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A. Melanocytes navigator

  1. Derived from neural crest cells, migrate to various parts of the body
  2. Divided into epidermal/hair bulb melanocytes and rest of melanocytes in body
    1. Epidermal melanocytes make melanin throughout life
    2. Hair bulb melanocytes make melanin for variable period (then hair greys)
    3. Other melanocytes only active in embryonic life
  3. Histology
    1. Small, dark staining nucleus with clear cytoplasm
    2. Usually found between basal cells in skin
    3. Delicate melanin-laden dendrocytes visualized with silver staining
    4. Contain no tonofilaments or desmosomes
  4. Makes Tyrosinase, a specific enzyme for melanin pigment synthesis
  5. Melanocytes and DNA Damage [1]
    1. Melanocytes tolerate steady UV exposure by upregulating pigment levels
    2. Intermittent intense exposure to UV radiation after low UV baselines leads to damage
    3. Thus, melanoma risk associated with intermittent intense UV exposure

B. Melaninnavigator

  1. Major factor in determining differences in skin color
  2. Contained within cytoplasmic organelles called melanosomes
  3. Melanosomes are produced by melanocytes
  4. Melanin is a complex, high molecular weight polymer, insoluble in most liquids
  5. Synthesis dependent on tyrosinase, an enzyme specific for melanin synthesis
    1. Tyrosinase is a copper enzyme that catalyzes two critical synthetic steps
    2. These are Steps: Tyrosine to Dopa to Dopaquinone
    3. Tyrosinase is absent in some patients with albinism

C. Melanosomesnavigator

  1. Four Stages are currently delineated in the formation of melanosomes
  2. Stage 1
    1. Tyrosinase enzyme synthesized on rough ER ribosomes
    2. Phospholipid vesicles with proteins are fashioned by Golgi apparatus
    3. Tyrosinase molecules aggregate to small fibers surrounded by vacuole
  3. Stage II
    1. The membranous vacuole assumes oval shape
    2. Tyrosinase fibers now found within the vacuole (periodic fiber distribution)
  4. Stage III
    1. Melanin deposition begins
    2. Melanin accumulates on the inner membrane (loss of demonstrable fibers)
  5. Stage IV
    1. Deposition of melanin continues until entire organelle is electron dense
    2. Tyrosinase activity ceases (probably due to equilibrium reached)
  6. Transfer of Melanosomes
    1. Melanosomes are deposited in the dendritic arms of melanocytes
    2. Melanin transferred to epidermal cells by ? phagocytic process
    3. In this process, keratinocyte engulfs melanosome containing tips of dendrites
    4. Transferred melanosomes exist as individuals or clusters, depending on size
    5. Larger melanosomes tend to remain discrete
  7. Normal Pigmentation
    1. Black persons' keratinocytes contain large, single melanosomes, non-aggregated
    2. Most other races contain small, predominantly aggregated melanosomes
    3. Constitutive Skin color is determined genetically
    4. Facultative changes result from various stimuli or disease processes
    5. Melanocyte stimulating hormone (MSH) plays major role in facultative changes

D. Stimulation of Pigmentationnavigator

  1. Melanocyte Stimulating Hormone (MSH)
  2. Estrogen and Testosterone
  3. Vitamin D3 (Cholecalciferol)
  4. Arachidonic acid and prostaglandin metabolites
  5. Interleukin 1 may antagonize effects of MSH
  6. UV exposure induces melanin expression

E. Dysplastic Nevi [6] navigator

  1. Characteristics
    1. Macular lesion usually with irregular fuzzy borders
    2. Size usually >5 mm
    3. Color variability carries a high risk for hyistologic dysplasia
  2. Prevalence ~12% of population
  3. Acquired in adolescence, continue until adulthood
  4. Not uncommon in children, where high suspicion should be maintained
  5. Clinical significance associated with ~15 fold increased risk of melanoma [2]
  6. Several familial syndromes usually with melanoma risk have been defined (see below) [3]
  7. Increasing numbers of dysplastic nevi increase risk for melanoma
  8. Distribution
    1. Trunk and upper limbs most common
    2. Buttocks, groin, scalp and breast also
  9. Dysplastic Nevus Syndrome
    1. Usually refers to specific syndrome with the following triad:
    2. At least 100 nevi
    3. At least 1 nevus >7mm diameter
    4. At least 1 nevus with clinically atypical features
  10. Diagnosis
    1. Requires both cytologic and architectural abnormalities
    2. Universally accepted diagnostic criteria not defined to date
    3. Increasing numbers and atypical properties increase risk for melanoma
    4. Evaluation of families with melanoma for gerline CDKN2A mutations (see above) [4]
  11. Sunscreens may reduce numbers of nevi
  12. Prophylactic excision of clinically dysplastic nevi is generally unclear
  13. Current estimates only 1 in ~10,000 dysplastic nevi will progress to melanoma per year

