disorders of hyperpigmentation

DISORDERS OF PIGMENTATION

APPROACH TO A PATIENT WITH DISORDER OF PIGMENTATION

History Onset : birth, infancy or laterCause: sun exposure, drugs, occupationSystemic complaintsFamily history: neurofibromatosis, tuberous

sclerosis, vitiligo

Examination:Type of lesion: brown, blue, hypopigmented

(check sensation), depigmented Shape: Ash leaf macules (tuberous slerosis)

Koebner phenomenon (vitiligo) Distribution pattern : linear/segmental (nevus

depigmentosus), symmetric (vitiligo), specific sites (melasma, Addison’s disease)

Examination aids:1. Hand lens2. Oblique lighting for elevation or depression

3. Dermatoscopy4. Wood’s lamp - 365 nm. Epidermal pigmentary

anomalies made more prominent

5. Histology:

a) H and E for presence or absence of melanin

b) Dopa reaction - melanocytes stain dark

c) Silver stains - melanin stains black

CLASSIFICATION OF PIGMENTARY DISORDERS

I. HYPOPIGMENTATIONII. HYPERPIGMENTATIONIII. DYSCHROMIA

HYPERPIGMENTATION

DISORDERS OF HYPERPIGMENTATIONMay be epidermal or dermalEpidermal hyperpigmentation due to

- Increased melanin with normal number of melanocytes

- Increased number of melanocytes Dermal hyperpigmentation

- Melanin pigments appears blue-gray due to Tyndall effect

- Melanin from epidermis transferred to dermis - Melanin formed in dermal melanocytes

CLASSIFICATION – EPIDERMAL “8”

1. Physiologic:Pigmentary demarcation lines, sun tanning

2. Genetic and Developmental: Lentigines, Freckles, Peutz-Jeghers

syndrome, Melanocytic nevus, Café-au-lait spots, Xeroderma pigmentosum, Becker’s nevus, Nevus spilus, Acanthosis nigricans

3. Post-inflammatory: Eczema, Psoriasis, Lichen planus, Lupus

erythematosus, Scleroderma, Morphoea4. Infection:

Tinea versicolor, Tinea nigra5. Nutritional:

Kwashiorkor, Pellagra, Vit.B12, Vit.C, Folic acid deficiency

6. Physical:Trauma, Radiation dermatitis

7. Endocrine: Melasma, Addison’s disease, Cushing’s

syndrome, Phaeochromocytoma, Acromegaly, Hyperthyroidism

8. Neoplastic: Malignant melanoma, Seborrhoeic

keratosis, Pigmented basal cell carcinoma

Genetic and Developmental:Mongolian spots, Nevus of Ota/Ito, Incontinentia

pigmentiInflammatory: Stasis dermatitis, Post inflammatory to eczema and

fixed drug eruptionChemicals and Drugs: Anti-malarials, OCP, Minocycline, Clofazimine,

Topical hydroquinone, Amiodarone, zidovudine, psychotropic drugs, heavy metals and chemotherapeutic agents

DERMAL PIGMENTATION

Endocrine: Melasma

Physical:Thermal burns, Post traumatic, Tattoos

Infection: Syphilis, Yaws, Pinta

Neoplastic: Metastasis of melanoma

Nutritional:Chronic nutritional deficiency

Metabolic: Hemochromatosis, Alkaptonuria, Macular /

Lichen amyloidosisMiscellaneous:

Pigmented purpuric dermatosis, Purpura

MELASMA(CHLOASMA /MASK OF

PREGNANCY)

KEY FEATURES• Common acquired hypermelanosis• At least 90% of patients are women.• Increased prevalence in individuals who are Hispanic, or of

Asian, African or Middle Eastern descent (i.e. those with more darkly pigmented skin).

• Most common location is the face, followed by the forearms.• Symmetric patches of hyperpigmentation with irregular

borders due to melanin within the epidermis &/or dermis.• Exacerbating factors include pregnancy, use of oral

contraceptives and sun exposure.

