Non-melanin pigmentation: A narrative review

Introduction

Skin colour varies between individuals and is generally determined by the presence of melanocytes, carotene, oxygenated haemoglobin, and local blood flow. The colours reflected from the skin are important indicators of dermatologic and systemic disorders. The three qualities of visible light include chroma (purity), value (lightness or darkness), and hue (colour).¹ Hue or colour is the most obvious visible characteristic used in clinical assessments and can help in the diagnosis of dermatological and internal diseases. This article provides a synopsis of the conditions that comprise non-melanin pigmentation. We carried out a PubMed search using the following keywords: “pigmentation, non-melanin, melanin, xanthoderma, blue-coloured, yellow-coloured, metals, hypopigmentation, hyperpigmentation, vascular.” Articles from the last 15 years were included for the review. Eighty-six articles were studied, and the conditions were listed and analysed regarding pathogenesis. Those conditions where the primary pathology does not pertain to melanin were included in the review.

Pigmentary disorders can be classified into hypopigmentary and hyperpigmentary disorders, while non-melanin pigmentary conditions can be divided into:

• 1.

  Blue-coloured lesions

• 2.

  Hypopigmented lesions due to vascular aetiology

• 3.

  Yellow-coloured lesions

• 4.

  Green-coloured lesions

• 5.

  Miscellaneous causes

1. Blue-coloured lesions

Melanocytes in the dermis can give a bluish hue due to the resultant Tyndall effect. Based on the cause, blue-coloured lesions can be broadly divided into:

• Naevi²

• Vascular lesions and venous malformation

• Blue lesions secondary to thermal injury

• Infections and infestations

• Miscellaneous

• Various naevi that present as bluish lesions have been described in Table 1.

• Vascular lesions and venous malformation

The dermal placement of blood vessels gives a bluish hue to the skin. Conditions that present as bluish vascular lesions include:

• Blueberry muffin baby: A characteristic neonatal eruption that reflects dermal erythropoiesis. Lesions are erythematous to bluish purple, circular or oval macules, papules, and nodules that can be present in a generalised distribution.³

• Blue rubber bleb naevus syndrome: It is characterised by multiple venous malformations affecting the skin and internal viscera, mainly the gastrointestinal tract. Lesions are usually asymptomatic but symptoms can occur secondary to pressure on surrounding structures.⁴

• Venous lake: It presents as a soft, bluish papule on the lower lip of middle-aged and elderly population. The condition occurs due to vascular ectasia and is treated with excision, cryotherapy, coagulation, and laser.

• Blue lesions secondary to thermal injury

Continuous exposure to cold temperature causes vasospasm in the dermal vessels, which imparts a bluish hue to the skin. A few such conditions that present as bluish lesions are:

• Cutis marmorata - This is a physiological response in newborn infants, who develop distinct marbling of the skin which disappears on rewarming.

• Acrocyanosis- It is seen commonly in females and presents as persistent, painless, mottled, deep blue or cyanotic discolouration of the hands, feet, and face.

• Raynaud’s phenomenon- It is a triphasic change in skin colour seen over fingers and toes, which may be a sign of an underlying autoimmune connective tissue disorder. The initial phase of pallor is followed by a blue discolouration [Figure 1], and then erythema.

• Frostbite - It is characterised by haemorrhagic blisters with skin necrosis and a blue-grey discolouration of the skin, followed later by burning, throbbing, and shooting pains.

• Infections and infestations

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Figure 1:

Bluish discolouration of hands seen in Raynaud’s phenomenon.

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Infectious disorders that manifest as bluish lesions include:

• Herman’s spot and Koplik’s spots- In measles, blue-grey stippling may appear on the tonsils (Herman’s spot). Punctuate blue-white lesions surrounded by erythematous rim on buccal mucosa against the second molar (Koplik’s spots) are pathognomonic. Similar spots may be seen on the conjunctivae at the medial canthi.

• Blue ball sign- In lymphogranuloma venereum, oedema and livid colour of the overlying skin are seen over the bubo.

• Maculae ceruleae- This refers to bluish macules on the lower abdomen and upper thigh in people infested with Pthirus pubis. These have also been reported secondary to bites from Pediculosis humanus capitis.⁵

• Blue-green fluorescence on Wood’s lamp- Microsporum species that causes tinea capitis shows a blue-green fluorescence under Wood’s lamp.

