Melanogenesis

&
Pigmentary abnormalities in
genetic diseases

Dr Jiss Elizabeth Sebastian

Moderator Dr Priti Pallabi Panigrahi

• Melanocytes are the cells responsible for melanin production
• Precursor melanoblast are derived from neural crest and migrate
to epidermis during first two months of IUL

• In human skin melanocytes are present in

→basal layer of epidermis
→hair follicles
apart from skin are present in inner ear,eye and meninges

• Basal layer of epidermis ≈ 1melanocyte for 6-10 basal

keratinocytes in normal sun protected skin
this ratio can be as high as 1:1 in areas like face,shin ,genitalia…
• melanocytes in hair follicle undergo cyclic modifications with
hair cycle
• melanocytes stem cells reside in hair follicle bulge
• Melanin is synthesised in
vesicles ,melanosome
membrane bound
intracellular organells
• Melanocytes are dendritic
cells
• Melanosomes are
transfered via this
dendrities to surronding
keratinocytes
• Keratinocytes,actively ingest
the tips of this dendrities to
imbib melanosomes
A melanocyte transferes melanosomes to ≈36 keratinocytes
Epidermal melanin unit

Within keratinocytes melanin present as supranuclear caps to

maximise protection quenching of oxidative free radicals
generated
Racial and ethnic differences in skin colour are not due to
differences in number of melanocytes rather due to
Pale skin Dark skin

• Fewer melanosomes more number

• Smaller size larger size
• Packaged within membrane bound dispersed singly
complexes
• Maturity ≤ 3 maturity ≥3
• Degraded fast at s.spinosum slow,may be +
s.corneum
• Main content is pheomelanin eumelanin
 Stages of maturation of melanosomes
• Melanocytes are synthesized in the
golgi body of melanocytesand pass
through a series of stages in which
various enyzmes acts on precurosrs to
producedensly pigmented granules

Stage1 →spherical,no melanin deposition

Stage2 →oval,matrix in form of parallel

longitudinal filaments high tyrosinase
activity

Stage3 →oval,high tyrosinae

activity,moderate deposition of melanin

Stage4 →oval,heavy deposition of

melanin,minimum tyrosinae activity
• Special stain for melanin
MASSON- FONTANA
ammoniacal silver nitrate is
oxidied to brown-black
pigments

• IHC markers
HMB-45
S-100
 Biosynthesis of melanin
Raper-Mason pathway
• Melanins are indole derivaties of 3,4 dihydroxy phenyl
alanine( DOPA), formed in melanosomes through a series of
oxidative steps
l –Tyrosine

TYROSINASE/ Try OXIDASE/DOPAoxidase

rate limiting step

DOPA
TYROSINASE

DOPA quinone
 DOPA quinone (,highly reactive intermediate)

in presence of sulfhydryl compounds • In absence of sulfhydryl

Like cysteine, glutathione • compunds rearranges
Cyclo DOPA

cysteinyl /glutathionyl DOPA

DOPA chrome,rearranges to

DHI DHICA
( oxidized and polymerised )
Pheomelanin

Black melanin brown melanin

MELANOSOME TRANSPORT & TRASFER TO
KERATINOCYTES
• While melanin is being deposited in melanosomes they migrate
along the cell body into the dendrites

• This transport takes place along microtubules ,which are arranged

parallel to long axis of dendrites & is controlled by two classes of
microtubule associated protein → kinesins and dyneins

• As they reach tip of dendrite are captured by binding to

myosin –Va and attaches them to actin cytoskeleon beneath
plasma membrane of melanocyte

This attachement occurs via Rab27 &melanophilin

• UV radiation results in augmented transport

several ways are suggested for transfer of melanosome
to keratinocytes

exocytosis→melanosome membrane fused with

melanocyte plasma membrane, released to
intercellular space &phagocytosed by keratinocytes
cytophagocytosis→keratinocytes phagocytose tip
of melanocyte dendrite
fusion→ transfer via fusion of melanocyte &
keratinocyte plasma membrane

high resolution photo shows formation of

slender ,filiform cytoplasmic projections at tip of
dendrites → filopodia
REGULATION OF MELANOCYTE FUNCTION

