Hair and Pigmentation Disorders

Hirsutism

Hirsutism is excessive growth of terminal hair in a female patient in an androgen-dependent, “male-pattern” distribution, classically involving the upper lip, chin, chest, linea alba, lower abdomen, back, and inner thighs. It must be distinguished from hypertrichosis, which is generalized excess hair growth independent of androgens and may involve vellus hair. For USMLE Step 1, hirsutism is best understood as a disorder of androgen excess, increased peripheral androgen sensitivity, or both.

Hair biology and androgen mechanism

Hair follicles cycle through anagen growth, catagen involution, and telogen resting phases. Follicles produce either fine, lightly pigmented vellus hair or coarse, pigmented terminal hair. In androgen-sensitive skin, androgens convert vellus follicles into terminal follicles. The key peripheral enzyme is 5α-reductase, which converts testosterone to dihydrotestosterone (DHT), a more potent androgen receptor agonist. DHT binds intracellular androgen receptors, translocates to the nucleus, and alters transcription of genes regulating follicular size and hair shaft diameter.

Androgens in women arise from the ovaries, adrenal cortex, and peripheral conversion in adipose tissue and skin. Important circulating androgens include testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEA-S). DHEA-S is produced almost entirely by the adrenal zona reticularis and is therefore useful for localizing adrenal androgen excess. Testosterone circulates mostly bound to sex hormone-binding globulin (SHBG); only free testosterone is biologically active. Hyperinsulinemia decreases hepatic SHBG production and increases ovarian theca cell androgen synthesis, explaining why insulin resistance worsens hirsutism in polycystic ovary syndrome.

Major etiologies

Cause	Mechanism	High-yield clues
Polycystic ovary syndrome	Increased LH-driven theca cell androgen production; insulin resistance lowers SHBG	Most common cause; oligomenorrhea, infertility, acne, obesity; enlarged ovaries with multiple follicles
Idiopathic hirsutism	Normal serum androgens with increased follicular 5α-reductase activity or androgen receptor sensitivity	Normal menses, normal ovulation, gradual onset after puberty
Nonclassic congenital adrenal hyperplasia	Partial 21-hydroxylase deficiency increases adrenal androgen synthesis	Elevated morning 17-hydroxyprogesterone; may present after puberty
Androgen-secreting tumor	Ovarian or adrenal neoplasm secretes testosterone or DHEA-S	Rapid onset, severe hirsutism, virilization, very high androgens
Cushing syndrome	ACTH or adrenal tumor increases cortisol and adrenal androgens	Central obesity, purple striae, proximal muscle weakness, hypertension
Drugs	Exogenous androgenic stimulation or hypertrichosis	Danazol, anabolic steroids, testosterone; also minoxidil, cyclosporine, phenytoin cause hypertrichosis

Clinical evaluation and scoring

The standard clinical scoring system is the modified Ferriman-Gallwey score. Nine androgen-sensitive body areas are graded from 0 to 4, producing a total score from 0 to 36. A score of ≥8 is often used to define hirsutism in White and Black women, while lower thresholds may apply in East Asian populations and higher thresholds in Mediterranean, Middle Eastern, or South Asian populations. This scoring system is imperfect because cosmetic hair removal can underestimate severity, and ethnicity strongly affects baseline hair density.

Features suggesting marked androgen excess include virilization: deepening voice, clitoromegaly, increased muscle mass, male-pattern balding, and severe acne. Rapid progression over months is concerning for a tumor. Menstrual irregularity suggests anovulation and favors PCOS or endocrinopathy rather than idiopathic hirsutism.

Key laboratory thresholds

• Total testosterone: marked elevation, especially >150–200 ng/dL, raises concern for an ovarian androgen-secreting tumor.
• DHEA-S: severe elevation, classically >700 µg/dL, suggests an adrenal source such as adrenal carcinoma or adenoma.
• 17-hydroxyprogesterone: morning value >200 ng/dL suggests nonclassic congenital adrenal hyperplasia; confirmation may require ACTH stimulation testing.
• Pregnancy test, TSH, and prolactin are often relevant when menstrual irregularity is present because pregnancy, thyroid disease, and hyperprolactinemia can disrupt ovulation.