• Blue neck syndrome- It is a common condition seen in northern Kerala that is caused by a nematode. The affected skin has a dull, dry, matt surface with a characteristic bluish-black colour, distinctive pigmentation of skin folds, and surface clearly visible as nonpigmented grooves.⁶

• Miscellaneous causes of bluish pigmentation

• Blue sclera – It is seen in patients with Ehlers-Danlos syndrome, pseudoxanthoma elasticum, osteogenesis imperfecta, Marfan’s syndrome, and alkaptonuria.

• Blue Scrotum Sign of Bryant – The condition was described by JH Bryant for scrotal ecchymosis associated with a ruptured abdominal aortic aneurysm. Non-traumatic discolouration beneath the intact scrotal or penile epithelium occurs due to extravasation of blood in the retroperitoneum.⁷

• Blue-grey pigmentation secondary to drugs- Drugs like amiodarone, chloroquine and hydroxychloroquine, tricyclic antidepressants (imipramine, desipramine), and heavy metals cause pigmentation that is pronounced on sun-exposed areas of the body.

• Blue chromonychia- Blue discolouration of nails is secondary to drugs like minocycline, zidovudine, cyclophosphamide, doxorubicin, and bleomycin. Cocktail chemotherapy may also cause blue chromonychia due to matrix melanocyte activation. Exposure to silver salts, Wilson’s disease (causing azure lunula), glomus tumour of a nail, and digital arterio-venous malformation can cause blue nail.

Blue colour in dermatoscopy

Colour in dermoscopy depends on the location of pigment in the skin. Blue colour corresponds to pigmented structures located in the dermis.⁸ Bluish hue on dermoscopy is seen in the following conditions:

• Blue rubber bleb naevus syndrome: Red-purple globules with verrucous surface, lacunas separated by a white linear structure corresponding to fibrous demarcations.

• Basal cell carcinoma- Blue grey globules [Figure 3]/ovoid nests/maple leaf pattern with arborising vessels, blue-white veil, milky red area, and ulcerations/crusts.

• Melanomas- Atypical pigment network with irregular brown-black dots/globules and streaks. Pigmentation with multiple colours is asymmetrically distributed. Blue-whitish veil and polymorphic vessels are common in invasive melanoma.

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Figure 2a:

Bluish macules in the lumbosacral region in an infant suggestive of congenital dermal melanocytosis.

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Figure 2b:

Naevus of Ota in a young female.

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Figure 3:

Blue-grey globules seen on dermoscopy in a patient with basal cell carcinoma (Heine delta, polarised, 10x magnification).

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2. Hypopigmented lesions due to vascular aetiology

The incidence of vascular disorders manifesting as hypopigmentation is difficult to estimate because cases are usually mild and often underdiagnosed. A few of the conditions are described below:

• Naevus anemicus

It is an uncommon, congenital, nonprogressive entity with a prevalence of 1% to 2% and a slight female preponderance. It manifests as solitary or multiple ill-defined, irregularly shaped, confluent hypopigmented macules that blend into the normal skin over the trunk, face, and extremities.

Increased response of the alpha-2 receptors of the lesional vasculature to catecholamines leads to hypopigmentation of the skin. Vigorously rubbing the lesion and surrounding skin or applying ice or heat will accentuate the lesion due to reactive erythema in the surrounding skin while the lesional skin remains pale.

Diagnosis is by diascopy, where the naevus blends into the surrounding pale skin. Firm stroking through lesional and non-lesional skin will not elicit the triple response of Lewis. Dermoscopy reveals a lack of blood vessels in the lesion’s centre with a compensatory flare in the surrounding skin.⁹ Biopsy shows a normal number and distribution of melanocytes as well as melanin.

• Bier’s spots (Pseudo leukoderma angiospasticum)

Bier spots are a benign physiological vascular anomaly characterised by multiple, asymptomatic, small, hypopigmented macules on the extensor surface of extremities in young adults. It arises due to the response of cutaneous vessels to venous hypertension or small vessel vasoconstriction, inducing tissue hypoxia. They disappear after raising the affected extremity or when pressure is applied to the surrounding skin. Dermoscopy shows pale white macules with white structureless areas lacking vessels, which may disappear when the arms are raised.¹⁰

• Woronoff’s ring

A ring-like zone of hypopigmentation surrounds resolving psoriasis lesions [Figure 4]. It was also described as a “pseudoatrophic” annular zone surrounding acanthotic psoriatic plaques.

