrome in patients with and without a 16-base pair duplication in the
HPS1 gene. Arch Dermatol 1999; 135:774.
Wei A, et al: A comprehensive analysis reveals mutational spectra and
common alleles in Chinese patients with oculocutaneous albinism. J
Invest Dermatol 2009 Oct 29 (Epub ahead of print).
Wei ML: Hermansky-Pudlak syndrome: a disease of protein trafficking
and organelle function. Pigment Cell Res 2006; 19:19.

Waardenburg syndrome
Four genotypic variants of Waardenburg syndrome exist, with
overlapping phenotypic features; all are autosomal-dominant.
Types 1 and 3 are caused by mutations in the PAX3 gene,
encoding a transcription factor. Type 2 is caused by mutations
in the MITF gene, also encoding a transcription factor, and
type 4 is due to either a heterozygous mutation in the SOX10
gene (encoding a transcription factor), or homozygous mutations in the endothelin-3 (EDN3) or the endothelin B receptor
(EDNR3) gene. These mutations impair the ability of melanoblasts to reach their final target sites (inner ear, eye, skin)
during embryogenesis.
Patients with this syndrome have features of piebaldism,
with a white forelock, hypopigmentation, premature graying,
and other characteristic findings including synophrys, congenital deafness, dystopia canthorum (broad nasal root), and
ocular changes, including heterochromia iridis (Fig. 36-15).
Types 1 and 3 are both characterized by dystopia canthorum;
in type 1, white forelock and depigmented skin patches are
more frequent; while in type 3, limb anomalies occur. In type
2, no dystopia canthorum is observed, but hearing loss and
heterochromia iridis are more frequently found. Type 4
Waardenburgs syndrome is identical to type 3, except that it
is associated with Hirschprung disease.

Oculocutaneous albinism

agent, can slow the progression of pulmonary fibrosis in HPS1

patients with significant residual lung function (initial forced
ventilatory capacity >50%). Lung transplantation can be
considered.
HPS2 is caused by a mutation in the gene (AP3B1) coding
for the 3A subunit of AP3, a molecule necessary for normal
protein trafficking to the lysosome. HPS2 is notable for
immunodeficiency and persistent neutropenia, with patients
suffering recurrent bacterial infections of the upper respiratory
system and middle ear, possibly due to the lack of antigen
presentation by the CD1b molecule, since CD1b fails to gain
access to the lysosome. Initially, patients may be misdiagnosed
as having CHS due to pigment dilution and recurrent infections. However, the large intracellular granules of CHS are
absent. Mild pulmonary fibrosis and a mild hearing defect can
be associated with HPS2.
HPS3, HPS5, and HPS6 have mild clinical findings, without
reported pulmonary or gastrointestinal involvement. They are
due to mutations in three proteins that make up BLOC2.
HPS 7 and 8 are very rare and present with a phenotype of
oculocutaneous albinism and a bleeding tendency due to
platelet dysfunction. The HPS7 gene (DTNBP1) encodes dysbindin; the HPS8 gene is BLOC1S3.

Piebaldism
Piebaldism is a rare, autosomal-dominant syndrome with variable phenotype, presenting at birth. The characteristic clinical
features are a white forelock and patchy absence of skin
pigment (Fig. 36-16). The depigmented lesions are static and
characteristically occur on the anterior and posterior trunk,
mid-upper arm to wrist, mid-thigh to mid-calf, and shins. A
characteristic feature of piebaldism is the presence of hyperpigmented macules within the areas lacking pigmentation and
also on normally pigmented skin. The depigmented lesions
may repigment spontaneously, or especially after injury. The
white forelock is a triangular or diamond-shaped midline
white macule on the frontal scalp or forehead, and is the only

Fig. 36-15 Waardenburg syndrome with heterochromia iridis.

Disorders of melanoblast migration and survival

These disorders cause spotting, i.e. patches of white hair
and/or unpigmented skin.

Fig. 36-16 Piebaldism, vitiligo-like depigmentation.

861

Disturbances of Pigmentation

36

manifestation in 8090% of patients. The medial portions of

the eyebrows and eyelashes may be white. Histologically,
melanocytes are completely absent in the white macules.
Piebaldism is caused by mutations in the KIT gene (gene
product kit proto-oncogene), encoding a cell surface receptor
for the steel factor, an embryonic growth factor. The phenotypic differences between families are caused by different locations of mutations in the gene. A mild phenotype occurs in
cases associated with mutations in the ligand-binding region,
whereas more severe phenotypes occur from mutations in
the tyrosine kinase region of the receptor. The white lesions
may respond to camouflage cosmetics or surgical corrections
(see discussion under vitiligo). Hirschprung disease and
neurofibromatosis type I have rarely been associated with
piebaldism.

CrossMcKusickBreen syndrome
Also known as Cross syndrome, oculocerebral hypopigmentation syndrome, or hypopigmentation and microphthalmia,

862

this extremely rare disorder is characterized by white skin,

blond hair with a yellowgray metallic sheen, small eyes with
cloudy corneas, jerky nystagmus, gingival fibromatosis, and
severe mental and physical retardation.
Spritz RA: Molecular basis of human piebaldism. J Invest Dermatol
1994; 103(Suppl):137.
Thomas I, et al: Piebaldism: an update. Int J Dermatol 2004; 43:716.

Bonus images for this chapter can be found online at

http://www.expertconsult.com
Fig.
Fig.
Fig.
Fig.
Fig.

36-1
36-2
36-3
36-4
36-5

Dermatopathia pigmentosa reticularis.

Vitiligo, characteristic periorificial location.
Hemochromatosis.
Idiopathic guttate hypomelanosis.
Piebaldism, white forelock.