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Summary Table

Category	Details
Risk Factors	Family history of albinism, consanguineous parents, certain ethnic populations (OCA2 more prevalent in sub-Saharan African populations; OCA1 distributed worldwide)
Etiology	Inherited defects in melanin biosynthesis pathway, most commonly mutations in the TYR gene (tyrosinase enzyme) for OCA1 or the OCA2/P gene for OCA2
Patient Presentation	Hypopigmented or absent pigmentation of skin, hair, and eyes from birth; parents report the child has poor vision, light sensitivity, and involuntary eye movements
Classic Physical Exam	White or very light hair, pale skin, iris transillumination, nystagmus, strabismus, foveal hypoplasia on fundoscopy, photophobia
Key Diagnostic Results	Clinical diagnosis based on phenotype and ophthalmologic exam; genetic testing confirms the subtype; skin biopsy shows melanocytes present but with reduced or absent melanin; hair bulb incubation test (historical) distinguishes tyrosinase-positive from tyrosinase-negative forms
Management	Strict photoprotection (broad-spectrum sunscreen, protective clothing), routine dermatologic surveillance for premalignant and malignant skin lesions, ophthalmologic correction (glasses, low-vision aids), genetic counseling
Keywords	"White hair since birth," "nystagmus," "photophobia," "iris transillumination," "tyrosinase deficiency," "autosomal recessive," "melanocytes present but no melanin," "increased skin cancer risk"

1. Pathophysiology

Albinism is a group of autosomal recessive (in most forms) genetic disorders resulting from defective melanin biosynthesis. The critical concept to understand is that melanocytes are present in normal numbers, but they cannot produce melanin properly. This distinguishes albinism from vitiligo, where melanocytes are destroyed or absent.

The melanin synthesis pathway begins with the amino acid tyrosine. The enzyme tyrosinase catalyzes the rate-limiting step: the hydroxylation of tyrosine to DOPA (dihydroxyphenylalanine) and then the oxidation of DOPA to dopaquinone. From dopaquinone, the pathway branches into eumelanin (brown-black pigment) and pheomelanin (red-yellow pigment). In OCA1, the TYR gene encoding tyrosinase is mutated, leading to complete (OCA1A) or partial (OCA1B) loss of enzyme activity. When tyrosinase is completely absent, no melanin of any type can be formed, producing the most severe phenotype with snow-white hair, milky skin, and blue-gray irides.

In OCA2, the second most common form, the defect lies in the OCA2 (P) gene, which encodes a melanosomal transmembrane protein involved in pH regulation of the melanosome. Melanosomes require an acidic environment for optimal tyrosinase function. When the P protein is dysfunctional, melanosomal pH is disrupted, and melanin production is reduced but not entirely abolished. This is why OCA2 patients often retain some pigment, and pigmentation may increase slightly with age.

The ocular findings in albinism are explained by the role of melanin in eye development. During embryogenesis, retinal pigment epithelium (RPE) melanin is required for proper development of the fovea and for correct routing of optic nerve fibers at the optic chiasm. Without adequate melanin, foveal hypoplasia occurs (the foveal pit fails to develop normally), which accounts for the permanently reduced visual acuity. Additionally, there is misrouting of the optic nerve fibers: an excessive proportion of temporal retinal fibers cross at the chiasm to the contralateral hemisphere, resulting in abnormal binocular vision and contributing to nystagmus and strabismus. This misrouting can be detected by visual evoked potentials (VEPs), which show asymmetric responses.

The lack of melanin in the iris means the iris cannot block light effectively, producing iris transillumination on slit-lamp examination. The iris appears translucent or reddish because light passes through the poorly pigmented stroma and reflects off the retinal vasculature.

From a dermatologic standpoint, melanin normally serves as a natural photoprotectant by absorbing ultraviolet (UV) radiation and scavenging free radicals. Without this shield, patients with albinism suffer cumulative UV-induced DNA damage. This explains the dramatically elevated risk of squamous cell carcinoma and other UV-related skin malignancies, particularly in tropical regions with high sun exposure.

