The melanocortin system: medical management of congenital melanotic naevi
The pathogenesis and molecular biology of Congenital Pigmented Naevi are now understood in great detail, especially in relation to Proto-oncogene mutations c-met, c-kit and the MC1R Melanocortin pepitide. The “red hair gene” is an Autosomal Recessive Gene (Chromosome 16) with mutation in the MC1R Protein. This mutation is related to the pathogenesis of Congenital Melanotic Naevi. The classification of Congenital Melanotic Naevi and molecular biology of Melanocortin System is presented, and the potency of Melanocortin Ligands and their antagonists are discussed with reference to Melancortin Drug Development, and the potential to reverse giant naevus pigmentation. Whilst cosmetic camouflage is very effective treatment modality, current research heralds the development of melanocortin-based drugs for the reversal of naevus pigmentation, the treatment of skin cancer and other cutaneous disorders.
Congenital melanocytic naevi (CMN) are proliferations of benign melanocytes that are present at birth or develop shortly after birth .
Other melanocytic naevi, but were not present at birth, are termed:
- congenital naevus-like naevi
- congenital type naevi
- tardive naevi.
Naevi may also form from other skin cells eg vascular naevi. Some of these are also congenital.
Classification of Congenital Melanocytic Naevi (CMN)
CMN are usually classified by size.
- Small congenital melanocytic naevi are <1.5 cm in diameter
- Medium congenital melanocytic naevi are 1.5 – 19.9 cm
- Giant congenital melanocytic naevi are ≥20 cm in diameter
A modification of the above classification  :
- Small congenital melanocytic naevi are <1.5 cm in diameter
- Medium congenital melanocytic naevi are 1.5 – 10 cm
- Large congenital melanocytic naevi are 11 – 20 cm
Giant congenital naevi are further subdivided into:
- G1 (21–30 cm)
- G2 (31–40 cm)
- G3 (>40 cm)
– Inherited flat tan mark
– Usually oval in shape
– Multiple café-au-lait macules may be a sign of neurofibromatosis
|Speckled lentiginous naevus||
– Also called naevus spilus
– Dark spots on a flat tan background
– Smaller melanocytic lesions
– On periphery of central congenital melanocytic naevus
– Present in >70 % of large congenital melanocytic naevi
– Naevi that appear after birth
– Slower growth and less synthesis of melanin than congenital naevi 
– Name relates to anatomical location of naevus
– Bathing trunk naevi involve central areas usually covered by a bathing costume
– Coat sleeve nevi involve an entire arm and proximal shoulder
– Affects some congenital melanocytic naevi
– Surrounding skin becomes lighter
– Central lesion may also become lighter and smaller
– Due to immune destruction of melanocytes
Tab. 1: Classification of Congenital Melanotoc Naevi.
- – Small 1 : 100 births [1-3]
- – Medium 1 : 1000 births 
- – Giant 1 : 20, 000 live births [1-3]
They occur in all races and ethnic groups, and males and females are at equal risk.
- Single or Multi-shaded
- round or oval shaped pigmented patches .
- Hyertrichosis may be a feature
- The surface may be slightly rough or bumpy.
Growth is usually proportionally with the child. As a rough guide, the likely adult size of a congenital naevus can be calculated as follows:
- Lower limbs: adult size is x 3.3 size at birth
- Upper limbs / torso: adult size is x 2.8 size at birth
- Head: adult size is x 1.7 size at birth
Congenital naevi may become smaller and thus less obvious. Rarely some may even disappear. Particularly around puberty they become darker, raised, bumpy and hairy.
- Usually asymptomatic
- Pruritis – especially larger lesions.
- Sebaceous and eccrine gland atrophy may contribute to skin dryness and itch.
- Skin erosion / ulceration of skin
- Skin fragility – weakening of dermal epidermal junction
- Cosmesis – anxiety and impaired self image
- increased risk of developing cutaneous melanoma, neurocutaneous melanoma and rarely other tumours.
Genetic abnormalities and melanocyte proliferation between the 5 – 24 weeks of gestation. If proliferation starts early in development, giant and medium sized congenital melanocytic naevi are formed . At the same time, smaller congenital melanocytic naevi are formed, after the melanoblasts have migrated from the neural crest to the skin . In some cases, there are also overgrowth of hair-forming cells and epidermis, forming an organoid naevus.