PATHOGENESIS

• Exact pathogenesis of melasma is unknown.• Genetic influences• UV irradiation: following exposure, hyperfunctional melanocytes within

involved skin produce increased amounts of melanin, The key role of UV irradiation is supported by;

1. fading of lesions during winter months. 2. distribution pattern demonstrating involvement of sun-exposed

regions. 3. sparing of relatively sun-protected sites such as the philtrum.

• Estrogens: predilection for women & association with pregnancy & OCP.• Other medications: e.g. phenytoin, phototoxic drugs.• Medical disorders: e.g. autoimmune thyroid disease.

CLINICAL FEATURES

• Light to dark brown or brown–gray patches with irregular borders

• Primarily on the face. • The areas of hypermelanosis are distributed

symmetrically in three classic clinical patterns:

(1) Centrofacial (most common), involving the forehead, cheeks, nose, upper lip (sparing the philtrum) and chin.

(2) Malar, affecting the cheeks and nose.(3) Mandibular, along the jawline.

Less common sites include the extensor aspect of the forearms & mid upper chest.

CLINICAL FEATURES

• Lesions often first appear or are accentuated following exposure to UV irradiation or during pregnancy.

• In lightly pigmented individuals, this “mask of pregnancy” frequently diminishes or disappears after parturition, but it tends to persist in women with more darkly pigmented skin.

• Melasma has also been subdivided into four types based upon the primary location of the pigment: epidermal, dermal or mixed using Wood’s lamp examination.

CLINICAL FEATURES

TYPE OF MELASMA CLINICAL FEATURES

Epidermal• Well-defined border • Dark brown color • Appears more obvious under black light • Responds well to treatment

Dermal• The most common type • Ill-defined border • Light brown or bluish in color • Unchanged under Wood’s light or become less obvious • Responds poorly to treatment

Mixed• Combination of bluish, light and dark brown patches • Mixed pattern seen under black light • Partial improvement with treatment

Indeterminate • in patients with very dark skin pigmentation inapparent under Wood’s lamp.

CLINICAL TYPES OF MELASMA

HISTOPATHOLOGY

• Increased melanin deposition is observed in all layers of the epidermis.

• Epidermal melanocytes are normal to increased in number, and they are enlarged with prominent dendrites.

• An increased number of melanophages.• While a Wood’s lamp has been used to localize melanin

pigment to either the epidermis or dermis (i.e. epidermal versus dermal melasma), histopathologic studies and confocal microscopy have shown that there is often a mixture of the two forms in an individual patient.

HISTOPATHOLOGY

(b) Perilesional normal skin, pigmented (c) Lesional: Epidermal hyperpigmentation. No inflammation, no dermal pigment

HISTOPATHOLOGY

HISTOPATHOLOGY

(a) Photomicrograph showing epidermal melasma with increased concentration of melanin pigment in the epidermis (H and E, ×200); (b) Masson–Fontana stain; ×200)

HISTOPATHOLOGY

(c) Increase in the number of melanocytes and underlying solar elastosis (H and E, ×200); (d) Melanin incontinence in the dermis (Masson–Fontana; ×200)

TREATMENT

• Patient motivation are necessary for any treatment regimen for melasma to be successful.

• For epidermal melasma, 2 months of therapy are typically required to initiate lightening and 6 months of treatment are often needed to achieve satisfactory results.

• Cosmetic camouflage helps in case of recalcitrant melasma.• Recurrence is the norm despite precautionary measures such

as strict sun protection.• After achieving the desired bleaching, use as needed to

maintain results.

TREATMENT

1. Avoid underlying cause: a) Discontinuation of OCP.b) Sun protection, including hats, clothing (if extrafacial), avoidance daily application of a broad spectrum sunscreen SPF 30+, can help to prevent accentuation of the pigmentation by UV exposure.

