Vitiligo

• Leukoderma and hypopigmentation refer to lightening of the skin, classically due to decreased epidermal melanin (hypomelanosis).
• Melanocytopenic hypomelanosis: reduction in the number of melanocytes, from defects in pigment cell differentiation, proliferation, migration, and/or survival.
• Melanopenic hypomelanosis: normal number of melanocytes but decreased melanin synthesis or transfer to keratinocytes; underlying abnormalities often involve melanosomes.
• Key considerations in evaluating hypopigmentation: age of onset (congenital vs acquired), degree of pigment loss (hypo- vs amelanosis), presence/absence of preceding inflammation, anatomic location, distribution pattern (circumscribed, diffuse, linear, guttate).
• Vitiligo: common multifactorial disorder involving disappearance of melanocytes due to immune disturbance; localized (including segmental) or generalized distribution.
• Hereditary hypomelanosis ranges from congenital, stable, circumscribed amelanosis (piebaldism, Waardenburg syndrome) to diffuse pigmentary dilution of skin/hair/eyes (oculocutaneous albinism and related conditions).
• Postinflammatory, infectious, and chemical hypomelanosis, halo nevi, and melanoma-associated leukoderma are other etiologies of circumscribed hypo-/amelanosis.
• Blaschko-linear hypopigmentation and idiopathic guttate hypomelanosis are the most common causes of linear and guttate hypopigmentation, respectively.

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• Leukoderma / hypopigmentation: general terms for lightening of skin; classically melanin-related, but may be hemoglobin-related (decreased blood supply).
• Hypomelanosis: reduction of melanin within the skin.
• Amelanosis: total absence of melanin.
• Depigmentation: usually implies total loss of skin color, most commonly from disappearance of pre-existing melanin pigmentation (e.g., vitiligo).
• Pigmentary dilution: generalized lightening of skin and hair (e.g., oculocutaneous albinism); may only be apparent compared with unaffected relatives.
• Cutaneous hypomelanosis classified into two groups:
• Melanocytopenic hypomelanosis: reduction in number of epidermal and/or follicular melanocytes.
• Melanopenic hypomelanosis: normal number of melanocytes but failure to synthesize normal amounts of melanin and/or transfer it to keratinocytes.
• Melanocytopenic hypomelanosis may be hereditary/congenital (defect in melanoblast differentiation, proliferation, migration, and/or survival) or acquired (destruction from external trauma [e.g., cryosurgery] or immune attack).
• Melanopenic hypomelanosis may result from melanosomal abnormalities affecting biogenesis, melanization, transfer, or degradation.

• Full examination under visible light and Wood's lamp (~365 nm) recommended.
• Wood's lamp particularly useful in circumscribed leukodermas, phototypes I/II, and neonates.
• Greater loss of epidermal pigmentation → more marked contrast on Wood's lamp.
• Helps differentiate hypomelanotic macules from hemoglobin-related leukodermas (e.g., nevus anemicus becomes inapparent under Wood's lamp).
• Most leukodermas diagnosed clinically via history and physical examination.
• Distribution pattern helps narrow differential: circumscribed (e.g., vitiligo), diffuse (e.g., albinism), linear, or guttate (e.g., idiopathic guttate hypomelanosis).
• Other pertinent features: age of onset, presence/absence of preceding inflammation, anatomic location, degree of pigment loss.
• Histologic examination most useful for hypomelanoses associated with inflammatory processes (e.g., sarcoidosis, lichen sclerosus, mycosis fungoides).

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• Acquired disorder characterized by circumscribed depigmented macules and patches due to loss of epidermal melanocytes.
• Leukotrichia within areas of involvement is due to loss of follicular melanocytes.

• Worldwide prevalence: ~0.5%–1% of general population.
• Onset any time from shortly after birth to late adulthood; average age of onset ~30 years.
• Patients often attribute onset to life events (physical injury, sunburn, emotional distress, illness, pregnancy), but with the exception of the Koebner phenomenon, not proven that these factors directly precipitate vitiligo.

Genetics

• Both twin and family studies support genetic factors.
• US/UK survey: 7% of first-degree relatives of vitiligo probands had vitiligo.
• 23% concordance rate in monozygotic twins → supports additional environmental role.
• Genome-wide linkage analyses identified susceptibility loci and candidate genes, many involved in melanogenesis, immune regulation, or apoptosis, shared with other pigmentary/autoimmune/autoinflammatory disorders.

Selected susceptibility loci and candidate genes for vitiligo

Involved in immune regulation:

• PTPN22 — Protein tyrosine phosphatase, non-receptor type 22
• FOXD3* — Forkhead box D3 (*in one family, a functional promoter variant associated with autosomal dominant inheritance of atypical vitiligo: early onset, widespread, progressive depigmentation)
• IFIH1 — Interferon induced with helicase C domain 1
• CTLA4 — Cytotoxic T lymphocyte-associated protein 4
• FOXP1 — Forkhead box P1
• CD80 — CD80 molecule
• LPP — LIM domain containing preferred translocation partner in lipoma
• CLNK — Cytokine dependent hematopoietic cell linker
• TSLP — Thymic stromal lymphopoietin
• BACH2 — BTB domain and CNC homolog 2
• HLA (various genes), BTNL2 — MHC classes I–III, butyrophilin-like 2
• CCR6 — Chemokine (C-C motif) receptor 6
• SMOC2 — SPARC related modular calcium binding 2
• SLA — Src-like-adaptor
• IL2RA — Interleukin 2 receptor α
• CD44 — CD44 molecule
• CXCR5 — C-X-C motif chemokine receptor 5
• IKZF4 — IKAROS family zinc finger 4
• SH2B3 — SH2B adaptor protein 3
• VDR — Vitamin D receptor
• NLRP1 (formerly NALP1) — NOD-like receptor family, pyrin domain containing 1
• TNFRSF11A — TNF receptor superfamily member 11a (RANK)
• TICAM1 — Toll-like receptor adaptor molecule 1
• PTPN1 — Protein tyrosine phosphatase, non-receptor type 1
• UBASH3A, AIRE — Ubiquitin associated and SH3 domain containing A, autoimmune regulator
• XBP1 — X-box binding protein 1
• C1QTNF6 — C1q and TNF related protein 6
• TOB2 — Transducer of ERBB2, 2
• FOXP3 — Forkhead box P3

Involved in apoptosis and/or cytotoxicity:

• FASL — Fas ligand
• RERE — Arginine–glutamic acid dipeptide (RE) repeats
• SLC29A3 — Solute carrier family 29 member 3
• CASP7 — Caspase 7
• GZMB — Granzyme B

Melanocyte-related:

• IRF4 — Interferon regulatory factor 4
• FGFR1OP, RNASET2 — Fibroblast growth factor receptor 1 oncogene partner, ribonuclease T2
• ZMIZ1 — Zinc finger MIZ-type containing 1
• TYR — Tyrosinase
• PMEL — Premelanosome protein
• OCA2, HERC2 — OCA2 transmembrane protein, HECT and RLD domain containing E3 ubiquitin protein ligase 2
• MC1R — Melanocortin-1 receptor
• ASIP — Agouti signaling protein
• Additional GWAS-identified loci: 7p13, 7q11, 9q22, and (in Chinese patients) 4q13–q21.

Pathogenic pathway

• With genetic susceptibility background, intrinsic melanocyte abnormalities render them vulnerable to oxidative stress.
• Oxidative stress impairs WNT signaling (normally promotes differentiation of melanocyte precursors, facilitating repigmentation during therapy).
• Cascade of immune activation:
• Melanocytes release DAMPs (damage-associated molecular patterns): HSP-70 (heat shock protein 70) and HMGB1 (high mobility group box protein B1).
• Stimulates plasmacytoid dendritic cells and innate lymphoid cells to secrete IFN-α and IFN-γ.
• Activated keratinocytes produce CXCL9 and CXCL10 (C-X-C chemokine ligands 9 & 10).
• Recruitment of CD4+ helper and CD8+ cytotoxic T cells expressing CXCR3 (C-X-C chemokine receptor 3).
• T cells produce IFN-γ and TNF → destruction of melanocytes.
• Mechanism (Fig 66.1 detail): melanocyte stress → STAT1 phosphorylation via JAK1/JAK2 → IFN-γ signals through IFN-γR → phosphorylated STAT1 homodimerizes, translocates to nucleus → transcribes CXCL9/CXCL10 → autoreactive CD8+ T cells (CXCR3+) follow chemokine gradient to skin, kill melanocytes.
• Therapeutic implication: JAK inhibitors or anti-CXCR3 antibodies can target this IFN-γ–STAT1–CXCL9/10 axis.
• Resident memory T cells explain recurrence of vitiligo within previously affected skin; express CD69, CD103, CD49a (latter marks a cytotoxic subset).

Pathogenic hypotheses for vitiligo

1. Autoimmune destruction of melanocytes

• Evidence FOR: epidemiologic association with autoimmune disorders; immunoregulatory gene variants shared with autoimmune diseases; autoantibodies against melanocyte proteins (TYR, TYRP1, DCT, MCHR1, SOX10); destruction of engrafted human skin on nude mice after injection with vitiligo patient sera; CD8+ T cell infiltration of perilesional skin; skin-homing melanocyte-specific cytotoxic T cells (e.g., against Melan-A/MART-1) detectable in peripheral blood; generalized vitiligo reported after bone marrow transplant from donors with vitiligo; TCR transgenic mice recognizing a tyrosinase epitope develop depigmented lesions resembling human vitiligo.
• Evidence AGAINST: limited evidence for autoimmune pathogenesis of segmental vitiligo; unclear whether primary immune attack targets normal melanocytes or is triggered secondarily by damage from exogenous/endogenous factors.

1. Intrinsic melanocyte defect (adhesive properties and/or survival factors)

• Evidence FOR: abnormalities of cultured vitiligo melanocytes (dilation of rough ER, abnormal TYRP1 synthesis/processing, increased sensitivity to oxidative stress e.g. UVB); transepidermal melanocytorrhagy from defective adhesion (detachment/transepidermal loss in vivo, induction by mechanical stress explaining Koebner phenomenon, decreased adhesion to collagen type IV, "stubby" dendrites in perilesional unstable vitiligo); reduced melanocyte survival/dysregulated apoptosis (progressive hair follicle melanocyte loss in bcl-2−/− mice; apoptosis-regulating gene variants; deficiency of SCF, KIT, MITF in vitiligo skin; vitiligo-like depigmentation and hair graying with KIT-targeting TKIs).
• Evidence AGAINST: melanocytorrhagy observed only in lesional/perilesional areas, appears secondary; no alteration of apoptosis regulatory molecule expression vs normal melanocytes.

1. Defective defense against oxidative stress

• Evidence FOR: high in vivo epidermal H2O2 levels, with sources including accumulation of oxidized pteridines (6-biopterin bluish fluorescence, 7-biopterin yellow/green fluorescence), increased catecholamine biosynthesis with increased monoamine oxidase A activity, inhibition of thioredoxin/thioredoxin reductase by calcium (defective calcium transfer/homeostasis), oxidative degradation of catalase (low protective enzyme levels).
• Evidence AGAINST: unclear if cause vs consequence of immune attack/intrinsic defect; no conclusive benefit from pseudocatalase or systemic antioxidants in clinical studies.
• A "convergence theory" proposes vitiligo results from combination of several mechanisms.
• Less-supported hypotheses: destruction by neurochemical substances or viral infection (e.g., cytomegalovirus).
• Abbreviations: DCT, dopachrome tautomerase; MCHR1, melanin-concentrating hormone receptor 1; MITF, microphthalmia-associated transcription factor; SCF, stem cell factor; TYR, tyrosinase; TYRP1, tyrosinase-related protein 1; UVB, ultraviolet B.

Characteristics of vitiligo lesions

• Most common presentation: totally amelanotic (milk- or chalk-white) macules/patches surrounded by normal skin.
• Well-developed lesions: discrete margins, round/oval/irregular/linear in shape; borders usually convex (as if depigmentation is "invading" surrounding pigmented skin).
• At onset/active spreading: may be ill-defined and hypomelanotic rather than amelanotic.
• Occasionally hyperpigmented border; blue color can result when vitiligo develops in areas of postinflammatory dermal pigmentation.
• Lesions enlarge centrifugally over time, rate slow or rapid; range mm to cm, variable sizes within an area.
• In lightly pigmented individuals, lesions may be subtle/inapparent without Wood's lamp or tanning of uninvolved skin.
• Usually asymptomatic; pruritus occasionally noted, especially in active lesions.
• Frequently localizes to sites normally relatively hyperpigmented: face, dorsal hands, nipples, axillae, umbilicus, sacral/inguinal/anogenital regions.
• Facial vitiligo typically periorificial (around eyes/mouth); extremities favor elbows, knees, digits, flexor wrists, dorsal ankles, shins.
• Also common at sites of repeated trauma/pressure/friction (body folds, clothing contact).
• Palmoplantar and oral mucosal involvement often difficult to visualize without Wood's lamp in lightly pigmented individuals.
• Acrofacial vitiligo: periungual involvement of one or more digits may be associated with lip depigmentation (either can be isolated finding).
• Leukotrichia: incidence 10% to >60% (vitiligo often spares follicular melanocytes); does NOT correlate with disease activity.
• Isomorphic Koebner phenomenon: development of vitiligo within trauma sites (surgical excision, thermal burn); more common with progressive vitiligo; a minimal threshold of injury appears required.