Melanin is a broad term for a group of natural pigments found in most organisms (arachnids are one of the few groups in which it has not been detected). Melanin is a two staged process:
- oxidation of the amino acid tyrosine
- secondary polymerisation.
The pigment is produced in a specialized group of cells known as melanocytes. There are three basic types of melanin:
Molecular Biology 
Proto–oncogenes c-met and c-kit  have important roles in the development of melanocytes. Hepatocyte growth factor, a cytokine that regulates the proliferation and migration of melanocytes, may also be important in the development of congenital melanocytic naevi .
c-Met is a proto-oncogene that encodes a protein, hepatocyte growth factor receptor (HGFR) [1, 2].
This possesses tyrosine-kinase activity .
MET proto-oncogene is translated into a trans-membrane MET protein which is a receptor for tyrosine kinase (RTK) through transphosphorylation.
MET is a trans-membrane receptor that is essential for embryonic development and wound healing.
- Hepatocyte growth factor (HGF) is the only known ligand of the MET receptor.
- MET is normally expressed by cells of epithelial origin
- Expression of HGF is restricted to cells of mesenchymal origin.
- Upon HGF stimulation, MET induces several biological responses that collectively give rise to
- a programme known as invasive growth.
- Abnormal MET activation in cancer correlates with poor prognosis
- aberrantly active MET triggers tumour growth, angiogenesis, and facilitates metastasis.
- MET is deregulated in many types of human malignancies, including cancers of kidney, liver, stomach, breast, and brain.
Normally, only stem cells and progenitor cells express MET, which allows these cells to grow invasively in order to generate new tissues in an embryo or regenerate damaged tissues in an adult.
However, cancer stem cells are thought to hijack the ability of normal stem cells to express MET, and thus become the cause of cancer persistence and metastatic spread to other sites in the body.
Various mutations in the MET gene are associated with papillary renal carcinoma .
Proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117, also known as Mast/stem cell growth factor receptor (SCFR), is a protein that in humans is encoded by the KIT gene.
Hematopoietic stem cells (HSC), multipotent progenitors (MPP), and common myeloid progenitors (CMP) express high levels of CD117. In addition, mast cells, melanocytes in the skin, and interstitial cells of Cajal in the digestive tract express CD117.
CD117 is a cytokine receptor expressed on the surface of hematopoietic stem cells as well as other cell types. Altered forms of this receptor may be associated with some types of cancer. CD117 is a receptor tyrosine kinase type III, which binds to stem cell factor. Signalling through CD117 plays a role in cell survival, proliferation, and differentiation.
Activating mutations in this gene are associated with gastrointestinal stromal tumors, testicular seminoma, mast cell disease, melanoma, acute myeloid leukemia, while inactivating mutations are associated with the genetic defect piebaldism.
CD117 is a proto-oncogene. Overexpression or mutations of this protein can lead to cancer.
- mast cell disease
- gastrointestinal stromal tumors (GISTs).
The site of mutation determines the efficacy of immunotherapy:
- imatinib, a CD117 inhibitor, targets mutation in exon 11 (e.g. GISTs)
- dasatinib and nilotinib targets mutation in exon 17 (e.g. seminomas and leukemia)
|Potency of Ligands||Antagonists||Primary Functions|
|MC1R||á-MSH = ACTH > â-MSH > ã-MSH||Agouti||Pigmentation, inflammation|
|MC3R||á-MSH = â-MSH = ã-MSH = ACTH||Agouti, AGRP||Energy homeostasis|
|MC4R||á-MSH = ACTH > â-MSH > ã-MSH||Agouti, AGRP||Energy homeostasis, erectile function|
|MC5R||á-MSH > ACTH > â-MSH > ã-MSH||Sebaceous gland secretion|
Tab. 2: The Melanocortin System. MC1R = melanocortin receptor-1; MSH =melanocyte-stimulating hormone; ACTH = adrenocorticotropic hormone; AGRP = agouti-related protein.
Melanocortin Drug Development
On the basis of their prominent regulatory role in many of these functions, the development of melanocortin-based drugs is presently in the developmental phase, for the treatment of skin cancer and other cutaneous disorders, including Giant CMN, obesity, anorexia nervosa, cachexia, erectile dysfunction, inflammatory diseases, pain, and nerve injury.