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Figure 4:

Woronoff’s ring (black arrow)

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Pathogenesis includes disturbed vascularisation and prostaglandin metabolism with decreased levels of endoglin, a scavenger of transforming growth factor beta. The production of IL-17, IL-22, and Tumour Necrosis Factor-α by pathogenic CD8⁺ T-cells in psoriasis leads to synergistic action on melanocytes, increasing their proliferation while inhibiting melanogenesis.¹¹

It may develop spontaneously; after ultraviolet phototherapy, topical anthralin or steroids; or with systemic drugs such as fumaric acid esters or the TNF-α antagonist adalimumab. It has been reported in a patient with a deficiency of interleukin-36 receptor antagonist (DITRA) on Anakinra.¹²

• Other causes

Anaemia: The pallor of skin is seen in all types of anaemia due to a lack of oxyhaemoglobin.

Raynaud’s phenomenon: The triphasic colour change (described above) from blue to white occurs due to vasoconstriction of the small blood vessels.

3. Yellow coloured lesions

The main chromophores that reflect yellow light are carotenoids and bilirubin. Bilirubin is a breakdown product of haemoglobin that gives a yellowish hue. Exogenous chromophores can be directly applied or inserted into the skin, such as cadmium sulphide in tattoos, and through dietary ingestion. The latter includes carotenoids that impart a yellowish-orange discolouration to the skin.

Yellow to orange discolouration of the skin is called xanthoderma, which is a term derived from the Greek meaning ‘‘yellow skin.’’ Main disorders that present as xanthoderma are jaundice and carotenoderma.¹³

• Jaundice (icterus), is a yellow discolouration of epithelia caused by bilirubin deposition in elastic tissues. The conjunctivae, episcleral and sublingual tissues are rich in elastic fibres and are usually affected before the skin. Jaundice is always accompanied by hyperbilirubinemia and typically becomes clinically apparent when serum bilirubin exceeds 3.0 mg/dL.

• Carotenoderma: Condition characterised by yellow to yellowish brown discolouration of the skin. This can occur due to excessive dietary intake of carotenoids (α- and β-carotene, beta-cryptoxanthin, lycopene, lutein, and zeaxanthin), decreased metabolism of carotenoids, and increased serum lipids. Carotenoderma can also be categorised as primary (increased oral intake of foods rich in carotenoids- pumpkin, carrots, bell peppers, eggs, broccoli, tomato, grapefruit, leafy greens) or secondary (underlying diseases that cause an increase in serum carotenoids).¹⁴ Conditions like diabetes mellitus, hypothyroidism, nephrotic syndrome, and liver disease are associated with hypercarotenemia.

Carotenes are deposited in the epidermis, within the lipids in the stratum corneum. These may persist clinically for up to 5 months after normalisation of dietary intake. Hypercarotenemia presents with a yellow hue predominant on the acral surfaces and the nasolabial folds, sparing the sclera and mucous membranes. Sparing of sclera helps in differentiating from jaundice.

Lycopene is excreted by sebaceous and eccrine glands, which are partly reabsorbed by the horny layer of the skin.¹⁵ Red fruits and vegetables, such as apricots, tomatoes, watermelons, pink guavas, and pink grapefruits, are important sources of lycopene. Topical tanning products containing dihydroxyacetone react with epidermal lipids on topical application to form melanoidin, creating a yellow-brown colour, more pronounced on palms due to increased skin thickness and basal layer penetration.¹⁶ Involvement of the soft palate and liver parenchyma is the hallmark of lycopenemia.

There are several other conditions with abnormalities in keratin, elastic and connective tissue, lipid metabolism, and metabolic, inflammatory, or organ dysfunction that present with yellow-coloured lesions. These are described in Table 2, while Table 3 shows categorisation of yellow-coloured lesions according to morphology. Few disorders can cause yellow discolouration of nails or hair. These have been highlighted in Table 4.

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Figure 5:

Lichen aureus with yellow-orange pigmentation.