Clinical classification of vitiligo

• 2012 Vitiligo Global Issues Consensus Conference: "vitiligo" = umbrella term for all non-segmental forms.
• Segmental vitiligo: clinically unambiguous segmental distribution.
• Mixed vitiligo: coexistence of segmental and non-segmental vitiligo.
• Additional classification scheme (localized vs generalized):

Localized:

• Segmental: one or more body segments, roughly quadrilateral shapes, not crossing the midline; rapid onset; often associated leukotrichia.
• Focal: undetermined/unclassified — localized macules not clearly segmental; more definitive classification often possible after 1–2 years follow-up.
• Mucosal: only mucous membranes involved.

Generalized:

• Vulgaris: scattered patches widely distributed.
• Acrofacial: distal extremities and face.
• Universal: complete or, more commonly, nearly complete depigmentation.

• >90% of vitiligo patients have vulgaris or acrofacial variants.
• Segmental vitiligo more common in children (~15%–30% of pediatric vitiligo) than adults (<5%–10%).

Clinical variants

• Follicular vitiligo: leukotrichia without epidermal depigmentation; scalp/eyebrows/eyelashes may show localized poliosis or scattered white hairs, or total scalp hair depigmentation.
• Vitiligo ponctué: multiple, small, discrete amelanotic macules (confetti-like), sometimes superimposed on a hyperpigmented macule.
• Inflammatory vitiligo ("vitiligo with raised inflammatory borders"): erythema at margin; a figurate papulosquamous variant also reported.
• Trichrome vitiligo: hypopigmented zone between normal and depigmented skin, fairly uniform hue (not gradual progression); intermediate melanocyte number; suggests slower centrifugal progression.
• Quadrichrome and pentachrome vitiligo: also described.
• Hypochromic vitiligo: described in skin phototypes V and VI; persistent hypopigmented macules in seborrheic distribution, coalescing on face, scattered on neck/trunk/scalp; no prior inflammation history; decreased melanocyte density histologically.

Disease course

• Onset usually insidious; often noticed in sun-exposed areas during summer (tanning increases contrast).
• Clinical erythema or pruritus rarely precedes vitiligo.
• Course unpredictable: new macules, centrifugal enlargement, or both.
• Features associated with active progression: hypomelanotic lesions with poorly defined borders, confetti-like lesions.
• Generalized vitiligo: usually slow spread but may stabilize long-term or evolve rapidly; rarely total body involvement within weeks/days.
• Segmental vitiligo: usually reaches full extent within 1–2 years, remains restricted to initial segmental area.
• Presence of halo nevi and leukotrichia increases likelihood of evolution from segmental to mixed vitiligo.
• Sun-induced or spontaneous repigmentation not uncommon; complete stable repigmentation is rare.
• Assessment scales: VASI (vitiligo area scoring index), VETF (Vitiligo European Task Force) score, VES (vitiligo extent score) — validated quantitative scales; also PGA (physician global assessment) and VSAS (vitiligo signs of activity score).

Ocular involvement

• Uveal tract (iris, ciliary body, choroid) and retinal pigment epithelium contain pigment cells.
• Uveitis = most significant ocular abnormality associated with vitiligo.
• Vogt–Koyanagi–Harada (VKH) syndrome characterized by: (1) uveitis; (2) aseptic meningitis; (3) otic involvement (e.g., dysacusia); (4) vitiligo, especially face/sacral region, with associated poliosis.
• Amelanotic skin histology (classically appears after extracutaneous symptoms): infiltrate primarily of CD4+ lymphocytes — prominent role for cell-mediated immunity.
• Non-inflammatory depigmented lesions of ocular fundus in some vitiligo patients (focal melanocyte loss).
• Association between vitiligo and high-frequency sensorineural hearing loss noted in systematic reviews (possibly cochlear melanocyte role); clearcut evidence of otic abnormalities not yet demonstrated.
• Alezzandrini syndrome: rare disorder — unilateral whitening of scalp hair, eyebrows, eyelashes; ipsilateral facial skin depigmentation; visual changes (decreased visual acuity, atrophic iris in affected eye); pathogenesis unknown, believed closely related to VKH syndrome.

Associated disorders

• Generalized vitiligo associated with increased risk of additional autoimmune diseases, especially with family history of vitiligo/autoimmunity.
• Many vitiligo susceptibility genes shared with other autoimmune/atopic diseases, usually same high-risk alleles.
• Up to 20% of vitiligo patients have at least one comorbid autoimmune disorder.
• Most common: autoimmune thyroid disease — affects ~15% of adults and ~5%–15% of children with vitiligo.
• Other associated autoimmune conditions: alopecia areata (~2%–4% of vitiligo patients), pernicious anemia, type 1 diabetes mellitus, myasthenia gravis, connective tissue diseases (lupus erythematosus [discoid and systemic], Sjögren syndrome, rheumatoid arthritis).
• Epidemiologic links also with psoriasis, atopic diseases, inflammatory bowel disease, metabolic syndrome.
• Vitiligo can occur in setting of chronic graft-versus-host disease.
• Psychosocial conditions: depression, anxiety, adjustment disorders.
• APECED (autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy) syndrome: autosomal recessive, patients often develop vitiligo.
• Gene: AIRE (autoimmune regulator) — encodes transcription factor promoting expression of tissue-specific self-antigens in thymus (facilitates peripheral tolerance).
• Failure to delete autoreactive T cells → autoimmune disease.
• Mouse model: AIRE deficiency → TYRP1-specific T cells enhance immune responses against melanoma.

Childhood vitiligo

• Vitiligo vulgaris most common clinical type in children, but frequency of segmental vitiligo (~15%–30%) significantly increased vs adults (<5%–10%).
• Incidence of associated endocrinopathies is less than in adult vitiligo population.
• Family history of vitiligo associated with earlier age of onset.

• Melanocytes typically absent or present in very small numbers.
• Epidermal melanocyte density assessed via immunohistochemical stains: Melan-A (MART-1), MITF, HMB45, or DOPA incubation (detects tyrosinase activity).
• Ultrastructural studies performed for research; few hypomelanotic disorders have specific ultrastructural findings.

• Complete depigmentation/amelanosis: chemical or drug-induced (e.g., imatinib) leukoderma, postinflammatory depigmentation, leukodermas of melanoma and scleroderma, late stages of treponematosis and onchocerciasis, and (for congenital lesions) piebaldism.
• Single circular depigmented lesion on trunk of young person → may represent stage III halo nevus.
• Early lesions/partial pigment loss: distinguish from postinflammatory hypopigmentation, idiopathic guttate hypomelanosis, tinea versicolor, other cutaneous infections (e.g., leprosy).
• Nevus depigmentosus: decrease (not absence) of pigment; distinguished by stability and early onset (though may not be apparent until mid-childhood in lightly pigmented individuals).
• Potent topical corticosteroids can also lead to hypomelanosis.

• Goals: stabilization of depigmentation process, repigmentation, and maintenance of repigmentation.
• Immunomodulatory therapies limit disease progression; repigmentation requires repopulation of epidermal melanocytes from neighboring pigmented hair follicles, surrounding uninvolved epidermis, and/or lesional interfollicular melanocyte precursors.
• Regimen depends on extent, location, activity of disease, and patient's age, skin type, motivation.
• Minimum 6 months needed to determine treatment efficacy.
• Best response: face, neck, mid extremities, trunk. Most resistant: distal extremities and lips.
• Repigmentation initially perifollicular pattern and/or from periphery.
• After therapeutic repigmentation, recurrent depigmentation rate is ~40%.

Topical corticosteroids

• Useful for localized vitiligo in adults/children; highest response in newer lesions and face/neck.
• Meta-analysis: ~half of patients with vitiligo ≤20% BSA achieved >75% repigmentation with class 1 (superpotent) or class 2–3 (high potency) topical corticosteroids.
• Cutaneous atrophy: 14% (class 1) and 2% (class 2–3).
• To minimize side effects: class 1 corticosteroids used in 6- to 8-week cycles or twice weekly, alternating with topical tacrolimus, topical ruxolitinib, or less potent corticosteroid.
• Discontinue if no visible improvement after 4–6 months.
• Intralesional corticosteroids less commonly used (pain of injection, higher risk of atrophy [≥30%]).

Topical calcineurin inhibitors (TCIs)

• For face/neck lesions: tacrolimus or pimecrolimus has similar efficacy to topical corticosteroids.
• RCT: 65% of adults applying tacrolimus 0.1% ointment twice daily for 24 weeks achieved ≥75% repigmentation of facial vitiligo vs 0% for vehicle.
• TCIs less effective than potent topical corticosteroids for extrafacial sites.
• Systematic review (n=1499): TCI monotherapy (median 3 months) → ≥75% repigmentation in ~20% overall, ~30% of children, 35% of face/neck lesions vs only 2% of trunk/extremity lesions.
• Combining TCI with NB-UVB or excimer laser: synergistic effect, repigmentation ≥50%.
• Can be used with topical corticosteroids rotationally, or as maintenance therapy.
• RCT: bi-weekly tacrolimus 0.1% ointment to previously affected sites reduced recurrent depigmentation rate to 10% vs 40% with placebo.

Topical Janus kinase (JAK) inhibitors

• Ruxolitinib 1.5% cream: JAK1/2 inhibitor, FDA-approved for non-segmental vitiligo involving ≤10% BSA in patients ≥12 years.
• Two phase III RCTs (n=674 total): ~30% treated with ruxolitinib 1.5% cream BID for 24 weeks achieved ≥75% improvement in facial VASI vs 7%–11% vehicle.
• Most common AE: acne at application sites.
• JAK inhibitor class-wide black box warning: potential increased risks of serious infection, death, cancer, cardiovascular events, and thrombosis.

Photo(chemo)therapy

Narrowband UVB (NB-UVB)

• First-line therapy for adults and children ≥6 years with generalized vitiligo, especially ≥15% BSA or cosmetically sensitive areas.
• Superior to broadband UVB.
• Vitiligo Working Group recommendation: initiate at 200 mJ/cm² for all skin phototypes.
• Dose increased 10%–20% at each subsequent treatment until mild, asymptomatic lesional erythema, up to maximum 1500 mJ/cm² (face) and 3000 mJ/cm² (body).
• Administered 2–3 times/week on non-consecutive days.
• Discontinue if no repigmentation after 50 mildly erythrogenic exposures.
• Short-term side effects: painful erythema, pruritus, xerosis; no long-term side effects (e.g., carcinogenesis) reported to date.
• Advantages over PUVA: shorter treatment times, no GI side effects, reduced phototoxic reactions, less accentuation of contrast, no need for post-treatment photoprotection.
• Can be used in children, pregnant/lactating women, hepatic/renal dysfunction patients.
• Home NB-UVB units are a convenient option for reliable patients.

Psoralen plus UVA (PUVA)

• Psoralens (usually 8-methoxypsoralen) combined with UVA light; oral or topical (topical PUVA); PUVASOL = natural sunlight exposure.
• Oral PUVA no longer recommended given greater efficacy/ease/lack of systemic side effects of NB-UVB.
• Topical PUVA or PUVASOL useful for localized lesions; risk of phototoxicity with blistering or koebnerization.
• Low concentration (≤0.1%) psoralen used (dilution of commercial preparations); initial UVA dose 0.25 J/cm², increased in 10%–20% increments until mild erythema.

Excimer laser and lamp

• Delivers UVB at peak 308 nm (similar to NB-UVB's 311 nm peak).
• Equal to superior efficacy vs NB-UVB; shorter duration of treatment; avoids darkening of unaffected skin.
• Primarily indicated for segmental vitiligo and other forms involving <10% BSA.
• Treated 2–3 times weekly, typically 25–50 sessions total; repigmentation rate depends on total number of sessions, not frequency.
• Can be enhanced with concomitant TCIs, topical corticosteroids, topical JAK inhibitors, or oral corticosteroid mini-pulses.

Oral corticosteroid mini-pulse therapy

• Option for rapidly progressive vitiligo (RCTs on efficacy/safety lacking).
• Typical regimen: oral dexamethasone 2.5–5 mg on two consecutive days each week for 3–6 months.
• Halts disease expansion in ~90% of patients; usually does NOT induce significant repigmentation.
• Side effects: insomnia, agitation, weight gain, acne, hypertrichosis.
• Relapse common after discontinuation — concomitant/maintenance therapy (e.g., NB-UVB) recommended.

Other systemic immunomodulators

• Case reports/small studies: methotrexate, oral JAK inhibitors (tofacitinib, ruxolitinib, baricitinib).
• Phase II RCT in adults with active non-segmental vitiligo (n=364): oral JAK3/TEC inhibitor ritlecitinib for 24 weeks (50 mg daily ± 100 or 200 mg loading dose daily for 4 weeks) → ~20% achieved ≥75% improvement in facial VASI vs ~2% placebo.
• IL-15 signaling-targeting strategies under investigation.

Antioxidants

• Rationale: deficiencies in innate antioxidant processes contribute to pathogenesis.
• Agents used (often with phototherapy): oral α-lipoic acid, Polypodium leucotomos, Ginkgo biloba, vitamins C and E.
• Individually weak evidence; meta-analysis suggests possible benefit when combined with phototherapy.
• Small RCTs: oral Polypodium leucotomos extract + NB-UVB associated with increased repigmentation of head/neck vs NB-UVB alone.
• Small RCT: oral gliadin-protected superoxide dismutase + NB-UVB vs NB-UVB alone — statistically insignificant VES improvement (20% vs 9%), suggesting potential benefit.

Afamelanotide

• α-MSH analogue stimulating melanogenesis/melanocyte proliferation via binding MC1R.
• RCT: monthly subcutaneous implants + NB-UVB increased speed/extent of repigmentation vs NB-UVB alone, especially in skin phototypes IV–VI.
• Can cause excessive tanning of non-lesional skin, increasing contrast and reducing cosmetic acceptance in lightly pigmented patients.
• Additional studies needed to determine indications/limitations.