Antagonists and inverse agonists include:
- MC1 selective Agouti signalling peptide
- Selective Agouti-related peptide (inverse agonist at both MC3 and MC4)
- SHU-9119 (agonist at MC1 and MC5, antagonist at MC3 and MC4)
Melanocortins and Pigmentation
Activation of MC1R by á-MSH stimulates eumelanin synthesis. Conversely, antagonism of á-MSH action by agouti favours phaeomelanin synthesis. MC1R has also been reported to be upregulated by UV radiation.
Melanocortin-1-receptor gene MC1R
Kinsler et al  have demonstrated an association with melanocortin-1-receptor gene (MC1R) — known to result in red hair, freckles, and pale skin, and Cutaneous Melanotic Naevus.
Congenital melanocytic nevi (CMN) are pigmented birthmarks that affect up to 80 % of the skin surface area. The increased frequency of CMN in families of severely affected individuals is suggestive of a predisposing germline genotype. Kinsler et al noted a high prevalence of red hair in affected families, and considered a role for MC1R in this condition. A cohort of 166 CMN subjects underwent pigmentary phenotyping, with MC1R genotyping in 113. Results were compared with a local control group of 60 unrelated children and with 300 UK children without CMN. CMN subjects had higher prevalences of red hair and a red-haired parent than local controls and had a higher rate of compound heterozygosity and homozygosity for MC1R variants. The presence of a V92M or R allele (D84E, R151C, R160W, D294H) was associated with increasing size of the CMN, implying a growth-promoting effect of these alleles. Unexpectedly, the V92M and R151C alleles were also strongly associated with birth weight in the CMN cohort, a finding confirmed in the control group. The effect of germline MC1R genotype on development and severity of CMN led us to investigate potential broader effects on growth, revealing a role for MC1R in normal fetal development.
The MC1R gene has more than 100 known variants. In this study, a third of children with CMN had a first- or second-degree family history of any size of CMN. Small CMN are very common, occurring in one in every 100 babies. These children had a higher instance of at least one MC1R allele than children without a family history of CMN.
Two specific variants, V92M and R151C are strongly associated with increased birth weight, suggesting a previously unknown role for MC1R in normal foetal development. In children with CMN, the presence of these and a few other alleles appear also to correlate with increased size of the CMN.
Red Hair 
- Incidence 1-2 %
- More frequent in Northern / Western Europe ancestory (2-6 %)
- Autosomal Recessive Gene (Chromosome 16) with mutation in the MC1R Protein
- Colour varies from burgundy to bright copper
- Related to high levels of pheomelanin and low levels of eumelanin
- In Scotland and Ireland 40 % and 46 % respectively are thought to carry the recessive red hair gene
- During the Spanish Inquisition all redheads were identified as being Jewish
- In the USA an estimated 2-6 % of the population are redheads (i.e. n= 6-18 million)
The significance of red hair and fair skin is related to the ability to make Vitamin D under low light conditions.
Features of the MC1R Recessive Gene
- Red hair
- Non-tanning skin (alleles for red hair and skin pigmentation are close to each other)
- 80 % of redheads have an MC1R gene variant
- Phenotypic expression of lighter skin and red hair are interrelated
- MC1R is not the only gene for red hair production (HCL2 chromosome 4 may have role)
- v sensitivity and cutaneous malignancy
- basal cell carcinoma
- squamous cell carcinoma
- malignant melanoma
- Pain tolerance and Injury
- Redheads – different sensitivity to pain
- More sensitive to thermal pain (naturally low Vitamin K levels)
- Redheads are less sensitive to pain from multiple modalities
- Noxious stimuli
- Electrically induced pain
- Redheads require greater amounts of anaesthetic
- Female Redheads require less pentazocine
- Female Redheads have greater response to pentazocine than men
- Female Redheads greater response to morphine-6-glucuronide
The increased tolerance to pain can be explained by a mutation in a hormone receptor which can respond to two hormones melanocyte stimulating hormone (MSH) and endorphins.
Both derive from the same precursor molecule Proopiomelanocortin (POMC) and are structurally similar.
Specifically redheads have a mutated MC1R gene that produces an altered receptor for MSH on the melanocytes.
Binding at this mutated receptor site results in the production of reddish pheomelain rather than eumelanin.
MC1R also occurs in the brain where it is one of a large number of POMC receptors apparently not only responding to MSH but also to endorphins. This explains the pain tolerance recorded in redheads.
There is little or no evidence to support the belief that patients with red hair have a higher incidence of haemorrhage or suffer other bleeding complications. But one study reports a higher incidence of bruising.