2. Topical hydroquinone (2–4%) may lead to lightening over 3–6 months if the increase in pigmentation is limited to the epidermis.

3. Topical tretinoin: as a monotherapy can be helpful, but the required treatment period is often 24 weeks or longer. It thins the skin, penetration of other agents & have direct effect in melanisation.

4. Triple combination: The most common topical regimen is a combination of hydroquinone (2–4%), tretinoin (0.05–0.1%) and a corticosteroid (class V–VII).

TREATMENT

5. Vitamin C (ascorbic acid).6. Azelaic acid 20%7. Kojic acid 1-4%8. Chemical peels: α-hydroxy acids (Glycolic acid)& salicylic acid used

as adjunctive therapy.9. Dermabrasion: variable results and can cause scarring and

dyspigmentation.10. Laser therapy & IPL: has limited benefits, especially for individuals

with darkly pigmented skin, and it may lead to hypopigmentation. Q-switched ruby, alexandrite & Nd:YAG lasers are variably successful in removing dermal pigment, especially epidermal PIH.

HYDROQUINONE (HQ)• A skin-bleaching agent used for

treatment for melasma and other disorders of hyperpigmentation.

• It is topical tyrosinase inhibitor.INDICATIONS 1. Melasma2. Ephelides3. Solar lentigens4. Postinflammatory hyperpigmentation 5. Hyperpigmented scars e.g. post-

acne scars.

MECHANISMS OF ACTION 1. Competitive inhibition with tyrosine: as a substrate for tyrosinase.2. Damage to melanosomes and melanocytes: selectively by production of

highly reactive oxygen radicals.

HYDROQUINONE

HOW TO USE HYDROQUINONE• Test for skin sensitivity before using by applying the cream to a small

patch of hyperpigmented skin. If no redness or itching occurs within 24 hours, begin treatment.

• Clean and dry the skin before applying a thin film of cream once or twice daily to the area(s) in need of bleaching. Rub into the skin well.

• Apply just enough to cover the affected areas and avoid applying to normal skin, as this will lighten as well. Hence wash your hands after applying unless these are areas of treatment.

• Do not apply near the eyes, mouth, and other mucous membranes.• If no bleaching effect is seen after 3 mo. of Tx, stop using it.

HYDROQUINONESIDE EFFECTS1. Irritant contact dermatitis: mild itching or

stinging and reddening of the skin.

2. Allergic contact dermatitis: less often-severe burning, itching, crusting, or swelling.

3. Postinflammatory hyperpigmentation,

4. Exogenous ochronosis

5. Leukoderma.

OCHRONOSIS• Ochronosis is the bluish black discoloration of

certain tissues, such as the ear cartilage and the ocular tissue, seen with alkaptonuria, a metabolic disorder. Additionally, ochronosis can occasionally occur from exposure to various substances such as:

1. Hydroquinone.

2. Phenol.3. Trinitrophenol. 4. Resorcinol. • Irregular patches with characteristic pin-point,

caviar-like papules affecting sun-exposed skin. Uncommon and is usually caused by prolonged use of hydroquinone at a concentration >2%.

5. Mercury.

6. Benzene.

7. Antimalarials.

• Is a strong derivative of hydroquinone

• Almost always causes nearly irreversible complete depigmentation of the skin.

• Typically used for depigmentation therapy in patients with extensive vitiligo applied once to twice daily to the affected areas for 9–12 months or longer.

• Depigmentation is not only in the areas of application but also in distant sites.

MONOBENZYL ETHER OF HYDROQUINONE (MBEH) 20%

MECHANISMS OF BLEACHING AGENTS

POSTINFLAMMATORY HYPERPIGMENTATION (PIH)

PIHKEY FEATURES

• Extremely common, especially in individuals with more darkly pigmented skin

• Develops after inflammation or injury to the skin, but preceding inflammation may be transient or subclinical

• The increased melanin may be primarily within the dermis (e .g . following lichen planus) or in the epidermis (e .g . following acne or atopic dermatitis)

• Epidermal hyperpigmentation fades more readily than dermal hyperpigmentation

Individuals with darkly pigmented skin tend to have a greater frequency, severity and duration of PIH than those with lighter complexions.