Surgical therapies

• Option for patients failing medical therapy — autologous transplantation.
• General selection criteria: stable disease for ≥6–12 months, absence of Koebner phenomenon, no tendency for scar/keloid formation, age >12 years.
• Minigraft test (retention/spread of pigment at recipient site, no koebnerization at donor site after 2–3 months) can aid selection.
• Techniques:
• Minigrafting: simplest technique; small punch grafts (1–2 mm) from uninvolved skin, separated by 5–8 mm. Potential unfavorable outcomes: cobblestone effect, variegated appearance, sinking pits.
• Micropunch grafting: motorized 0.8 mm punch instrument; reduces above complications.
• Suction blister epidermal grafting: advantage — no scarring at donor site, reusable donor site; risks — graft failure, koebnerization.
• Grafting of cultured autologous melanocytes: expensive, requires specialized lab expertise; pure melanocytes or admixed with keratinocytes.
• Grafting of non-cultured epidermal cell suspensions: avoids in vitro culture/mitogens.
• Grafting of individual hairs: for repigmenting vitiligo leukotrichia.
• Most techniques require clinical expertise.

Combination therapies

• Higher rates of repigmentation vs monotherapy: e.g., phototherapy after surgical procedures, combining topical/systemic agents (TCIs, corticosteroids, JAK inhibitors, antioxidants) with NB-UVB or excimer laser.
• Recent meta-analysis: insufficient evidence to support combining excimer laser/lamp with topical vitamin D derivatives.

Maintenance therapies

• Relapse rate for repigmented vitiligo ~40%.
• RCT: twice weekly tacrolimus 0.1% ointment significantly reduces recurrent depigmentation in successfully treated adults.
• Additional studies needed for other maintenance agents/regimens.

Micropigmentation

• Permanent dermal micropigmentation using non-allergenic iron oxide pigment (tattooing) to camouflage recalcitrant vitiligo areas.
• Especially useful for lips, nipples, distal fingers (poor repigmentation rates with standard treatment).
• Color may not match perfectly, can fade over time; immediate, dramatic aesthetic improvement.

Depigmentation

• Option for patients with widespread, treatment-resistant vitiligo with limited normally pigmented skin in exposed sites.
• Patients must be carefully chosen (adults, understanding of significant appearance change, lifelong strict photoprotection required — sunscreens, clothing, umbrellas).
• Most common agent: 20% monobenzyl ether of hydroquinone (MBEH), applied 1–2×/day for 9–12 months or longer.
• MBEH is potent irritant/allergen; open application test can precede widespread use.
• Response initiates in 1–3 months; loss of pigment can occur at distant sites.
• Depigmentation considered permanent, but repigmentation (especially perifollicular in pigmented-hair areas) can occur after sunburn/intense sun exposure.
• Monomethyl ether of hydroquinone (MMEH) 20% cream: alternative.
• Side effects: contact dermatitis, exogenous ochronosis, leukomelanoderma en confetti.
• Q-switched ruby laser: faster depigmentation than bleaching agent; also used with topical 4-methoxyphenol.
• Q-switched alexandrite laser: also described for depigmentation.

Psychological support

• Vitiligo severely impacts quality of life in many patients.
• No "magic" treatment yet, but always something beneficial to offer.
• Explaining nature of disease process and potential/limits of therapies is important; better than fatalistic "cosmetic only" attitude.
• Concealment strategies can be part of management.
• Support groups and psychological counseling are important supplementary therapies.

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• Most frequent depigmenting disorder, affecting 0.3%–0.5% of the population worldwide
• Acquired disease involving multiple genes and nongenetic environmental factors
• Characterized by progressive autoimmune-mediated destruction of epidermal melanocytes
• Typical presentation: patches of white skin and hair
• Cause of physiological and social stigma
• Increased risk for other autoimmune diseases, unpredictable evolution, and unsatisfactory therapeutic outcomes

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• Prevalence reasonably consistent among populations:
• ~0.38% Caucasians
• 0.34% Afro-Caribbeans
• 0.46% Indians
• Somewhat less frequent in Han Chinese: 0.093%
• Both genders affected equally; women overrepresented among patients seeking care
• Can develop at any age; mean age of onset in Caucasians ~24 years
• Generalized vitiligo (GV) = most common subtype; an autoimmune disease
• Associated with other autoimmune diseases in ~20%–30%, most frequently:
• Autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease)
• Rheumatoid arthritis
• Psoriasis
• Type 1 diabetes (usually adult-onset)
• Pernicious anemia
• SLE
• Addison disease

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• Multifactorial, polygenic disorder; complex pathogenesis not yet well understood
• Most accepted theory: genetic and nongenetic factors interact to influence melanocyte function and survival → eventually autoimmune destruction of melanocytes
• Other suggested explanations:
• Defects of melanocyte adhesion
• Neurogenic damage
• Biochemical damage
• Autocytotoxicity
• Others

Genetics of Vitiligo

• Most cases sporadic; ~15%–20% have ≥1 affected first-degree relative
• Familial aggregation: non-Mendelian pattern → polygenic, multifactorial inheritance
• Monozygotic twin concordance 23% → both genetic and nongenetic (presumably environmental) factors play major roles
• Almost all genetic studies focus on GV
• Immune-function genes implicated in GV susceptibility (linkage/association studies):
• MHC, CTLA4, PTPN22, IL10, MBL2, NALP1 (NLRP1)
• Large GWA study of European Caucasian GV patients/families: at least ten loci contribute to GV risk
• Seven also associated with other autoimmune diseases:

1. HLA class I
2. HLA class II
3. PTPN22
4. LPP
5. IL2RA
6. UBASH3A
7. C1QTNF6

• Two encode immune-function proteins: RERE, GZMB
• TYR encodes tyrosinase — key enzyme of melanin biosynthesis and the major GV autoantigen
• Segmental vitiligo (SV) appears genetically distinct from GV
• Generally sporadic occurrence, unilateral distribution → suggested somatic mosaicism for de novo mutations
• Perhaps in genes critical for melanoblast/melanocyte development or survival (hypothesis not yet confirmed)

Autoimmune Hypothesis

• Compelling biological evidence for an autoimmune basis of GV
• GV epidemiologically associated with other autoimmune diseases in patients and close relatives → heritable autoimmune diathesis
• Humoral immunity:
• First implicated by circulating antimelanocyte autoantibodies targeting tyrosinase, tyrosinase-related protein-1, dopachrome tautomerase, others
• Can kill melanocytes in vitro and in vivo
• Currently thought to reflect secondary humoral responses to melanocyte destruction, NOT a primary cause
• Cellular immunity (greater role):
• Inflammatory infiltrate sometimes at margins of active GV lesions, mainly cytotoxic T lymphocytes
• T cells express type-1 cytokine profile and colocalize with epidermal melanocytes
• Hypothesized to be cytolytic toward remaining melanocytes via the granzyme/perforin pathway
• Chemical leukoderma ("occupational vitiligo") — immune mechanism also suggested:
• Exposure to large doses of phenolic compounds, usually 4-tertiary butyl phenol (4-TBP), and others (e.g., in cleaning solutions)
• Usually initially involves hands and forearms (site of contact)
• Unclear whether agents are directly toxic or whether genetically susceptible individuals sustain melanocyte injury from aliphatic phenolic derivatives → melanocyte death → release of antigenic intracellular proteins → loss of tolerance → autoimmunity
• Melanoma immunotherapy-associated depigmentation:
• Vitiligo-like depigmentation during IL-2 immunotherapy for cutaneous melanoma, possibly via IL-2 stimulation of T-cell growth and activation
• Melanoma-associated antigens (MART-1, gp100, tyrosinase) are expressed on normal melanocytes → cross-reaction of antimelanoma responses with normal melanocytes

Biochemical Hypothesis

• Vitiligo may be a disease of the entire epidermis: biochemical abnormalities of both melanocytes and keratinocytes
• Morphological/functional abnormalities thought to have a genetic background
• Ultrastructural abnormalities of perilesional keratinocytes related to impaired mitochondrial activity → thought to affect production of melanocyte growth factors and cytokines regulating melanocyte survival
• Essential finding: elevated H2O2 in affected epidermis
• Caused in part by reduced enzymatic antioxidant capacity of keratinocytes and melanocytes
• Defective antioxidant defense → increased melanocyte susceptibility to immunologic cytotoxicity and reactive oxygen species

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• Principal manifestation: acquired milk-white macules with fairly homogeneous depigmentation and well-defined borders
• Classification by distribution, extension, number of patches:
• Generalized (vulgaris, acrofacial, mixed)
• Universalis
• Localized (focal, segmental, mucosal)
• Alternative classification: segmental vs nonsegmental (distinctive clinical features and natural histories)
• Non-SV = all cases not classified as segmental, including localized, generalized, and acrofacial

Clinical Types

• Vitiligo vulgaris: multiple scattered lesions, more or less symmetrical; most common presentation of GV
• Acrofacial vitiligo: distal fingers and facial orifices in a circumferential pattern; subtype of GV
• Mixed vitiligo: combination of acrofacial + vulgaris, or segmental + acrofacial
• Vitiligo universalis: complete or nearly complete depigmentation of whole body; most severe form of GV
• Focal vitiligo: one/few macule(s) in one area, not segmental; considered a precursor form of GV
• Mucosal vitiligo: reserved for depigmentation of mucous membrane alone
• Segmental vitiligo (SV):
• Unilateral dermatomal distribution; does NOT cross the midline
• Generally affects young children
• Typically remains localized; lesions persist unchanged for many years
• Concomitant autoimmune diseases uncommon compared with GV

Distribution and Triggers

• Predilection for sun-exposed regions, body folds, periorificial areas; any site possible
• Suggested precipitating factors: physical trauma, sunburn, psychological stress, inflammation, pregnancy, contraceptives, vitamin deficiency, many others
• No specific environmental triggers proven
• Koebner phenomenon: vitiligo at sites of skin trauma (koebnerization under brassiere)

Hair Involvement

• Leukotrichia (depigmented hair within vitiligo macules): variable, 10%–60%
• Indicates destruction of the follicular melanocyte reservoir → predicts poor therapeutic response
• Premature graying reported in up to 37%; poor definition/quantitation makes this association uncertain

Specific Rare Clinical Phenotypes

• Trichrome vitiligo: patches of intermediate hue (hypopigmentation) between normal and completely depigmented skin
• Quadrichrome vitiligo: fourth color (dark brown) at sites of perifollicular repigmentation; more often in darker skin phototypes
• Pentachrome vitiligo: five shades — (1) white, (2) tan, (3) medium brown, (4) dark brown, (5) black
• Confetti vitiligo (vitiligo ponctué): tiny punctate depigmented macules on a hyperpigmented macule or on normal skin
• Red vitiligo: depigmented lesions with a raised erythematous border
• Blue vitiligo: blue–gray skin; histologically absence of epidermal melanocytes + numerous dermal melanophages

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Comorbid Associations

• GV often associated with other conditions, principally autoimmune diseases
• Most prevalent: autoimmune thyroid dysfunction — hypothyroidism (Hashimoto) or hyperthyroidism (Graves)
• Also increased: rheumatoid arthritis, psoriasis, type 1 DM (usually adult-onset), pernicious anemia, SLE, Addison disease
• Most of these (including GV) occur in combinations as components of:
• APECED (APS1)
• Schmidt (APS2) multiple autoimmune syndromes
• Vogt–Koyanagi–Harada (VKH) syndrome: multiorgan disorder of pigmented structures — eye, inner ear, meninges, skin
• Role of cell-mediated immunity, particularly CD4+ T cells and Th1 cytokines
• Alezzandrini syndrome (very rare): facial skin depigmentation, poliosis, deafness, unilateral tapetoretinal degeneration
• Many now believe VKH and Alezzandrini = different expressions of the same disease

Depigmentation Other Than Vitiligo

• In melanoma patients, three contexts:

1. Partial depigmentation ("regression") of the tumor
2. Leukoderma acquisitum centrifugum around the tumor
3. Vitiligo-like depigmentation at distant sites

• Vitiligo-like depigmentation = marker of immunity against melanoma and favorable prognosis, especially in advanced stages
• Halo nevi: most common form of leukoderma acquisitum centrifugum, around pigmented nevi
• Often progress to spontaneous disappearance of the nevus, presumably via lymphocyte-mediated destruction of nevus cells

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• Established principally on clinical grounds: distribution, extent, natural history

Laboratory

• Screening tests (association with autoimmune disease):
• T4 and TSH
• Antinuclear antibodies
• Complete blood count
• Consider serum antithyroglobulin and antithyroid peroxidase antibodies, particularly with signs/symptoms of thyroid disease

Histology

• Skin biopsy rarely necessary
• Epidermis devoid of melanocytes in lesional areas
• Sometimes sparse dermal, perivascular, perifollicular lymphocytic infiltrates at margins of early and active lesions → cell-mediated destruction of melanocytes in situ
• Some reports: melanocytes may never be completely absent; residual melanocytes may recover functionality — highly debated, therapeutic implications

Differential Diagnoses for Generalized Vitiligo

• From Taïeb A, Picardo M (N Engl J Med 2009)

Differential Diagnoses for Localized Vitiligo

• Nevus depigmentosus: solitary hypopigmented macule, well circumscribed with irregular borders, stable in size, solitary, most often present at birth
• Nevus anemicus: hypochromic pale lesion with well-defined borders and irregular margins; often solitary, on the trunk; histology and EM show no abnormality in melanocytes or melanization

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• Course of GV unpredictable, typically gradually progressive and difficult to control
• Sometimes spreads; other times activity stops and remains stable for long periods
• Indicators of relatively poor prognosis:
• Long disease duration
• Koebner phenomenon
• Leukotrichia
• Mucosal involvement

