Disorders of Pigmentation

Skin pigmentation serves as the body’s defense against ultraviolet rays.

It also holds cultural and social significance and may determine an individual’s station in life.

Disorders of pigmentation can understandably provoke anxiety.

Skin color is a result of a mix of pigments including melanin, oxyhemoglobin (in blood), and carotene (in the stratum corneum and subcutaneous fat).

These disorders can be hyperpigmented or hypopigmented.

They can also be generalized or patchy.

Generalized hypopigmentation is associated with conditions like albinism, phenylketonuria, and hypopituitarism.

Patchy loss occurs in cases such as vitiligo, after inflammation, post-exposure to certain chemicals, and with certain infections.

Pathologic changes can be congenital, as in giant congenital nevi, or acquired, as in vitiligo.

• Neural crest derived cells migrate to the epidermis during early embryonic development.
• They produce melanin pigment that absorbs and scatters UV rays while acting as a free radical scavenger.
• Important in CNS development.
• They are primarily located in the basal layer, with dendritic processes extending to the spinous layers.

Physiology of Melanogenesis

• An epidermal unit is formed by maintaining a consistent relationship between a melanocyte and approximately 36 keratinocytes.
• Melanin is synthesized within a membrane-bound organelle called the melanosome.
• Tyrosinase is a rate-limiting enzyme in the production of melanin.
• The end-product is eumelanin, a brown substance.

Pheomelanin is an alternative form of melanin that is red/yellow in color and results from the interaction of cysteine with dopaquinone.

Following production, transfer of melanin occurs via the dendrites of melanocytes to the keratinocytes and is eventually sloughed off as melanin dust in the epidermis.

Components of Normal Skin Color

Characteristic	Black Skin	Light Skin
Tyrosinase activity	↑	↓
Melanizing melanocytes	↑	↓
Melanosomes	↑	↓
Melanosomes Size	Larger	Smaller
Arrangement of Melanosomes	Singly distributed	Occur in clumps
Melanin Type	Eumelanin	Pheomelanin

Causes of Hypopigmentation

Cause	Example
Chemicals	Hydroquinone, Substituted phenols
Endocrine	Hypopituitarism
Genetic	Phenylketonuria, Albinism, Tuberous sclerosis, Piebaldism
Infection	Pityriasis versicolor, Leprosy, Yaws
Post-Inflammatory	Eczema, Cryotherapy
Others	Vitiligo, Halo nevus

Albinism is an autosomal recessive condition in which the melanocytes fail to synthesize pigment in the epidermis, hair bulb, and eye.

There are several syndromes of albinism, all of which are autosomal recessive and show a lack of pigment in the skin, hair, iris, and retina.

Melanocyte numbers are normal, but melanosom production fails due to defective gene control of tyrosinase.

Clinical Presentation

• The skin is white or pink, the hair white, and pigmentation is lacking in the eye.
• Albinos have poor sight, photophobia, and nystagmus.
• In the tropics, albinos risk premature skin photoaging and the early onset of skin tumors, especially squamous cell carcinomas.

Classification/Types

Albinism is classified into two main groups: oculocutaneous albinism (OCA) and ocular albinism (OA).

Oculocutaneous Albinism (OCA)

• OCA is the most common type of albinism.
• Affects the skin, hair, and eyes.
• People with OCA have:
• Very pale skin
• White or blonde hair
• Pink eyes
• They may also have vision problems:
• Nystagmus (involuntary eye movements)
• Strabismus (crossed eyes)
• Photophobia (sensitivity to light)
• There are four types of OCA:
• OCA1: Most severe. Very little or no melanin production. Severe vision problems.
• OCA2: Milder. Some melanin production. Lighter skin, blonde/light brown hair. Some vision problems.
• OCA3: Caused by TYRP1 gene mutation. More melanin production. Light skin/hair, blue/brown eyes. Some vision problems.
• OCA4: Rarest. Some melanin production but less efficient. Light skin/hair, blue/brown eyes. Some vision problems.

Ocular Albinism (OA)

• OA affects only the eyes.
• People with OA have normal skin and hair color.
• They have vision problems:
• Nystagmus
• Strabismus
• Photophobia
• There are three types of OA:
• OA1: Most common. Caused by GPR143 gene mutation.
• OA2: Caused by OCA2 gene mutation.
• OA3: Caused by SLC45A2 gene mutation.

In addition to OCA and OA, there are other types of albinism:

• Hermansky-Pudlak Syndrome: Rare genetic disorder affecting skin, eyes, platelets. Pale skin, light hair, nystagmus, bleeding disorder.
• Chediak-Higashi Syndrome: Rare genetic disorder affecting skin, eyes, immune system. Pale skin, light hair, nystagmus, weakened immune system.