Discrete macules exactly on the sites previously affected by inflammatory disorder.

PIH

PATHOGENESIS

• Epidermal PIH: there is increased melanin production and/or transfer to keratinocytes. Inflammatory mediators prostaglandins, leukotrienes, interleukin-1 and other products that enhance pigment production may play a role in this process.

• Dermal PIH: melanin falls into the dermis via a damaged basement membrane, where it is phagocytosed by and subsequently resides within dermal macrophages (referred to as melanophages) that tend to persist for long periods of time (e.g. years).

PIH

CLINICAL FEATURES

• Asymptomatic hyperpigmented macules and patches• Range in color from either tan to dark brown (epidermal melanin) or

gray–blue to gray–brown (dermal melanin). • Primary lesions of the underlying inflammatory disorder may or may

not be evident admixed with the hyperpigmentation or elsewhere. When primary lesions are absent, the size, shape and distribution pattern of hyperpigmented lesions can provide clues to the underlying etiology.

• PIH can be exacerbated by continued inflammation, trauma or exposure to ultraviolet (UV) irradiation.

• Upon treatment of the underlying disorder, epidermal PIH generally resolves over time, although fading may require months or years in darkly pigmented individuals. Dermal melanosis tends to persist longer and is sometimes permanent.

CLINICAL FEATURES

CLINICAL FEATURES

CLINICAL FEATURES

DISORDERS THAT COMMONLY LEAD TO EPIDERMAL PIH:

1. Acne2. Insect bites3. Pyodermas4. Atopic dermatitis5. Psoriasis 6. Pityriasis rosea

CLINICAL FEATURES

DERMAL PIH:• Associated with dermatoses

characterized by degeneration of the basal layer of the epidermis and inflammation at the dermal–epidermal junction, such as:

1. Lichen planus2. Lichenoid drug reactions3. Lupus erythematosus 4. Fixed drug eruptions.

LINEAR PIH:Occurs following;1. Contact dermatitis with a linear

pattern (e.g. phytophotodermatitis or due to poison ivy).

2. Linear inflammatory dermatosis (e.g. koebnerized psoriasis),

3. Linear trauma (e.g. burns, abrasions, dermatitis artefacta).

4. Chemical phlebitis. 5. Less often, PIH follows the lines of

Blaschko because the antecedent inflammatory dermatosis did so, e.g. linear lichen planus.

CLINICAL FEATURES

PATHOLOGY

• Epidermal PIH is characterized by increased pigment in keratinocytes.

• Dermal PIH is characterized by melanophages within the dermis.

TREATMENT

1. Treatment of underlying dermatosis if successfully treated, PIH eventually improves in most patients.

2. Sun protection, including daily application of a broad spectrum sunscreen, help to prevent accentuation of the pigmentation by UVR.

3. Topical hydroquinone (2–4%) may lead to lightening over 3–6 months if the increase in pigmentation is limited to the epidermis.

4. Topical combinations e.g. Kligman formula 5. Vitamin C cream6. Azelaic acid. 7. Chemical peels: α-hydroxy acids (Glycolic acid) 8. Laser therapy & IPL: has limited benefits, especially for individuals

with darkly pigmented skin, and it may lead to hypopigmentation. Q-switched ruby, alexandrite & Nd:YAG lasers are variably successful in removing dermal pigment, especially epidermal PIH.

ERYTHEMA DYSCHROMICUM PERSTANS (ASHY DERMATOSIS/

CINDERELLA DERMATOSIS)

KEY FEATURES

• Most common in individuals with skin phototypes III–IV.• Gray–brown to blue–gray macules and patches in a symmetric

distribution.