2. Classification and Clinical Manifestation

Oculocutaneous Albinism (OCA) Subtypes

Subtype	Gene / Protein	Inheritance	Skin & Hair	Ocular Findings	Distinguishing Features
OCA1A	TYR / Tyrosinase (complete loss)	AR	Snow-white hair and skin throughout life; no pigment development	Severe: nystagmus, foveal hypoplasia, iris transillumination, visual acuity often 20/200 or worse	Most severe form; no melanin production at all; hair bulb tyrosinase-negative
OCA1B	TYR / Tyrosinase (reduced activity)	AR	White hair at birth; may develop yellow or light brown pigment over time	Moderate to severe	Some residual tyrosinase activity; pigment may accumulate with age ("yellow albinism")
OCA2	OCA2 (P gene) / P protein	AR	Variable; cream to light tan skin; yellow to light brown hair	Moderate	Most common form worldwide; most common in African populations; pigmented nevi may develop
OCA3	TYRP1 / Tyrosinase-related protein 1	AR	Reddish-brown skin and ginger-red hair	Mild to moderate	Previously called "rufous albinism"; primarily described in African populations
OCA4	SLC45A2 / MATP	AR	Variable; similar to OCA2	Moderate	More common in East Asian populations, particularly Japanese

Syndromic Forms of Albinism

Syndrome	Gene	Key Associated Features	Why It Is Tested
Hermansky-Pudlak Syndrome (HPS)	Multiple HPS genes (HPS1 through HPS10)	OCA + bleeding diathesis (platelet storage pool deficiency) + pulmonary fibrosis + granulomatous colitis	Vignette: albino patient with easy bruising, prolonged bleeding, or restrictive lung disease; platelet dense granule deficiency on electron microscopy
Chediak-Higashi Syndrome (CHS)	LYST / CHS1	OCA + recurrent pyogenic infections + peripheral neuropathy + "accelerated phase" (hemophagocytic lymphohistiocytosis)	Vignette: albino child with recurrent bacterial infections; peripheral smear shows giant cytoplasmic granules in neutrophils and other leukocytes
Griscelli Syndrome	RAB27A, MYO5A, MLPH	Silvery-gray hair + immunodeficiency (type 2) or neurologic impairment (type 1)	Hair shaft microscopy shows large, irregular melanin clumps (vs. even distribution in normal hair)

Ocular Albinism

Type	Gene	Inheritance	Key Feature
OA1 (Nettleship-Falls)	GPR143	X-linked recessive	Ocular findings only (nystagmus, foveal hypoplasia, iris transillumination); skin and hair pigmentation is grossly normal; carrier females may show a mosaic "mud-splattered" fundus pattern

3. Diagnostic Workup

Test	Role	Expected Finding
Clinical examination	Best initial assessment	Hypopigmentation of skin/hair/eyes; nystagmus; photophobia
Ophthalmologic exam (slit lamp + fundoscopy)	Essential initial workup	Iris transillumination, foveal hypoplasia, optic nerve misrouting signs
Visual evoked potentials (VEP)	Supportive / confirmatory for optic misrouting	Asymmetric cortical responses indicating excessive decussation at chiasm
Genetic / molecular testing	Gold standard / confirmatory	Identifies the causative gene mutation and determines the exact subtype
Skin biopsy (if performed)	Rarely needed; supports diagnosis	Melanocytes present in normal number; melanosomes reduced or poorly melanized
Hair bulb incubation test	Historical / rarely used today	OCA1A: no pigment formed when hair bulb incubated with tyrosine; OCA1B/OCA2: some pigment develops
Platelet electron microscopy	If HPS suspected	Absent platelet dense bodies
Peripheral blood smear	If CHS suspected	Giant granules in leukocytes

The diagnosis of albinism is primarily clinical. When a newborn or infant presents with generalized hypopigmentation of skin, hair, and eyes, accompanied by nystagmus and photophobia, the diagnosis is usually apparent. The ophthalmologic examination is a cornerstone of the initial workup: slit-lamp evaluation reveals iris transillumination defects, and fundoscopy demonstrates foveal hypoplasia (absence of the normal foveal light reflex and underdeveloped foveal pit). These ocular findings are present in essentially all forms of albinism, including OCA and ocular albinism.

