CHAPTER 8

DISORDERS OF PIGMENTATION

I. Biology of Melanin Pigmentation in Humans（メラニン生物学と色素異常症）

A.   Skin Color and Melanin Pigmentation（皮膚色と色素沈着）

1.    Normal skin color: red, yellow, brown and blue

 a.  Red: hemoglobin in capillary

 b.  Yellow: exgenously produced carotenoids

 c.  Brown: endogenously produced melanin

 d.  Blue: reduced hemoglobin in the dermis

2.    Melanin is the major determinant of differences in skin color among individuals.

3.    Melanin is produced by the pigment cell, melanocyte, in skin color among individuals.

4.    Melanin synthesis occurs within the secretory granule, melanosome.

5.    The melanocyte transfers the melanosomes to surrounding keratinocytes (Malpighian cells) and the melanosomes are thereby distributed throughout the epidermis by the outward movement of keratinocytes.

B.   Epidermal Melanin Unit（表皮メラニン単位）and Tanning Reactions（陽性反応）

1.    The various amount of melanin and degradation of melanosomes in keratinocytes produce the wide spectrum of human skin color found in the various races. This is controlled by the Epidermal Melanin Unit.

2.    Epidermal Melanin Unit: a symbiotic association of a melanocyte with keratinocytes (usually 36) in the human epidermis.

3.    Two major components of human skin color: constitutive skin color and facultative (inducible) skin color or tan.

4.    Constitutive skin color: the amount of cutaneous melanin pigmentation generated according to cellular genetic program; the level of pigmentation acquired in those parts of the body habitually shielded from light.

5.    Facultative skin color or tan: short-lived immediate tanning and long-lived delayed tanning reactions. Both elicited by direct exposure to UV radiation.

The Responses of Melanocytes and the Induction of Melanogenesis after
Exposure to Sunlight

C.   Melanocyte（メラノサイト）

1.    Derive from embryonic neural crest tissue and migrate to the basal layer of epidermis 6-8 weeks of embryonic development in humans.

2.    No racial difference of melanocyte frequency at any given cutaneous site with UV exposure.

3.    Site-to-site variation in the single individual.

4.    Population density: 900/mm² on the trunk to 2400/mm² on the foreskin.

5.    Differences in racial pigmentation: not from differences in melanocyte number but differences in melanocyte activity, melanosome size, degree of melanosome melanization and melanosome degradation pattern in keratinocytes.

6.    With increasing age, the number of active melanocytes decreases.

D.   Melanosome（メラノソーム）

1.    Oval or ellipsoidal granules within the melanocyte.

2.    Two major forms of melanosomes: eumelanosomes containing eumelanin (brown black pigment) and pheomelanosomes containing pheomelanin (yellow red pigment).

3.    Four stages of maturation, stage I to IV.

4.    The size of melanosomes in under genetic control. Melanosomes from Negroid skin; 1.0 to 1.3 :m and those of Caucasoids: 0.6 to 0.7 :m.

5.    The degree of melanization and number of melanosomes and racial difference: In the epidermis of very pale Caucasoids with blue eyes and red hair, few melanosomes and few, if any stage III and IV; in Negroid epidermal melanocytes, many large melanosomes in stage IV.

E.   Tyrosinase（チロシナーゼ）

1.    An aerobic oxidase requiring molecular oxygen and copper to perform its oxidative function. The major enzyme responsible for melanin synthesis.

2.    Tyrosinase related protein (TRP): TRP-1, its biologic function in humans is not yet clarified, but in mice it is encoded to the production of brown pigment. TRP-2 has a dopachrome tautomerase activity in both humans and animals.

3.    Melanocyte stimulating hormone (MSH): increases tyrosinase activity through activation of cAMP cascade.

F.    Melanin（メラニン）

1.    Two major forms of melanin pigments in mammals: eumelanin and pheomelanin.

2.    Common metabolic pathway in both eumelanin and pheomelanin: initiate from oxidation of tyrosine to dopa and subsequent oxidation of dopa to dopaquinone.

