Hypopigmentation and depigmentation

Hypopigmentation is partial loss of skin colour and depigmentation is complete loss, from reduced melanin production, reduced melanocyte number or reduced melanin transfer.

Classification by extent. Localised, segmental, generalised and universal.

Classification by mechanism. Melanocyte destruction (vitiligo, chemical leucoderma, melanoma associated leucoderma), melanocyte absence or dysfunction (piebaldism, albinism, Waardenburg syndrome), reduced pigment production or transfer (postinflammatory change, pityriasis alba, pityriasis versicolor, nutritional deficiency) and structural change in the skin (scarring, lichen sclerosus, morphoea).

Classification of vitiligo. Nonsegmental vitiligo is bilateral and often symmetrical (acrofacial, mucosal, generalised, universal). Segmental vitiligo is unilateral, starts early, stabilises within 1 to 2 years and often involves hair (leucotrichia). Mixed vitiligo combines both. Prevalence is about 0.5 to 2% of the population in most regions.

Mechanisms of vitiligo. CD8 positive T cell attack on melanocytes, driven by interferon gamma signalling through Janus kinase signalling with CXCL10 release, on a background of genetic susceptibility and oxidative stress. Koebner phenomenon (new patches at sites of trauma or friction) marks active disease.

Key distinctions. Chalk white, sharply marginated patches that stay white under Wood lamp suggest vitiligo. Hypopigmented patches with scale suggest pityriasis versicolor or eczema. A hypopigmented patch with loss of sensation suggests leprosy. A stable, pale, irregular patch present from birth suggests naevus depigmentosus or naevus anaemicus.

History

• Age at onset, tempo, distribution, progression over months, preceding inflammation, sunburn, trauma, friction or surgery.
• Itch or scale (inflammatory or fungal cause), numbness or weakness (leprosy), and contact with a person with leprosy in an endemic region.
• Exposures: rubber, phenolic and catechol compounds in adhesives, hair dyes, bindi adhesive, hydroquinone based skin lightening products, topical or injected corticosteroids.
• Personal and family history of vitiligo, premature greying, thyroid disease, type 1 diabetes, pernicious anaemia, Addison disease, alopecia areata, psoriasis and rheumatoid arthritis.
• Seizures, developmental delay, visual problems, hearing loss, uveitis, headache, meningism.
• Nutritional status, malabsorption, prior melanoma or immunotherapy for cancer, HIV, syphilis exposure.
• Psychological and social impact, particularly on the face and hands.

Examination

• Wood lamp examination in a dark room: depigmented skin appears bright white and well defined, while hypopigmented skin shows less contrast. Wood lamp separates epidermal from dermal change and helps in fair skin.
• Distribution, symmetry, margins (trichrome, quadrichrome, inflammatory border, confetti depigmentation), hair colour in the patch, mucosal and genital involvement, and the Koebner phenomenon.
• Scale (pityriasis versicolor, eczema), atrophy and sclerosis (lichen sclerosus, morphoea), and induration.
• Sensory testing of the patch (light touch with cotton, pin prick, temperature), palpation of peripheral nerves (great auricular, ulnar, radial cutaneous, common peroneal, posterior tibial), and ulnar and peroneal nerve function.
• Eyes (uveitis, retinal changes, iris transillumination in albinism), hearing, neurocutaneous stigmata (shagreen patch, facial angiofibromas, periungual fibromas, café au lait macules), thyroid size, and nails.
• Lymph nodes and full skin examination for a primary melanoma.
• Dermoscopy: perifollicular pigment retention in repigmenting vitiligo, scale in fungal disease.

Red flags

• Anaesthetic or hypoaesthetic hypopigmented patch, thickened nerve, trophic ulcers or neuropathy (leprosy).
• Infiltrated, poikilodermatous or scaly hypopigmented patches that are slowly spreading (hypopigmented mycosis fungoides).
• In an infant, 3 or more hypopigmented macules of 5 mm or more, with seizures or developmental delay (tuberous sclerosis complex).
• Depigmentation with uveitis, tinnitus, headache or meningism (Vogt-Koyanagi-Harada disease).
• White atrophic genital plaques with purpura, fissures, scarring or ulceration (lichen sclerosus carries a risk of squamous carcinoma).
• New depigmentation in a patient with prior melanoma, or after checkpoint inhibitor therapy.
• Recurrent infections, bleeding tendency or neurological decline with pigment dilution and silvery hair (Chediak-Higashi and Griscelli syndromes).
• Rapid spread of depigmentation after a skin cancer or sun exposure with other autoimmune features.

