Chapter 19

Disorders of pigmentation
 Normal skin colour
• Mixture of pigments:
– Oxyhaemoglobin in the blood within the dermis - red
– Melanin (Responsible for the shades of brown)
– Carotene (yellow, mainly in SC fat –because they have carotene- & horny layer)
• Skin pigmentation measured by skin reflectance
• Skin colour seems to have evolved as:
– Block the damage to DNA caused by UV radiation
– Photolysis of the essential metabolite, folate
– Allow vitamin D to be synthesized in the skin
 Melanogenesis
• Liver: hydroxylation of phenylalanine by phenylalanine hydroxylase give tyrosine
• Skin:
– Melanocytes are the only cells contain tyrosinase (dopa oxidase) the rate-limiting
enzyme – most important enzyme-
– Tyrosine 🡪 Eu (brown) /phaeomelanin (red) their ratio determine color of skin, hair,
and eyes
• Melanin is made within melanosomes, tiny particles (0.1 × 0.7 μm), shaped:
– American footballs (eumelanosomes)
– British soccer balls (phaeomelanosomes)
• Eventually, fully melanized melanosomes pass into the dendritic processes of the
melanocyte to be injected into neighbouring keratinocytes.
• Melanosomes are engulfed in lysosomal packages (melanosome
complexes)
• Such secretory lysosomes are common to various haematopoietic cells &
melanocytes.
• This explains why some genetic disorders of pigmentation are linked
with abnormal immune function such as
– Hermansky–Pudlak syndrome
– Chediak–Higashi syndrome
• Hair colour
– Brown/black contain eumelanin
– Red contain phaeomelanin & trichochromes.

• Negroids are black

– Not because they have more melanocytes
– But because they have more and larger melanosome
– Which are broken down less rapidly in the melanosome complexes.

• Melanins protect against UVR damage by

– Absorbing and scattering the rays
– Scavenging free radicals
Melanogenesis increased by several stimuli, the most important is UVR.
1. Immediate pigment darkening (IPD)
• Longwave ultraviolet (UVA 320–400 nm).
• Darkening occurs over minutes to days, dependent on UV dose & Constitutive skin colour
• Responsible for the well-known phenomenon of a ‘false tan’
• Not new melanin production
• Oxidation of preformed melanin
• Redistribution of melanin from perinuclear to peripheral dendrites.

2. Delayed tanning (DT): with continuous exposure

• Production of new pigment
• 3–4 days after exposure to
• Medium-wave ultraviolet (UVB: 290–320 nm)
• Proliferation of melanocytes
• Increase in tyrosinase activity and melanosome production
• Increased transfer of new melanosomes to their surrounding keratinocytes
 Decreased melanin pigmentation
Hypopigmentation
Causes: a-pigmented (acronym)
• A: autimmune: vitiligo
• Pi: post-inflammatory
• G: genetics
• M: malignancy & medical
• E: endocrine
• N: nevi
• Te: trauma exogenous (chemicals)
• D: drugs
Fig. 19.2 The mechanisms involved in some types of hypopigmentation.
 Oculocutaneous albinism
• Genetic condition, AR, present since birth (important to differentiate it from vitiligo)
• Defect
– Synthesis or packaging of melanin in the melanocyte
– Transfer of melanosomes to surrounding keratinocytes
• The most common type, little or no melanin is made in
– Skin and eyes (oculocutaneous albinism) more common
– Eyes alone (ocular albinism)
• Hair bulb test (2types):
1. Tyrosinase negative
2. Tyrosinase positive
• Roughly equal numbers of
the two types are found in
most communities
• To know if whether
complete or partial loss of
the enzyme which has
prognostic value
• Both being inherited as
AR
 Presentation and course
• The whole epidermis is white
• Pigment is also lacking in the hair, iris and retina
• Poor sight
• Photophobia
• Rotatory nystagmus
• As they grow older, tyrosinase positive albinos
– Gain a little pigment in their skin, iris and hair.
– Negroid skin becomes yellow–brown
– The hair becomes yellow
– May also develop freckles
• Sunburn is common
• Albinos have non-pigmented melanocytic naevi and may develop amelanotic malignant
melanomas.
Complications:
• Sun-induced skin cancers
• Most common is SCC, but melanoma and basal skin carcinoma happen too.
• Annual screening is important for early diagnosis and treatment
• More prone to sun burn.
DDx:
• Piebaldism
• Vitiligo

Investigations: diagnosis is clinical

• DNA-based diagnostic screening of
– Amniotic fluid cells
– Chorionic villi sampling
• Hair bulb test
• Prenatal diagnosis
 Treatment

