Melanogenesis.doc 2

melanin is not just for color.....

1. Epidermal melanin unit and melanogenesis Dr . RANJAN DASH

2. HEADS TO BE HIGHLIGHTED UPON BASIS OF SKIN PIGMENTATION MELANOSOMES-types ,synthesis & maturation SYNTHESIS OF MELANIN TRANSPORT OF MELANIN DISORDERS OF HYPOMELANOSIS DISORDERS OF HYPERMELANOSIS

3. SHADES Of COLOuR DIFFERENT COLOR OF SKIN IS DUE TO : 1. Presence of CHROMATOPHORES (pigment containing cells ) 2. Presence & Distribution of Pigments(coloured particles) 3. Hormonal and Neural control REASON FOR VARIABLE SHADES OF COLORATION 1. CAMOUFLAGE ( protective resemblance),mimesis / crypsis 2. Aggressive Resemblance Best example is CHAMELEON

4. COLOUR OF HUMAN SKIN Determined by : melanin haemoglobin carotenoids At the level of Epidermis : Melanin , the major determinant and carotenoids At the level of Dermis - by oxygenated haemoglobin (red) in capillaries - by reduced haemoglobin (blue) in venules Constitutive skin colour : genetically predetermined Facultative skin colour : induced by sun exposure(UV), hormones & other regulatory factors

5. BIOLOGY OF MELANOCYTES derive from pluripotent neural crest cells that differentiate into numerous cell lineages including neurons, glia,smooth muscle, craniofacial bone, cartilage, and melanocytes. Progenitor melanoblasts migrate dorsolaterally between the mesodermal and ectodermal layers reach the hair follicles and the skin as well as inner ear cochlea, choroid, ciliary body, and iris. Melanoblast migration and differentiation influenced by signaling molecules Wnt , (ET)-3, bone morphogenetic proteins (BMPs), steel factor (SF) , and hepatocyte growth factor .

6. EMBYOGENESIS OF MELANOCYTES Melanoblasts migrate dorsolaterally and then ventrally around the trunk to the ventral midline & differentiation into melanocytes. During embryogenesis, melanin producing melanocytes are found diffusely throughout the dermis. By the end of gestation, active dermal melanocytes disappear, except in three anatomic locations 1. the head and neck, 2. the dorsal aspects of the distal extremities 3. the presacral area that coincide with the most common sites for dermal melanocytosis and dermal melanocytomas (blue nevi)

7. Cutaneous melanocytes Melanocytes in skin synthesize & store melanin in cytosolic organelles called melanosomes A constant need for synthesis & transfer of melanosomes from melanocytes to keratinocytes to maintain cutaneous pigmentation. Melanocyte density/square mm ranges from 550 to 1500, with the highest concentration within face & genitalia Association of a melanocyte with approximately 30–40 surrounding keratinocytes to which it transfers melanosomes

8. B. Hair follicle melanocytes Follicular melanin unit undergoes cyclic modifications along with the hair cycle located in the proximal hair bulb during anagen proliferate, migrate, and undergo maturation during early to mid anagen. Melanogenesis and melanin transfer to keratinocytes occurs throughout anagen. Melanocyteneventually apoptose during late catagen in hair, melanocyte transfer melanin to differentiated keratinocytes that ultimately form the hair shaft. determine hair color by the amount of melanin transferred, as well as by the ratio of eumelanin ( black–brown ) to pheomelanin ( red–yellow )

9. C . Ocular Melanocytes - Unlike cutaneous melanocytes, ocular melanocytes are in contact only with each other & don’t transfer melanosomes . -Albinos may have visual abnormalities due to absence of melanin D . Otic Melanocytes - reside in cochlea & are important for hearing loss of otic melanocytes may leads to deafness as in Waardenburg syndrome TYPE II

10. Colour variation of skin Depends upon :> 1) Melanogenic activity within the melanocyte 2) The proportion of mature melanosomes 3) Size of melanosomes 4) Type of melanin (eumelanin, or pheomelanin ) 5) Melanosomes transfer & distribution within the keratinocyte

11. MELANOSOMES Definition : membrane-bound unique organelle within the cytoplasm of melanocytes in which in which melanin pigments are synthesized, deposited and transported. And depending on the type of melanin (eumelanin or pheomelanin ) synthesized, melanosomes can be divided into: Eumelanosome and Pheomelanosome