Regulated by both extrinsic and intrinsic factors

intrinsic factors endocrine

paracrine
autocrine

extrinsic factor UV light

• Endocrine
1) MSH & other melanocortins,
secreted by corticotrophs of anterior piuitary
other cells like keratinocytes of skin,
augmented by UV radiation
secreted as precursor protein → POMC
eg.α MSH ,β MSH,ϒ MSH& lipotrophins ….

Receptor → MC1R ,melanocortin 1 receptor

melanosomes by default produce pheomelanin

binding of MSH to MC1R→ eumelanin production
• 2) estrogen
melanocytes express estrogen receptor
a high level of estrogen esp estradiol ,like in
pregnancy ,stimulates melanogenesis

3) ACTH
secerted as POMC, along with other melanocortins
also binds to MC1R
basis of hyperpigmentation in addisons & nelsons disease
PARACRINE & AUTOCRINE
Growth factors from surronding cells paracrine
Most of them are produced by keratinocytes and their production increased wih
UV radiation

• Endothelin-1, → upregulate MC1R & affiniy for MSH

•Steel facor → antibodies can prevent UV induced
anning
•Neurotrophins
→ keratinocyte derived neurotrophin,is chemotactic for melanocytes
and induced dendricity
also increase anti apotoptic proteins in melanocytes

•NO →both autocrine and parcrine

• bFGF (basic FGF) → essential for melanocyte
growth in culture,from keratinocytes,is a potent
mitogen for melanocytes

• Inflammtory mediators like IL-1α,IL-6,TNF-α etc

prostaglandins,leukotriens&thromboxanes are main
inducers of tyrosinase
→ post inflammtory hyperpigmentation
 UV light

• Repeated exposures to UVR lead to an increase in the number

of stage IV melanosomes transferred to keratinocytes, as well
as an increase in the number of active melanocytes.
transcription of the tyrosinase gene,leading to increased
activity
• ↑MSH production by keratinocytes
• ↑ in the size of melanocytes
• ↑ the number or activity of MC1-R on melanocyte
• response of cultured melanocytes to UVR
→growth arrest & ↑ melanogenesis
Two types of melanin pigmentation

Constitutive skin colour→ amount of melanin

pigmentation which is genetically determined in the
absence of sun exposure & other influences

Facultative pigmentaion (inducible )→ tan skin colour

which results from sun exposure & other
endocrine,autocrine and paracrine factors
Facultative pigmentation can of two types

1. Immediate tanning → also called immmediate pigment darkening,occurs within

5-10 of sun exposure and fades within mintues to days depending on UV dose and
complexion of individual
mainly by UVA & lesser extent by visible light
its seen in darker individuals and is due to melanosomal relocation

2.Delayed tanning → occurs within 3-5 days following exposure,both UVA & UVB
peaks in 10 days and gradually fades over weeks
↑ epidermal melanocytes,melanocyte dendriticity,and melanosome transfer to
keratinocytes with greater melanization of indiviadual mealnosomes
provides additioanl photoprotection
PIGMENTAORY ABNORMALITES IN
GENETIC DISEASES

1.Hypopigmenation disorders
disorders of melanoblast migration and development
disordes of melanosome biogenesis
disrders of melanosome transport and transfer
hyperpigmentation disorders due to mosaicism

2.Hyperpigmenation disorders
3.Dyschromatoses
HYPOPIGMENTATION DISORDERS

DISOREDERS OF MELANOBLAST MIGRATION

1 Piebaldism rare ,AD,
well demarcated hypopigmented patches
may present as only white forlock
stable & present since birth (vitiligo)
Hyperpigmented patches which appear at the border or centre
of hypopigmented lesions are quite distinctive