• Avoidance of sun exposure

• Protection with opaque clothing
• Wide-brimmed hats
• Sunscreen creams
• Early diagnosis and treatment of skin tumors (annual screening)
• Ophthalmology referral for ocular issues.
 Other types of albinism
Hermansky–Pudlak syndrome Chediak–Higashi syndrome
• Rare • Oculocutaneous albinism
• AR • Marked susceptibility to
infections (abnormal inclusions
• Oculocutaneous albinism
in phagocytic leucocytes).
• Platelet storage disease
• Prolonged bleeding
• Neutropenia
• Pulmonary fibrosis
• Granulomatous colitis
Piebaldism Waardenburg’s syndrome
• AD (KIT proto-oncogene)
• White forelock of hair • Variant of Piebaldism
• Patches of depigmentation • White forelock (20%)
• Lying symmetrically on the • Hypertelorism (distance
between two eyes)
– Limbs
• Prominent inner third of the
– Trunk eyebrows
– Central part of the face, especially the chin • Irides of different colour
• No melanocytes in hypopigmented areas. • Deafness
• Often mistaken for vitiligo
• May improve with age
• No effective treatment (counsel that it improves
with age, and use general protection measures)
• Latin word vitellus meaning ‘veal’ (pale, pink flesh)
• Acquired circumscribed depigmentation, found in all races
• Inheritance is polygenic (multiple genes are implicated in pathogenesis)
Cause and types
• Complete loss of melanocytes from affected areas.
• 2 main patterns:
1. Generalized vitiligo (more than segmental)

Vitiligo
– Including the acrofacial variant in 50%
– Usually starts after the 2nd decade.
– Family history (30%)
– Most frequent in those with autoimmune disease. (Autoimmune thyroiditis, alopecia errata,
pernicious anemia)
– Melanocytes are the target of a cell-mediated autoimmune attack or
– Self-destruct because of an inability to remove toxic melanin precursors
2. Localized vitiligo
– Restricted to one part of the body,
– Occurs earlier than generalized vitiligo
– Not associated with autoimmune diseases
• Trauma and sunburn can precipitate both types, so koebner phenomena is seen here or if due to sun
light photo koebner phenomenon.
 Clinical course
Generalized type Localized type
• Sharply defined • Look like the generalized type
• Symmetrical • Segmental/ focal distribution
• Spontaneous repigmentation occurs more
• White patches are common on
often than in generalized vitiligo
– Backs of the hands
– Wrists
– Fronts of knees
– Neck
– Around body orifices
• Hair of the scalp and beard may depigment too. Poor prognosis.
• Trichrome vitiligo: in Caucasoids, the surrounding skin is sometimes partially depigmented or
hyperpigmented.
• The course is unpredictable: lesions may remain static or spread
• Sometimes following minor trauma (Köbner phenomenon)
• Repigment spontaneously from the hair follicles
Generalized vitiligo Fig. 19.4 Striking patchy vitiligo Localized vitiligo
on the knees.
 Differential diagnosis
1. Contact with depigmenting chemicals such as
– Hydroquinones
– Substituted phenols in the rubber industry
– History is important here
2. Pityriasis versicolor
– Fine scaling
– Less complete pigment loss (hypopigmentation = wood’s light: pale)
3. Post-inflammatory depigmentation (vast majority it’s hypopigmenatation not de)
– May look very like vitiligo
– Less white
– Improves spontaneously
4. Piebaldism are present at birth.
5. Leprosy must be excluded by sensory testing & GE.
6. Other tropical diseases
– Leishmaniasis
– Yaws
– Pinta
 Treatment
• Treatment is unsatisfactory
• Sun avoidance and screening
• White people
– Best left untreated in most
– Camouflage preparations (dihydroxyacetone)
• Black patients with extensive vitiligo can be completely and irreversibly depigmented by creams
containing the monobenzyl ether of hydroquinone
• Potent or very potent topical corticosteroid
• Calcineurin inhibitors (0.1% tacrolimus ointment)
• Psoralens
• UVB
• Irradiating skin with a 308-nm excimer laser and antioxidant therapy with Ginkgo biloba extract or
catalase
• Autologous skin grafts
 Post-inflammatory hypopigmentation
and RARELY depigementation
• The more severe the inflammation, the more likely pigment is to decrease
• May follow
– Eczema
– Psoriasis
– Sarcoidosis
– Lupus erythematosus
– Rarely, lichen planus.
– Cryotherapy or a burn.
– Pityriasis alba
• Most significant in Negroids and Asians
• With time, the skin usually repigments. Partial temporary loss, due to effect of
inflammatory mediators on various steps of melanogenesis. Once inflammation is
controlled skin repigments.
 Pityriasis alba
• Common on the faces of children
• The initial lesion: variant of eczema (pinkish
with fine scaling) so we ask in history about a
previous red, scaly, itchy rash.
• Leaving one or more pale, slightly scaly
areas
• Exposure to the sun makes the patches more
obvious. Because normal skin gains pigment
but affected areas remain pale, more contrast.
• A minor feature of atopic eczema.
• Reassurance that this is not vitiligo, it’s
temporary, with time the skin will repigment.
• DDx: p. versicolor
Disorders with increased pigmentation
(hypermelanosis/hyperpigemntation)
Causes: pigmented (acronyme)
• Pi: Post-inflammatory
• G: Genetics
• M: Malignancy and Metabolic
• E: Endocrine
• N: Nutritional
• Te: Trauma exogenous (chemicals)
• D: Drugs
Fig. 19.7 The mechanisms of some types of hyperpigmentation. UVR, ultraviolet radiation.
Freckles (ephelides)
• Very common
• Most often in the red haired or blond person
• Sharply demarcated
• Light brown ginger macules
• Usually < 5 mm in diameter.
• They multiply and become darker with sun exposure.
• Increased melanin in the basal layer of the epidermis without
– Any increase in the number of melanocytes (no increased risk
of melanoma)
– Elongation of the rete ridges
• No treatment is necessary, except for cosmetic reasons
(medical: topical bleaching agents, physical: laser, cryotherapy)
 Melanotic macule of the lip
• Common lesion
• Benign
• Its histology is similar to that
of a freckle