12. SYNTHESIS & DISTRIBUTION OF MELANIN IN THE EPIDERMIS 1) Transcription of proteins required for melanin synthesis 2) Melanosome biogenesis 3) Sorting of melanogenic proteins into melanosomes to initiate melanin synthesis within the melanosome 4) Transport of the mature melanosomes to the tips of melanocyte dendrites migrates via microtubules 5) Transfer of melanosomes to keratinocyte

13. TRANSFER OF MELANOSOME TO KERATINOCYTE 1 . EXOCYTOSIS - fusion of the melanosomal membrane with the melanocyte plasma membrane - melanosome is released to the intercellular space - phagocytosis by surrounding keratinocytes occur 2 . CYTOPHAGOCYTOSIS : projection of dendrites into keratinocyte cytoplasm then keratinocytes cytophagocytose the tip of a melanocyte dendrite. 3. Fusion of melanocyte & keratinocyte plasma membrane create a space through which melanosomes are transferred 4. Shedding of melanosome -filled vesicles followed by phagocytosis of the vesicles by keratinocyte

14. FACTORS REGULATING MELANIN SYNTHESIS A . Specific genes B . Hormones: 1.MSH 2. ACTH 3. Estrogens C . Biochemical factors: IL-1 2, IL-6 , TNF-alpha , basic fibroblast growth factor ( bFGF ) 5- Endothelin-1, 3 D. External factors: 1- UV light (amount and wave-length) 2- melanocyte stimulating chemicals like photosensitizers

15. Microphthalmia-AssociatedTranscription Factor(MITF) MITF, a basic-helix-loop-helix and leucine zipper transcription factor, the master gene for melanocyte survival A key factor regulating the transcription of the major melanogenic proteins, tyrosinase , TRP-1, TRP-2 , PKC-β In melanocytes, it is the MITF-M isoform that stimulates transcription of tyrosinase and PKC-b. MITF binds to conserved consensus elements in gene promoters, specifically the M- (AGTCATGTGCT) and E- (CATGTG) boxes. MITF comprises a family of nine isoforms : (1) MITFM, (2) -A, (3) -B, (4) –H , (5) -C, (6) -D, (7) -E, (8) -J, and (9) -Mc. MITF-M expression is highly specific for melanocytic cells.

16. Disorders of pigmentation AMELANOSIS HYPOMELANOSIS HYPERMELENOSIS

17. Piebaldism AD disorder of   melanocyte  development a/w Kit/SNCA gene mutation  Common characteristics include a congenital white  forelock , scattered normal pigmented and hypopigmented   macules  and a triangular shaped depigmented patch on the forehead.. In some cases, piebaldism occurs together with severe developmental problems, as in  Waardenburg syndrome  and  Hirschsprung's disease . A kind of  neurocristopathy , involving defects of various neural crest cell lineages that include melanocytes, but also involving many other tissues derived from the neural crest

18. WAARDENBURG’S SYNDROME autosomal dominant disorder White forelock Hypertelorism Congenital deafness Hypomelanotic macules Heterochromic irides

19. TUBEROUS SCLEROSIS AD neurocutaneous syndrome with skin lesions, mental retardation and epilepsy Skin lesions are ash-leaf macules , angiofibromas and shagreen patches Ash-leaf macules - present at birth in > 90% cases, so important in early diagnosis Oval or ash-leaf shaped, hypopigmented macules , look prominent in Wood’s lamp Long axis is axial on limbs and transverse on trunk

20. HERMANSKYPUDLAK SYNDROME   autosomal  recessive disorder Albinism and eye problems: (photophobia), strabismus (crossed eyes), and nystagmus (involuntary eye movements) Bleeding disorders: due to platelet dysfunction. Cellular storage disorders: The syndrome causes a wax-like substance ( ceroid ) to accumulate in the body tissues and cause damage, especially in the lungs and kidneys CHEDIAKHIGASHI SYNDROME A rare   autosomal recessive  disorder that arises from a mutation of a lysosomal trafficking regulator protein, [  which leads to a decrease in  phagocytosis . results in recurrent   pyogenic  infections,  albinism and peripheral  neuropathy