3.    Eumelanin synthesis: after dopaquinone, through either auto-oxidation or the presence of dopachrome tautomerase, dihydroxyindole (DHI) or dihydroxyindole-2-carboxylic acid (DHICA) is formed and they will then become auto-oxidized to make eumelanin.

4.    Pheomelanin: after dopachrome, sulphur (from either gluthathione or cysteine) is incorporated to form cysteinyldopa, which subsequently is auto-oxidized to pheomelanin.

5.    Synthesis of eumelanin and pheomelanin is under genetic control.

6.    Human epidermal melanocytes synthesize mostly eumelanin.

II. Disorders of Abnormal Melanin Pigmentation in Humans

A.   Three Categories of Melanin Pigmentary Disturbances（メラニン色素沈着障害）

1.    Hypomelanosis (leukoderma, white or lighter than individual's normal color)（色素脱失）

2.    Brown hypermelanosis (melanoderma)(褐色性色素沈着)

3.    Slate or blue hypermelanosis (ceruloderma)（青色性色素沈着）

B.   Hypomelanosis（色素沈着）; Melanocytopenic and Melanopenic Disorders

1.    Melanocytopenic: absent melanocytes, e.g., vitiligo（尋常性白斑） and piebaldism（まだら症）

2.    Melanopenic: normal population of melanocytes, but reduced melanin synthesis, e.g., tuberous sclerosis and nevus depigmentosus

C.   Hypermelanosis（色素沈着症）; Melanotic, Melanocytotoxic, and Non-Melanotic

1.    Melanotic: normal population of melanocytes but increased melanin synthesis, e.g., melasma and post-inflammatory pigmentation

2.    Melanocytotoxic: increased population of melanocytes, e.g., oculodermal melanocytosis

3.    Non-melanotic: minocycline, tattoos（刺青）, etc.

D.   Wood's Lamp

UV-A (320-400 nm) and visible light (above 400 nm), facilitates the recognition of pigmentary disorders. Whiter in hypomelanosis, accentuated in brown hypermelanosis and less apparent in dermal melanosis.

III. Hypomelanosis Disorders（色素脱失症）

A.   Tuberous Sclerosis (Pringle's Disease)（結節性硬化症）

1.    Definition: neurocutaneous syndrome, autosomal dominant (25%) and spontaneous (75%)

2.    Triad: adenoma sebaceum (98%), seizure (86%) and mental retardation (48%)

3.    White polyclonal macules (79-90%)

4.    Ash leaf or thumb print

5.    Fibromas: periungual and subungual, and intraoral

6.    CNS, skin and eyes are commonly affected, heart, lungs, kidneys and bones are less

B.   Albinism（白皮症）

1.    Congenital: congenital disorder of melanin synthesis affecting skin, hair and eyes

2.    Occurrence 1:20,000

3.    Universal hypomelanosis limited to:

 a.  Eye and skin: oculocutaneous

 b.  Eye alone: ocular

4.    Tyrosinase positive: hair follicle-dopa incubation positive

       Tyrosinase negative: hair follicle-dopa incubation negative

5.    Variants of oculocutaneous albinism (OCA)

 a.  Tyrosinase negative OCA

 b.  Tyrosinase positive OCA

 c.  Yellow mutant OCA

 d.  Platinum OCA

 e.  Hermansky-Pudluk syndrome

 f.   Brown OCA

 g.  Rufous OCA

 h.  Cross syndrome

 i.   Chediak-Higashi syndrome

 j.   Black locks-albinism deafness syndrome

6.    Course: very light sensitive, actinic skin damages and development of skin cancers

7.    Treatment: sunscreen

C.   Phenylketonuria（フェニルケトン尿症）

1.    Definition

 a.  A relatively rare hereditary disorder due to a defect in or lack of the hepatic enzyme, phenylalanine hydroxylase

 b.  Occurrence 1:10,000

2.    Pathophysiology

 a.  Pathogenesis: a defect of phenylalanine hydroxylase leads to a metabolic block in the oxidation of phenylalanine to form melanin. An accumulation of phenylalanine and its derivatives in the blood and urine (phenylketonuria).