Neurocutaneous melanosis [1, 2]
Neurocutaneous melanocytosis is a rare syndrome defined by the proliferation of melanocytes in the central nervous system (brain and spinal cord) and the presence of a congenital melanocytic naevus The majority of cases are associated with a giant congenital melanocytic naevus and satellite lesions.
It is estimated neurocutaneous melanosis affects 5–10 % of people that have a giant congenital melanocytic naevus. However it is likely that the majority of cases remain asymptomatic, and the true incidence remains unknown. The melanocytes in the brain and spinal cord may often be detected by an MRI scan but the use of these scans is controversial, because the condition is not easily treatable.
Neurocutaneous melanocytosis may present with symptoms of raised intracranial pressure, such as Headache, Vomiting, Irritability, Focal cranial nerve signs, Seizures, Hydrocephalus (increased water around the brain), Delayed development
Is made on clinical appearance, dermoscopy – to reveal the pattern of pigmentation, symmetry and / or lack of symmetry and biopsy.
Benign Pigmented Naevi
· regularly meshed
· homogeneous pigment,
· thinning at periphery
· Black /brown / grey
· thickened and irregular network,
· Network-like structure
· Ridges and furrows
· Finger-like pattern
· Moth-eaten border
· brown or black
· peripheral black, brown, blue-grey (pepper-like)
Present, may have “ground glass” appearance
Some – regular vascular pattern
· Atypical vascular pattern
· linear / dotted vessels = neovascularization.
Hairpin blood vessels
Present, white scar-like areas or bluish-white areas
Some congenital / papillomatous melanocytic naevi
Tab. 3: DERMOSCOPY.
Dermoscopy is one of several non-invasive techniques which permit accurate clinical diagnosis of pigmented lesions. Oil or alcohol solution is applied to the surface of the dermatoscope to improve the clarity of the magnified image and subsurface structures.
Dermoscopy is very helpful to distinguish melanocytic versus non-melanocytic lesions, and pattern analysis can be employed to assist in differentiating benign from malignant melanocytic lesions.
Algorithms  and checklists, increase the diagnostic accuracy:
- Menzie’s method
- the seven-point method
- pattern recognition
- ABCD algorithm, have been shown to improve diagnostic accuracy.
CMN usually larger than acquired naevi (those that appear after 2 years of age). The naevus cells often extend deeper into the dermis, fat layer, and deeper structures. They characteristically cluster around blood vessels, hair follicles, sebaceous and eccrine glands, and other skin structures.
Congenital naevus cells tend to involve collagen bundles in the deeper layers of the skin more than is the case in an acquired naevus [1, 2]
Endogenous Antagonists to MC1R 
Perhaps one of the most interesting aspects of the melanocortin system is that it has two endogenous antagonists, agouti* and AGRP.
These proteins are unique in that no inhibitory proteins have been identified for any of the seven-transmembrane receptor family. Agouti and AGRP are paracrine signalling molecules, which are endogenous antagonists of the MCRs.
Agouti and AGRP have the potential in vivo to regulate their respective MCRs, even in the absence of melanocortins.
*agouti refers to a hair colour pattern commonly seen in mammals, which is characterized by a subapical yellow band on an otherwise black or brown background.
Dominant mutations of the agouti gene cause mice to develop yellow fur, obesity, insulin resistance, increased somatic growth, and a predisposition to tumour genesis.
The normal role of agouti, however, is to act in conjunction with α-MSH and MC1R to determine mammalian coat colour. Agouti is produced by the dermal papillae cell and acts on the adjacent melanocyte to block melanocortin action at MC1R.
This interaction has a major effect on pigmentation. Pharmacologically, agouti is a high-affinity, competitive antagonist of the melanocortin peptides at MC1R and MC4R.
In rodents, agouti is expressed only in skin. The human homolog of agouti, called agouti-signaling protein (ASP), has a wider pattern of expression, including adipose tissue, testis, ovary, and heart and lower levels of expression in foreskin, kidney, and liver. At the present time, the physiological function(s) of ASP in humans is unknown.
Mahogany and syndecan-3 are proteins that modulate the activity of agouti and AGRP, respectively.
Mahogany is a single-pass transmembrane protein that is expressed primarily in brain, including the hypothalamus, and skin and is involved in mammalian coat colouration.