Special groups

• Children: pityriasis alba, postinflammatory change, naevus depigmentosus and tuberous sclerosis are common causes. Vitiligo starting in childhood is often segmental.
• Pregnancy: vitiligo may progress or stay stable. Topical corticosteroids of moderate potency are acceptable; avoid ruxolitinib cream, oral Janus kinase inhibitors and psoralens.
• Region specific: leprosy, post kala azar dermal leishmaniasis, onchocerciasis, pinta and yaws, and skin lightening product use are more frequent in endemic regions.

Depigmentation with melanocyte loss

• Nonsegmental vitiligo.
• Segmental vitiligo.
• Chemical leucoderma (occupational or cosmetic).
• Melanoma associated leucoderma and immunotherapy associated vitiligo.
• Halo naevus.
• Vogt-Koyanagi-Harada disease.
• Lichen sclerosus.

Congenital or genetic

• Piebaldism.
• Waardenburg syndrome.
• Oculocutaneous albinism.
• Hermansky-Pudlak, Chediak-Higashi and Griscelli syndromes.
• Tuberous sclerosis complex (ash leaf macules).
• Hypomelanosis of Ito.
• Naevus depigmentosus and naevus anaemicus.

Postinflammatory and fungal

• Postinflammatory hypopigmentation (eczema, psoriasis, lichen planus, burns, cryotherapy, laser, intralesional and topical corticosteroid).
• Pityriasis alba.
• Pityriasis versicolor.
• Idiopathic guttate hypomelanosis.
• Progressive macular hypomelanosis.

Infective

• Leprosy (indeterminate, tuberculoid and borderline forms).
• Post kala azar dermal leishmaniasis.
• Onchocerciasis (leopard skin).
• Pinta and late yaws.
• Secondary syphilis (leucoderma).

Inflammatory, neoplastic and systemic

• Hypopigmented mycosis fungoides.
• Morphoea and systemic sclerosis.
• Sarcoidosis.
• Nutritional causes: kwashiorkor, copper deficiency, vitamin B12 deficiency.
• Hypopituitarism.
• Drug and chemical causes: hydroquinone, monobenzone, imatinib, chloroquine, arsenic.

Step 1. Establish the pattern. Depigmented or hypopigmented, symmetry, scale, sensation, hair involvement and age at onset.

Step 2. Bedside tests

• Wood lamp.
• Sensory testing of the patch and nerve palpation.
• Potassium hydroxide microscopy of scale (pityriasis versicolor shows short hyphae with round yeast forms).
• Dermoscopy.

Step 3. Tests in vitiligo. Diagnosis is clinical. Check TSH, with thyroid peroxidase antibodies when TSH is abnormal or symptoms exist, fasting glucose or HbA1c, full blood count and vitamin B12. Add morning cortisol, ANA, coeliac serology or other autoantibodies only when symptoms point to them. Evidence for repeat annual screening is limited. Ophthalmology and audiology if there are visual or hearing symptoms.

Step 4. Targeted tests

• Leprosy: slit skin smear with Ziehl-Neelsen stain from the earlobes and active edge of lesions, and biopsy including a nerve twig. Tuberculoid disease may be smear negative. Nerve conduction studies when neuropathy is present.
• Biopsy (4 mm punch) for suspected mycosis fungoides (2 or more sites, with T cell receptor clonality), lichen sclerosus, morphoea, sarcoidosis or atypical disease.
• Syphilis serology and HIV test.
• Slit skin smears for Leishmania in post kala azar dermal leishmaniasis, and skin snips for microfilariae in onchocerciasis.
• Brain MRI, echocardiography, renal ultrasound and ophthalmic examination, with TSC1 and TSC2 gene testing, in tuberculous sclerosis complex.
• Genetic testing (TYR, OCA2, KIT, PAX3 and others) in suspected albinism, piebaldism and Waardenburg syndrome.
• Nutritional tests: albumin, serum copper, vitamin B12.

Disease activity in vitiligo. Progression within 6 months, confetti depigmentation, trichrome pattern, inflammatory border and Koebner phenomenon indicate active disease. Stability is judged by no new lesions or extension for 6 to 12 months.

Limits. Biopsy is rarely needed in vitiligo and shows absent melanocytes. Leprosy smears have limited sensitivity in paucibacillary disease, so diagnosis rests on clinical features with nerve involvement. Hypopigmented mycosis fungoides is often missed on a single biopsy.

General measures. Broad spectrum sunscreen SPF 50 on depigmented skin because it burns easily and has no protective melanin. Cosmetic camouflage, psychological support and, in fair skin, tanning of normal skin to be avoided because it increases contrast.