Genetic testing has become the confirmatory standard. Targeted gene panel testing or whole exome sequencing identifies the causative mutation, which is important for three reasons: (1) it confirms the subtype and provides prognostic information, (2) it enables accurate genetic counseling for the family regarding recurrence risk, and (3) it distinguishes syndromic from non-syndromic forms. For example, identifying an HPS gene mutation alerts clinicians to screen for bleeding complications and pulmonary fibrosis.

If a syndromic form is suspected clinically, additional targeted workup is necessary. A patient with albinism and unexplained bruising or prolonged bleeding time should raise suspicion for Hermansky-Pudlak syndrome; platelet aggregation studies will show absent secondary aggregation wave, and electron microscopy of platelets confirms absent dense granules. A patient with albinism and recurrent severe bacterial infections warrants a peripheral smear looking for the pathognomonic giant cytoplasmic granules of Chediak-Higashi syndrome.

The hair bulb incubation test is now largely of historical interest but is still occasionally referenced: a plucked hair bulb is incubated with L-tyrosine or L-DOPA. In OCA1A, no pigment forms (tyrosinase-negative). In OCA1B and OCA2, some pigment develops (tyrosinase-positive). This test has been largely replaced by molecular diagnostics.

4. Management and Treatment

Domain	Intervention	Details
Skin protection	Broad-spectrum sunscreen (SPF 30+)	Apply to all exposed skin, reapply every 2 hours during sun exposure; UVA + UVB coverage
Skin protection	Protective clothing, wide-brimmed hats, UV-blocking sunglasses	Physical barriers are preferred as first-line photoprotection
Dermatologic surveillance	Routine skin exams	Annual full-body skin examination (more frequent in high-risk settings such as tropical climates); biopsy suspicious lesions early
Ophthalmologic care	Refractive correction	Glasses or contact lenses for refractive error; low-vision aids as needed
Ophthalmologic care	Strabismus management	Patching, prism lenses, or surgical correction if indicated
Ophthalmologic care	Tinted or photochromic lenses	Reduces photophobia and glare
Genetic counseling	Family counseling	AR inheritance: 25% recurrence risk for each pregnancy if both parents are carriers
Syndromic management (HPS)	Avoid antiplatelet agents; desmopressin (DDAVP) for bleeding; monitor pulmonary function	Pulmonary fibrosis (in HPS-1 and HPS-4) may require pirfenidone; platelet transfusion for severe bleeding
Syndromic management (CHS)	Bone marrow transplantation	Only curative therapy for the immunologic and hematologic defects of CHS; must be performed before the "accelerated phase"

There is no cure for albinism, and no treatment restores normal melanin production.

Management is entirely supportive and preventive.

Photoprotection is the single most important intervention for long-term morbidity and mortality. In tropical and equatorial regions, where UV exposure is intense and sustained, patients with albinism face a dramatically elevated lifetime risk of actinic keratoses, squamous cell carcinoma, and basal cell carcinoma. Many affected individuals in sub-Saharan Africa develop skin cancers before age 30. Broad-spectrum sunscreen with a minimum SPF of 30 should be applied daily to all exposed areas, with reapplication every 2 hours during outdoor activities. Physical barriers (long sleeves, hats, UV-protective sunglasses) are equally or more important than chemical sunscreens and should be used consistently.

Ophthalmologic management focuses on optimizing visual function, since foveal hypoplasia and optic misrouting cause permanent visual impairment that cannot be corrected surgically. Refractive errors (commonly high astigmatism and hyperopia) should be corrected with appropriate lenses. Low-vision aids, large-print materials, preferential classroom seating, and educational accommodations are often necessary. Nystagmus may diminish slightly with age but does not resolve. Strabismus surgery may be considered for cosmetic or functional benefit.

For Hermansky-Pudlak syndrome, the bleeding diathesis requires avoidance of aspirin and NSAIDs (which further impair platelet function). DDAVP (desmopressin, 0.3 mcg/kg IV) can be used preoperatively or during bleeding episodes to improve hemostasis. Platelet transfusions are reserved for severe or life-threatening hemorrhage. Patients with HPS subtypes 1 and 4 should undergo baseline and serial pulmonary function testing, as progressive pulmonary fibrosis is a leading cause of death in these subtypes. Pirfenidone has been studied as an antifibrotic agent in this context.