Oculocutaneous Albinism

Oculocutaneous Albinism Type 1

• Type 1A: Complete absence of pigment in the skin, hair, and eyes.
• Type 1B: Moderate pigmentation in these tissues or pigment in hair follicles of cooler areas of the body, such as the arms and legs (termed OCA type 1TS, i.e., temperature sensitive).
• All forms of type 1 present with:
• Photophobia
• Moderate-to-severe reduced visual acuity
• Nystagmus
• The latter two ocular dysfunctions result from a misrouting of the optic fibers from the retina to the visual cortex of the brain.
• The genetic defect is in the gene encoding for the tyrosinase enzyme, located on the long arm of chromosome 11.

Oculocutaneous Albinism Type 2

• Does not present with complete absence of pigment.
• Manifests with a minimal-to-moderate amount of pigment remaining in the skin, hair, and eyes.
• Common in Africans.
• Many patients develop pigmented freckles, lentigines, and/or nevi with age.
• The ocular presentations are similar to those in oculocutaneous albinism type 1.
• The defect is in the p gene, which is located on the long arm of chromosome 15.
• This gene produces the p protein, which is involved in the transport of tyrosine across the melanosome membrane.

Ocular Albinism

• Albinism is limited to the eyes.
• All the eye findings of albinism are present.
• Skin and hair color are within normal limits but are usually lighter than those in non-affected siblings.
• At least three forms of this condition (OA1, OA2, and OA3) have been reported.

Ocular Albinism 1 (OA1 Nettleship-Falls Type)

• In this form, only the hemizygote male has the complete manifestation.
• Some abnormal pigmentation of the retina may be present in heterozygote carriers.
• The gene for this condition is located on the short arm of the X chromosome.

Other Forms of Albinism

Hermansky-Pudlak Syndrome

• Tyrosinase-positive oculocutaneous albinism
• Platelet dysfunction (owing to the absence of platelet-dense bodies) and an accumulation of a ceroid-like material in tissues.
• The degree of albinism is variable. The condition is most prevalent in Puerto Rico.
• Bleeding tendencies, often manifested as epistaxis, and a prolonged bleeding time are common.
• The accumulation of this material in tissues results in restrictive lung disease, inflammatory bowel disease, kidney failure, and cardiomyopathy during the 3rd or 4th decade of life.
• The basic defect is thought to be a membrane abnormality involving melanosomes, lysosomes, and platelet-dense bodies.

Chédiak-Higashi Syndrome

• Patients with this rare autosomal recessive condition have partial albinism.
• Susceptibility to infection with the presence of giant peroxidase-positive lysosomal granules in granulocytes.
• These patients have a reduced number of melanosomes, which are abnormally large (macromelanosomes).
• Patients who survive early childhood may develop a lymphofollicular malignancy.

Cross-McKusick-Breen Syndrome

• Consists of tyrosinase-positive albinism with ocular abnormalities, retardation, spasticity, and athetosis.
• Some patients have darkly pigmented hairs distributed among hair without color in the eyebrows and eyelashes.

Investigations

The Hair bulb tyrosinase assay is used to differentiate between oculocutaneous albinism type 1 and the other forms of albinism.

Scalp hair bulbs are gently plucked from the patient and placed in a 0.1% solution of L-dihydroxyphenylalanine (L-DOPA) for up to 4 hours.

If the sample is from a patient with oculocutaneous albinism type 1, the hair bulbs remain white.

In contrast, samples from all other forms of albinism turn dark during the incubation period.

Complications

• Actinic keratoses
• Cancers – squamous cell cancer

Management

• Strict sun avoidance is essential.
• Wearing opaque clothing, a wide-brimmed hat, and using sunscreens are necessary.
• Prenatal diagnosis is possible.

Vitiligo is a common cause of acquired hypomelanosis characterized by depigmented white patches on the skin. This is due to the destruction of melanocytes, and similar depigmentation can be found in the mucous membranes and eyes.

Epidemiology

• Has been found in all cultures.
• Affects 0.5 – 2% of the world population.
• Prevalence of 1% in the United States.
• Equal affectation of both sexes.
• Commonly found in the younger age group between 10-30 years.

Aetiology

• Aetiology is unknown.
• Evidence to support melanocyte destruction is strong.
• Autoimmune theory appears to be the most widely accepted due to associations with pernicious anemia, thyroid disease, and Addison's disease.
• Neurogenic and self-destruct theories.