 b.  Hypomelanosis of the skin and hair; normal population of functioning melanocytes but decreased melanization of melanosomes due to the decreased availability of tyrosine and competitive inhibition of tyrosine oxidation due to the excessive amount of phenylalanine.

 c.  Mental retardation due to toxic brain damage consequent upon the accumulation of phenylalanine and its metabolites.

 d.  Diagnosis: Green coloration of the urine with 5% ferric chloride.

 e.  Prognosis: Poor, unless treatment is given very early.

3.    Treatment

       A phenylalanine poor diet

D.   Piebaldism（まだら症）

1.    Autosomally dominant

2.    Irregularly-shaped areas without pigmentation present from birth.

3.    White forelock (85%) arising from a depigmented area in the center of the forehead.

4.    Small islands of hyperpigmentation within the depigmented area.

5.    In continention pigmentic acrimonious.

E.   Vitiligo（尋常性白斑）

1.    Definition

A common, acquired disease due to the absence of functioning melanocytes in the skin.

2.    Pathophysiology

 a.  Pathogenesis: unknown

 b.  Three major hypotheses:

1)   Neural: segmental distribution of vitiligo, neurochemical mediators

2)   Immune: association of autoimmune diseases, aberration of immune surveillance, activated Ts/c which destroy melanocytes

3)   Autocytotoxic: free radicals from melanin metabolites or toxic melanin intermediates destroy melanocytes

 c.  Clinical findings: sharply circumscribed patches of depigmentation

 d.  Classification: localized, generalized, universal

3.    Treatment

 a.  PUVA

 b.  Beta-carotene

 c.  Topical corticosteroids

Hypomelanoses: Clinical and Historic Guidelines to Differential Diagnosis

IV. Hypermelanotic Disorders - Melanoderma

A.   Peutz-Jegher Syndrome（ポイツ・イェガース症候群）

1.    Definition: Autosomal dominant, appearing before the age of 30

2.    Gastrointestinal polyps:

 a.  Most frequent in small bowel

 b.  Become symptomatic between the ages of 10 and 30

 c.  May cause ulceration, and become malignant

3.    Pigmented macules (bizarre, freckle-like) on the lips and skin

B.   Cafe-Au-Lait Macules（カフェオーレ斑）

1.    Definition: Melanotic pigmentation with increased melanin pigments, but without changes of melanocyte population

2.    Association:

 a.  Neurofibromatosis（神経線維腫症）

 b.  Albright's syndrome（アルブライト症候群）

V. Hypermelanotic Disorders-Ceruloderma（青色性色素沈着症）

A.   Mongolian Spot（蒙古斑）

1.    Dermal melanocytosis

2.    Blue black spots present at birth in more than 90% of Asiatic races and American Indians

3.    Lumbosacral skin and buttock

B.   Nevus Ota (Oculodermal Melanocytosis)

Acquired, unilateral, blue or grey brown macules on the eye and surrounding skin innervated by the first and second branches of trigeminal nerve.

C.   Incontinentia Pigmenti（色素失調症）

1.    Definition: Neurocutaneous hereditary disease with onset in the neonatal period, involving various other skin symptoms and anomalies of the eyes, CNS and skeletal systems.

2.    X-linked dominant with lethality in males

3.    97% female and 3% male

4.    Whorled brown pigmentation on the trunk and extremities

5.    Three stages of evolution

 a.  Vesiculobullous stage at birth or within 1 or 2 weeks

 b.  Verrucous stage: 2-6 weeks

 c.  Pigmentary stage: 12-26 weeks

6.    Leukocytosis and eosinophilia (up to 60% at vesiculobullous stage

7.    Accompanying symptoms: 50%, disorders of tooth development, eye and CNS anomalies