|Year : 2014 | Volume
| Issue : 2 | Page : 44-51
Physiologic pigmentation: Molecular mechanisms and clinical diversity
Cecilia A Larocca1, Roopal V Kundu2, Neelam A Vashi1
1 Department of Dermatology, Boston University School of Medicine, Boston, MA, USA
2 Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
|Date of Web Publication||15-Dec-2014|
Neelam A Vashi
Department of Dermatology, 609 Albany Street J602, Boston, MA 02118
Source of Support: None, Conflict of Interest: None
Dyschromia is one of the leading diagnoses in skin of color of populations. Inclusive within this broad realm of diagnoses includes physiologic pigmentation, which refers to normal biologic variations in skin coloration. In order to properly diagnose and manage disorders of pigmentation, one must be aware of the normal variations in skin pigmentation. Our review summarizes molecular mechanisms and the diverse patterns of physiologic pigmentation that may be encountered in the clinic and that are especially common in richly pigmented individuals.
Keywords: Hyperpigmentation, melanin, melanocytes, physiologic pigmentation
|How to cite this article:|
Larocca CA, Kundu RV, Vashi NA. Physiologic pigmentation: Molecular mechanisms and clinical diversity. Pigment Int 2014;1:44-51
| Physiologic Pigmentation|| |
Physiologic pigmentation refers to the normal biology dictating the type and amount of melanin synthesized and the genetically and embryologically determined patterns of pigmentation, which occur by definition in the absence of inherited or acquired disorders of pigmentation. The diversity of appreciable skin coloration is further impacted by differences in vascular density, pigments such as carotene or lycopene, collagen composition in the dermis, and the thickness of the stratum corneum.  We will review the molecular processes responsible for physiologic pigmentation and its associated clinical phenotypes [Table 1]. It is important for physicians to be aware of these normal variations in pigmentation, which are especially common in individuals with darker skin types, as they may cause distress to patients and lead to unnecessary diagnostic evaluations and procedures.
| Melanin Synthesis|| |
Melanocyte origin and function
Normal pigmentation requires the migration and survival of melanoblasts (melanocyte precursors) and Schwann cell precursors,  which are neural crest-derived cells, to the basal layer of the epidermis, hair matrix, and outer root sheath of hair follicles.  In the epidermis, melanocytes send projections to about 30-40 basal keratinocytes, forming the epidermal melanin unit.  The epidermal density of melanocytes varies by anatomic region, with the highest density in the genital region. However, there is little variation in melanocytic density between different skin types. 
Melanocytes are the sole producer of the pigment melanin, which is derived from the metabolism of the amino acid L-tyrosine or L-phenylalanine.  The key rate-limiting enzyme is tyrosinase, which is responsible for the first biochemical reaction in this process. Tyrosine is metabolized within lysosome-like organelles called melanosomes, which accumulate the deposited melanin and traffic down dendritic-like projections of melanocytes where they are transferred to adjacent keratinocytes. 
Formation and function of melanosome
Melanosome development is divided into four stages.  Stage I melanosomes are spherical compartments with no melanin deposited. Stage II melanosomes have an oval shape and parallel longitudinal filaments, the scaffold where melanin is deposited, with minimal melanin content and high tyrosinase activity. Stage III melanosomes have an oval organelle with moderately organized deposition of melanin and high tyrosinase activity. Stage IV melanosomes have an oval organelle with heavy deposition of melanin and minimum tyrosinase activity.
Tyrosine is metabolized into two types of melanin: eumelanin (brown-black melanin) or pheomelanin (yellow-red melanin).  Tyrosinase activity leads to the synthesis of eumelanin, but decreased tyrosinase activity leads to the default synthesis of pheomelanin.  The ratio of pheomelanin to eumelanin is further impacted by the availability of tyrosine and sulfhydryl-containing reducing agents in the cell.  Individuals with richly pigmented skin have a higher eumelanin to pheomelanin ratio. 