Pharmacology and treatment principles

Hair growth changes slowly because terminal follicles persist through long anagen phases; treatment response usually requires at least 6 months. The core first-line pharmacologic approach for patients not seeking pregnancy is a combined oral contraceptive pill. Estrogen increases hepatic SHBG, lowering free testosterone, while progestin suppresses LH and reduces ovarian androgen synthesis. Antiandrogens are teratogenic to male fetuses and require reliable contraception.

Therapy	Mechanism	Typical dose / key fact
Combined oral contraceptives	Decrease LH-mediated ovarian androgen production; increase SHBG	First-line when contraception acceptable; effect assessed after ~6 months
Spironolactone	Androgen receptor antagonist; inhibits steroidogenesis and 5α-reductase	50–100 mg orally twice daily; adverse effects include hyperkalemia, menstrual irregularity, breast tenderness; avoid pregnancy
Finasteride	Inhibits type II 5α-reductase, decreasing DHT	5 mg orally daily used off-label; teratogenic risk to male fetus
Eflornithine cream	Irreversibly inhibits ornithine decarboxylase, slowing hair shaft production	13.9% cream applied twice daily to facial hair; does not remove existing hair
Laser photoepilation	Selective photothermolysis of melanin-containing follicles	Best for dark hair/light skin; risk of dyspigmentation in darker skin types

Exam integration: hirsutism plus oligomenorrhea, obesity, insulin resistance, and elevated LH:FSH ratio points toward PCOS. Hirsutism with hypertension and hypokalemia suggests mineralocorticoid excess only if an adrenal process is present, whereas hirsutism with virilization and rapidly rising testosterone strongly suggests an androgen-secreting tumor.

Alopecia Areata

Alopecia areata is an autoimmune, nonscarring hair loss disorder characterized by sudden, well-demarcated patches of hair loss. “Nonscarring” means the hair follicle stem cell niche in the bulge region is preserved, so regrowth is biologically possible. It affects approximately 1%–2% lifetime risk in the general population, with many cases beginning before age 40. On USMLE Step 1, the key association is autoimmune attack on anagen hair follicles, often with other autoimmune diseases.

Pathophysiology

Normal anagen hair follicles have relative immune privilege: they express low levels of MHC class I molecules and produce local immunosuppressive signals, limiting immune recognition of follicular antigens. In alopecia areata, this immune privilege collapses. Autoreactive CD8⁺ T cells, especially NKG2D⁺ cytotoxic T cells, target the hair bulb during the anagen phase. Cytokines such as interferon-γ and interleukin-15 amplify inflammation through the JAK-STAT pathway. This explains why Janus kinase inhibitors can promote regrowth in severe disease.

Histologically, alopecia areata classically shows a peribulbar lymphocytic infiltrate around anagen follicles, described as a “swarm of bees”. The follicle is injured but not destroyed; therefore, unlike scarring alopecias such as lichen planopilaris or discoid lupus erythematosus, follicular openings remain visible.

Clinical Features and Classifications

The classic presentation is a round or oval patch of complete hair loss on the scalp with smooth, normal-appearing skin. Short broken hairs that taper proximally, called exclamation point hairs, may be seen at the active border. Dermoscopy may show yellow dots, black dots, broken hairs, and exclamation point hairs. Nail findings include fine pitting, trachyonychia, longitudinal ridging, and, rarely, onycholysis.

Subtype	Definition	High-yield association
Patchy alopecia areata	One or more discrete patches of nonscarring hair loss	Most common form
Alopecia totalis	Loss of all scalp hair	More severe, lower spontaneous remission rate
Alopecia universalis	Loss of scalp and body hair	Strong autoimmune association
Ophiasis pattern	Band-like hair loss along temporal and occipital scalp margins	Poor prognostic pattern

Severity Scoring and Prognosis

The standard research and clinical severity tool is the SALT score, or Severity of Alopecia Tool. The scalp is divided into regions weighted by surface area: vertex 40%, right profile 18%, left profile 18%, and posterior scalp 24%. Percent hair loss in each region is multiplied by its weight and summed. A SALT score of 0 indicates no scalp hair loss; SALT 100 indicates complete scalp hair loss. Many modern trials define severe alopecia areata as SALT ≥50.