For Chediak-Higashi syndrome, the only curative treatment for the immunologic defect is allogeneic hematopoietic stem cell transplantation (HSCT). This should ideally be performed early, before the onset of the "accelerated phase" (hemophagocytic lymphohistiocytosis), which carries high mortality. HSCT corrects the immune deficiency and hematologic abnormalities but does not reverse the oculocutaneous albinism or the progressive neurologic decline.

5. Differential Diagnosis and Distractors

DifferentiaL	Why It Is Similar	Key Discriminator
Vitiligo	Both present with depigmented skin	Vitiligo is acquired, typically patchy, and has absent melanocytes on biopsy; albinism is congenital, generalized, and melanocytes are present but non-functional. Vitiligo has no ocular findings.
Piebaldism	Congenital depigmented patches	Piebaldism shows a white forelock and well-demarcated depigmented patches with a characteristic distribution; it is autosomal dominant (KIT gene). No ocular involvement. The depigmentation is localized, not generalized.
Waardenburg Syndrome	Congenital pigmentary changes + potential hearing loss	Features include heterochromia iridis, white forelock, sensorineural hearing loss, and lateral displacement of medial canthi (dystopia canthorum). Pigmentary changes are patchy, not generalized. Autosomal dominant inheritance.
Phenylketonuria (PKU)	Fair skin, light hair, blue eyes	PKU is caused by phenylalanine hydroxylase deficiency, leading to reduced melanin (since phenylalanine competitively inhibits tyrosine uptake). However, PKU also presents with intellectual disability, musty body odor, eczema, and seizures. Newborn screening detects elevated phenylalanine.
Angelman Syndrome	Hypopigmentation in some cases	Deletion of 15q11-q13 (maternal) can include the OCA2 gene, causing mild hypopigmentation. However, Angelman also features severe intellectual disability, seizures, ataxia, "happy puppet" demeanor, and absent speech.
Tuberous Sclerosis (ash-leaf spots)	Hypopigmented skin lesions in a child	Ash-leaf macules are localized, not generalized; other features include seizures, angiofibromas, shagreen patches, cortical tubers. Wood lamp exam highlights the macules.
Chediak-Higashi vs. isolated OCA	Both present with oculocutaneous albinism	CHS is distinguished by recurrent infections and giant granules on smear; isolated OCA has no immunodeficiency or hematologic abnormality.

6. Traps and High-Yield Pearls

The most common way students lose points on albinism questions is by failing to recognize the syndromic forms. A straightforward vignette of a pale child with nystagmus is easy. The trap comes when the test-writer adds a second feature: "easy bruising" (think Hermansky-Pudlak) or "recurrent skin abscesses" (think Chediak-Higashi). Students who do not link these associated findings to the underlying albinism will miss the diagnosis entirely or select an incomplete answer.

Another frequent error is confusing albinism with vitiligo. Both involve hypopigmentation, but the distinction is fundamental: albinism is congenital and generalized with melanocytes present; vitiligo is acquired and patchy with melanocytes absent. If the vignette describes a child who was "normal at birth and developed white patches over time," that is vitiligo, not albinism.

Students also sometimes overlook that ocular findings are universal in albinism and are often the clue that distinguishes it from other causes of congenital hypopigmentation. If a fair-skinned child has nystagmus, foveal hypoplasia, and iris transillumination, the diagnosis is albinism regardless of the degree of cutaneous pigment reduction.

Finally, remember that the inheritance of most OCA forms is autosomal recessive, meaning both parents are typically unaffected carriers. The exception tested most often is ocular albinism type 1 (Nettleship-Falls), which is X-linked recessive, so it predominantly affects males while carrier females may show subtle mosaic fundus findings. When a vignette describes an affected boy with a maternal uncle who has similar ocular problems but normal skin, think X-linked ocular albinism.

The core competency being tested is the ability to (1) recognize the clinical phenotype of albinism, (2) correctly identify the associated syndromic conditions based on additional clinical clues, and (3) understand the genetic basis and inheritance pattern well enough to provide accurate counseling and predict recurrence risk.

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