• Favors the neck, trunk and proximal extremities.• A consistently effective treatment is not currently available.

• It is an asymptomatic, slowly progressive eruption that is characterized by circumscribed areas of dermal pigmentation.

• Although there have been reports of this entity worldwide, the majority of patients with EDP are from Latin America.

Ashy dermatosis

PATHOGENESIS

• The etiology of EDP remains unknown.• Occasionally, the condition is associated with;

1. Infections (whipworm, human immunodeficiency virus),2. The ingestion of toxins (ammonium nitrate, cobalt,

radio contrast media, pesticides, fungicides).3. Medications (ethambutol, penicillins, benzodiazepines).4. Endocrinopathies (thyroid disease).

In the vast majority of patients, an underlying etiology is never found.• In Mexican patients, the presence of the HLA-DR4 allele

may be associated with EDP.

Ashy dermatosis

CLINICAL FEATURES

• Oval, circular or irregularly shaped macules and patches that are 0.5 to 3 cm in diameter.

• Slate-gray to blue–brown in color• Develop gradually & symmetrically. • The initial site of involvement is

often the trunk, with subsequent spread to the neck, proximal upper extremities, & sometimes the face.

• The mucous membranes are spared, and the palms, soles and scalp are rarely affected.

Ashy dermatosis

CLINICAL FEATURES

• Occasionally, early stage lesions have a thin, raised, erythematous papular border, which is a unique characteristic of the eruption, which tends to resolve over a few months.

• The long axis of lesions may follow skin cleavage lines.

• Peripheral hypopigmentation may be seen in older lesions.

• EDP is usually asymptomatic but can be mildly pruritic.

• The disease progresses slowly & usually doesn’t regress in adults.

Ashy dermatosis

CLINICAL FEATURES Ashy dermatosis

HISTOPATHOLOGY Ashy dermatosis

HISTOPATHOLOGY

IN EARLY (“ACTIVE”) LESIONS:• vacuolar degeneration of the

basal cell layer, a perivascular mononuclear cell infiltrate in the upper dermis.

• Increased epidermal melanin • Dermal melanophages are seen. • Colloid bodies and dermal

hemosiderin may be present.

Ashy dermatosis

IN LATER (“INACTIVE”) LESIONS:• Number of dermal melanophages is increased. • Hydropic changes are absent. • The dermal mononuclear cell infiltrate is minimal.

TREATMENT

• Treatment is difficult and no consistently effective treatment. • Spontaneous remission may occur especially prepubertal children,

and therefore, no treatment may be an option. • Camouflage creams and make-ups also may be suggested.• MANY TREATMENTS HAVE BEEN TRIED, INCLUDING;1. Clofazimine 100 mg/d for 3 months 2. Dapsone 100 mg/d for 3months 3. Topical or systemic corticosteroids 4. Retinoids5. Vitamin C6. Vitamin A7. Oral antibiotics8. Antimalarials

Ashy dermatosis

9. Griseofulvin10. Chemical peels11. Narrow band UVB therapy:

in the lichenoid inflammatory infiltrate / provides camouflage, which hides the dermal pigmentation by stimulating pigment production.

PIGMENTARY DEMARCATION LINES (PDL,

FUTCHER’S OR VOIGHT’S LINES)

PDL• Pigmentary demarcation lines are borders of abrupt

transition between more deeply pigmented skin (usually dorsal surfaces) and that of lighter pigmentation (usually ventral surfaces).

• They’re normal physiologic pattern of human pigmentation.• They do not correspond to Blaschko’s lines or dermatomal

lines but to Voigt’ lines.• More often apparent in individuals with darkly pigmented

skin.• They are bilateral, perfectly symmetrical and present from

infancy & stable over time through adulthood. • No treatment is indicated.

• Group A - lines along anterolateral portion of the upper arms with variable extension across the chest.