Prognosis is variable. Limited patchy disease may spontaneously regrow, often within months; approximately 34%–50% of patients with limited disease may have substantial regrowth within 1 year. Poor prognostic factors include childhood onset, extensive loss, alopecia totalis or universalis, ophiasis pattern, nail involvement, atopy, family history, and coexisting autoimmune disease.

Associated Conditions

Alopecia areata is associated with autoimmune thyroid disease, vitiligo, type 1 diabetes mellitus, pernicious anemia, celiac disease, systemic lupus erythematosus, and atopic disease. Routine indiscriminate laboratory screening is not always necessary, but thyroid testing is often considered when symptoms, goiter, family history, or other autoimmune features are present.

Differential Diagnosis

Disorder	Distinguishing features
Tinea capitis	Scaling, erythema, lymphadenopathy; fungal hyphae on KOH; common in children
Trichotillomania	Irregular patches with hairs of varying length; compulsive hair pulling
Telogen effluvium	Diffuse shedding after stressor, illness, childbirth, or medication; positive hair pull test
Androgenic alopecia	Gradual patterned thinning; androgen-sensitive follicles; miniaturization
Scarring alopecia	Loss of follicular ostia, inflammation, scale, dyspigmentation, permanent follicle destruction

Pharmacology and Treatment Principles

For Step 1, the most important principle is that therapy either suppresses local immune attack or modifies cytokine signaling. For limited patchy disease, intralesional corticosteroids are commonly used. Triamcinolone acetonide is often injected at 2.5–10 mg/mL, typically every 4–6 weeks, with total dose often limited to about 20 mg per session to reduce local adverse effects such as skin atrophy and hypopigmentation. High-potency topical corticosteroids may also be used, especially in children or needle-averse patients.

For extensive disease, systemic options include JAK inhibitors. Baricitinib, an oral JAK1/JAK2 inhibitor, is used at 2 mg or 4 mg once daily. In the phase 3 BRAVE-AA1 and BRAVE-AA2 trials of severe alopecia areata, the proportion achieving SALT ≤20 at week 36 was approximately 36%–39% with baricitinib 4 mg versus about 3%–6% with placebo. Ritlecitinib, a JAK3/TEC family kinase inhibitor, is given as 50 mg once daily and is approved for patients age 12 years and older. JAK inhibitors carry important risks, including serious infection, herpes zoster, laboratory abnormalities, thrombosis, and major adverse cardiovascular events, reflecting the role of JAK-STAT signaling in immune function.

Other therapies include topical minoxidil as an adjunct to support regrowth, topical contact immunotherapy such as diphenylcyclopropenone, and systemic corticosteroids in selected rapidly progressive cases. However, the core exam concept remains: alopecia areata is a T-cell-mediated autoimmune, nonscarring alopecia of anagen follicles with preserved potential for regrowth.

Androgenic Alopecia

Androgenic alopecia, also called androgenetic alopecia or “pattern hair loss,” is the most common cause of chronic, nonscarring hair loss. It is characterized by progressive miniaturization of terminal hairs into thin, short, hypopigmented vellus-like hairs in genetically susceptible scalp regions. It affects approximately 50% of men by age 50 and up to 40% of women by age 70. For USMLE Step 1, the key concept is that androgenic alopecia is an androgen-dependent, genetically influenced disorder of hair follicle cycling, not an inflammatory destruction of follicles.

Normal Hair Biology Relevant to Androgenic Alopecia

Scalp follicles normally cycle through anagen growth, catagen involution, and telogen resting phases. About 85–90% of scalp hairs are in anagen, <1% in catagen, and 10–15% in telogen. Normal daily shedding is approximately 50–100 hairs/day. In androgenic alopecia, the main abnormality is progressive shortening of anagen with relative lengthening of telogen, causing hairs to become smaller with each cycle.