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Fundamentals of Vitiligo Therapy: Melanocyte Repopulation

• Key principle: repopulate depigmented interfollicular epidermis with active melanocytes able to migrate, survive, and synthesize melanin
• Repigmentation may be spontaneous or therapy-induced
• Spontaneous repigmentation:
• Unpredictable, often clinically insignificant, cosmetically unacceptable
• Occurs in fewer than 50%, most commonly in younger patients and sun-exposed areas (natural sunlight as inducer)
• Most frequent pattern: perifollicular (after PUVA); others marginal, diffuse, combined
• Principal melanocyte source: precursors from outer root sheath (ORS) / bulge of hair follicle
• Secondary reservoir: near lesional borders
• Middle and lower ORS: DOPA-negative, amelanotic melanocytes
• Recruited in response to UV, corticosteroids, other stimuli
• ORS melanocyte number increases significantly; some become active → proliferation and maturation
• Activated ORS melanocytes acquire all structural/enzymatic proteins for melanogenesis; migrate up the hair follicle into epidermis → spread centrifugally → perifollicular pigment islands
• Then become larger cells with intense DOPA oxidase activity
• Assessment of response: proportion of subjects achieving a specified degree; >50% or >75% repigmentation = good response (study-dependent)
• Wood's lamp (UVA) useful to monitor response:
• Without epidermal melanin, more UVA photons reach dermis → absorbed by collagen → fluoresces bright visible light
• Ambient visible light is less absorbed by normal epidermal melanin than UVA and produces no dermal fluorescence
• Under Wood's light: vitiligo brighter, normal skin darker; enhanced detail of intermediate tones

Therapeutic Approaches

• Strategies designed to:
• Inhibit the immune response → reduce melanocyte destruction
• Enhance epidermal repopulation: recovery of damaged melanocytes in situ, reactivation of residual melanocytes, in-migration from neighboring skin or hair follicles
• Unclear to what extent treatments must suppress autoimmunity vs stimulate repopulation for maximum efficacy

Treatments for Vitiligo

UV Radiation Therapy — Mechanisms

• Includes NB-UVB (311 nm), BB-UVB (290–320 nm), and photochemotherapy
• Acts as skin immunomodulator:
• Regulates inflammatory cytokines
• Depletes Langerhans cells
• Modulates regulatory T cells
• Polarizes immune response toward Th2
• → reduces or stabilizes depigmentation
• Coordinates pathways by which melanogenic cytokines stimulate melanogenesis
• May induce release of epidermal factors stimulating melanocyte proliferation and migration (not substantiated in repigmenting lesions)
• Paracrine factors from UV-exposed keratinocytes regulating melanocytes thought to be under p53 regulation (further studies needed)

Narrowband UVB

• Peak emission 311 nm
• Most effective and safest current therapy → treatment of choice for moderate-to-severe GV
• vs PUVA: higher repigmentation rates and better color matching
• Fewer short-term adverse reactions (painful erythema) and apparently fewer long-term side effects (epidermal thickening, atrophy, photocarcinogenesis) than PUVA
• High rates (≥75% repigmentation) in at least 40% of patients
• Most common protocol:
• Twice weekly
• Fixed starting dose 0.21 J/cm2
• Increase by 20% each session until minimal erythema dose reached (lowest dose giving visible erythema on depigmented skin at 24 hours)
• ~9 months for maximal repigmentation
• At least 3 months before classifying as nonresponsive
• Most responsive: face, trunk, limbs; least responsive: hands and feet

Photochemotherapy (PUVA)

• Until recently, mainstay for widespread vitiligo
• Topical or oral 8-methoxypsoralen + UVA (320–400 nm)
• Oral methoxsalen 0.4 mg/kg, 1–2 hours before UVA
• Topical PUVA: methoxsalen 0.1% applied 30–60 minutes before exposure
• Indicated for <20% BSA
• Painful burns (phototoxicity) difficult to avoid
• Oral psoralens: more extensive involvement or failure of topical PUVA (see Chapter 237)
• After oral treatment: UVA-blocking glasses; broad-spectrum sunscreens and protective clothing recommended
• Darker complexions respond best (possibly tolerate higher exposures)
• Side effects: see Chapter 237
• NOT recommended under age 12 years — long-term risks of cataract and skin cancer

Corticosteroids

Topical Corticosteroids

• First-line for localized vitiligo; highly recommended for facial or small lesions and children
• Advantages: easy application, high compliance, low cost
• vs PUVA (predominantly perifollicular): steroids give more diffuse repigmentation, quicker but less stable
• Microscopy of steroid-repigmented skin: marked repopulation by functional, dendritic, DOPA-positive melanocytes with many normal-sized/shaped melanosomes (unlike melanocytes at pigment margins of untreated vitiligo)
• Large meta-analysis (RCTs, 29 patient series): class 3 and 4 corticosteroids most effective for localized vitiligo
• Regimen:
• High-potency fluorinated steroid (e.g., clobetasol propionate 0.05% ointment) for 1–2 months
• Taper to lower potency (e.g., hydrocortisone butyrate 0.1% cream)
• Caution on/around eyelids: can increase intraocular pressure and exacerbate glaucoma
• Limiting factors: recurrence after cessation; side effects — skin atrophy, telangiectases, striae, rarely contact dermatitis
• Combination therapy (steroid + UVB, steroid + calcineurin inhibitor, steroid + vitamin D analog) may be beneficial: synergy on pigment restoration and immune suppression at lower individual doses

Systemic Corticosteroids

• Pulse therapy and short courses to halt rapid spread of depigmentation in some GV

Calcineurin Inhibitors

• Restore the altered cytokine network
• Tacrolimus inhibits T-cell activation by downregulating transcription of IL-2, IL-3, IL-4, IL-5, IFN-γ, TNF-α, GM-CSF
• Direct effect on melanocyte growth and migration during repigmentation reported
• Topical agents: tacrolimus ointment 0.03%–0.1%, pimecrolimus 1%
• Preferred for localized lesions of face and neck
• Seem more effective combined with UV from high-fluency UVB devices
• Advantages: selective action, absence of skin atrophy and of systemic absorption
• More studies needed on effectiveness and possible cutaneous and extracutaneous cancer risks

Topical Vitamin D Derivatives

• Calcipotriol ointment 0.005%, tacalcitol ointment 20 μg/g
• Mechanism: skin immunosuppression (halts local autoimmunity) + direct activation of melanocytic precursors and melanogenic pathways
• More efficient in combination therapy: targets melanocyte growth (corticotherapy or UV) and differentiation (vitamin D analog)
• Indicated for localized disease; benefits: no skin atrophy, easy application
• Role controversial: some studies substantial benefit, others ineffective

Pseudocatalase

• Reconstitutes deficient catalase activity → degrades excess H2O2, allows enzyme recovery
• Monotherapy or with NB-UVB: apparent efficacy in uncontrolled trials; other studies no substantial benefit → needs validation

Laser Therapy

• 308-nm excimer laser (XeCl) and monochromatic excimer light (MEL) for localized vitiligo
• Similar to NB-UVB, fewer side effects (one lesion treated at a time)
• Optimal aesthetic results, minor contrast with normal skin
• XeCl: laser-coherent monochromatic emission; MEL: generates and selectively delivers 308-nm UVB
• No data on cancer risk or long-term side effects → caution advised

Surgical Treatment

• Autologous skin grafts only for stable vitiligo refractory/partially responsive to medical treatment, generally limited extent (<3% BSA)
• Most frequent side effects: infection, postinflammatory hyperpigmentation, unaesthetic repigmentation, cobblestoning, scarring
• UV therapy hastens and improves repigmentation when combined with surgery
• Five principal groups of autologous graft approaches
• In the United States, any procedure with manipulated (e.g., cultured) cells must be done in a GMP facility

Noncultured Epidermal Suspensions

• Suspensions with keratinocytes and melanocytes
• Obtained by 0.25% trypsin digestion of thin donor skin
• Injected into blisters raised by liquid nitrogen freezing or seeded on sites denuded by superficial dermabrasion
• Advantage: no scarring if donor and recipient sites carefully handled

Thin Dermal–Epidermal Grafts

• Harvested at 0.1–0.3 mm depth; placed on abraded recipient areas next to each other
• Secured with dressings under mild pressure for 1 week; repigmentation over following weeks
• Good results on dorsal hands and fingers

Minigrafting

• Most commonly used current surgical method
• Recipient perforations with 1.0–1.2-mm punches, 3–4 mm apart
• Donor minigrafts with similar punch; transferred with fine forceps or hypodermic needle
• Repigmentation spreads up to 2–5 mm around each graft by coalescence
• Good for refractory lip leukoderma; high risk of cobblestoning
• Advantage: simplicity

Epidermal Grafting

• Harvested at negative pressure (suction) with custom devices
• Preferred donor sites: inner thigh, flexor forearm
• Recipient epidermis removed by liquid nitrogen freezing, superficial dermabrasion, or laser ablation
• Used successfully for lip vitiligo
• Main advantage: no scarring at donor or recipient sites

In Vitro-Cultured Epidermis with Melanocytes and Melanocyte Suspensions

• Epidermis with melanocytes:
• Epidermal suspension from small donor sample by 0.25% trypsin, seeded in culture flasks
• After 3 weeks, epidermal sheets harvested and transplanted onto recipient sites denuded by liquid nitrogen, dermabrasion, lasers, or diathermosurgery
• Hyaluronic artificial matrix for growing keratinocytes and melanocytes used successfully
• Melanocyte suspensions:
• Defined culture media such as Ham's F12
• Transplanted at density up to 100,000 melanocytes/cm2; covered for 1 week
• Large cell numbers from small donor site → treat extensive areas in a single session

Micropigmentation

• For mucous and mucocutaneous lesions
• Tattooing inert pigment into dermis (within collagen bundles, extracellular) at 1–2 mm depth by multiple electrically driven needles
• Pigments: white, yellow, black, red, brown combinations

Depigmentation

• For some adults with extensive vitiligo — depigment residual pigmented patches on face and exposed areas
• 20% monobenzyl ether of hydroquinone (MBEH; monobenzone)
• Induces melanocyte loss via necrotic death without caspase activation or DNA fragmentation
• Patch test for 48 hours first (hypersensitivity)
• Then twice-daily application for at least a year → irreversible depigmentation (response at 4, 6, 8 months)
• Sun protection essential to prevent nonmelanoma skin cancers

Treatment Algorithm for Vitiligo

• Determine extent of involvement
• <20% of skin surface → topical corticosteroids, immunomodulators, or calcipotriol (or combination)
• If no response → topical PUVA or targeted phototherapy
• ≥20% of skin surface → phototherapy: NB-UVB, PUVA, or PUVASOL
• If no response → skin grafting or melanocyte transplantation
• If no response and skin involvement >50% → depigmentation

Camouflage, Sun Protection, and Psychological Support

• Cosmetic camouflage on face/exposed areas and concealing clothing improve QOL
• Modern dyes/creams waterproof, wide range of shades
• Avoid tanning (enhances contrast)
• Sunscreens prevent sunburn of depigmented skin
• Problematic: moderate sun exposure (heliotherapy) can induce melanocyte repopulation
• Suggested that friction from repeated sunscreen application might exacerbate disease — no supporting evidence
• Depigmented skin shows increased UVB tolerance over time (photoadaptation), partly based on phototype; pigmentary and nonpigmentary influences; mechanism unknown
• Psychological support: listening, reassurance, advice on treatment and capacity for improvement
• Psychiatric evaluation for marked low self-esteem and depression

Nontraditional Treatments

• Alternatives for patients who failed or are unsuitable for above therapies
• Most common: vitamin and nutritional supplements, immunomodulators, human placental extracts, khellin, topical and systemic phenylalanine, many others
• No convincing evidence any are effective

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• Many hypotheses from patients, support groups, alternative medicine purveyors
• No compelling evidence any prevention approach is effective
• No useful approach to identify individuals at high risk for developing vitiligo

• Visible skin pigmentation = combination of amount of melanin, type of melanin (eumelanin vs pheomelanin), degree of vascularity, presence of carotene, thickness of stratum corneum
• Other materials can be deposited abnormally in skin → exogenous pigmentation
• Eumelanin = primary brown pigment; pheomelanin = yellow/red pigment, also produced solely in melanocytes
• Melanin formed from tyrosine via tyrosinase in melanosomes of melanocytes; multitude of genes expressed only in melanosomes involved in melanin production/delivery
• Melanosomes = lysosome-related organelles (LROs); require both adequate melanin manufacture AND appropriate melanosome transport within melanocyte
• Melanosomes transferred from one melanocyte to a group of 36 keratinocytes = the epidermal melanin unit
• Variation in skin color between people relates to degree of melanization of melanosomes, their number, and distribution in the epidermal melanin unit
• Loss/reduction of pigmentation may relate to loss of melanocytes, or inability of melanocytes to produce melanin or transport melanosomes correctly
• Wood's light: hyperpigmented lesions that enhance = increased epidermal melanocyte number/activity; lesions that do NOT enhance = melanin located in dermis
• Wood's light greatly enhances depigmented lesions (complete pigment loss) but does NOT enhance lesions with partial pigment loss (hypopigmentation)