Mutation in KIT gene

impaired melanocyte migration,
KIT gene codes for a transmembrane receptor ,present on
melanocytes important for normal development and migration
of melanocytes
2)Waardenburg syndrome

AD/AR
Piebaldism with sensorineural hearing loss
Molecular classification WS(1-4)

Various combinatons
achromia (hair ,skin or pattern same as piebaldism)
congenital SN hearing loss
partial /total heterochromia irides
medial eyebrow hyperplasia(synophrys)
broad nasal root
dystopia canthorum ( increased intercanthal distance
wih normal interpupillary distance)
• mutation in PAX3 transcription factor WS1&3
activates melanoblasts and other cells to proliferate and
migrate from neural crest

Mutaion of MITF gene WS 3

Mutation in gene for endothelin B receptor or its ligand

WS4
can be associated with Hirschprugs disease

The facial dysmorphism seen in WS is due to the fact that

several of the genes responsible for WS,encode transcription
factors important during embryogenesis
Deafness reflects the role of melanocytes in development of
inner ear
DISORDES OF MELANOSOME BIOGENESIS

1) oculocutaneous albinism
characterized by diffuse pigmentary dilution due to a total or partial
absence of melanin pigment within melanocytes of the skin,hair follicls and
eyes

Number of melanocytes are normal within epidermis and follicular

melanocytes
Most common of inherited hypomelanonsis
AR
Genetically heterogeneous group

molecular classification OCA (1-7),based on mutant

gene
• OCA Type 1
Mutation in gene for tyrosinase enzyme
OCA 1A Total loss of activity
OCA1B Partial activity
with melanin synthesis in cooler areas of body,when mutation is temp
sensitive
• OCA Type2
mutation in gene coding for P protein,transmembrane protein
Important in melanin biosynthesis,processing and transport of
melanosomal proteins and in maintaing acidic ph in melanosomes

• OCA Type3 (Rufos albinism)

mutation in gene for TYRP1
it stabilize tyrosinase ,also catalysesoxidation of DHICA monomers into
eumelanin
Pheomelanin accumulation
• The degree of pigmenatary dilution depends on the mutation,with
colplete loss in OCA Type 1A,even nevi are achromic

• In other types collectively known as Tyrosinase positive types

pigmentation is highly variable,pigmentaion can improve with
age ,patients can also develop dark –brown freckles ,

• All types of OCA and OA have similar ocular findings

photophobia
varying degree of congenital nystagmus
reduced pigmentation of RPE
foveal hypolasia
decreased visual acuity
2)Hermansky –Pudlak syndrome

AR,
Triad of
oculocutaneous albinism,
bleeding disorders
storage of abnormal fat-protein compound in lysosomes

molecular classification 9 types

Most of the HPS types have mutation in genes which encode biogenesis
of lysosome related organells like melanosomes or as in HPS -2 due to a
decfect in protein sorting to lysosomes and related orgnelles
• Platelet function analyzer time (PFA-100) time and bleeding
time prolonged,although platelet count is normal

• Ultrastructuraly absence of dense bodies within plateles

• Premature death often due to progresive pulmonary fibrosis

systemic manifestation intersitial pulmonary fibrosis and
granulomatous colitis secondary to cercoid lipofuscin within
lysosomes,less often cardiomyopathy and renal failure
3) CHEDIAK-HIGASHI SYNDROME

oculocutaneous albinism
immunodeficency
Neurological symptomes

mutation in LYST gene, Lysosome trafficking regulator gene

Encodes a protein which regulates fission/fusion of lysosome –related oragnelles

Melanocytes giant pigment granules

Neutropenia with CPS Giant inclusion in neutrophils diagnostic

Neurological manifestations are usually

progressive intellectual decline
CN palsy
↓ DTR
abnormal gait
• PHENYLKETONURIA

An in born error of metabolism due to mutation in gene for

Phenylalanine hydroxylase (PAH)

