Clinical dermatology Review article CED

Clinical and Experimental Dermatology

Approach to hypopigmentation disorders in adults

H. L. Tey
National Skin Centre, Singapore City, Singapore

doi:10.1111/j.1365-2230.2010.03853.x

Summary Acquired hypopigmentation disorders in adults can be classified on the basis of lesion
extent, and can generally be divided into disorders with localized, widespread or
generalized lesions. Clinical findings, comprising the degree of pigment loss
(hypopigmentation and depigmentation) and associated morphological findings (e.g.
epidermal changes, infiltration and induration), are used to further distinguish the
disorders. Diagnosing the disorders is important because the underlying causes may be
treatable and some of the disorders are associated with malignancies. A systemic
approach is useful for this clinical condition, as the causes are heterogeneous and
investigations are usually nondiagnostic.

Introduction Types of hypopigmentation disorders

Pigmentation of the skin is mainly due to melanin and
blood. Hypopigmentation refers to any form of decreased
pigmentation, whereas hypomelanosis specifically refers
to a decrease in melanin content. Depigmentation, on
the other hand, refers to the complete absence of
pigment and is almost always due to a deficiency in
melanin.
The categorization of hypopigmentation disorders is
generally based on their aetiology (congenital or
acquired), age of onset (childhood or adulthood) and
extent of lesions (localized or generalized). Further
differentiation can be made on the basis of clinical
findings, such as degree of pigment loss, associated
morphological signs, and sites, of involvement. In the
approach presented in this paper, acquired hypopig-
mentation disorders that typically arise in adulthood
have been categorized according to the extent of the
lesions (localized, widespread or generalized) and
whether the lesions are depigmented or hypopigmented
(Fig. 1).
Correspondence: Dr Hong Liang Tey, National Skin Centre, 1, Mandalay
Road, Singapore 308205, Singapore
E-mail: teyhongliang111@yahoo.com
Conflict of interest: none declared.
Accepted for publication 30 December 2009
Localized hypopigmentation
Localized hypopigmentation disorders are a common
presentation in adults. The commonest cause of depig-
mented lesions is vitiligo. Vitiligo is characterized clini-
cally by depigmented macules and patches that
correspond histologically to a decrease or absence of
melanocytes in the epidermis and less often the hair
follicles. The commonest age of onset is 1030 years of
age, with a mean age of 20 years. In general, vitiligo can
be categorized into localized, generalized and universal
forms. Localized forms can be segmental, focal or
mucosal. The generalized forms are more common, and
can be acrofacial or the vulgaris type. Acrofacial vitiligo
consists of depigmented patches around the fingers and
periorificial regions, whereas vitiligo vulgaris presents as
widely scattered patches. Several diseases can mimic
vitiligo vulgaris, including melanoma-associated
leucoderma, chemical or occupational leucoderma, and
VogtKoyanagiHarada (VKH) syndrome.
In vitiligo vulgaris, depigmentation is generally sym-
metrical. It usually starts on the hands, face and feet,
and spreads centripetally to the trunk. In contrast, in
melanoma-associated leucoderma, depigmentation is
asymmetrical and more commonly starts on the trunk
and spreads centrifugally towards the neck, face and
limbs.1

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Approach to hypopigmentation disorders in adults H. L. Tey

Adult onset

Localized Widespread Generalized

Progressive macular
Depigmented Hypopigmented Depigmented Hypopigmented
hypomelanosis

Post-inflammatory Idiopathic guttate

Vitiligo hypomelanosis Vitiligo universalis Endocrinopathies
hypopigmentation

Associated morphological Panhypopituitarism

Chemical leucoderma
signs present

Epidermal
Melanoma associated Hypogonadism
changes
leucoderma

Vogt-Koyanagi- Pityriasis versicolor

Nutritional deficiencies
Harada syndrome

Mycosis
Copper
fungoides

Induration Selenium

Lichen sclerosus

Morphea

Infiltration

Tuberculoid
leprosy

Sacoidosis

Follicular
mucinosis

Figure 1 Approach to adult-onset hypopigmentation disorders.