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• Voigt-Futcher lines: classified by anatomic location, orientation, degree of pigmentation (hyper- or hypopigmentation)
• Group A: outer upper arms, variable extension across chest
• Group B: posteromedial lower limb
• Group C: paired median/paramedian chest lines, midline abdominal extension
• Group D: medial, over spine
• Group E: bilaterally symmetric, obliquely oriented, hypopigmented macules on chest
• Groups F, G, H: facial pigmentary demarcation lines
• More easily seen in darker-skinned patients; 17% of Black patients have type A bilateral lines, 2% unilaterally
• Group B lines often appear for the first time during pregnancy
• Group D lines are rare, reported in Japanese patients
• Acquired, idiopathic, patterned facial pigmentation (AIPFP): encompasses facial pigmentary demarcation lines plus idiopathic periorbital/perioral pigmentation
• Patterned, bilateral, homogeneous, various brown shades with variable gray undertone
• Periorbital/perioral hyperpigmentation: onset late teens/early 20s; other facial hyperpigmentation forms occur later (average age >30)
• Periorbital pigmentation demarcated by band of normal skin beneath upper eyebrow superiorly, orbital rim inferiorly; may extend to lateral cheek/nose root
• One-third of perioral pigmentation patients have family history
• May represent variations of embryologic pigmentation
• Acquired dermal melanocytosis (ADM) — must distinguish from pigmentary demarcation lines
• Much rarer; primarily Asian and Hispanic/Latina women, male:female ratio 1:17
• Face most common site; includes bilateral and unilateral nevus of Ota–like macules (Hori nevus and Sun nevus, respectively)
• Can first appear during pregnancy or with estrogen/progesterone therapy
• Blue-gray patches with superimposed brown macules; infrequently trunk/extremities affected
• Does NOT enhance with Wood's light
• May be localized (post-trauma) or diffuse; UV light and PUVA are possible precipitants
• Biopsy: melanocytes in the dermis, similar to mongolian spot, nevus of Ota, nevus of Ito
• Represents activation of melanin production by residual dermal melanocytes (adjacent "normal" skin biopsies also show dermal melanocytosis)

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• Occurs in purpura, hemochromatosis, hemorrhagic diseases, stasis dermatitis
• Distinguished clinically from postinflammatory dermal melanosis by golden-brown hue (vs brown/gray-blue of epidermal/dermal melanin respectively); biopsy sometimes needed
• Extravasation of iron from poorly functioning venous catheter → local limb hemosiderosis
• Multiple transfusions (>20) → cutaneous iron deposits in about 20% of patients
• Drinking tea while ingesting iron-containing solution → iron staining of tongue/teeth, simulating black hairy tongue

• Some medications (e.g., minocycline) deposit in skin, complex with iron and melanin → uniquely colored (usually blue-gray) deposits (see Chapter 6)

• Any natural/iatrogenic inflammatory condition → hyperpigmentation or hypopigmentation
• More common in Fitzpatrick skin types IV, V, VI (especially IV/V); lighter-skinned patients may show postinflammatory erythema instead; affects both sexes equally
• Two mechanisms of hyperpigmentation: (1) increased epidermal pigmentation via increased melanocyte activity; (2) dermal melanosis from melanin dropout from epidermis into dermis
• Wood's light helps distinguish the two patterns; hyperpigmented lesions tan-brown, may have gray hue (dermal melanin)
• Hypopigmented lesions prominently lighter than surroundings; histology: melanin in upper dermis/around upper dermal vessels, primarily in melanophages
• Pattern of dermal melanosis does NOT predict lighter vs darker outcome → pathologists often report "postinflammatory pigmentary alteration (PIPA)"
• Often resolves spontaneously if inciting process stops
• Treatment: hypopigmentation → treat underlying disease (e.g., pityriasis alba); hyperpigmentation → sun protection critical; hydroquinone if enhances with Wood's light; topical retinoids enhance hydroquinone effect; hydroxy acids used; isolated reports of thiamidol, niacinamide, azelaic acid, kojic acid, tranexamic acid
• Laser/chemical peels: use extreme caution — unpredictable, may worsen pigmentation
• Darker patients with lichenoid diseases (e.g., lichen planus): dyspigmentation can last years

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• Common disorder; two predisposing factors: sun exposure and sex hormones
• Affects darker-complexioned individuals: East, West, Southeast Asians, Hispanic/Latinos, Black persons in high-sun areas, Fitzpatrick IV/V
• Subtle melasma (by UV light exam) may be seen in up to 30% of middle-aged Asian females
• Men also affected, especially those from Central America
• Pathogenesis unknown but sun exposure is primary trigger
• Affects face (sun-exposed), worsens in summer
• Lower minimal erythema dose (MED), pigment more easily with UV
• Association between number of melanocytic nevi and melasma development
• Prevalence increases with age in both sexes
• Solar elastosis more marked in melasma-affected skin
• Reduced WIF-1 (Wnt antagonist) expression → increased Wnt expression → Wnt stimulates melanogenesis
• Second most important trigger = female hormones
• More common/severe in women; frequent during pregnancy, OC use, HRT at menopause
• Discontinuing OC/HRT rarely clears pigmentation (may last years); melasma of pregnancy usually clears within a few months of delivery
• Associated with thyroid autoimmunity, phenytoin, finasteride therapy
• Clinical: brown patches on malar prominences, forehead; forearms may be affected
• Three patterns: centrofacial, malar, mandibular — centrofacial and malar most common but most patients have multiple types (classification not very therapeutically useful)
• Sharply demarcated patches
• Classic classification epidermal vs dermal (by Wood's light enhancement), but most cases show BOTH epidermal and dermal melanin
• Nuclear changes within keratinocytes indicate altered epidermal melanin units
• Dermal melanophages are a NORMAL finding in sun-exposed Asian skin
• Independent of Wood's light findings, a therapeutic trial of hypopigmenting agent should be offered
• Treatment:
• Tinted sunblock (broad-spectrum UV filters + iron oxides to block visible light) daily — modestly improves melasma, enhances bleaching cream efficacy, prevents new lesions
• Hydroquinone (gold standard, moderately efficacious): 2% (previously OTC, restricted by CARES Act Sept 2020) to 4%
• Retinoid creams added to increase efficacy; tretinoin alone less effective than hydroquinone
• Triple combination (hydroquinone + tretinoin + topical corticosteroid) = most effective topical regimen; ascorbic acid may be added; twice-weekly application effective for maintenance
• Overuse → fixed erythema, telangiectasias, acneiform eruptions, hypertrichosis
• Hydroquinone can cause irritant dermatitis; overuse hypothetically → exogenous ochronosis (limited data)
• Higher concentrations if 4% ineffective; store hydroquinone in opaque container/refrigerate to extend shelf life
• Typical regimen: 12 weeks then break, cyclic (e.g., daily summer, weekends fall, none winter, weekends spring)
• Satellite pigmentation and local ochronosis = potential complications of higher-concentration preparations
• Other agents (minimal-moderate efficacy): azelaic acid, niacinamide, kojic acid, tranexamic acid, PRP, vitamin C, cysteamine, methimazole, arbutin — generally less effective than 4% hydroquinone but useful if hydroquinone-intolerant
• Oral tranexamic acid (TXA): role in refractory melasma; 250mg BID x3 months + sunscreen showed improvement in one study; caution — low but real risk of thrombotic events; screen PT/PTT, INR, CBC, renal function; TXA is teratogenic; relapse hyperpigmentation possible on cessation
• Peels (glycolic, salicylic, TCA, tretinoin 1%): not reproducibly enhance 4% hydroquinone efficacy, can cause hyperpigmentation if irritation ensues
• Microneedling: enhances penetration, combined with TXA, ascorbic acid, PRP
• Light-based modalities: use with caution — may cause hyperpigmentation, irritation, hypopigmentation, scarring
• IPL: sometimes improves but high relapse rate, may worsen pigmentation
• Pulsed dye laser: may enhance combination topical treatment
• Low-fluence Q-switch 1064nm Nd:YAG, fractional ablative 2940nm Er:YAG, fractional ablative CO2 lasers: beneficial in meta-analysis but recurrences occur; lasers not widely recommended for melasma currently

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• Linked by similar clinical features: reticulate pigmentation of various sites + characteristic histology (adenoid pigmented proliferations of rete ridges of interfollicular and infundibular follicular epidermis, at times with focal acantholysis)
• Patients may have overlapping features of several syndromes; genetic bases increasingly discovered
• Some genodermatoses with reticulate hyperpigmentation covered elsewhere (Chapter 22): Naegeli-Franceschetti-Jadassohn syndrome, dyskeratosis congenita

• Originally/still primarily reported in Japanese; also found in Europe, India, Caribbean
• Also called DSH or symmetric dyschromatosis of the extremities
• Inherited most often AD, though AR kindreds reported
• Progressive hyperpigmented and hypopigmented macules, often mixed reticulate pattern, concentrated on dorsal extremities (especially dorsal hands/feet); pinpoint to pea-sized
• Freckle-like macules on face; long forearm hair, hypo/hyperpigmented hair, acral hypertrophy, dental abnormalities also reported
• Onset infancy/early childhood, usually stops spreading before adolescence; lesions last for life (rare spontaneous resolution reported)
• EM: degeneration of melanocytes within lesions
• AD form caused by mutation in ADAR1 gene; a type of Aicardi-Goutières syndrome caused by biallelic ADAR1 mutations (Chapter 7), but lacks reticulated hyperpigmentation features

• DUH: rare AD genodermatosis; asymptomatic hyper- and hypopigmented macules, generalized on trunk/limbs, sometimes face
• Irregular size/shape, appear in infancy/childhood (often first months of life); palms, soles, mucous membranes usually spared
• Most patients otherwise well; infrequent associations: ocular/auditory abnormalities, photosensitivity, developmental delay, short stature
• Histology: normal melanocyte numbers in lighter and darker skin, but more melanized mature melanosomes in darker areas, empty immature melanosomes in hypopigmented areas
• Three subtypes: DUH-1 and DUH-3 = AD; DUH-2 = recessive
• SASH1 mutations → DUH-1 (Chinese families)
• ABCB6 mutations → DUH-3 (familial and sporadic); abnormal protein localizes to melanocyte dendrites, likely involved in melanosome transport; mutant protein remains in Golgi, disrupting transport
• DUH-2: much rarer, AR, putative gene location chromosome 12q21-q23
• Familial progressive hyperpigmentation (FPH): AD, hyperpigmented patches in early infancy, progresses with age; hypopigmented lesions ABSENT (distinguishes from DUH-2, which it otherwise resembles)
• Familial progressive hyperpigmentation and hypopigmentation (FPHH): AD, diffuse partly blotchy hyperpigmentation, hyperpigmented macules, café au lait macules, larger hypopigmented ash-leaf macules on face/neck/trunk/limbs at birth or early infancy; lesions increase in size/number with age
• FPHH and FPH associated with mutations in same chromosome 12 region as DUH-2, mapping to KITLG (steel factor/mast cell growth factor/stem cell factor) — ligand of c-KIT; gain-of-function mutations
• c-KIT mutations also implicated in mastocytomas; report of patient with both FPH and mastocytomas

• Rare AD pigmentary disorder; pigmentation usually appears at puberty/early adolescence, may present later in adulthood
• Affects intertriginous areas: axillae, neck, genitalia, inframammary/sternal areas; dorsal hands sometimes involved
• Reticular pigmentation; periphery has discrete brownish-black macules surrounding partly confluent central pigmented area; progresses very slowly; mildly affected = dappled pigmentation
• Follicular variant reported
• Acneiform, pitted (sometimes pigmented) scars around mouth frequent
• Comedonal and cystic lesions on flexures/axillae; hidradenitis suppurativa–like lesions in groin/axilla may occur
• Worse in hot weather; squamous cell carcinoma of buttocks/perianal area described
• Histology: lentiginous adenoid proliferations of rete ridges + small horn cysts (resembles reticulated seborrheic keratosis); comedones may be present
• Classic AD DDD caused by mutations in keratin 5 gene (KRT5)
• Similar mutations occur with Galli-Galli disease → suggests both are variants of same disorder
• In KRT5-negative DDD patients: mutations found in POGLUT1 and POFUT1 (essential Notch pathway regulators), and PSENEN
• Families with PSENEN mutations have both hidradenitis and DDD, though HS typically seen only in obese family members

• Now recognized as acantholytic variant of DDD, also caused by KRT5 mutations
• Skin lesions: 1–2mm, slightly keratotic, red to dark-brown papules, focally confluent in reticulate pattern
• Favors skinfolds; may also affect neck, axillae, upper extremities, dorsal hands, trunk, groin, scrotum, lower extremities
• Histology: prominent digitate downgrowth of rete ridges (identical to DDD); characteristic feature = suprabasilar cleft and suprapapillary epidermal thinning; NO dyskeratosis (distinguishes from Grover disease)
• Ablative laser treatment led to axillary symptom resolution in one patient

• Rare AD disease, initially recognized in Japan, now seen in many countries
• Pigmented, angulated, irregular freckle-like lesions with atrophy, reticulate pattern on dorsal feet/hands
• Onset first-second decades, gradually progresses, slowly darkens; axillae, groin, trunk, proximal extremities may be affected
• 50% of Japanese patients have punctate pits on palms/soles; linear irregular breaks in dermatoglyphics of palms are characteristic — helps distinguish from other "reticulate flexural anomalies"
• Patients with mixed DDD/RPK features reported
• Caused by loss-of-function mutation in ADAM10 (also affects NOTCH pathway, explains similarities with DDD)

• Extremely rare dominant ectodermal dysplasia; triad: generalized reticulate hyperpigmentation, noncicatricial alopecia, onychodystrophy
• Additional associations: loss of dermatoglyphics, hypo/hyperhidrosis, pigmented oral mucosa lesions, palmoplantar hyperkeratosis, nonscarring blisters of dorsal hands/feet; wiry scalp hair and digital fibromatosis reported
• Both NFJS (Naegeli-Franceschetti-Jadassohn syndrome) and DPR caused by mutations in keratin 14 gene (KRT14)
• NFJS differentiated from DPR: NFJS has dental anomalies and pigmentation may fade over time