Molecular genetics of skin pigmentation
Skin pigmentation is a complex genetic trait regulated by over 150 alleles.  Several signaling pathways have been found to play a role in melanogenesis, melanocyte differentiation and survival. The main signaling pathway is mediated via the melanocortin-1 receptor (MCR1), which is activated by α-melanocyte-stimulating hormone and adrenocorticotropic hormone.  Activated MCR1, in turn, activates adenylate cyclase to increase intracellular cAMP levels and cAMP responsive-element-binding protein (CREB) transcription factor family members. CREB, along with key transcription factors SOX10, PAX3, and LEF-1/TCF are responsible for expression of microphthalmia-associated transcription factor (MITF) expression. MITF is the critical regulator of genes involved in synthesis, transport, and stabilization of tyrosinase and tyrosinase-related proteins. 
KIT, endothelin (ET3/EDNRB), and Wnt related pathways also activate melanogenesis. These pathways make use of cAMP-dependent and independent signaling mechanisms, many of which crosstalk, in melanogenesis including: protein kinase-C-beta, protein kinase-A, mitogen-activated protein kinase, phosphatidylinositol 3'- kinase, and nitric oxide.  Genes involved in melanosome formation and trafficking include gp100/Pmel17, MART-1/Melan-A, and the ocular albinism type 1 G-protein-coupled receptor. Melanosomes are phagocytosed by keratinocytes as a result of keratinocyte growth factor (KGF) signaling via KGF receptor (fibroblast growth factor receptor 2b) and by activation of protease-activated receptor 2. Additional factors known to increase pigment production include: basic fibroblast growth factor, endothelin-1, interleukin-1, estrogen, and ultraviolet (UV) light. 
Determinants of skin color
Skin color is determined by the amount, type, and efficiency of transferring melanosomes to keratinocytes.  Fair skin has largely stage II-III melanosomes. Darkly pigmented skin has primarily stage IV melanosomes. Furthermore, mutations or variations in the functional activity of important signaling pathways mentioned above can impact pigmentation. For example, individuals with red hair have mutations in the MCR1 and are unable to increase intracellular cAMP levels, which normally leads to increased tyrosinase activity, and therefore mainly synthesize pheomelanin. 
Darker skinned individuals have more notable pigmentary alterations and are more likely to experience post-inflammatory hyperpigmentation. This is likely a result of increased baseline activity of melanin biosynthetic pathways and the presence of stage IV melanosomes, which are more resistant to degradation.
| Clinical Phenotypes of Physiologic Pigmentation|| |
Pigmentary demarcation lines
Within individuals, most notable in dark skin types, there are normal differences in skin pigmentation observed at specific sites on the body, known as pigmentary demarcation lines (PDL). These abrupt changes from light to dark pigmentation, also known as Futcher or Voigt lines, are bilateral symmetric findings [Table 2].
Eight types of PDL (A to H) have been described [Figure 1]:
|Figure 1: Pigmentary demarcation lines Group A (a) relative hypopigmentation of the inner aspect of the upper extremity Group C (b) hypopigmented paramedian line with midline abdominal extension Group E-subtle symmetrical hypopigmented macules on the chest|
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- Type A: Lateral aspect of upper anterior portion of arms (occasionally across the pectoral area), most common type
- Type B: Posterior medial portion of lower limb
- Type C: Vertical hypopigmentation line in sternal and para-sternal areas
- Type D: Vertical line in spinal or para-spinal area
- Type E: Hypopigmented oval areas, streaks, or bands on bilateral aspects of the chest, from the mid-third of clavicle to periareolar skin
- Type F: V-shaped hyperpigmented line between the malar prominence and the temple
- Type G: W-shaped hyperpigmented lines between the malar prominence and the temple
- Type H: Linear bands of hyperpigmentation from the angle of the mouth to the lateral aspects of the chin.