Fig. 19.9 Melanotic macule of the lip:

slow to evolve and benign, as suggested
by its even colour and sharp
margin.
 Lentigo
• It is a harmless (benign) hyperplasia of melanocytes which is linear
in its spread.

• Classified into: Simple and senile lentigines.

• Small (Ranging from 1 mm-1 cm)
• Round (May have an irregular outline)
• Flat, Light or dark brown macule.
• may appear on any body site
• Usually discrete
 Lentigo
Simple lentigines
• Most often in childhood
• Few scattered lesions
• Often on areas not exposed to sun, including the mucus membrane
• Evenly pigmented.
 Lentigo
Senile or solar lentigines
• Common after middle age
• Limited in distribution to sun exposed skin. On the backs of the hands
(‘age spots’,‘liver spots’) & face.
• Should be distinguished from
– Freckles
– Junctional melanocytic naevi
– Lentigo maligna
Fig. 19.8 Histology of a freckle and Freckle
Treatment usually unnecessary
1. Sun avoidance & Sunscreens
2. Melanin-specific high energy lasers (ugly lesions).
3. Liver spots lighten or clear with the daily application of
• 0.1% tretinoin cream
• 2–4% hydroquinone
• Combination with
• Retinoid Fig. 19.10 Senile lentigines on the back
• α-hydroxy acid of an elderly hand (‘liver spots’). Note
accompanying atrophy.
• Topical corticosteroid
4. Careful cryotherapy
 Lentiginosis
• Widespread distribution of lentigines, does not follow a specific pattern
• Appear in early age
• We have to look for associations (GI, cardiac, pulmonary)
• Also they have increased risk of melanoma due to increased number of melanocytes
• Have to consider that they may be a part of other syndromes; like:
– Peutz–Jeghers syndrome
– Cronkhite–Canada syndrome
– LEOPARD syndrome
– LAMB
• We have to look for GI tumours especially with Cronkhite–Canada syndrome
• LAMB is associated with cardia abnormalties (atriral myxomas)
 Peutz–Jeghers syndrome
• AD
• Profuse lentigines around the lips
• Scattered lentigines also occur on the buccal mucosa, gums,
hard palate, hands and feet.
• Associated with polyposis of the small intestine, which may
lead to recurrent intussusception and, rarely, to malignant
transformation of the polyps. Fig. 19.12 Profuse lentigines on and
around the lips in the Peutz–Jeghers
• 10% of affected women have ovarian tumours. syndrome.
 Cronkhite–Canada syndrome
• Rare
• Multiple lentigines on the backs of the hands
• More diffuse pigmentation of the palms and volar
aspects of the fingers.
• It may also be associated with gastrointestinal
polyposis.
• Alopecia and nail abnormalities
LEOPARD syndrome
Acronym
• L: generalized lentiginosis
• E: ECG 🡪 cardiac abnormalities
• O: ocular hypertelorism
• P: pulmonary stenosis
• A: abnormal genitalia
• R: retardation of growth
• D: deafness
 Melasma (chloasma)
• Acquired
• Symmetrical
• Occurring on sun-exposed skin, especially the face.
• Well defined & their edges may be scalloped.
• Much more common in women.
• The hypermelanosis becomes darker after exposure to the sun.
• Causes
– Sunlight (most important factor in pathogenesis)
– Pregnancy ‘the mask of pregnancy’ (less role than sunlight)
– Oestrogens
– OCPs
– Scented cosmetics
– Thyroid dysfunction
– Photosensitizing drugs
• The placenta may secrete sex hormones that stimulate melanocytes.
• Over-expression of α-MSH has been demonstrated in lesional skin.
• Most of the extra melanin lies in the epidermis, but there is some in the dermis too, making treatment difficult.
 Treatment
Treatment is unsatisfactory
1. Sunscreen
2. Bleaching agents (contain hydroquinone)
3. Stubborn cases the hydroquinone may be combined with a topical steroid
& retinoid for short-term use.
4. Chemical peels have become popular. α-Hydroxy acids, especially glycolic
acid.