• Rare inherited disease; males: reticulate hyperpigmentation, hypopigmentation, hypohidrosis, characteristic facial features (flared eyebrows, upswept hairline)
• Systemic manifestations: GI inflammation, respiratory infections, failure to thrive, corneal opacification
• Heterozygous female carriers: milder disease, patchy pigmentary skin along lines of Blaschko
• Caused by mutations in POLA1

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• Present at birth; 1–3mm flaccid, superficial fragile pustules; may already have resolved in utero leaving pigmented macules
• Lesions occur anywhere; numerous lesions and lesions up to 1cm reported
• New pustules AFTER birth should raise suspicion for erythema toxicum neonatorum or infections (S. aureus, HSV)
• In dark-skinned infants, pigmented macules may persist for weeks-months after pustules heal
• More frequent in skin types III–VI (~5%) vs types I–II (<1%); may be more common after vaginal vs cesarean delivery
• Histology: intracorneal/subcorneal aggregates predominantly of neutrophils (eosinophils may be found too); dermal inflammation = mix of neutrophils and eosinophils

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• Hyperpigmented macules on lips/oral mucosa, GI polyposis, greatly increased cancer risk
• Dark-brown/black macules typically on lips (especially lower lip) in infancy/early childhood; similar lesions on buccal mucosa, tongue, gingiva, perianal mucosa; also around mouth, central face, perianally, backs of hands (fingers, toes, tops of feet)
• >2/3 of patients have hand/foot lesions; 95% have perioral lesions
• Skin lesions grow in size/number until puberty then regress; buccal pigmented macules tend to persist
• Diagnostic criteria (any of 4): (1) ≥2 histologically confirmed PJS polyps; (2) any number of PJS polyps + family history of PJS; (3) characteristic mucocutaneous pigmentation + family history of PJS; (4) any number of PJS polyps + characteristic mucocutaneous pigmentation
• STK11 gene mutation found in 85–90% of patients meeting criteria; almost half have de novo mutations; PJS can occur without STK11 mutation
• Polyps most common in small intestine, also stomach, colon, least commonly rectum; polyposis causes repeated abdominal pain/vomiting; bleeding and intussusception common (intussusception 47%); rate of intussusception and cancerous polyps increases with age
• Boys with PJS often show estrogen excess evidence: gynecomastia, advanced bone age
• 10–18-fold greater lifetime cancer risk (81–94%) vs general population
• Greatest risk = GI malignancy (130-fold increase): colon (39%), stomach (29%), small intestine (13%)
• Cancers begin around age 30; extraintestinal sites: breast, lungs, male/female GU tract, pancreas (100-fold increase)
• Prevalence of cancers by site: pancreas (26%), breast (54%, can be bilateral), ovary (21%)
• Sertoli-Leydig cell stromal tumors in 9% of PJS males; sex cord tumors with annular tubules in female PJS patients
• 40% of patients develop significant GI/GU complications by age 6 → GI screening may need to begin as early as age 4–5, with testicular exam in males
• Caused by germline mutation of STK11/LKB1 tumor suppressor gene; truncation mutations more severely affected than missense (genotype/phenotype correlation)
• In Chinese PJS patients, mutations in multiple other genes identified — multiple genes can cause syndrome
• Differential diagnosis:
• Laugier-Hunziker syndrome: mucosal pigmentation + pigmented nail streaks
• Carney syndrome: Sertoli cell tumors, gynecomastia + mucocutaneous pigmentation — may be mistaken for PJS
• Cronkhite-Canada syndrome: melanotic macules on fingers + GI polyposis, generalized uniform skin darkening, extensive alopecia, onychodystrophy; polyps usually benign adenomas, may involve entire GI tract; protein-losing enteropathy may develop (correlates with degree of polyposis); onset typically after age 30, sporadic, generally benign; hypogeusia (reduced taste) = dominant initial symptom, followed by diarrhea and ectodermal changes; majority of cases reported from Japan; zinc therapy may improve hypogeusia/other symptoms

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• Fine metallic particle deposits in skin; may be hematogenous or directly inoculated; silver/gold discolorations discussed in Chapter 6

• Acute poisoning: flushing day 1; facial edema days 2–5; morbilliform eruption days 4–6; hepatic dysfunction with eruption of discrete red-brown papules in intertriginous areas (lower abdomen, buttocks, lateral upper chest); regresses after 2–3 weeks, may have acral desquamation
• 3 months after exposure: Mees lines, total leukonychia, Beau lines, onychodystrophy; periungual pigmentation in up to half of acutely poisoned patients at 3 months
• Arsenic ubiquitous — metalloids, alloys, chemical compounds; deposited in water, soil, vegetation
• High arsenic drinking water regions: Pakistan, India (West Bengal, Eastern India), Mongolia, China, Cambodia, Vietnam
• Polymorphisms in arsenic-methylation pathways (monomethylarsonic acid → dimethylarsinic acid) may confer higher risk
• Arsenic exposure → significant reduction in circulating helper T cells (possibly contributing to cancer risk)
• XPD gene polymorphisms = risk factor for arsenic-induced skin lesions
• Skin lesions usually occur only when drinking water arsenic ≥50 µg/L
• Two characteristic forms of chronic skin disease:

1. Cutaneous hyperpigmentation (most common, earliest side effect): diffuse, most prominent on trunk; patchy accentuation in inguinal folds, areolae, palmar creases — can simulate Addison disease; hypopigmented areas scattered within → "raindrop" appearance; focal melanotic macules
2. Punctate keratoses on palms/soles (characteristic); diffuse palmoplantar keratoderma rare

• Blackfoot disease: arsenic-induced peripheral vascular disease → vasospasm, peripheral gangrene; severe peripheral neuropathy also occurs
• 1998 Japan curry-poisoning outbreak: 4 deaths, 63 ill; facial edema, transient flushing erythema, conjunctival hemorrhage, intertriginous maculopapular eruptions, acral desquamation in >half
• Similar flexural eruption seen with arsenic trioxide treatment for acute promyelocytic leukemia
• Histology of arsenical palm/sole keratosis: hyperkeratosis, parakeratosis, acanthosis, papillomatosis
• 6–7% of hyperkeratotic lesions show basilar atypia; about 1% show cancer
• Arsenic → nonmelanoma skin cancers: Bowen disease = majority of arsenic-induced cancers (sun-exposed or protected skin); basal cell carcinomas frequent, usually multiple, most common on trunk, can be in sun-protected sites; SCC may also occur
• Acitretin may improve arsenical keratoses; arsenic exposure → increased risk of lung, liver, renal carcinoma

• Chronic poisoning → "lead hue" (lividity, pallor); lead deposit in gums = "lead line"

• Historically soluble iron compounds used to treat allergic contact/other dermatitides; in eroded areas, iron deposited like a tattoo
• Monsel solution can produce similar tattooing → aluminum chloride now preferred, especially for melanocytic lesion biopsies (Monsel tattooing can mimic recurrent disease)
• To minimize tattooing: apply Monsel with cotton-tip barely moistened, roll across wound just blotted dry

• Caused by mutations in ≥5 different genes involved in iron absorption
• Very common in White European population — most mutations at C282Y and H63D loci in HFE gene
• Two AR forms of juvenile hereditary hemochromatosis: Hemojuvelin and Hepcidin gene mutations
• Transferrin receptor 2 gene mutations → AR adult-onset form
• Ferroportin mutation → AD adult-onset form
• Only a minority with common genetic defects develop disease; men affected more frequently/earlier (usually age 30–50); widespread genetic testing has decreased age of diagnosis, increased number of asymptomatic affected females
• Characteristic cutaneous manifestation: gray to brown generalized mucocutaneous hyperpigmentation, enhanced in sun-exposed areas (forearms, dorsal hands, face) and inguinal area
• Mucous membrane pigmentation in up to 20% of patients
• Pigmentation: ~30% of affected males, <10% of diagnosed females
• Biopsy: dermal iron deposition, but visible pigmentation = increased epidermal melanin in basal cell layer
• Other skin changes: koilonychia, localized ichthyosis; alopecia common; pruritus can occur
• Porphyria cutanea tarda occurs more commonly with hemochromatosis (iron overload inhibits hepatic uroporphyrinogen decarboxylase)
• Chronic venous insufficiency + C282Y mutation → 6-fold increased risk of lower leg ulceration — some suggest testing at-risk patients early
• Most seriously affected organ = liver: hepatomegaly, elevated LFTs, cirrhosis, hepatocellular carcinoma
• Endocrine: hypogonadism (primary complaint); arthropathy (classically metacarpophalangeal joints) in ~50% women, 40% men; cardiac: heart failure, arrhythmias
• Alcohol, smoking, coexistent hepatitis C increase likelihood of clinical disease in genetically predisposed
• Diagnosis: elevated plasma iron, elevated serum iron-binding protein; transferrin saturation (TS = serum iron/TIBC) useful screen — score ≤45 normal (except premenopausal women, where >35 may be abnormal); high serum ferritin also present
• Genotyping performed when TS >45 + elevated ferritin, confirms diagnosis
• Liver biopsy reserved for: elevated LFTs, ferritin >1000 µg/L, or age >40
• Treatment: phlebotomy until ferritin 50–100 µg/L; erythrocytapheresis and chelation occasionally used
• Avoid vitamin C supplementation (worsens disease); avoid raw seafood (Vibrio vulnificus risk)
• Phlebotomy can prevent cirrhosis; once cirrhosis present, hepatocellular carcinoma may occur in 30%

• Titanium-containing ointment → yellowish penile papules in one patient
• Titanium orthopedic screws near skin → cutaneous blue-black hyperpigmentation
• Degenerating artificial knee joints → periprosthetic black pigment (titanium deposition); rarely migrates to skin → dermal blue-gray shin patches
• Reported due to intralesional/topical triamcinolone in alopecia areata patient
• Melanin stains positive, but polarizing foreign material seen; x-ray spectrophotometry reveals titanium in tissue
• Titanium dioxide used in cosmetics/sunscreens without significant pigmentation reports

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• Common acquired disorder, more frequent in women; usually after age 40; prevalence increases with age, exceeding 90% in Koreans over age 60
• Lesions chiefly on shins and forearms (suggests sun exposure role); widespread lesions occur with UV phototherapy
• Individual lesions small (average 2–5mm), hypopigmented macules; usually 10–30 but numerous may occur; a few can occur on face
• Irregularly shaped, sharply defined, similar to depigmented ephelides
• Histology: epidermal atrophy, reduced numbers of hypoactive melanocytes, superficial dermal fibrosis
• Remaining melanocytes show senescence (small pilot study); another study demonstrated fibroblast senescence
• Skin injury (cryotherapy, phenol, fractional CO2 laser) can improve appearance
• Topical calcineurin inhibitors (stimulate melanocyte migration/activity) can be therapeutic
• Tattoo needles delivering 5-fluorouracil investigated — may help melanocyte migration by decreasing fibrosis
• Leukoderma punctata: occurs in light-skinned patients typically <40 undergoing phototherapy; may mimic IGH but resolves spontaneously on cessation
• Eruptive hypomelanosis: reported after prodromal lymphadenitis/pharyngitis; symmetric, uniform hypopigmented macules over extensor surfaces; resolves after 2–8 weeks without treatment

• Usually young female patients; poorly demarcated, generally symmetric, hypopigmented broad macules to patches
• Most involve midback and abdomen; face tends to be spared
• Cutibacterium acnes identified as possible trigger
• Treatment: phototherapy, retinoids, topical antimicrobial therapy

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• Usually begins childhood/young adulthood, peak onset ages 10–30; can occur earlier; about half begin before age 20
• Prevalence 0.5–2% in most countries; >8% in some regions of India
• Females disproportionately represented among care-seekers — unclear if truly more affected or more likely to seek care; up to 40% of cases may go undiagnosed
• Has developed in bone marrow transplant/lymphocyte infusion recipients from vitiligo donors

• Acquired pigmentary anomaly: depigmented white patches with normal or hyperpigmented border
• Trichrome vitiligo: intermediate tan zones/lesions halfway between normal and depigmented, especially in early progressive disease
• Markers of active/progressive disease: confetti-like depigmented macules near lesion borders, inflammatory lesions (pink, scaly at border of new lesions), Koebner phenomenon
• Blue-gray hyperpigmented macules (melanin incontinence) may be present focally
• Hairs in vitiliginous areas usually become white; rarely red inflammatory border
• Patches various sizes/configurations, margins usually smooth and convex
• Six types by extent/distribution:
• Localized/focal: single or few macules in one area, often trigeminal area (especially children)
• Segmental: unilateral, blaschkoid pattern, earlier in life, less associated with autoimmune phenomena
• Generalized: common symmetric type (most common overall)
• Universal: entire body surface depigmented
• Acrofacial: distal fingers + facial orifices (lips and tips)
• Mucosal
• Generalized pattern: symmetric; most common sites = face, upper chest, dorsal hands, axillae, groin; skin around orifices favored (eyes, nose, mouth, ears, nipples, umbilicus, penis, vulva, anus)
• Lesions appear at trauma sites → favors elbows/knees
• Focal vitiligo distinguished from segmental: focal affects one nondermatomal site or asymmetric single region
• Segmental vitiligo and pigmentary mosaicism do NOT respond to typical vitiligo therapy
• Halo phenomenon: initial local pigment loss around melanocytic nevi/melanomas — not all halo nevus/melanoma patients develop vitiligo
• Vitiligo-like leukoderma in ~1% of melanoma patients; in previously diagnosed melanoma suggests metastatic disease; paradoxically better prognosis (indicates autoimmune response against melanocytes)
• Vitiligo lesions burn readily in sun (lack pigment); with repeated exposure can develop photoadaptation allowing increasing UV phototherapy doses
• Risk of nonmelanoma skin cancer in vitiligo lesions appears LOWER than unaffected skin (likely due to overactive immune system in lesions)
• Ocular abnormalities increased: iritis, retinal pigmentary abnormalities (no visual complaints); idiopathic uveitis also associated with vitiligo/poliosis