Chemical leucoderma usually occurs after exposure to
industrial chemicals such as phenols, hydroquinones,
catechols and mercaptoamines. The lesions can mimic
vitiligo, with depigmentation occurring in areas distant
from the sites of exposure. History-taking is particularly
important in these cases to identify exposure to such
chemicals and to check if any of the patients colleagues
exposed to the same chemicals also have depigmenta-
tion. Chemical leucoderma tends to present first as small
macules that coalesce and spread; a more abrupt
appearance of larger depigmented patches with peri-
follicular sparing is more suggestive of vitiligo (Fig. 2a).
VKH or uveomeningitic syndrome is a systemic
disease affecting organs with melanocytes, and is
characterized by bilateral uveitis, and by neurological,
auditory and cutaneous defects. VKH syndrome classi-
cally comprises three sequential phases: meningoen-
cephalitis, ophthalmicauditory phase and convalescent
phase. Cutaneous signs develop in the convalescent
phase and they typically occur several weeks to months
after the onset of ocular inflammation. The pigmenta-
tion changes include vitiligo, poliosis and uveal depig-
mentation, and halo naevi may also occur. The
depigmentation in VKH syndrome has a similar
symmetry to that seen in vitiligo vulgaris, but tends to
be permanent and affects the perilimbus of the cornea in
most patients (known as the Sugiura sign).
Post-inflammatory hypopigmentation is a common
cause of localized hypopigmentation, and is a particular
problem in dark-skinned people. The diagnosis of
postinflammatory hypopigmentation is usually straight-
forward when the primary lesions are present. However,
there are some inflammatory diseases in which the
lesions are hypopigmented from the onset and preceding
inflammatory changes may be clinically absent. Exam-
ples include pityriasis versicolor, mycosis fungoides
(MF), lichen sclerosus (LS), morphoea (localized slero-
derma), generalized scleroderma (systemic sclerosis),
tuberculoid leprosy, sarcoidosis and follicular mucino-
sis.2 The presence of other morphological changes, such

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830 Journal compilation  2010 British Association of Dermatologists Clinical and Experimental Dermatology, 35, 829834

(a)
Figure 2 (a) VogtKoyanagiHaruda
syndrome: extensive depigmentation.
(b) Hypopigmented mycosis fungoides:
irregular, scattered, hypopigmented
patches with ill-defined borders involving
areas not exposed to sun.
as scaling, epidermal atrophy, alopecia, induration and
infiltration, suggest the coexistence of an additional
disorder.
The presence of epidermal changes is a clue to
diseases in which pathological processes disrupt the
normal turnover of the epidermis. The presence of
scaling is indicative of pityriasis versicolor. However,
this scaling is usually fine and is often not apparent
until the lesions are scratched. This condition typically
occurs on the trunk of teenagers and young adults
when their sebaceous glands become more active after
the onset of puberty. There is also an inverse form of
pityriasis versicolor in which lesions are distributed on
the face, flexural regions or localized areas on the limbs
instead, and this form is more often seen in immuno-
compromised patients. The causative organism is
Malassezia furfur, and it has been suggested that the
organisms metabolites, such as azelaic acid, induce
hypopigmentation by inhibiting tyrosinase and injuring
melanocytes.3
If the hypopigmented lesions are associated with an
atrophic epidermal surface, the hypopigmented variant
of MF, LS and morphoea are to be considered.
Although the typical lesions of MF (erythematous
patches, plaques and nodules) can result in postin-
flammatory hypopigmentation, there is a variant in
which hypopigmented patches are the only presenta-
tion. This variant presents with scattered irregular
hypopigmented patches (Fig. 2b), and occasionally
depigmentation is seen. Its preferential location on
the buttocks and other areas of the body not exposed
to sun are important features and clues to its diagno-
sis. Histologically, epidermotropism of atypical
 2010 The Author(s)
Journal compilation  2010 British Association of Dermatologists Clinical and Experimental Dermatology, 35, 829834
Approach to hypopigmentation disorders in adults H. L. Tey
(b)
lymphocytes may be seen, together with a decrease
or absence of epidermal melanin and presence of
pigmentary incontinence.
If induration is felt on palpation, it indicates the
presence of dense collagen, which characterizes LS and
morphoea. LS is a pruritic chronic inflammatory der-
matosis that results in hypopigmented to depigmented
porcelain-white plaques, which are associated with
epidermal atrophy and dermal induration. It most often
affects women in their 50s and 60s, and has anogenital
and extragenital features. Possible pathogenetic mech-
anisms in the development of this leucoderma include
decreased melanin production, blocked transfer of
melanosomes to keratinocytes, and loss of melano-
cytes.4 LS and morphoea have been considered closely
related by many authors but this remains controversial.
Hypopigmentation is not uncommonly seen in lesions
of morphoea and systemic sclerosis. The lesions may
mimic vitiligo, and clues to the diagnosis of scleroderma
include the presence of perifollicular hyperpigmentation
(forming a salt and pepper dyschromatosis) and
induration of the dermis. The epidermal melanocytes
in the interfollicular regions disappear but those in the
near vicinity of hair follicles are retained.5 This is in
contrast to vitiligo, in which melanocytes in both
regions are affected. In repigmenting vitiligo, repig-
mentation starts in the perifollicular region, and differ-
entiation from scleroderma can sometimes be very
difficult.
If the hypopigmented lesions are associated with an
infiltrated dermal consistency, the differential diagnosis
includes tuberculoid leprosy, sarcoidosis and follicular
mucinosis (FM). Tuberculoid leprosy is characterized by
831
Approach to hypopigmentation disorders in adults H. L. Tey

(a) (b)

Figure 3 (a) Tuberculoid leprosy: large hypopigmented patches with an erythematous inflammatory border and diminished sensation on
the abdomen and chest. A biopsy was taken from the superior edge of the abdominal patch. (b) Dermatoscopy of the edge of the lesion
(original magnification 10). The right half features the hypopigmented patch, and a yellowish tinge (due to granulomas) can be seen.
The inflamed erythematous border occupies the central left side of the photograph.