Pigmentary demarcation lines can be present as early as the 1 st day of life. It is thought that the majority of these lines may become apparent in childhood, given that the prevalence of PDL is similar in childhood compared to adulthood, 77% versus 70% respectively, based on one survey of 380 individuals.  However, no systematic evaluation has been undertaken to determine the range and the average age of onset of PDL. In contrast, evaluation of PDL of the face in the Indian population found age of onset was during puberty. In addition, there are case reports that describe the onset of PDL in women during pregnancy. ,, There is no documented sex predilection for PDL of the trunk and extremities, but one study found facial PDL to be more common in women. 
It is not known what causes this variation in pigmentation. It is possible that PDL identify "embryonic suture lines," but it remains debated whether PDL topography follows the lines of Blaschko or if they are related to cutaneous innervation (dermatomes). , The lines of Blaschko are thought to represent the cutaneous dorsal to ventral migration pattern of precursor cells during embryologic development and thus may clinically represent phenotypic patterns of mosaicism. Systematic evaluation of facial PDL by Sarma et al. proposes that pigmentation patterns follow the lines of Blaschko.  However, Sarma et al. asserts that the final boundaries are determined by the timing of mutation during development, which takes into account postmigration proliferation of the melanoblast. This gives rise to the concept of the "embryologic pigmentary unit," where a primitive melanocytic precursor gives rise to a region of pigmentation that has a specific orientation, shape, and distribution pattern that is not necessarily linear, i.e. hyperpigmented patches may be larger if mutations developed earlier during development or smaller if mutation occurred at a later time. Others believe that PDL correspond to a subset of lines of Voigt, which separate dermatomes arising from different non-consecutive dorsal roots, and that it is differences in neuronal territories, controlled by different homeobox genes during development, that affects pigmentation.  These pigmentation patterns have variable inheritance patterns but appear to be autosomal dominant in certain families. If PDL are a result of mosaicism in an individual, this pigmentation pattern cannot be inherited in an autosomal dominant fashion, as mosaicism is a result of post-zygotic events.
Periorbital hyperpigmentation, commonly referred to as dark circles predominantly on the lower eyelids, has a multifactorial etiology, which can be inherited and/or acquired [Table 2].  Dark circles may appear as a result of thin translucent skin allowing visualization of underlying vascular network, shadow effect due to skin laxity and tear troughs, post-inflammatory hyperpigmentation, extension of PDL, or the genetic (constitutional) type.  These pigmentation patterns have unclear inheritance patterns but appear to be autosomal dominant in certain families. Secondary causes of periorbital hyperpigmentation, which includes eyelid dermatitis secondary to atopic dermatitis, allergic contact dermatitis, or seasonal allergies, must be excluded prior to designation of physiologic pigmentation.
Acquired idiopathic facial hyperpigmentation
Recently Sarma et al. published a case series of 187 individuals in India that identified several patterns of pigmentation on the face, thought to be idiopathic, constitutional, or physiologic pigmentation.  The observed patterns of pigmentation are symmetrical with relatively ill-defined borders and anatomically categorized as periorbital, zygomatic, malar, perioral, upper nasal, and mandibular pigmentation [Table 2]. In this series, the authors propose that this pattern of pigmentation, which includes periorbital hyperpigmentation and PDL of the face, may represent genetically determined increased pigmentary functional activity to various known and unknown yet natural factors like UV rays and aging, especially since they believe the patterns follow the lines of Blaschko of the face. Unlike PDL, this pattern of pigmentation appeared to arise in an older population, with mean age at presentation 33.37 ± 16.7 years, while periorbital and perioral pigmentation presents at younger ages (17.7 ± 12.37 and 21.86 ± 8.11 years, respectively). However, the authors recognize that age of onset was difficult to ascertain by the subjects in this retrospective study.
Given the limited systematic review of these pigmentation patterns, it is unclear whether PDL, periorbital hyperpigmentation, and acquired idiopathic facial hyperpigmentation represent a single phenomenon or if they represent different genetic principles.