• Group B - along posteromedial aspect of the thighs extends from the perineum to the popliteal fossa & occasionally to the ankle.

• Group C - Paired paramedian lines on chest hypopigmented band on the mid chest with midline abdominal extension.

• Group D – vertical line in a pre- or paraspinal location

PDL- CAN BE DIVIDED INTO FIVE CATEGORIES:

• Group E - bilateral symmetrical, obliquely oriented

hypopigmented macules & patches in a zone that runs from mid third of the clavicle to the periareolar skin.

PDL

• More than 70% of blacks have one or more lines

• These are much less common in whites

• Type B lines often appear for the first time during pregnancy

PDL

PDL

CAFÉ AU LAIT MACULES (CALM)

CAFÉ AU LAIT MACULES (CALM)

Circumscribed, hyperpigmented brown macules or patches two to three shades darker than uninvolved skin with irregular margins, 2-5 cm in size.

May be present at birth Isolated CALM may occur in 10-20% of normal population.No increase in the number of melanocytes Five or more CALM of size >0.5 cm in prepubertal age

group and >1.5 cm in an adult are strongly suggestive of neurofibromatosis type 1

May be associated with another genetic syndrome

CAFÉ AU LAIT MACULES (CALM)

DOWLING–DEGOS DISEASE (DDD/PIGMENTED RETICULATE ANOMALY

OF THE FLEXURES)

DDD- KEY FEATURES

• Reticulated hyperpigmentation in intertriginous sites.• Comedone-like lesions on the back and neck.• Pitted facial scars.• Uncommon autosomal dominant with variable

penetrance.

• Caused by loss-of-function mutations in the gene that encodes keratin 5 (KRT5).

DDD- CLINICAL FEATURES

• Onset is typically during the third to fourth decade of life.

• The reticulated hyperpigmentation is admixed with and sometimes composed of lentigo-like brown macules; small brown papules with variable hyperkeratosis may also develop.

DDD- CLINICAL FEATURES

• Findings progressively increase over time, initially appearing in the axillae & groin with later involvement of intergluteal & inframammary folds, neck, trunk & inner aspects of the arms & thighs.

• Some patients report pruritus of the affected flexural areas.

DDD- CLINICAL FEATURES

• Comedone-like lesions on the back or neck,

• Pitted perioral scars• Epidermoid cysts and

hidradenitis suppurativa represent additional features in some patients.

DDD- CLINICAL FEATURES

• Finger-like rete ridges with thinning of the suprapapillary epithelium antler-like downgrowth with pigmentation at the tip.

• Dermal melanophages and a mild perivascular lymphohistiocytic infiltrate are also observed

DDD- HISTOPATHOLOGY

DDD- HISTOPATHOLOGY

• As Dowling-Degos is a genetic disease there is no curative treatment.

• Topical hydroquinone tretinoin, adapalene azelaic acid, and corticosteroids have been used with varying success but there was rapid recurrence after stopping of treatment.

• Improvement following treatment with the erbium:YAG laser has also been reported.

DDD- TREATMENT

ADDISON’S DISEASE

• Chronic adrenal insufficiency or hypocortisolism is a rare endocrine disorder.

• Refers specifically to primary adrenal insufficiency, in which the adrenal glands themselves malfunction.

• Characterized by hyperpigmentation of the skin & mucous membranes most pronounced in sun exposed areas, sites of pressure & genitalia.

ADDISON’S DISEASE

ADDISON’S DISEASE

ADDISON’S DISEASE

ADDISON’S DISEASE

ADDISON’S DISEASE

ADDISON’S DISEASE

Diffuse skin hyperpigmentation, increased pigmentation of the palmar creases and wrists compared to a normal female control (far right), her hyperpigmentation resolved

ADDISON’S DISEASE

REFERENCES

• Dr. Angelo Smith M.D WHPL• Bolognia 3rd ed.• www.ijdvl.com• http://dermnetnz.org• www.edoj.org.eg