Clinical Presentation

• Vitiligo manifests as acquired white or hypopigmented macules or patches.
• The lesions are usually well-demarcated and can be round, oval, or linear in shape.
• Lesions can be generalized or localized, with the former being more common.
• Occasionally, almost the entire surface area is affected, referred to as total vitiligo.
• The most common sites of involvement include the face, neck, and scalp. Many common sites are areas subjected to repeated trauma, including:
• Bony prominences
• Extensor forearm
• Ventral wrists
• Dorsal hands
• Digital phalanges
• Vitiligo often occurs around body orifices such as the lips, genitals, gingiva, areolas, and nipples.
• Trichrome vitiligo - white, light brown, dark brown.
• Koebner’s phenomenon.
• Inflammatory vitiligo - pruritic, elevated erythematous margin.

Patterns

• Focal vitiligo: one or several macules in a single site
• Generalized vitiligo: more common, widespread distribution, usually symmetrical
• Segmental vitiligo: develops in one unilateral region and does not extend beyond that region.

Associated Findings

• Poliosis
• Alopecia areata
• Halo nevi
• Chorioretinitis/iritis
• Addison’s disease
• Diabetes mellitus
• Graves’ disease/Hashimoto’s thyroiditis

Laboratory Investigations

• The diagnosis is mainly clinical but biopsy may be helpful to distinguish from other differentials.
• Biopsy – normal skin with absence of melanocytes, lymphocytes in epidermis.
• Wood’s lamp is used to inspect it, especially in light-skinned people.
• Screening for other autoimmune disorders may be necessary.

Course and Prognosis

• Chronic disorder.
• Course is highly variable.
• Typically, initial rapid progression with subsequent stability.
• Spontaneous repigmentation can occur, especially with exposure to the sun.

Management

• Treatment is highly variable and individualized.
• Camouflage cosmetics can be applied.
• Sunscreens help the lightly pigmented patient by reducing the tanning and contrast of the non-vitiligo areas.

Repigmentation

• Topical steroids: Class I ointments.
• Topical calcineurin inhibitors: for sun-exposed areas, e.g. tacrolimus, pimecrolimus.
• PUVA (photochemotherapy) – topical, systemic.
• Minigrafting.
• Rarely, depigmentation using monobenzyl ether of hydroquinone is considered when vitiligo is near universal and other treatments have failed.
• This process is irreversible.

• Congenital autosomal dominant disorder
• Characterized by sharply demarcated amelanotic patches that occur most frequently on the forehead, anterior scalp (producing a white forelock), ventral trunk, elbows, and knees.
• Lesions are usually stable, and children are otherwise completely normal.
• Due to permanent localized absence of melanocytes and melanosomes or reduced numbers of abnormally large melanocytes.

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• It results from mutations in the KIT proto-oncogene, which encodes the cellular transmembrane tyrosinase kinase for mast/stem cell growth factor.
• Differentiated from vitiligo because of onset at a very early age, non-progression of lesions, and asymmetry of the lesions.
• Treatment is mainly cosmetic camouflaging.

• This congenital skin disorder is frequently associated with defects in several organ systems.
• There is no evidence for genetic transmission; chromosomal mosaicism and chromosomal translocations have been reported.
• The skin lesions of hypomelanosis of Ito are generally present at birth but may be acquired within the first 2 years of life.
• The lesions consist of bizarre, patterned, hypopigmented macules arranged over the body surface in sharply demarcated whorls, streaks, and patches that follow the lines of Blaschko.
• The palms, soles, and mucous membranes are spared. The hypopigmentation remains unchanged throughout childhood but fades during adulthood.

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• Mental retardation
• Seizures
• Microcephaly
• Muscular hypotonia
• Scoliosis and thoracic and limb deformities.
• Minor ophthalmologic defects (strabismus, nystagmus)
• Cardiac defects.

Tuberous sclerosis is a genetic disorder that causes tumors to grow in the brain, kidneys, heart, lungs, skin, and other organs. It is caused by mutations in two genes, TSC1 and TSC2.

People with TSC may have a variety of skin changes, including:

• Ash leaf spots: Small, white spots often found on the trunk and limbs (present in about 70% of people with TSC).
• Shagreen patches: Smooth, bumpy patches often found on the lower back or buttocks (present in about 50% of people with TSC).
• Confetti angiomas: Small, red or pink spots often found on the face, neck, and chest (present in about 30% of people with TSC).
• Verrucous papules: Wart-like growths often found on the face, neck, and scalp (present in about 20% of people with TSC).
• Hypomelanotic macules: Areas of lighter skin often found on the trunk and limbs (present in about 10% of people with TSC).

The skin changes associated with TSC are not harmful, but they can be a sign of the disorder. If you have any of these skin changes, it is important to see a doctor to get a diagnosis.