• Autoimmune disease, primarily autoreactive CD8+ T cells and IFN-γ as key cytokine
• Increased risk of other autoimmune diseases: autoimmune thyroid disease = most common association, should screen clinically in every vitiligo patient (some advocate baseline blood tests in all); in children, reasonable to avoid routine bloodwork (stressful)
• Other associations: type 1 diabetes mellitus, pernicious anemia, Addison disease, alopecia areata, connective tissue disease, rheumatoid arthritis, myasthenia gravis
• Sensorineural hypoacusis increased; cochlear dysfunction found in 60% of vitiligo patients in one study
• Vitiligo occurs in 13% of APECED syndrome patients (mutations in AIRE gene); AIRE polymorphisms more common in vitiligo patients
• Up to 30% of vitiligo patients have affected relative; not simple AD/AR — multifactorial genetic basis; GWAS identified 40+ genetic loci
• Drug-induced vitiligo: interferons, imiquimod, biologics (including adalimumab), checkpoint inhibitor therapy
• In melanoma patients on PD-1 inhibitors, vitiligo development may be a favorable prognostic indicator
• Reported following COVID-19 infection
• Significant psychological impact (anxiety, depression) in children and adults — should be documented and used to guide therapy; children may not show psychological complications early but develop QOL impairment as young adults

• Absence of melanocytes; usually no inflammatory infiltrate, but lichenoid/spongiotic inflammation may be seen at active inflammatory edge (explains scaling/hyperpigmentation around some lesions)

• Wood's light key (lesions depigmented)
• Morphea and lichen sclerosus: hypopigmented, associated with skin texture change
• Pityriasis alba: fine scale, poorly defined
• Tinea versicolor: favors central back/chest, fine scale, yeast/hyphae on KOH
• Tertiary pinta: travel history + serology
• Severe chronic actinic dermatitis: may develop vitiligo-like depigmentation
• Chemical leukoderma: closely resembles vitiligo (see below)

• Spontaneous repigmentation in no more than a quarter of cases; response typically slow (weeks-months)
• Segmental vitiligo = least responsive (but pigmentary mosaicism confusion may overstate this)
• Two-step approach: (1) stopping progression, (2) repigmenting depigmented areas
• Rapidly progressive generalized disease: short course systemic corticosteroids considered
• Early treatment → better response; likelihood of response higher if hair still pigmented in affected skin (recruiting follicular melanocytes)
• Phototherapy may initially worsen appearance by pigmenting surrounding normal skin (accentuating depigmented areas), particularly in Fitzpatrick I/II
• Anatomic location predicts response likelihood/rate independent of modality: higher hair follicle density → easier repigmentation (melanocyte migration from follicle)
• Face: excellent prognosis
• Dorsal hands/feet: only 10–20% response to most treatments
• Trunk: intermediate response
• Mucosal (lips), periungual, dorsal hand: more challenging
• Camouflage: option for those not concerned with treatment; sun protection + cosmetic camouflage
• Dihydroxyacetone (self-tanning creams): brown dye stain; lower concentrations for lighter phototypes (golden/tan); high concentrations = dark brown for type V/VI; needs reapplication every 5–10 days (sloughs off)
• Esthetician consultation recommended for color matching; Cavilon "No Sting Barrier Film" spray over camouflage may prevent rub-off
• Topical treatment: appropriate for limited areas (<10–20% BSA); occlusion may enhance efficacy
• Potent-superpotent topical corticosteroids: 2-month trial; children — lower potency and/or 5 days/week application
• Up to 80% of facial vitiligo patients achieve >90% repigmentation (diffuse pattern, not perifollicular as on trunk); only 40% achieve >90% on trunk
• Total treatment length limited to 4–6 months; monitor for acne, atrophy, telangiectasias
• Low-dose intralesional triamcinolone rarely reported effective; caution re: atrophy; response durable after stopping
• Topical pimecrolimus/tacrolimus: particularly efficacious for facial vitiligo, as effective as superpotent steroids in some series, avoid steroid complications; higher response if initiated in summer; continual application often required (new lesions in untreated areas suggest no systemic effect); may enhance NB-UVB efficacy for facial vitiligo
• Topical calcipotriene/vitamin D analogs: variable results, lack efficacy alone; combination data mixed
• Topical methotrexate 1%: beneficial in single report
• JAK inhibitors: given IFN-γ importance in pathophysiology
• TRuE-V 1 and 2 trials: topical ruxolitinib (JAK1/2 inhibitor) in 450 patients vs 224 controls — improvement at 24 weeks, greater at 52 weeks → FDA approval
• Oral ritlecitinib (highly selective JAK3 inhibitor): phase IIb RCT, effective and well tolerated
• Multiple other JAK inhibitors under investigation (topical and systemic)
• Phototherapy: NB-UVB 2–3x/weekly = preferred; avoids prolonged eye protection and psoralen-induced nausea of PUVA
• ~half achieve >75% repigmentation of face, trunk, proximal arms/legs; hand/foot lesions repigment in <25%
• Children may have slightly higher response than adults
• >20% BSA involvement: only ~5% show complete repigmentation
• Repigmentation may begin after 15–25 treatments; significant improvement may take 100–200 treatments (6–24 months); maximum improvement on average after ~9 months
• If no follicular repigmentation after 3 months → discontinue
• Home phototherapy good option for UV-responsive patients
• Contraindications: known photosensitivity, porphyria, SLE
• Excimer laser: as/more effective than NB-UVB, more rapid response; usable on limited areas
• 25% of treated patches repigment completely; treatment-resistant areas (elbows, knees, wrists, dorsal hands/feet) only 2% rate of ≥75% repigmentation
• Adding topical corticosteroid to excimer enhances efficacy
• Topical agents + phototherapy synergistic: topical steroids, tacrolimus, JAK inhibitors combined with NB-UVB
• Afamelanotide (synthetic MSH analog, monthly implant): may enhance NB-UVB efficacy
• Oral khellin or l-phenylalanine and antioxidants: variable, not always reproducible benefit
• Topical PUVA: 8-methoxypsoralen 0.01–0.1% + UVA for focal/limited lesions; frequent blistering complications even with professional treatment (difficult for home use); widely used successfully in India with lower complication rates than US
• Systemic immunosuppressives: appropriate for rapidly progressive disease to reduce total pigment loss
• Systemic corticosteroids tapered over months; once arrested, convert to phototherapy
• Azathioprine should NOT be combined with phototherapy (malignancy risk)
• Long-term systemic immunosuppressive use NOT recommended (unacceptable toxicity)
• Simvastatin: evaluated after promising case report (anti-inflammatory, antioxidant); larger studies failed to show sufficient benefit
• Surgical treatments: for limited lesions unresponsive to other methods; time-consuming
• Recommended primarily for treatment-resistant/segmental vitiligo (does not reactivate with injury)
• Requires stable disease (no new/expanding lesions for 1 year); NOT effective if Koebner phenomenon or active disease
• Reserved for exposed sites <2–3% BSA (expense)
• Techniques: punch grafting, ultrathin epidermal grafts, suction blister grafting, autologous epidermal cell suspension transplantation
• UV phototherapy often given post-surgery
• Refractory head/neck lesions: skin injury via various lasers + sunlight, or CO2 laser + 5-fluorouracil
• Total Depigmentation: consider if >50–80% BSA affected; permanent, goal = total depigmentation
• Satellite/distant depigmentation may occur even with limited application areas
• Monobenzone (monobenzyl ether of hydroquinone) 20% BID x3–6 months to residual pigmented areas; up to 10 months to complete
• ~1 in 6 patients experience acute dermatitis (usually confined to pigmented areas, rarely limits treatment)
• Psychiatric consultation recommended before depigmentation (permanent change)
• Topical 4-methoxyphenol 20% (mequinol, monomethyl ether of hydroquinone) also used
• Q-switched laser: selectively destroys melanocytes, can achieve depigmentation; can combine with topical depigmenting agent

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• Acquired, depigmented dermatosis from repeated chemical exposure; frequently misdiagnosed as vitiligo
• Patients with vitiligo or family history of vitiligo at much greater risk
• Diagnostic criteria:

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

• Majority caused by aromatic/aliphatic derivatives of phenols and catechols: p-tert-butylphenol (shoe adhesive), amylphenol, butylcatechol, alkyl phenols
• Also implicated: sulfhydryls, mercurials, arsenics, cinnamic aldehyde, p-phenylenediamine, chloroquine, azelaic acid
• Some compounds structurally similar to tyrosine, converted by tyrosine-related protein-1 to melanocyte-toxic compounds; process differs from depigmentation after allergic contact dermatitis
• Lesions concentrated in areas of repeated substance contact
• First recognized occupational vitiligo cases: rubber garment/glove workers exposed to monobenzyl ether of hydroquinone
• Phenolic antiseptic detergents (hospitals/industrial cleaners) → chemical leukoderma in janitorial/housekeeping employees
• Adhesives/glues in shoes, wristbands, adhesive tape, rubber products (bras, girdles, panties, condoms); self-sticking bindis (Indian cosmetic) → forehead leukoderma; ECG electrodes → round hypopigmented contact spots
• Radiation therapy and imiquimod (genital wart treatment) can also cause vitiligo-resembling depigmentation
• Most common location: face (40% of cases), then hands/feet; scalp rarely affected
• Site-exposure associations: hair dye (scalp rim, not scalp), deodorant (axilla), detergent, adhesives (face, bindis), rubber sandals (feet), black socks/shoes (feet), rubber condoms (penis)
• Pruritus in >20% of patients (rare complaint in true vitiligo)
• Clinical: sharply marginated macules/patches, often with "confetti" or pea-sized macules at periphery — atypical for idiopathic vitiligo, suggests chemical leukoderma
• >25% of patients have lesions outside contact area; in ~10%, new lesions continue after exposure stops
• Treatment: avoidance + measures used for idiopathic vitiligo
• Prognosis: no underlying vitiligo → repigmentation in up to 75%; if underlying vitiligo → repigmentation in only 20%
• Histology: absence of melanocytes, identical to true vitiligo

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• Rare multisystem disease affecting eyes, skin, auditory system, CNS; less common in skin types I/II; twice as common in females; affects all ages
• Four phases:

1. Prodromal/meningoencephalitic phase: fever, malaise, headache, nausea, vomiting; CNS involvement (meningismus, headaches, mental status changes, CSF pleocytosis, tinnitus, dysacusis); recovery usually complete
2. Uveitic phase: anterior and/or posterior uveitis, inflammation of other eye parts
3. Convalescent phase: begins 3 weeks–3 months after uveitis onset, usually as it improves; characterized by noncicatricial alopecia, vitiligo-like depigmentation, poliosis of scalp/eyebrows/eyelashes/axillary hair; vitiligo-like lesions occur in only 20–60% of VKHS patients; back/buttocks may be initial or only site; skin lesions must begin AFTER ocular symptoms to be diagnostic
4. Chronic recurrent phase: recurrent uveitis attacks; most ocular complications occur here (permanent decreased visual acuity, cataracts, glaucoma)

• Cell-mediated autoimmune disease; autoantigen(s) thought expressed solely in melanin-containing cells; target antigens may be tyrosinase family proteins
• Supporting evidence: vitiligo, IFN therapy for hepatitis C, and melanoma can all be associated with VKHS appearance
• Aggressive immunosuppression (systemic corticosteroids + cyclosporine, azathioprine, mycophenolate, tacrolimus, infliximab) may preserve ocular function and prevent complications
• Th17 CD4+ cells stimulated by high IL-23, secreting IL-17, present in VKHS patients with active uveitis
• ≥10 patients with psoriasis + VKHS reported: present at older age than VKHS-only, often share HLA genotypes with both conditions (DR4, Cw6)
• Reported following infection including SARS-CoV-2

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• Extremely rare (<10 reported cases): unilateral degenerative retinal pigment epithelial degeneration + ipsilateral facial vitiligo + ipsilateral poliosis + ipsilateral sensorineural deafness
• Patients with multiple pigmentary anomaly syndromes (Alezzandrini, VKHS, Waardenburg syndrome, vitiligo) can all have hearing problems

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• Postinflammatory leukoderma may result from many inflammatory dermatoses: pityriasis rosea, psoriasis, herpes zoster, secondary syphilis, morphea
• Sarcoidosis, tinea versicolor, mycosis fungoides, leprosy, scleroderma, pityriasis lichenoides chronica may present with hypopigmented lesions (only rarely truly depigmented)
• Burns, scars, postdermabrasion, intralesional steroid injections with depigmentation = other examples
• Chemical leukodermas discussed in vitiligo section
• IL-17 and TNF-α synergistically suppress pigmentation-related signaling and melanin production, partly through induction of β-defensin 3 (antagonist for melanocortin 1/MC1R) — may explain hypopigmentation complicating psoriasis and other inflammatory dermatoses

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• Melanosomes are members of the LRO family
• Four groups of genetic defects:

1. Mutations in genes controlling melanoblast migration (e.g., Waardenburg syndrome)
2. Mutations in genes controlling enzymes of melanin synthesis (e.g., oculocutaneous albinism)
3. Mutations in genes of melanosome structural proteins (membrane/scaffolding on which melanins deposited — e.g., Chédiak-Higashi, Hermansky-Pudlak syndromes)
4. Mutations in genes controlling melanosome-trafficking proteins (surface proteins directing melanosome movement from Golgi to periphery — e.g., Griscelli syndrome)