Syndecan-3 is a heparan sulphate proteoglycan, a class of single-pass transmembrane molecules whose ectodomain is shed from the cell surface in response to defined stimuli.
Syndecans are molecules that bind extracellular ligands. Overexpression in transgenic mice may be associated with obesity. Food deprivation increases hypothalamic syndecan-3 more than fourfold.
CMN – Risk of Melanoma
The following characteristics of congenital melanocytic naevus are associated with the increased risk of development of melanoma:
- Large or giant size
- Axial or paravertebral location (crossing the spine)
- Multiple congenital satellite naevi
- Neurocutaneous melanosis
- Early childhood
The risk of melanoma:
- Small and medium sized CMN <1 %.
- Giant congenital naevi (lifetime estimates are 5 – 10 %)
- particularly in lesions that lie across the spine
- or where there are multiple satellite lesions.
- Melanoma-genesis may occur deep inside the naevus or within any neuromelanosis found in the brain and spinal cord.
- Other tissues that contain melanocytes may also be a source of melanoma such as the gastrointestinal tract mucosa.
- In 24 % of cases, the origin of the melanoma cannot be identified .
Melanoma associated with congenital melanocytic naevi or neuromelanosis can be very difficult to detect and treat. The risk of development of melanoma is greater in early childhood; 70 % of melanomas associated with giant congenital melanocytic naevi are diagnosed by the age of ten years [1,3].
Rarely, other types of tumour may develop within giant congenital melanocytic naevi including benign tumours (lipomas, schwannomas) and other malignant tumours (including sarcomas).
- Close-up photographs.
- Digital surveillance using dermoscopic images (mole mapping)
- It is advisable to continue close observation in those at risk of neurocutaneous melanosis even after the primary lesion has been excised .
Prognosis of melanoma associated with congenital melanocytic naevus
- Melanoma and Giant CMN have an unfavourable prognosis
- Melanoma arises in deeper origin of the tumour
More difficult to detect – later stage at presentation.
- Deeper location also facilitates earlier blood / lymph spread
- 24% of melanomas already metastased at diagnosis.
CMN – Treatment
- age of the subject,
- the lesion size,
- location and depth
- risk of developing malignant change within the lesion.
The only definite indication for surgery in a giant congenital melanocytic naevus is when a melanoma develops within it.
Cosmetic Camouflage 
Makeup should be applied in the following sequence:
- Foundation, preceded if required by Under-Eye Concealers.
- Corrections And Improvements
- Eye Makeup
- Lip Makeup.
Makeup Tuition Software
Makeup Software is become increasingly available. Some is fairly basic permitting different hairstyles etc. Sophisticated tuition software is also available which offer a colour analysis package and makeup advice.
There are 3 basic approaches to cosmetic camouflage:
They often thicker and more opaque than regular foundation makeup, effectively covering healed incision lines from surgery, scars and / or bruises. They are usually available as creams with a variety of shades to match the natural colour of the skin and may be blended with colour correctors to achieve a good colour match. Liquid colour-matched concealers also closely resemble normal skin.
Colour correction is used to disguise the yellowish shade of a bruise or the overall redness from a burn They come in tints, purple corrector blended with concealer neutralises yellow skin tones and green corrector yields a brown tone to neutralise redness.
Contouring corrects the irregular facial surface contours, creating a dimension using light and shadow. Dark colours make swellings or protrusions appear to recede, while light colours make surface depressions appear shallower.
To achieve contouring you need a highlighter, which is about 2 shades lighter than the concealer, and a contour shadow, which is about 2 shades darker. Powdered blush-type products are best suited for contouring. Camouflage makeup needs to be removed from your face and neck every night before bed. Because of their waterproof nature, an oily cleansing cream or lotion may be needed to wipe off the makeup followed by cleaning with soap and water or a normal facial cleansing routine.
Liquid camouflage products and camouflage cosmetics used elsewhere on the body can be left on for 3 or 4 days before removing them and re-applying.
Thin Lizzy Cosmetic Products may be purchased on line and are effective camouflage agents for the concealment of skin naevi, tattoos etc. A shade guide is available on line for colour matching the skin.