In addition to skin changes, people with TSC may also have other symptoms, such as:

• Seizures: About 50% of people with TSC have seizures.
• Intellectual disability: About 30% of people with TSC have intellectual disability.
• Learning disabilities: About 50% of people with TSC have learning disabilities.
• Behavioral problems: About 30% of people with TSC have behavioral problems.
• Heart problems: About 10% of people with TSC have heart problems.
• Kidney problems: About 10% of people with TSC have kidney problems.

There is no cure for TSC, but there are treatments that can help manage the symptoms. Treatment for skin changes may include:

• Covering the spots with makeup or clothing.
• Using sunscreen to protect the skin from the sun.
• Cryotherapy (freezing the spots).
• Laser therapy.
• Surgery to remove the spots.

Treatment for other symptoms of TSC may include:

• Medications to control seizures.
• Special education and therapy to help with learning and behavior problems.
• Surgery to correct heart or kidney problems.

Cause	Example
Drugs	Minocyclines, phenothiazines, amiodarone, oestrogens
Endocrine	Addison’s dx, chloasma, Cushing’s syndrome
Genetic	Peutz-Jeghers dx, freckles, Neurofibromatosis, race
Metabolic	Haemochromatosis, porphyrias, biliary cirrhosis
Nutritional	Carotenemia, malabsorption, pellagra
Post Inflammatory	Eczema, lichen planus
Others	Malignant melanoma, acanthosis nigricans, naevi

Hyperpigmentation and Pigment Disorders

• Hyperpigmentation is mostly hypermelanosis but sometimes other pigments color the skin:
• Iron deposition (with melanin) in haemochromatosis.
• Carotene (causing an orange discoloration) in carotenaemia - usually due to excessive carrot consumption.
• Freckles are small, light-brown macules, typically facial, which darken on sun exposure.
• Normal basal-layer melanocyte numbers but increased melanin.
• Lentigines are also brown macules but are scattered and do not darken in the sun.
• Increased number of melanocytes.

Chloasma

Chloasma is a patterned macular facial pigmentation occurring with pregnancy and in women on oral contraceptives. The pigmentation is symmetrical and often involves the forehead. Pregnancy stimulates melanocytes generally, and also increases pigmentation of the nipples and lower abdomen, and in existing melanocytic naevi. Chloasma improves spontaneously. Sunscreens and camouflage cosmetics can help.

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome is a rare autosomal dominant condition. Lentigines around the lips, buccal mucosa, and fingers are associated with small bowel polyps. The polyps may cause intussusception and rarely undergo malignant change.

Addison's Disease

Addison's disease is characterized by hypoadrenalism with pituitary overproduction of ACTH. The skin signs are due to excess ACTH, which stimulates melanogenesis. Pigmentation may be generalized or limited to the buccal mucosa palmar creases, scars, flexures, or areas subjected to friction. Addisonian-like pigmentation is also seen in Cushing's syndrome, hyperthyroidism, and acromegaly.

Café au Lait Spots

Café au lait spots are uniformly hyperpigmented, sharply demarcated macular lesions, the hues of which vary with the normal degree of pigmentation of the individual. They are tan or light brown in white individuals and may be dark brown in black children. Café-au-lait spots vary tremendously in size and may be large, covering a significant portion of the trunk or limb. Generally, the borders are smooth, but some have an exceedingly irregular border.

The lesions are characterized by increased numbers of melanocytes and melanin in the epidermis. One to three café-au-lait spots are common in normal children; approximately 10% of normal children have café-au-lait macules. They may be present at birth or develop during childhood.

They are associated with some disorders like Neurofibromatosis and Mccune Albright syndrome.

Melanocytic Nevi

Nevus skin lesions are characterized histopathologically by collections of well-differentiated cell types normally found in the skin. Melanocytic nevi are a benign cluster of melanocytic nevus cells that arise as a result of proliferation of melanocytes at the epidermal-dermal junction. Nevus cells may have the same origin as melanocytes and are probably identical to them.

Congenital Naevi

Congenital naevi are present at birth, may be protuberant or hairy, and have a small risk of malignant change.

Junctional Naevi

Junctional naevi are flat macules, often round or oval-shaped. Typically found on soles, palms, or genitalia.

Intradermal Naevi

Intradermal naevi are dome-shaped, usually skin-colored papules typically seen on the face.

Compound Naevi

Compound naevi are pigmented nodules or papules, sometimes warty or hairy.

Spitz Naevi

Spitz naevi are firm reddish-brown nodules typically seen on the face in children.

Blue Naevi

Blue naevi are steely-blue in color, mainly solitary, and found on the extremities.

Halo Naevi

'Halo' naevi show depigmentation where a naevus has involuted. Mostly seen on the trunk.

Becker's Naevi

Becker's naevi are pigmented hairy lesions on the upper back or chest, usually in males and appearing.