PROBLEMS IN PIGMENTATION

A. Leukoderma (White Skin)navigator
  1. Vitiligo (see below)
  2. Albinism (see below)
  3. Hypopituitarism: melanopenic
  4. Vitamin B12 deficiency: melanocytopenic
  5. Systemic Lupus (SLE): melanopenic
  6. Piebaldism
    1. Failure of migration of melanoblasts
    2. Due to mutations in Kit gene in humans
    3. Kit is a receptor tyrosine kinase
  7. Tuberous sclerosis
  8. Pityriasis alba
  9. Waardenberg Syndrome
    1. Genetic defects with dominant pigmentation disorders
    2. Three distinct syndromes
    3. WS 1 due to Pax-3 transcription factor mutations
    4. WS 2 due to Mitf(mi) transcription factor mutations
    5. WS 3 due to Pax-3 mutations as well
  10. Alezzandrini's Syndrome
    1. Facial vitiligo (unliteral)
    2. Ipsilateral deafness
    3. Ipsilateral degenerative retinitis
    4. Poliosis of eyebrows and eyelashes
    5. Usually appears in young adults

B. Melanoderma (Brown Skin)navigator

  1. Albright's syndrome
  2. Mongolian Spot
  3. Addison's Disease
  4. Pellagra (Thiamine deficiency)
  5. Systemic Lupus Erythematosus (SLE)
  6. Melanoma
  7. Nevus
  8. Melasma

C. Ceruloderma (Blue Skin)navigator

  1. Due to dermal hyperpigmentation
  2. Macular amyloidosis
  3. Metastatic melanoma
  4. Blue nevus
  5. Nevus of Ota
  6. Nevus of Ito
  7. Tatoo
  8. Drug deposition - for example, amiodarone

D. Vitiligo [5]navigator

  1. Areas of depigmented skin due to loss of epidermal melanocytes
  2. Prevalence 0.1-2.0%
  3. Incidence usually peaks in age 15-25 years
  4. Subsets
    1. Generalized - most common form, symmetrical areas of depigmentation
    2. Acro or acrofacial
    3. Localized
    4. Segmental - least common, usually in dermatomal distribution (often trigeminal region)
  5. Pathogenesis
    1. Nonmendelian inheritance, polygenic disorder
    2. Linkage to HLA haplotypes -DR4, -Dw7, -DR7, -DR1, -B13, -Cw56, -DR53, -A19
    3. Loss of epidermal keratinocytes associated with CD8+ cytotoxic lymphocytes
    4. Elevated levels of tumor necrosis factor alpha (TNFa) and interleukin 6 (IL6)
    5. Autoantibodies to surface and cytoplasmic melanocytic antigens
    6. Anti-tyrosinase (69K protein) autoantibodies found in some patients
    7. Commonly associated with other autoimmune diseases
    8. NALP1 (Nacht leucine-rich-repeat protein 1, regulator of innate immune system) gene on chromosome 17p13 mutations associated with vitiligo and multiple autoimmunity [10]
  6. Disease Associations
    1. Thyroiditis - usually Hashimoto's (screen all patients for anti-TPO antibodies)
    2. Diabetes mellitus Type 1
    3. Rheumatoid arthritis
    4. Alopecia areata
    5. Autoimmune polyglandular syndromes
    6. Psoriasis
    7. These diseases may be linked by mutations in NALP1 gene [10]
  7. Treatment
    1. Narrow-band UVB treatment is most effective and safe
    2. Psoralen-UVA treatment used in the past but more side effects than UVB
    3. Targeted light therapy of some efficacy in localized disease
    4. Surgical skin transplants have been used
    5. Tacrolimus topical ointment gives 50-100% repigmentation in most patients
    6. Topical clobetasol also effective but can cause skin atrophy