hypoaesthaesia within the lesions. There is usually a
limited number of well-defined hypopigmented macules
or patches, which may be raised with erythematous
borders (Figs 3a,b). Sensation can be tested conve-
niently in the clinic by using the pointed corner of a
folded piece of paper to compare the pain sensation
within the hypopigmented lesions and adjacent normal
skin. As the disease progresses, the sweat glands and
hair follicles may also be destroyed, resulting in xerosis,
scaliness and alopecia in the lesions. Indeterminate
leprosy, often the first feature of leprosy, is also
characterized by a few of such hypopigmented lesions.
Sarcoidosis is one of the great mimickers in derma-
tology. The clinical morphology of the lesions can vary
widely, and hypopigmented patches are one of the less
typical presentations (Fig. 4a). Hypopigmented sarcoid-
osis occurs more often in darkly pigmented people, and
favours the extremities.6 These hypopigmented lesions
may be the result of preceding interface dermatitis.7 As
in tuberculoid leprosy, the clues to the diagnosis of
sarcoidosis include detection of infiltration on palpation
of the dermis, presence of alopecia, and a yellowish tinge
(due to granulomas) on diascopy.
FM, also known as alopecia mucinosa, presents with
grouped follicular papules within infiltrated plaques or
patches, and these plaques and patches may sometimes
be hypopigmented (Fig. 4b). Lesions most commonly
occur on the face and scalp. Alopecia, which is usually
nonscarring, is common in the affected follicles. The
characteristic histological features consist of deposition
of mucin within the external root sheath and seba-
ceous glands, and perifollicular infiltration by lympho-
cytes, histiocytes and eosinophils. The importance of
diagnosing FM lies in its association with malignan-
cies, particularly, MF. In patients with hypopigmented
patches associated with follicular papules, FM should
be considered, particularly so in older patients because
they are more likely to have malignancy-associated
FM.
Widespread hypopigmentation
Some conditions are typified by hypopigmented lesions
occurring in a widespread manner. An example is
progressive macular hypomelanosis (PMH), which is
characterized by ill-defined, hypopigmented macules
and patches on the trunk, often confluent in the midline
and occasionally extending to the proximal limbs and
the neck. The condition usually remains stable over
decades and may spontaneously disappear over time.
PMH is characterized histologically by diminished pig-
ment in the epidermis. In a previous study using
electron microscopy, melanosomes that were trans-
ferred from melanocytes to keratinocytes, instead of
being single and mature, were aggregated and less
melanized.8 The diagnosis of PMH is made clnically, and
it should be differentiated from pityriasis versicolor,
pityriasis alba and MF.
Idiopathic guttate hypomelanosis (IGH) is a common
condition presenting in middle-aged and elderly people,
and presents as sharply defined white macules distrib-
uted in a widespread manner, usually on sun-exposed
areas of the limbs. The pathological hallmark of IGH
seems to be an absolute reduction in the number of
melanocytes.1 The other causes of guttate leucoderma
are listed in Table 1.
Generalized hypopigmentation
Acquired generalized hypopigmentation is rare in
adults. It may be present in nutritional deficiencies
and endocrinopathies, although these conditions are

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832 Journal compilation  2010 British Association of Dermatologists Clinical and Experimental Dermatology, 35, 829834
 Approach to hypopigmentation disorders in adults H. L. Tey

(a) (c)

(b)
Figure 4 (a) Sarcoidosis: hypopigmented
patches with a yellowish hue (which is
more obvious on diascopy) on the left
lateral face. (b) Follicular mucinosis:
grouped follicular papules within an
infiltrated hypopigmented plaque.
(c) Amyloidosis dyschromica cutis:
punctate hypopigmented macules on a
background of a slightly reticulated
hyperpigmented patch on the arm.

Table 1 Differential diagnoses of guttate leucoderma. tanning response to ultraviolet radiation has been
described, and administration of testosterone results in
Idiopathic guttate hypomelanosis
Plane warts
darkening of skin and restoration of the tanning
Post-inflammatory hypopigmentation from pityriasis lichenoides response.9
chronica
Guttate morphoea lichen sclerosus
Vitiligo ponctue Conclusion
Confetti-like macules in tuberous sclerosis and multiple endocrine
neoplasia type 1
A clinical approach to acquired hypopigmentation
Darier disease disorders in adults based on the extent of the disease
Grover disease is presented here. Further distinction of the disorders is
Amyloidosis dyschromica cutis (Fig. 4c) dependent on the clinical findings, including the degree
Post-PUVA: leucoderma punctata, disseminated hypopigmented
of pigment loss and associated morphological findings.
keratoses
A systemic approach is useful for this clinical condition,
PUVA, psoralen ultraviolet A. as the causes are heterogeneous and investigations are
usually nondiagnostic.

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