• Clinically classified as generalized (systemic) or localized; each subgroup has forms with/without comorbidities

• I. Systemic Hypopigmentation (Generalized)
• A. Without comorbidities: Oculocutaneous albinism types 1–4; Griscelli syndrome type 3
• B. With comorbidities: Bleeding — Hermansky-Pudlak syndrome; Infection — Chédiak-Higashi syndrome, Griscelli syndrome, Hermansky-Pudlak syndrome type 2
• II. Localized Hypopigmentation
• A. Without comorbidities: Nevus depigmentosus; Piebaldism
• B. With comorbidities: Deafness — Waardenburg syndrome; Megacolon/neural disorders — Hirschsprung disease type 2; Neural disorders — hypomelanosis of Ito

• Seven genetic forms of nonsyndromal oculocutaneous albinism (OCA) — all caused by disruption of parts of melanin synthesis pathway, all AR
• Prevalence varies widely globally, estimated ~1 in 17,000; ~1 in 70 persons carries an OCA mutation
• Genetic testing recommended given phenotypic overlap; genetic counseling recommended (both parents obligate carriers, 2/3 of healthy siblings at risk of being carriers); carriers asymptomatic

• Multisystem syndromes associated with albinism, caused by genes functioning in intracellular organelle formation/movement in specialized cells (melanocytes, neurons, immune cells, monocytes, platelets, type II lung epithelial cells) → many extracutaneous signs/symptoms
• Silver hair in some syndromes may show pigment clumping on microscopy, aiding diagnosis

Chédiak-Higashi Syndrome (CHS)

• Progressively degenerative, fatal disease: partial oculocutaneous albinism (decreased skin/eye/hair pigment), giant intracellular granules, pigment clumping in hair shafts, bleeding diathesis (absent/reduced platelet-dense bodies)
• Irregular melanin clumping within hair follicles; large irregular melanosomes seen on light microscopy and TEM of longitudinally cut hair — supports early diagnosis (GS can show similar clumping on light microscopy)
• Presents in childhood with skin/gut/lung infections (decreased NK- and T-cell cytotoxicity); common pathogens: S. aureus, streptococcus, gram-negatives, Candida, Aspergillus
• Immunoglobulins, antibody production, phagocytosis normal; neutropenia common, impaired leukocyte migration; NK cell function decreased; CTL cytotoxicity impaired
• Hair blond and sparse; ocular albinism with nystagmus, photophobia
• Darker-skinned races: affected patients lighter than parents/siblings, may have speckled hyper-/hypopigmentation
• Caused by mutations in LYST/CHS1 gene (exact function unknown); genes involved in lysosomes, LROs, trafficking/size regulation
• Melanosomes giant; platelets, eosinophils, basophils, monocytes have giant azurophilic intracellular granules
• ~85% of CHS patients develop hemophagocytic lymphohistiocytosis (HLH) ("accelerated phase") during infancy/childhood, can be fatal — unfettered lymphocyte proliferation creating lymphoma-like condition (fever, anemia, neutropenia, hepatosplenomegaly, lymphadenopathy)
• HLH likelihood relates to degree of CTL cytotoxicity deficiency, independent of genotype
• Hematopoietic stem cell transplantation (HSCT) before accelerated phase onset may be lifesaving, prevents infections
• Even with HSCT, adult survivors develop progressive neurologic involvement: dementia, spinocerebellar impairment, parkinsonism, spastic paraparesis

Hermansky-Pudlak Syndrome (HPS)

• AR disorder, multiple types: OCA + hemorrhagic diathesis (absent platelet dense bodies)
• Progressive accumulation of ceroid-like material in reticuloendothelial system/visceral organs — hypothesized to cause interstitial lung disease (HPS-ILD) and IBD (HPS-IBD)
• Hypopigmentation caused by impaired melanosome trafficking
• History of easy bruisability, epistaxis, gingival bleeding, hemoptysis, bleeding with surgery/childbirth; major bleeding in 40% of HPS patients
• Multiple genes code for proteins involved in LRO maturation/trafficking/function, forming complexes: AP-3, BLOC-1, BLOC-2, BLOC-3
• BLOC-1 genes (DTNPBP1, BLOC1S3, BLOC1S6, BLOC1S5) → HPS7, HPS8, HPS9, HPS11 (OCA + bleeding)
• BLOC-2 genes (HPS3, HPS5, HPS6) → HPS3, HPS5, HPS6 (milder phenotype, variable hypopigmentation, moderate bleeding)
• HPS1 and HPS4 → BLOC-3 complex proteins; patients develop pulmonary fibrosis
• AP-3 defects (AP3B1 or AP3D1 mutations) → HPS2 and HPS10, with immunodeficiency
• Most common subtype = HPS1; together with HPS4 accounts for 50% of worldwide known HPS cases
• 1 in 21 Puerto Ricans has a mutation (usually 16-bp duplication) in HPS1 gene; HPS accounts for 80% of Puerto Rican albinism cases; 1 in 1800 Puerto Ricans in northwest region has HPS
• HPS1 and HPS4 clinically similar (both form BLOC-3 complex)
• Skin pigmentation varies total absence to lighter than family members
• Ocular changes like OCA: iris transillumination, hypopigmented retina, visual impairment, horizontal nystagmus, strabismus
• Atypical nevi, acanthosis nigricans–like axillary/neck lesions, trichomegaly also occur
• Solar damage (lentigines, actinic keratoses, NMSC) in 80% of patients with the 16-bp HPS1 duplication
• Interstitial pulmonary fibrosis, IBD, renal failure, cardiomyopathy = late complications, can cause premature mortality ages 20–50
• ~60% of HPS patients have pulmonary symptoms, mean onset age 35
• Pirfenidone (antifibrotic) can slow pulmonary fibrosis progression in HPS1 patients with significant residual lung function (initial FVC >50%); lung transplant can be considered
• HPS2: caused by AP3B1 mutation (3βA subunit of AP-3, needed for lysosomal protein trafficking); notable for immunodeficiency (as is HPS10 from AP3D1) and persistent neutropenia with recurrent bacterial URI/middle ear infections
• Initially may be misdiagnosed as CHS (pigment dilution + recurrent infections), but large intracellular granules of CHS are ABSENT in HPS2
• Mild pulmonary fibrosis and mild hearing defect can be associated with HPS2

Griscelli Syndrome (GS)

• Myosin-5a/RAB27A/melanophilin tripartite protein complex required to capture mature melanosomes in peripheral actin network for transfer to keratinocytes
• Mutation in each gene causes one type of GS, distinct clinical phenotype for each type
• All types: rare, AR, mild skin/hair hypopigmentation (silver hair); light microscopy shows irregular pigment clumping
• Silvery hair + lack of bleeding tendency distinguishes GS from HPS; lack of immunodeficiency distinguishes GS from CHS
• GS1: MYO5A gene mutation (actin-associated myosin Va motor protein); primary neurologic dysfunction, no immunologic disease; GS1 and Elejalde syndrome thought to be same disease
• GS2: RAB27A gene mutation; silver hair, infections, HLH (usually virus-triggered); leukocyte brain infiltration can cause secondary neurologic disease, but no primary neural defects
• GS3: melanophilin (MLPH) mutation; results only in cutaneous hypopigmentation and silver hair

Vici Syndrome

• Extremely rare: hypopigmentation, immunodeficiency, agenesis of corpus callosum; caused by mutations in EPG5 gene (involved in autophagy)

P14/LAMTOR2 Deficiency

• Four children in a Mennonite family: P14 gene mutations, clinical phenotype of partial albinism, coarse facial features, short stature, neutropenia, immunodeficiency

• Cause "spotting" — patches of white hair and depigmented skin

Waardenburg Syndrome (WS)

• Features of piebaldism: white forelock, hypopigmentation, premature graying (absence of melanocytes in affected areas)
• Other findings: synophrys (eyebrows growing together), dystopia canthorum (lateral displacement of medial canthus), congenital deafness, ocular changes including heterochromia iridis
• Type I and III: both have dystopia canthorum; type I — white forelock/depigmented patches more frequent; type III (Klein-Waardenburg syndrome) — musculoskeletal anomalies (flexion contractures, upper limb muscle hypoplasia, camptodactyly)
• Type II: no dystopia canthorum, but hearing loss and heterochromia iridis more frequent
• Type IV: identical to type I except association with Hirschsprung disease (congenital megacolon) — neural crest cell migration into Auerbach plexus requires EDN3/EDNRB and SOX10
• SOX10 mutations associated with neurologic defects, poor phenotype/genotype correlation in SOX10-associated WS; developmental delay in many, suggesting other genes influence phenotype
• WS type IV from SOX10 + neurologic disease = PCWH (peripheral demyelinating neuropathy, central demyelinating leukodystrophy, Waardenburg syndrome, Hirschsprung disease)
• Six genes associated with WS:
• Types I and III: PAX3 mutations (transcription factor)
• Most type II: MITF mutations; some milder type II from SOX10, EDN3, EDNRB, SNA12, GJB2, ADGRV1
• Type IV: heterozygous SOX10 mutation OR homozygous EDN3 or EDNRB mutation
• Mutations impair melanoblast ability to reach final target sites (inner ear, eye, skin) during embryogenesis

Piebaldism

• Rare AD syndrome, variable phenotype, present at birth
• Characteristic features: white forelock, patchy absence of skin pigment
• Depigmented lesions congenital and STATIC (differentiates from vitiligo); characteristically on anterior/posterior trunk, mid-upper arm to wrist, midthigh to midcalf, shins
• Characteristic feature: hyperpigmented macules WITHIN depigmented areas and on normally pigmented skin; café-au-lait macules occasionally reported
• Depigmented lesions may repigment spontaneously, especially after injury
• White forelock: triangular/diamond-shaped midline white macule on frontal scalp/forehead; the ONLY manifestation in 80–90% of patients
• Medial portions of eyebrows/eyelashes may be white
• Histology: melanocytes completely absent in white macules
• Caused by mutations in KIT gene; phenotypic differences between families relate to mutation location
• Mild phenotype: haploinsufficiency or truncated mutation in TK domain
• Severe phenotype: dominant-negative inhibition from missense mutation in TK domain
• White lesions may respond to camouflage cosmetics or surgical correction (as for vitiligo)
• Rarely, neurofibromatosis type I has been associated with piebaldism

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• AR inherited trait: reduction/absence of melanin in skin, hair, eyes
• Eye problems frequent: moderate-severe visual acuity impairment, nystagmus, strabismus, photophobia
• Cutaneous phenotype broad across forms; ocular phenotype reasonably specific in most forms
• Most serious sequelae: gross visual disturbances and increased skin cancer risk
• All OCA patients/parents: aggressive sun protection (sunscreen, clothing, avoidance); vitamin D supplementation may be needed due to sun avoidance
• Examine for melanoma and NMSC-suspicious lesions; dermoscopy challenging given lack of pigment — consider biopsy of any nevus with different pattern or changing nevus, and reflectance confocal microscopy
• Some associated syndromes can cause premature mortality from other organ/system dysfunction

• Mutations in tyrosinase gene (TYR); ~40% of OCA worldwide; most severe form; most common type in Japanese, non-Hispanic Whites, Europeans; prevalence ~1 in 40,000
• Homozygous or compound heterozygous for TYR mutations
• Two forms — indistinguishable at birth:
• OCA1A: most severe — complete absence of tyrosinase activity and melanin in skin/eyes; visual acuity decreased to 20/400; hair/eyelashes/eyebrows white, skin white and does not tan; irises light blue to pink, fully translucent; amelanotic nevi may be present
• OCA1B: tyrosinase activity greatly reduced but not absent; skin/hair/eye color may increase beginning age 1–3 years, can tan; iris color may darken over time; originally called "yellow mutant" albinism
• OCA1-TS (temperature-sensitive, variant of OCA1B): TYR mutations produce enzyme with limited activity below 37°C (98°F), no activity above; white hair/skin/eyes at birth; at puberty dark hair develops in cooler acral areas (legs, arms, chest); visual acuity not as severely affected as OCA1A

• Prevalence 1 in 36,000 in White Europeans, up to 1 in 4000 in parts of Africa; most common form of OCA worldwide (~50%)
• Formerly "tyrosinase-positive" or "brown OCA"
• AR, mutations in OCA2 gene (formerly P-gene) — encodes integral melanosomal protein important for melanosome biogenesis, normal processing/transport of melanosomal proteins (tyrosinase, TYRP1)
• Cutaneous phenotype broad (near-normal to virtually no pigment); newborns have pigmented hair; nevi/ephelides common; pink irises usually NOT seen
• Visual defects less severe than OCA1; pigmentation increases with age, visual acuity improves infancy to adolescence
• Prader-Willi and Angelman syndromes caused by deletions in chromosomal region contiguous to/including OCA2 gene; ~1% of these syndrome patients also have OCA2

• Mutations in TYRP1 gene (maintains melanosome structure, affects melanocyte proliferation/cell death, essential cofactor for tyrosinase activity)
• Most frequently found in African patients; called "rufous" or red OCA
• Red hair, reddish-brown skin; visual abnormalities may not be detectable

• Mutations in SLC45A2 gene (membrane-associated protein)
• Variable hypopigmentation, phenotypically identical to OCA2; decreased visual acuity; nystagmus in many but not all

• Mapped to 4q24; described in Pakistani family: golden hair, white skin, nystagmus, photophobia, impaired visual acuity

• Mutations in SLC24A5; found in diverse ethnicities; heterogeneous phenotype (white to blond to dark brown hair)

• Mutation in C10orf11 gene (leucine-rich repeat protein family member); blond to brown hair, hypopigmentation, nystagmus

• Caused by TYRP2 mutations; mild hair/skin hypopigmentation, iris hypopigmentation, diminished visual acuity

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