21. SOME COMMON CONDITIONS OF HYPOMELANOSIS/AMELANOSIS

22. DISORDERS OF HYPERMELANOSIS May be epidermal or dermal Epidermal hyperpigmentation due to - Increased melanin with normal number of melanocytes - Increased number of melanocytes Dermal hyperpigmentation due to - Melanin from epidermis transferred to dermis - Melanin formed in dermal melanocytes - Melanin pigments appears blue-gray due to Tyndall effect

23. CLASSIFICATION OF HYPERMELANOSIS A . EPIDERMAL Physiologic: Pigmentary demarcation lines, sun tanning Genetic and Developmental: Lentigines , Freckles, Peutz-Jeghers syndrome, Melanocytic nevus, Café-au- lait spots, Xeroderma pigmentosum , Becker’s nevus, Acanthosis nigrican Post-inflammatory: Eczema, Psoriasis, Lichen planus , Lupus erythematosus , Scleroderma, Morphoea , Vagabond’s disease Nutritional: Kwashiorkor, Pellagra, Vit.B12, Vit.C , Folic acid deficiency Physical: Trauma, Radiation dermatitis Endocrine:  Melasma , Addison’s disease, Cushing’s syndrome, Phaeochromocytoma , Acromegaly , Hyperthyroidism Neoplastic : Malignant melanoma, Seborrhoeic keratosis , Pigmented basal cell carcinoma

24. Dermal Pigmentation Genetic and Developmental: Mongolian spots, Nevus of Ota/Ito, Incontinentia pigmenti Inflammatory: Stasis dermatitis, Post inflammatory to eczema and fixed drug eruption Chemicals and Drugs: Anti- malarials , OC Pills, Minocycline , Clofazimine , Topical hydroquinone, Tattoo

25. Endocrine: Melasma Physical: Thermal burns, Post traumatic Infection: Syphilis, Yaws, Pinta Neoplastic : Metastasis of melanoma Nutritional: Chronic nutritional deficiency Metabolic: Hemochromatosis , Alkaptonuria , Macular / Lichen amyloidosis Miscellaneous: Pigmented purpuric dermatosis , Purpura

26. Pigmentary Demarcation Lines (PDL) Also known as Futcher’s or Voight’s lines are borders of abrupt transition between more deeply pigmented skin and that of lighter pigmentation do not correspond to Blaschko’s lines or dermatomal lines but to voigt ’ lines Considered by some to be a variant of normal pigmentation

27. PDL TYPES Can be divided into five five categories: Group A - lines along the outer upper arms with variable extension across the chest Group B - lines along the posteromedial aspect of the lower limb Group C - Paired median or paramedian lines on the chest, with midline abdominal extension Group D - medial, over the spine Group E - bilaterally symmetrical, obliquely oriented, hypopigmented macules on the chest

28. Melanocytic Nevus Benign proliferations of cells at the dermo -epidermal junction May be congenital or acquired Acquired nevi are more common Appear in infancy or childhood, slowly grow and mature and then regress in older life Important for cosmetic reasons and as precursors for melanoma (esp. in white)

29. ACQUIRED NEVI Round or oval, uniformly coloured and sharply bordered lesions Appear after birth Increase in frequency during childhood & adolescence and plateaus during middle age Most of them start as junctional nevi which are flat and histologically confined to dermalepidermal junction Gradually mature to compound nevi which have nests and columns of nevus cells in dermis along with the junctional component. These are raised, rounded, brown or black Intradermal nevi : Compound nevi mature to intradermal nevi with nevus cells only in dermis having neuron like appearance. These are dome shaped, nonpigmented and may have one or more coarse hair

30. Nevus of OTA & ITO

31. BECKER’S NEVUS Acquired, pigmented, hairy plaque common on trunk, more common in males Appears in first or second decade Common sites: shoulder, chest, back May become verrucous with hair growth and then remains stable

32. CAFE AU LAIT MACULES (CALM) Circumscribed, brown macules with irregular margins, 2-5 cm in size Isolated CALM may occur in 10-20% of normal population No increase in the number of melanocytes Five or more CALM of size >0.5 cm in prepubertal age group and >1.5 cm in an adult are strongly suggestive of neurofibromatosis

33. MELASMA A common macular brown coloured lesion seen on face in males and females Common in pregnancy: Mask of pregnancy (clears in few months) Forehead, nose, cheeks affected. The three clinical patterns are: centrofacial , malar , mandibular Exacerbation on sun exposure Histologically may be epidermal, dermal or mixed

34. Some other condtions of hypremelanosis

35. emBrace yourself as you are…