The System comprises of three constituents:
- Concealer Cream (waterproof beeswax formulation)
- Applied with Black Brush
- Linear strokes quick and thick application
- Dab with finger tips
- Allow to dry
- Reapply as required for concealment
- Mineral Foundation Powder SPF 15
- Apply with Pink Kabuki Brush
- Swiping Rotation and Polishing movements for mineral application
- Repeat to desired result
- Effect is to warm up and illuminate the skin
- 6:1 Professional Powder
- Gentle application with fine Blue Brush
- Illuminates Skin to produce a natural glow
- Bronzing Effect
Giant Pigmented Naevi
The risk of malignant transformation in Giant Pigmented Naevi estimated at about 8 % may be an over estimation of malignant change, which be difficult to spot if the area is depigmented e.g. with laser, chemical peel, or bleaching agents.
Excision, in accordance with surgical aesthetic zone principles, does not necessarily produce excellent cosmesis, but is suggested to be the cosmetic treatment of choice.
In this case, excellent cosmetic camouflage of the lesion has been achieved, and this case emphasises the importance of a cosmetics education and tuition of the patient in the optimisation of facial aesthetics with cosmetic products.
The role of surgery as the primary treatment option therefore needs to be questioned and each case should be treated on an individual basis.
Small congenital naevi
If small congenital naevi are just growing at the same rate as the child, and are not changing in any other way, the usual practice is not to remove them until the child is old enough to co-operate with a local anaesthetic injection, usually around the age of 10 to 12 years. Even then, removal is not essential.
Prophylactic surgical removal
Treatment decisions should be tailored to individual patients, taking into account lesion size, location, appearance and leptomeningeal involvement.
Small CMN do not require prophylactic removal; however, they should be evaluated closely for changes in lesion asymmetry, border, colour, and diameter.
Intermediate-sized CMN may require prophylactic excision, especially if lesions appear atypical.
Prophylactic removal should be considered before the teenage years because risk for malignant melanoma is higher in postpubertal children.
Prophylactic removal of large CMN continues to be an area of controversy. Prophylactic surgical removal is performed if it is felt that there is a high risk that a melanoma may arise within the lesion. The following factors should be considered:
- Prophylactic excision of small lesions may be delayed until an age when the patient is old enough to make an informed choice
- Small or medium sized congenital melanocytic naevi are at a lower risk for developing malignant change, and such worrying change tends to occur later
- Irregular, lumpy or thick lesions or lesions that are difficult to clinically assess may have a lower threshold for consideration of surgical excision
- 50% of melanomas diagnosed in those with giant congenital melanocytic naevi occur at another site. Therefore surgical excision of the lesion may not eliminate the risk of melanoma
- Large or giant melanocytic lesions may be too large to excise completely
- Large lesions may require a skin flap or graft to close the surgical defect
- CNS imaging studies may be employed for all infants with large CMN. In one study, 30% of asymptomatic patients with large CMN were found to have leptomeningeal melanosis, suggesting that the incidence of CNS involvement is high. In 71% of infants with abnormal MRI scans, the CMN covered much of the spinal area and satellite nevi were seen on the scalp.
Complications of surgery
Complications that may occur after surgery include graft or flap failure, infection, wound breakdown, bleeding or haematoma and hypertrophic or keloid scar.
Other treatment options
Dermabrasion can allow partial removal of a large congenital naevus. However, deeper naevus cells may persist. Dermabrasion may lighten the colour of the naevus but may not reduce hair growth within it.
Tangential (shave) excision
Tangential or shave excision uses a blade to remove the top layers of the skin (epidermis and upper dermis). This may reduce the pigmentation but the lesion may not be completely removed. Shave excision may result in significant scarring.
Chemical peels using trichloroacetic acid or phenol may lighten the pigmentation of a superficial (surface) congenital naevus that is located in the upper layers of the skin
Laser treatment be considered if surgical intervention is not possible. They may result in lightening of the lesion. Suitable devices include ruby Q-switched lasers and carbon dioxide resurfacing lasers. Techniques that result in partial removal of a congenital naevus can make the lesion more difficult to assess during long term surveillance.
Advances in the understanding molecular biology of genes especially Proto–oncogenes c-met , c-kit  and the MC1R genes of the Melanocortin peptides are catalysing the development of therapies targeting gene mutations. This heralds the development of melanocortin-based drugs for the treatment of skin cancer and other cutaneous disorders, including Giant CMN, obesity, anorexia nervosa, cachexia, erectile dysfunction, inflammatory diseases, pain, and nerve injury. Currently Cosmetic camouflage offers an effective option for improvement of aesthetics whilst permitting the monitoring of lesions for malignant change.