E. Albinismnavigator

  1. Various genetic abnormalities cause albinism
    1. More common forms are due to deficiency of tyrosinase
    2. Ocular albinism linked to the P gene on chromosome 15q11-13
    3. Oculocutaneous albminism, Hermansky-Pudlak Syndrome, is due to chr 10 defect [6]
  2. Symptoms
    1. Milk-white skin
    2. Photophobia
    3. Nystagmus
  3. Oculocutaneous Albinism [6]
    1. Ocular and dermal albminism
    2. Storage pool deficiency - due to absence of platelet dense bodies
    3. Lysosomal accumulation of ceroid lipofuscin
    4. Nystagmus also occurs
    5. Visual acuity ~20/200
    6. Gene on chr 10q23 called HPS, 700 amino acid protein of unknown function

F. Melasmanavigator

  1. Spreading, hyperpigmented macules, usually on face
  2. Typically occurs in darker skinned women
    1. Occurs during changes in estrogen production or intake
    2. Pregnancy and new use of oral contraceptives are most common
    3. Usually related to sun exposure
  3. Other Associations
    1. Neurofibromatosis
    2. Becher's Nevus
    3. Nevus spirilus
    4. Melanoma
  4. Topical tretinoin lightens post-inflammatory hyperpigmentation in blacks

G. Inherited Disorders with Pigmented Skin Lesions [7]navigator

  1. Acquired Melanocytic Nevi
    1. Turner's Syndrome
    2. Familial Atypical Mole-Melanoma Syndrome (FAMM)
  2. Blue Nevi
    1. Familial multiple blue nevi
    2. Carney complex (LAMB or NAME)
    3. LAMB Syndrome: lentigenes, atrial myxoma, blue nevi
    4. NAME Syndrome: nevi, atrial myxoma, ephelides
  3. Carney Complex [3,8,9]
    1. Symptoms as above for NAME or LAMB also including adrenal abnormalities
    2. ~50% of cases due to mutations in PRKAR1 alpha gene on chromosome 17q2
    3. PRKAR1a encodes regulatory subunit of R1alpha of cAMP-dependent protein kinase A
  4. Cafe au Lait Macules
    1. Mainly with neurofibromatosis 1 and 2
    2. Mc-Cune-Albright Syndrome
    3. Multiple Endocrine Neoplasia (MEN) 1
    4. Tuberous sclerosis
    5. Bloom Syndrome
    6. Ataxia Telangiectasia
    7. Fanconi's Anemia
  5. Multiple Lentigines
    1. Peutz-Jeghers Syndrome
    2. Laugier-Hunziker Syndrome
    3. LEOPARD Syndrome
    4. Xeroderma Pigmentosum
  6. LEOPARD Syndrome
    1. Lentigines
    2. Electrocardiographic abnormalities
    3. Ocular hypertelorism
    4. Pulmonic stenosis
    5. Abnormal genitalia
    6. Retardation of growth
    7. Deafness
  7. Familial Melanoma [3]
    1. About 10% of melanoma associated with family history
    2. Hereditary melanoma (high risk alleles) represents ~1% of all melanomas
    3. True hereditary melanoma due to mutations in CDKN2A and CDK4
    4. CDK is cyclin dependent kinase involved in cell cycle regulation
    5. CDKN2A on chromosome 9p21 codes for 16K protein called p16
    6. p16 blocks CDK 4/6 complex from phosphorylating Rb protein
    7. Phosphorylation of Rb protein leads to expression of E2F transcription factors
    8. E2F transcription factors drive G1 to S phase transition of cell cycle
    9. p16 loss leads to hyperphosphorylation of Rb protein and allows cell cycle progression

References navigator

  1. Gilchrest BA, Eller MS, Geller AC, Yaar M. 1999. NEJM. 340(17):1341 abstract
  2. Stern RS, Nichols KT, Vakeva LH. 1997. NEJM. 336(15):1041 abstract
  3. Tsao H, Sober AJ, Niendorf KB, Zembowicz A. 2004. NEJM. 350(9):924 (Case Record) abstract
  4. Monzon J, Liu L, Brill H, et al. 1998. NEJM. 338(13):879 abstract
  5. Grimes PE. 2005. JAMA. 293(6):730 abstract
  6. Gahl WA, Brantly M, Kaiser-Kupfer MI, et al. 1998. NEJM. 338(18):1258 abstract
  7. Naeyaert JM and Brochez L. 2003. NEJM. 349(23):2233 abstract
  8. Edwards RJ, Moss T, Sandeman DR. 2003. Lancet. 362(9395):1541 (Case Report) abstract
  9. Stratakis CA, Sarlis N, Kirchner LS, et al. 1999. Ann Intern Med. 131(8):585 abstract
  10. Jin Y, Mailloux CM, Gowan K, et al. 2007. NEJM. 356(12):1216 abstract