Phenylalanine Tyrosine
PAH

Generalized pigmentary dilution of skin and hair in addition to

other features like severe MR ,seizures,.etc
all these complications arepreventable with prenatal diagnosis
and tyrosine supplementation & dietary restricion of PA
• DISORDERS OF MELANOSOME TRNASPORT AND
TRANSFE

1) Griscelli Prunieras
syndrome

GS1 mutation in Myosin Va

GS2 mutation in RAB 27 A
GS3 mutation in MLPH Melanophilin

As the melanosome reach tip of dendrite they are captured by

binding to myosin –Va and attaches them to actin
cytoskeleon beneath plasma membrane This attachement occurs
via Rab27 &melanophilin
• In all variants of here is abnormal accumulation of melanosomes in
melanocytes

• Pigmentatory dilution of skin and hair in addition

GS1 neurologic impairment
GS2 Immune abnormalities due to
defective release of cytotoxic
contents from haematopoietic cells

2)Elejalde syndrome pigmentary findings of GS with severe

neurological impairment

3)TUBEROUS SCLEROSIS ash leaf macule ,pigment transfer is

defective in TS
HYPOPIGMENTATION DUE TO
PIGMENTARY MOSAICISM

1)HYPOMELANOSIS OF ITO
(LINEAR NAEVOID HYPOPIGMENTATION )

Characterized by unusual U/L or B/L cutaneous macular

hypopigmented whorls ,streaks and patches corresponding to lines of
Blaschko
Due to mosaicism ,characterized by a clone of skin cells with a
decreased ability to make pigment
30% may have associated abnormalities of CNS,musculoskeletal system
or eye abnormality
2) Nevus depigmentosus
hypopigmented patches with irregular but well defined borders
Other genetic diseases with hypomelanosis

1)Albinism –deafness syndrome/Ziprkowski-Margolis

syndrome/woolf syndrome
X linked disorder with partial albinism and congenital
deafness
2)Cross syndrome/Kramer syndrome/oculocerebral
syndrome with hypopigmentation
generalized hypopigmentation of skin & hair
severe mental retardation
spastic tetraplegia with athetosis
ocular abnormalities
• GENETIC DISORDERS OF
HYPERPIGMENTATION

1)disorders with hyperpigmentation which follows lines of blaschko

LWNH
incontinentia pigmenti (3rd stage)
early epidermal nevus
Conradi-Hunermann-Happle syndrome
Café -au –lait macule of McCune -Albright syndrome

2)Reticulate pattern of hyperpigmenation

3) others
1)Linear and whorled nevoid
hypermelanosis

Swirls and streaks

of macular hyperpigmentation
along lines of Blaschko.

phenotype is just reverse of

hypomelanosis of ito

pigmenatary mosaicism with a

clone of skin cells with increased
pigment production

Rarely associated with extracutaneous

features like CVS,CNS &
neurological abnormalites
2) Incontinentia pigmenti
(Bloch Sulzberger syndrome)
XD multisystem ectodermal dysplasia
mutation in gene coding NEMO
NF –kβ essential modulator inhibitor of NF-kβ kinase

Mutation in this modulator gene leads to activation of genes involved in

inflammation,immunity c,ell survival & other pathways

Extra cutaneous manifestations include

missing/malformed teeth
onychodystrophy
cicatricial alopecia
ophtahlmological like retinal neo vascularization
CNS abnormalities but majority are normal neurologically
Stage 1 stage 2

Stage 3 Stage 4
3) Mc Cune Albright syndrome
large café –au –lait macules with irregular borders
or coast of maine apperance often following lines of
Blaschko