Vitiligo (active or stable, nonsegmental)

• Limited disease on the body: clobetasol propionate 0.05% ointment once daily for up to 2 months, then review. Maximum 50 g in any week. Monitor for atrophy and striae. Do not use on the face, flexures or genitals.
• Face, neck and flexures: tacrolimus 0.1% ointment twice daily for at least 6 months (burning at the start is common; pimecrolimus 1% cream is an alternative), or mometasone furoate 0.1% once daily for 2 to 3 months then twice weekly as maintenance.
• Ruxolitinib 1.5% cream (age 12 years and over): apply a thin layer twice daily to affected skin, up to 10% of body surface area, with no more than 60 g in any week. Assess at 24 weeks and continue if repigmentation is occurring. Class warnings for Janus kinase inhibitors apply to systemic absorption.
• Narrowband ultraviolet B phototherapy 2 to 3 times each week, with dose increased by 10 to 20% each session directed by erythema. Review at 3 months, and continue up to 12 months if repigmentation occurs. Combination with topical tacrolimus or corticosteroid improves response. Face and neck respond best, while hands and feet respond poorly.
• Rapidly spreading disease: dexamethasone 2.5 mg orally on 2 consecutive days each week for 3 to 6 months (evidence is limited). Monitor glucose, blood pressure, mood and bone health. Oral Janus kinase inhibitors are used off label by specialists.
• Surgical grafting (suction blister, punch or cultured epidermal suspension) for stable segmental or localised disease with no new lesions for at least 6 to 12 months.
• Extensive disease (over about 50% of body surface area) in a patient who accepts permanent change: monobenzone 20% cream twice daily to remaining pigmented skin, specialist use only, for 9 to 12 months. It causes irreversible depigmentation and strict sun protection is needed.
• Segmental vitiligo: topical therapy and early phototherapy; surgery after stability.

Other causes

• Pityriasis versicolor: ketoconazole 2% shampoo applied to the affected skin and washed after 5 minutes, daily for 5 to 7 days, or itraconazole 200 mg orally once daily with food for 7 days (monitor liver tests; avoid in heart failure; many CYP3A4 interactions; not in pregnancy). Skin colour returns over weeks to months. Prophylaxis with ketoconazole 2% shampoo monthly during hot weather.
• Pityriasis alba and postinflammatory hypopigmentation: emollients, sun protection and treatment of the underlying dermatosis. Hydrocortisone 1% or tacrolimus 0.1% for 2 to 4 weeks in pityriasis alba. Pigment returns over months.
• Leprosy: start multidrug therapy under a specialist programme. Paucibacillary disease: rifampicin 600 mg orally once monthly supervised plus dapsone 100 mg orally once daily for 6 months. Multibacillary disease: rifampicin 600 mg once monthly plus clofazimine 300 mg once monthly and 50 mg daily plus dapsone 100 mg daily, for 12 months. Doses for children are reduced by age and weight. Check G6PD before dapsone, and monitor full blood count and liver tests. Prednisolone 40 mg orally daily, tapered over 3 to 6 months, treats type 1 reactions and neuritis. Examine contacts. Notify public health.
• Secondary syphilis: benzathine benzylpenicillin 2.4 million units intramuscularly once.
• Lichen sclerosus: clobetasol propionate 0.05% ointment once daily for 4 weeks, then on alternate nights for 4 weeks, then twice weekly for 4 weeks, with long term follow up for squamous carcinoma.
• Hypopigmented mycosis fungoides: dermatology and haematology review, with phototherapy and topical therapy for early stage disease.
• Morphoea: potent topical corticosteroid and ultraviolet A1 phototherapy or methotrexate for progressive lesions, under specialist care.
• Tuberous sclerosis complex, piebaldism, albinism and Waardenburg syndrome: genetics and paediatric review. In albinism, SPF 50 sunscreen, protective clothing, annual skin checks, and ophthalmology for visual aids.
• Vogt-Koyanagi-Harada disease: same day ophthalmology and neurology review; high dose corticosteroid is started by specialists.
• Nutritional causes: correct the deficiency.
• Chemical leucoderma: stop the exposure and avoid the offending product.

Monitoring. Photograph patches at baseline and every 3 months. Count new lesions and areas of repigmentation. Check for atrophy with topical corticosteroids and for skin cancer with phototherapy.

Referral and escalation. Dermatology for generalised vitiligo, children, rapid progression or failure of 3 to 6 months of treatment. Same day ophthalmology for suspected Vogt-Koyanagi-Harada disease. Leprosy service for suspected leprosy. Genetics and neurology for suspected tuberous sclerosis complex. Endocrinology for associated autoimmune endocrine disease. Psychology when function or mood is affected.

Disposition. Most patients are managed as outpatients. Review every 3 months while on treatment. Safety net advice: return for new numbness, nerve pain or weakness, ulceration of a patch, a changing or enlarging lesion, eye symptoms, or hearing loss.