Pathogenesis: DHT, Dermal Papilla Cells, and Follicular Miniaturization

The central hormone is dihydrotestosterone (DHT), formed from testosterone by 5-alpha-reductase. Type II 5-alpha-reductase is especially important in hair follicles and the prostate; type I is expressed in sebaceous glands and skin. DHT binds the intracellular androgen receptor in dermal papilla cells, altering transcription of growth-regulatory factors. High-yield downstream effects include increased inhibitory signaling such as TGF-β and DKK-1, which suppress Wnt/β-catenin-mediated follicular growth. The follicle progressively miniaturizes: shaft diameter decreases, anagen duration shortens, and the terminal-to-vellus hair ratio falls.

The pattern reflects regional follicular androgen sensitivity. Frontal, bitemporal, and vertex scalp follicles are DHT-sensitive, whereas occipital scalp follicles are relatively androgen-resistant; this explains both the classic pattern and why occipital hair is used for transplantation. Genetics are polygenic, with important associations involving the androgen receptor gene on the X chromosome, but inheritance is not purely Mendelian.

Clinical Patterns and Staging

Pattern	Typical Findings	Common Staging System
Male-pattern androgenic alopecia	Bitemporal recession, frontal hairline recession, and vertex thinning; occipital rim usually spared	Hamilton-Norwood scale: class I minimal recession to class VII severe frontotemporal and vertex loss with preserved occipital/parietal fringe
Female-pattern hair loss	Diffuse thinning over the crown with preservation of the frontal hairline; widening of the central part	Ludwig scale: I mild, II moderate, III severe diffuse crown thinning; Savin scale further grades central part widening

Women with androgenic alopecia often have normal circulating androgen levels because follicular sensitivity, not systemic androgen excess, may be the main abnormality. However, rapid onset, severe acne, hirsutism, virilization, menstrual irregularity, or clitoromegaly should prompt evaluation for hyperandrogenic states such as polycystic ovary syndrome or androgen-secreting tumors.

Histology and Diagnosis

Diagnosis is usually clinical. The scalp is noninflamed and nonscarred, with preserved follicular openings. Dermoscopy may show hair shaft diameter variability, miniaturized hairs, and increased single-hair follicular units. Biopsy, when needed, shows miniaturized follicles, increased vellus-like hairs, and a decreased terminal-to-vellus ratio. A normal scalp ratio is often approximately 7:1; in androgenic alopecia it may fall to <4:1. Unlike scarring alopecias, sebaceous glands and follicular ostia are preserved.

High-Yield Differential Diagnosis

Disorder	Key Distinguishing Feature
Telogen effluvium	Diffuse shedding after stressor, illness, childbirth, iron deficiency, or drug exposure; no patterned miniaturization
Alopecia areata	Autoimmune, sharply demarcated patches; exclamation-point hairs; may involve nails
Tinea capitis	Scaling, broken hairs, lymphadenopathy; dermatophyte infection
Traction alopecia	Hair loss at sites of chronic tension, commonly temporal margins

Pharmacology and Treatment Principles

Step 1 emphasis is on mechanism. Topical minoxidil is a potassium channel opener and vasodilator that prolongs anagen and enlarges miniaturized follicles. It is FDA-approved for male and female pattern hair loss. Common regimens are 5% foam or solution for men and 5% foam once daily or 2% solution twice daily for women; solution is commonly applied as 1 mL twice daily. Visible benefit typically requires 4–6 months, maximal assessment may require 12 months, and stopping therapy leads to loss of retained hair within months. Adverse effects include irritant or allergic contact dermatitis, hypertrichosis, and initial shedding during early follicle cycling.

Finasteride selectively inhibits type II 5-alpha-reductase, decreasing scalp and serum DHT. The dose for male androgenic alopecia is 1 mg orally once daily; its plasma half-life is approximately 6–8 hours, longer in older adults. It is contraindicated in pregnancy because DHT is required for normal male external genital development. Adverse effects include decreased libido, erectile dysfunction, decreased ejaculate volume, and gynecomastia; it also lowers prostate-specific antigen by about 50%. In pivotal trials, finasteride increased scalp hair counts over 1–2 years compared with progressive loss on placebo. Dutasteride inhibits type I and II 5-alpha-reductase, is more potent, has a long half-life of about 5 weeks, and is used off-label for hair loss in some settings.