4) café-au –lait macules of segmental variety of

neurofibromatosis
• RETICULATED PATTERN OF HYPERPIGMENTATION

1) DYSKERATOSIS CONGENITA

Genetically heterogenous group

(AR/AD/X linked) with variable phenotype
Classically defined by
reticulated skin pigmentation,sarting in 1st decade mainly
on upper par of body
BM failure in 50-90%
premalignant leukoplakia
nail dystrophy
predisposition to malignancy important feature
haematological,epithelial….
Caused by mutations in multiple genes
coding for proteins involved in
telomere function and maintenance

DD-Fanconi anemia

AR , DNA repair defect

In addition to other abnormalities can have reticulate or patchy
hypo or hyper pigmentation
BM failure preseting as
pan cytopenia
Also predisposition to various abnormalities
2)NAEGELI-FRANCESCHETTI-JADASSOHN SYNDROME
& DERMATOPATHIA PIGMENTOSA RETICULARIS

Closely related AD ectodermal dysplasia syndromes

both
1.caused by mutation in gene for Keratin 14
2.have reticulate pattern of hyperpigmenation
3.complete absence of dermatoglyphics
4.abnormal sweating
5.palmoplantar keratoderma
6.denatal abnoramlites and nail dystrophy

Due to mutation in keratin 14 gene ,there is increased suseceptibility of

keratinocytes to TNF-α induced apoptosis
hyperpigmenation seconadry to pigment incontinence
NFJ syndrome lacks the prominent alopecia ( non scarring)and more
persistent hyperpigmentation that characterize DPR syndrome
 3)DOWLING DEGOS DISEASE

AD Also known as reticular pigmented anomaly of flexures

caused by loss of function mutation in keratin 5 gene
Keratin 5 has a role in melanosome trafficking

Onset of pigmentation is typically in adolesce or later and is

progressive,initailly appearing over axilae,later progressing to
other flexures
other features
comedo like lesion on back or neck
pitted perioral scars
hidradenitis suppurativa
epidermoid cyst
• HP antler like pattern
increased pigmentation of basal layer
with finger like projection of rete ridges

Galli Galli disease –acantholytic variant of

DDD
Also caused by mutation in keratin 5

A mis sense mutation in same region of keratin 5 causes

epidermolysis bullosa with mottled pigmenation
 3) RETICULATE ACROPIGMENTATION OF KITAMURA

AD,
atrophic hyperpigmented macules ,often with a reticular pattern
over dorsum of hand and feet ,may subsequently spread to
other parts of body gradually

Additional features
palmar and plantar pits with
breaks in dermatoglyphics

May be considered asa variant of DDD with a different distribution

• DYSCHROMATOSES
pigment pattern characyerized by presence of both
hypo and hyperpigmentation
Two classical dyschromatoses are
dyschromatosis symmetrica hereditaria
dyschromatosis univeraslis hereditara

In addition many syndromes can have dyschromatoses

Eg. Xeroderma pigmentosum
Dyskeratosis congenita
EBS with mottled pigmentation
chediak –Higashi & Griscelli syndrome….
 2)DYSCHROMATOSES
1)DYSCHROMATOSES UNIVERSALIS
SYMMETRICA HEREDITARIA HEREDITARIA(DUH/DHU)
Acropigmentation of Dohi
Symmetrical distribution of irregular Here hyper and hypopigmented
hypo and hyper pigmented
macues are in a generalized
macules on dorsal aspect of hand
and feet
distribution
AD
Reticulate acropigmentation of AD/ AR
Kitamura lacks hypopigmented Extracutaneous maifestaion
macules reported c
deafness
platelet and erythrocyte
abnormalites
glaucoma ,cataract etc
• Poikiloderma syndromes

poikiloderma is a constellation of skin

atrophy,reticulate pigmentation and telangiectasia
(RAT)
Eg
Rothmund –Thomson syndrone
Dyskeratosis congenita
Bloom syndrome
Kindler syndrome
Acrokeratotic poikiloderma of Weary
Poikiloderma with neutropenia
THANK YOU