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Figure 6a:

Fordyce spots (blue arrow) are seen as pinpoint yellow papules.

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Figure 6b:

Xanthelasma (blue arrow) in a patient with familial hypercholesterolemia.

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Yellow colour on dermatoscopy

Cutaneous mastocytoma presents as a red nodule, but dermoscopically appears yellow, which corresponds to keratin. Thus, the normal epidermis appears yellow in non-polarised light. Lipids present in sufficient volume will also be visible dermoscopically as a yellow colour.¹⁷

Yellow colour in histopathology

The common histologic findings that cause a yellow colour clinically are hyperkeratosis, intracellular or dermal deposition of lipids, and changes due to sebaceous and elastic tissue disorders.

4. Green-coloured lesions

Green lesions affecting the skin, hair, and nails are rare but can arise from diverse causes, categorised as exogenous or endogenous.^18-20 These have been summarised in Table 5.

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Figure 7:

Greenish discolouration of nail due to Pseudomonas infection.

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While some causes, such as dyes or infections, are benign, others, like chloromas or liver disorders, indicate serious conditions requiring immediate attention

5. Miscellaneous causes of non-melanin pigmentation

• (a)

  Pigmentation due to metals

Metals can impart various colours to the skin. Various conditions associated with metal-induced pigmentation are described below:

• Tattoos

Tattoo is the introduction of exogenous pigment, which gives the dermal colour of the desired pattern. It can be medical or decorative. Modern-day colourants are mainly organic, containing azo or polycyclic pigments, but mercury, titanium dioxide, antimony, cadmium, lead, chromium, cobalt, iron oxide, nickel, and arsenic present as contaminants impart different colours to the skin. Tattoo ink consists of a carrier and pigment. Metallic salts and organic dyes are used as pigments, while the carrier works like a solvent. The most commonly used colour is black, which consists of iron oxides and diverse carbons. Green ink consists of chromium and copper, yellow cadmium salts; blue ink is composed of chromium, cobalt, and copper salts; and red ink contains high levels of mercury. In vitro analysis of black, blue, and red inks has shown cytotoxicity, genotoxicity, and production of reactive oxygen species.²¹ Also, red tattoos produce more adverse reactions as compared to black tattoos [Figure 8].²² Till now, the FDA has not approved any pigment for injection into the skin for cosmetic purposes, and there are no legislations to promote safe tattooing.

• Argyria

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Figure 8:

Granulomatous reaction to red pigment in tattoo.

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Argyria or silver-induced cutaneous pigmentation is derived from the Greek word ‘argyria’, which means silver. Argyria can be generalised or localised.

• (i)

  Generalised argyria has been reported after consumption of silver-containing dietary supplements, homeopathic medication, and silver-coated betel or cardamom. It presents with diffuse blue-grey pigmentation, more pronounced in sun-exposed areas, sparing the creases.²³

• (ii)

  Localised cutaneous argyria is seen after percutaneous absorption of silver through sweat pores, wounds, or traumatic implantation, occupational exposure (e.g., silversmiths), silver filigree in hernia repairs, silver acupuncture needles, and ear or nose piercing with silver. Amalgam silver tattoo has been reported in the oral mucosa. It presents with blue-grey pigmented macules and papules.²⁴

• (iii)

  Argyria can affect nails (‘azure lunula’), oral mucosa, cornea and conjunctiva. Use of topical silver nitrate may also lead to grey-black staining of fingernails.

  • Chrysiasis: Chrysiasis is the permanent discolouration of the skin after prolonged exposure to parenteral gold. Gold was used in the past for various conditions and as ayurvedic (e.g., swarnabhasma) and homeopathic medications.

  Chrysiasis starts with a mauve discolouration in the periorbital area, which turns into greyish-blue or purplish-blue colour affecting the face and sparing the creases. Covered areas become pigmented after exposure to ultraviolet light. The severity is dose-dependent and deposition may also occur in the mucosa.²⁵ Localised cutaneous chrysiasis has been reported after implantation of gold-plated acupuncture needles and laser treatment in a patient who had received parenteral gold,.^26,27

• Arsenicosis

Chronic arsenic poisoning can occur through environmental, occupational, or medicinal exposure to arsenic. Environmental exposure is mainly through contaminated tube wells. Arsenic accumulates in keratin-rich tissues such as skin, nails, and hair.²⁸