Low-level laser therapy and hair transplantation may be used, but the core exam association remains: androgenic alopecia is a nonscarring, DHT-mediated miniaturization disorder with patterned involvement and preserved follicles.

Vitiligo

Vitiligo is an acquired disorder of pigmentation caused by selective loss of functioning melanocytes, producing sharply demarcated depigmented macules and patches. It affects approximately 0.5%–2% of the population, with about 50% of cases beginning before age 20 years. For USMLE Step 1, the key distinction is that vitiligo is a disorder of melanocyte destruction, whereas albinism is a disorder of melanin synthesis with melanocytes present.

Pathogenesis and Basic Science Mechanisms

Normal skin color depends on melanocytes in the basal epidermis synthesizing melanin within melanosomes and transferring melanosomes to keratinocytes. In vitiligo, melanocytes are absent or markedly reduced in affected skin. The dominant mechanism is autoimmune, mediated especially by CD8+ cytotoxic T cells targeting melanocyte antigens such as tyrosinase-related proteins. Interferon-γ released by T cells induces keratinocytes to produce CXCL9 and CXCL10, chemokines that recruit more CXCR3-positive T cells, amplifying melanocyte injury through the JAK-STAT pathway.

Additional contributing mechanisms include oxidative stress, defective melanocyte adhesion, and genetic susceptibility. Genome-wide studies link vitiligo to immune-regulatory loci, explaining its association with other autoimmune diseases. Histologically, vitiligo shows loss of melanocytes in the basal layer with little or no inflammation in stable lesions; active lesions may show a sparse lymphocytic infiltrate at the advancing edge.

Clinical Features and Classification

Lesions are classically well-circumscribed, chalk-white depigmented macules, often accentuated under a Wood lamp, which emits long-wave ultraviolet A light at approximately 365 nm. Common sites include the face, periorificial skin, dorsal hands, elbows, knees, axillae, genital skin, and areas of trauma. The Koebner phenomenon—new lesions at sites of skin injury—is high yield and reflects local immune activation after trauma.

Subtype	Pattern	High-yield associations
Nonsegmental vitiligo	Bilateral, symmetric; acrofacial, generalized, mucosal, or universal patterns	Most common; autoimmune associations; tends to relapse and progress
Segmental vitiligo	Unilateral, dermatomal or quasi-dermatomal distribution	Earlier onset; rapid initial spread then stabilization; less associated with systemic autoimmunity
Focal vitiligo	One or few localized patches not clearly segmental	May remain localized or evolve into nonsegmental disease

Associated Diseases and Screening Concepts

Vitiligo is strongly associated with autoimmune disease, especially autoimmune thyroid disease such as Hashimoto thyroiditis and Graves disease. Other associations include type 1 diabetes mellitus, pernicious anemia, Addison disease, alopecia areata, and autoimmune polyglandular syndromes. Thyroid autoantibodies are found in a significant minority of patients, and clinically apparent thyroid disease is reported in roughly 15%–25% depending on cohort. A normal adult TSH is commonly approximated as 0.4–4.0 mIU/L, though laboratory ranges vary. Step 1 questions may link vitiligo with other autoimmune findings such as anti-thyroid peroxidase antibodies or anti-intrinsic factor antibodies.

Diagnosis, Staging, and Differential Diagnosis

Diagnosis is usually clinical. Wood lamp examination helps distinguish complete depigmentation from hypopigmentation. Biopsy is rarely needed but would show absence of epidermal melanocytes on stains such as Melan-A or HMB-45.

Condition	Key distinction from vitiligo
Tinea versicolor	Hypopigmented or hyperpigmented scaly macules; Malassezia; KOH shows “spaghetti and meatballs”
Pityriasis alba	Ill-defined hypopigmented patches in children, often with atopic dermatitis
Postinflammatory hypopigmentation	History of preceding dermatitis, burn, infection, or procedure
Albinism	Congenital generalized hypopigmentation; melanocytes present but melanin synthesis impaired

Severity and activity can be quantified. The Vitiligo Area Scoring Index estimates body surface area involvement and degree of depigmentation; the F-VASI focuses on the face. The Vitiligo Disease Activity score ranges from +4 for disease active within the past 6 weeks to −1 for spontaneous repigmentation, helping distinguish unstable from stable disease.

Treatment Principles and Pharmacology

Therapy aims to suppress immune-mediated melanocyte destruction and stimulate repigmentation from residual melanocytes, especially in hair follicles. High-yield modalities include topical anti-inflammatory therapy and phototherapy.

Therapy	Mechanism and key numbers	Major adverse effects
Topical corticosteroids	Suppress cytokine transcription via glucocorticoid receptors; often used once daily for limited disease	Skin atrophy, striae, telangiectasias, hypothalamic-pituitary-adrenal suppression if extensive/high potency
Topical calcineurin inhibitors	Tacrolimus 0.03% or 0.1% ointment, often twice daily; blocks calcineurin-dependent NFAT activation and IL-2 transcription	Burning, irritation; useful on face/intertriginous areas because no skin atrophy
Narrowband UVB	Uses 311–313 nm light; induces local immunosuppression and melanocyte migration/proliferation	Erythema, burning; requires repeated sessions, commonly 2–3 times weekly
Excimer laser	Targeted 308 nm UVB for localized plaques	Blistering, hyperpigmentation
Topical ruxolitinib	1.5% JAK1/JAK2 inhibitor applied twice daily to nonsegmental vitiligo involving up to 10% BSA; interrupts IFN-γ/JAK-STAT signaling	Application-site acne/pruritus; boxed warnings extrapolated from systemic JAK inhibitors

In phase 3 TRuE-V1 and TRuE-V2 trials, approximately 29.8%–30.9% of patients receiving ruxolitinib cream achieved at least 75% improvement in F-VASI at week 24, compared with about 7.4%–11.4% with vehicle. Repigmentation is slow because melanocyte reservoirs must proliferate and migrate; meaningful improvement often requires months. Depigmentation therapy with agents such as monobenzone is reserved for extensive disease and is not a Step 1 management focus.

Melasma

Definition and Epidemiology

Melasma is an acquired disorder of facial hyperpigmentation characterized by symmetric, irregularly bordered, light-to-dark brown macules and patches. It is sometimes called chloasma when associated with pregnancy. It is common in individuals with Fitzpatrick skin types III–V and is far more frequent in women than men, with female-to-male ratios often reported around 9:1. Classic triggers include ultraviolet radiation, visible light, pregnancy, oral contraceptives, hormone therapy, and genetic predisposition.

Basic Science Mechanism

Melasma is a disorder of increased melanogenesis, not a primary malignant proliferation of melanocytes. Melanocytes, derived embryologically from the neural crest, reside in the basal epidermis and synthesize melanin within melanosomes, which are transferred to surrounding keratinocytes. The key rate-limiting enzyme is tyrosinase, which converts tyrosine to DOPA and then dopaquinone, initiating melanin synthesis.

Ultraviolet radiation stimulates pigmentation through several pathways. UVB radiation is approximately 280–320 nm and induces keratinocyte DNA damage, activating p53 and increasing transcription of pro-opiomelanocortin, which is cleaved to α-melanocyte-stimulating hormone. α-MSH binds MC1R on melanocytes, increasing cAMP and upregulating tyrosinase. UVA radiation is approximately 320–400 nm and contributes to oxidative stress and dermal photoaging. Visible light, approximately 400–700 nm, especially blue-violet wavelengths, can also worsen pigmentation, particularly in darker skin types.

Hormonal factors are high yield: estrogen and progesterone can enhance melanocyte activity, explaining associations with pregnancy and estrogen-containing oral contraceptives. Histology may show increased epidermal melanin, prominent melanophages in the dermis, solar elastosis, basement membrane disruption, increased vascularity, and mast cell infiltration. Thus, melasma has both pigmentary and photoaging/dermal inflammatory components.

Clinical Patterns and Classification

Classification	Subtypes	High-Yield Features
Anatomic pattern	Centrofacial, malar, mandibular	Centrofacial is most common; involves forehead, cheeks, upper lip, nose, and chin.
Pigment depth	Epidermal, dermal, mixed, indeterminate	Epidermal melasma is brown and usually responds best to topical therapy; dermal pigment appears gray-brown or blue-gray.
Wood lamp assessment	Accentuation versus no accentuation	Wood lamp emits near-UVA light at about 365 nm; epidermal pigment may accentuate, dermal pigment often does not. Accuracy is reduced in darker skin.