Skin manifestations occur after 2-9 years of exposure. It can be spotted, diffuse with scattered pale macules (‘raindrops on dusty road’), leukomelanosis, idiopathic guttate hypomelanosis-like lesions, and argyria-like pigmentation with hypopigmented macules [Figure 9a]. The pigmentation is more over flexures and areas of friction. Brownish discolouration and Mees lines may be seen on the nails. Hyperkeratotic papules & plaques are seen on the palms and soles. Diffuse keratoses and large verrucous growths can occur which may undergo malignant transformation. The risk of skin cancers increases with an increase in cumulative exposure, frequency, and size of hyperkeratosis.²⁹

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Figure 9a:

Arsenic toxicity with hyper and hypopigmented macules.

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Arsenic and ultraviolet (UV) rays are co-carcinogens. Arsenic inhibits DNA repair through the PARP1 enzyme, enhancing UV damage in keratinocytes and melanocytes.³⁰ It is associated with various skin and internal malignancies as well as peripheral vascular disease (‘black foot disease’), pancytopenia, non-cirrhotic portal hypertension, diabetes mellitus, cardiovascular disease, and perinatal conditions.

Other metals causing pigmentation have been highlighted in Table 6.^31-34

• (b)

  Chromhidrosis

It is a rare condition causing the secretion of coloured sweat. It has been classified into:

• 1.

  Apocrine chromhidrosis, seen after puberty, is confined to areas like the face and axilla, anogenital, and rarely the areola. Depending on the level of oxidation of the lipofuscin granules in the apocrine glands, the colour of sweat can be yellow, blue, green, and blue-black.³⁵

• 2.

  True eccrine chromhidrosis is a less common disorder. Exogenous causes are ingestion of water-soluble dyes such as tartrazine, various additives in food products, drugs such as quinine, rifampicin and heavy metals. The endogenous cause is hyperbilirubinemia. ³⁶

• 3.

  Pseudo-eccrine chromhidrosis occurs when the colourless sweat subsequently develops colour on reaching the skin in reaction with exogenous chromogenic bacterial products such as Corynebacterium, chemicals such as dihydroxyacetone, paints, and dyes.³⁷

• (c)

  Ochronosis

The term ‘ochronosis’ is derived from ochre (as a colour name, ‘brownish-yellow). Ochronosis can be endogenous or exogenous.

• 1.

  Endogenous ochronosis is the cutaneous manifestation of an autosomal recessive inborn error of metabolism, alkaptonuria, which is due to a deficiency of homogentisate 1,2-dioxygenase. Homogentisic acid accumulates in the body, leading to skin pigmentation, arthropathy, and dark urine. A chromatography assay in the urine for homogentisate is the gold standard for alkaptonuria.³⁸

• 2.

  Exogenous ochronosis is an acquired condition that clinically and histologically resembles alkaptonuria but does not have systemic manifestations. It presents as asymptomatic bilaterally symmetrical speckled blue-black macules and grey-brown macules, papules and nodules previously described as “caviar-like” bodies, affecting the malar areas, temples, lower cheeks and neck [Figure 9b]. It results from the use of topical hydroquinone, phenol, quinine injection, resorcinol, picric acid, mercury, and oral antimalarials.^39,40

• (d)

  Talon noir/tache noir: Also called “black heel,” presents as hyperpigmented macules over sites of repetitive heel trauma. It is caused by intraepidermal haemorrhage due to shearing forces.

• (e)

  Cydnidae pigmentation: Brownish-black pigmented macules develop due to secretions of burrowing bugs (Cydnidae). These secretions stain the skin on exposed sites. These resemble ink stains and can sometimes mimic other conditions like dermatitis artefacta.

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Figure 9b:

Ochronosis in a patient applying hydroquinone for 2 years continuously.

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Conclusion

Several conditions can present as non-melanin pigmentation. The colour change can vary from orange, yellow, pink, red, blue, green, or grey depending on the aetiology. The colour and pattern of pigmentation are important indicators of the underlying cause. While a few conditions are confined to the skin, several others provide clues to underlying systemic disease, which can go unrecognised in the absence of proper evaluation. It is important for the dermatologists to be well aware of these entities and provide appropriate treatment options to the patient.