Scoring and Severity Assessment

The classic research scoring system is the Melasma Area and Severity Index or MASI. It assesses four facial regions: forehead, right malar, left malar, and chin. Each region is scored for area, darkness, and homogeneity, with weighted contributions based on relative facial surface area. The maximum MASI score is 48. A simplified version, the modified MASI, removes homogeneity and is often used clinically and in trials. For Step 1, the key point is that melasma severity can be quantified by area and pigment intensity, but diagnosis is primarily clinical.

Differential Diagnosis

Condition	Distinguishing Clue
Postinflammatory hyperpigmentation	Occurs at sites of preceding acne, dermatitis, burns, or trauma.
Solar lentigines	Discrete, well-circumscribed “sun spots” on chronically sun-exposed skin.
Freckles	Small ephelides that darken with sun exposure; often childhood onset.
Exogenous ochronosis	Blue-black pigmentation, classically after prolonged hydroquinone use.
Addison disease	Diffuse hyperpigmentation including mucosa and palmar creases due to elevated ACTH/POMC derivatives.

Pharmacology and Treatment Principles

The foundational intervention is photoprotection. Patients should use broad-spectrum sunscreen with SPF 30 or higher; SPF primarily reflects protection against UVB erythema. Because visible light worsens melasma, tinted sunscreens containing iron oxides are particularly useful, as they block visible wavelengths better than standard transparent sunscreens.

Therapy	Typical Dose/Use	Mechanism and Adverse Effects
Hydroquinone	2–4% topical, usually once nightly	Inhibits tyrosinase and damages melanosomes. Adverse effects include irritation, contact dermatitis, hypopigmentation, and rare exogenous ochronosis with prolonged use.
Triple combination cream	Fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%, applied nightly for limited courses, often about 8 weeks	Combines tyrosinase inhibition, increased keratinocyte turnover, and anti-inflammatory effect. Steroid-related risks include atrophy, telangiectasia, and acneiform eruption if overused.
Azelaic acid	15–20% topical	Inhibits tyrosinase and has anti-inflammatory effects; often preferred when retinoids or hydroquinone are avoided.
Tranexamic acid	Common oral regimen: 250 mg twice daily; topical preparations often 2–5%	Antifibrinolytic that inhibits plasminogen activation; may reduce UV-induced melanocyte stimulation. Oral half-life is approximately 2–3 hours; use is limited by thromboembolic risk and contraindications.

Chemical peels and lasers can improve selected cases but may worsen pigmentation through irritation-induced inflammation, especially in darker skin types. In pregnancy, strict photoprotection is emphasized; topical retinoids are avoided, and therapies are chosen cautiously because melasma often improves postpartum but may recur with future hormonal exposure or ultraviolet/visible light exposure.

Albinism

Definition and Core Pathophysiology

Albinism refers to inherited disorders of reduced or absent melanin production in the skin, hair, and/or eyes. The key Step 1 distinction is that most forms have a normal number of melanocytes; the defect is in melanin synthesis, melanosome function, or melanosome transport. This contrasts with vitiligo, in which melanocytes are destroyed.

Melanin is produced in melanosomes, specialized organelles within melanocytes. Melanocytes are derived from the neural crest and transfer melanosomes to surrounding keratinocytes. The rate-limiting enzyme in melanin synthesis is tyrosinase, a copper-containing enzyme that catalyzes:

• Tyrosine → L-DOPA
• L-DOPA → dopaquinone

Dopaquinone is then directed toward eumelanin production, which is brown-black and photoprotective, or pheomelanin production, which is yellow-red and less photoprotective. Because melanin absorbs ultraviolet radiation, deficient melanin markedly increases susceptibility to actinic damage and cutaneous malignancy.

Major Classifications

Albinism is broadly divided into oculocutaneous albinism, involving skin, hair, and eyes, and ocular albinism, primarily involving the eyes. Most oculocutaneous forms are autosomal recessive.

Type	Gene / Defect	Inheritance	High-yield features
OCA1A	TYR; complete absence of tyrosinase activity	Autosomal recessive	White hair and very pale skin from birth; no tanning; pigment remains absent throughout life
OCA1B	TYR; partial tyrosinase activity	Autosomal recessive	Some pigment develops over time; may tan slightly
OCA2	OCA2 gene; abnormal melanosomal pH and tyrosinase processing	Autosomal recessive	Most common worldwide; more pigment than OCA1A; common in some African populations
OCA3	TYRP1	Autosomal recessive	“Rufous” albinism: reddish-brown skin and hair, classically described in darker-skinned populations
OCA4	SLC45A2; melanosome transporter	Autosomal recessive	Phenotypically similar to OCA2; relatively more common in East Asian populations
Ocular albinism type 1	GPR143; abnormal melanosome biogenesis	X-linked	Predominantly ocular findings; skin and hair may appear near normal

Clinical Findings

Cutaneous findings include diffuse hypopigmentation of the skin and hair, with severity depending on residual melanin production. Hair may be white, yellow, blond, light brown, or reddish. The eyes are often involved even when skin findings are mild, making ocular signs particularly high yield.

• Photophobia: reduced iris pigment allows excess light entry.
• Nystagmus: often congenital and horizontal.
• Reduced visual acuity: commonly due to foveal hypoplasia.
• Iris transillumination: light passes through a hypopigmented iris on slit-lamp examination.
• Strabismus and impaired binocular vision.
• Optic pathway misrouting: excessive crossing of retinal ganglion cell axons at the optic chiasm; a classic neurodevelopmental consequence of reduced ocular melanin.

The increased skin cancer risk reflects loss of melanin’s UV-absorbing function. UVB wavelengths are approximately 280–320 nm and are strongly associated with sunburn and DNA pyrimidine dimer formation; UVA wavelengths are approximately 320–400 nm and penetrate more deeply, contributing to photoaging and carcinogenesis. Patients with albinism are at increased risk of actinic keratoses, squamous cell carcinoma, basal cell carcinoma, and melanoma, especially with chronic sun exposure.

Syndromic Albinism: Step 1 Associations

Some disorders combine hypopigmentation with defects in lysosome-related organelles. These are especially important because they link pigmentation with immunology, hematology, and cell biology.

Syndrome	Gene / Mechanism	Key associated findings
Hermansky-Pudlak syndrome	Defective biogenesis of lysosome-related organelles; platelet dense granule deficiency	Oculocutaneous albinism, bleeding diathesis due to impaired platelet aggregation, pulmonary fibrosis, granulomatous colitis
Chediak-Higashi syndrome	LYST mutation; defective phagolysosome formation and microtubule-dependent trafficking	Partial albinism, recurrent pyogenic infections, peripheral neuropathy, giant granules in neutrophils, impaired NK cell function
Griscelli syndrome	Defects in melanosome transport, classically involving RAB27A, MYO5A, or MLPH	Silvery-gray hair; variable neurologic disease and immune dysfunction depending on subtype

Diagnosis and Prevention-Focused Management

Diagnosis is usually clinical and supported by ophthalmologic findings and genetic testing. There is no formal staging system analogous to cancer staging; severity is described by genotype, residual pigmentation, ocular involvement, and complications. Skin biopsy is generally not needed for classic presentations.

No medication reliably restores normal melanin production in inherited albinism. Management is therefore preventive and supportive. High-yield measures include broad-spectrum sunscreen, protective clothing, hats, and UV-blocking sunglasses. SPF 30 blocks approximately 97% of UVB radiation, whereas SPF 50 blocks approximately 98%; sunscreen should be applied generously and reapplied about every 2 hours during sun exposure and after swimming or sweating. Regular dermatologic surveillance is important because early recognition of premalignant and malignant lesions reduces morbidity. Ophthalmologic care addresses refractive error, low-vision support, strabismus, and photophobia.

For Step 1, remember the core pattern: normal melanocyte number with impaired melanin synthesis or melanosome biology, autosomal recessive inheritance for most oculocutaneous types, prominent ocular abnormalities, and increased UV-induced skin cancer risk.