Maturational hyperpigmentation is a common but only recently described phenomenon first observed in African American and Indian populations. It is described as dark brown-black pigmentation on the lateral face, including malar and zygomatic areas, but unlike PDL, has ill-defined borders as the pigmentation gradually blends with surrounding skin and can be of a more diffuse quality [Table 2].  Histologic evaluation of hyperpigmented skin reveals mild to moderate proliferation of melanocytes, minimal to absent dermal inflammation, and some reports of papillomatous epidermal proliferation. It usually develops in the 4 th -5 th decade of life. Its association with obesity and presence of papillomatous acanthosis has raised the possibility that these changes are representative of acanthosis nigricans. 
Physiologic hyperpigmentation in the oral cavity, which can include both a diffuse type of darkening and also individual melanotic macules, has been observed in predominately dark skinned populations.  One study of 1300 children found that 13.5% had some form of mucosal melanosis.  Pigmentation was noted to be diffuse and bilateral, but can also be seen limited to the gingiva (excluding the marginal border), buccal mucosa, lips, palate, and the fungiform papillae of the tongue.
An uncommon acquired form of oral hyperpigmentation has been described, called Laugier-Hunziker syndrome. This syndrome is a benign condition of acquired hyperpigmentation of the oral mucosal along with longitudinal melanonychia, but hyperpigmented macules can also be observed on the genitals, fingers, gums, tongue, sclera, perianal region, and esophagus.  No genetic basis for this phenotype has been identified. No systemic abnormalities or a predisposition to malignancy has been recorded in these patients. Histologically, pigmented lesions demonstrated basal cell hypermelanosis, increased melanophages in the papillary dermis, pigment incontinence, and melanocytes that are normal in number and morphology, although one report observed increased melanocytes. , This condition is considered a diagnosis of exclusion. The onset of pigmentation is gradual and thought to occur in middle-aged adults, but the limited reports of this condition prevent further characterization.
There are many exogenous causes and diseases that can cause mucosal pigmentation, predominately in the adult population, which should be considered [Table 3]; these include smoking, dental amalgam tattoos, drug-induced hyperpigmentation, post-inflammatory hyperpigmentation from other dermatologic diseases involving the mucosa (e.g. lichen planus), heavy metal poisoning, illicit drug use (e.g. heroin and methaqualone), and Addison's disease. ,
Melanotic macules, which are usually single lesions characterized by increased production and deposition of melanin in the basal layer, are also observed in the oral cavity. It is not known whether these lesions represent physiologic hyperpigmentation or are a result of inflammation. These lesions tend to arise in the fifth decade and have a female prominence (2:1).  In darker skinned individuals, the buccal mucosa was found to be more likely involved. 
In the pediatric population, the presence of brown, hyperpigmented macules should prompt for evaluation of genetic conditions prior to diagnosis of physiologic mucosal melanosis [Table 3]. Hyperpigmented macules on the lips and mucosa occur in conditions such as Peutz-Jegher syndrome, Carney Syndrome,  Bandler syndrome, and Cronkhite-Canada syndrome. 
- Peutz-Jeghers syndrome is an autosomal dominant genetic disease characterized by mutation in the STK11/LKB1 tumor-suppressor gene, which is part of the mammalian target of rapamycin (mTOR) pathway. Patients have hyperpigmentation of the lips and oral mucosa, polyposis of the small intestine, colon, stomach, and rectum. Hyperpigmentation presents in infancy or early childhood. These patients are at an increased risk of gastrointestinal and extra-intestinal cancer. 
- Carney Syndrome is an autosomal dominant disorder with mutations in the PRKARIA gene or related genes, which is characterized by mucocutaneous pigmented macules in the face, lips, eyelids, and oral mucosa. In addition, patients have pigmented macules in the conjunctiva and eyelids. These patients can develop several tumors. A unique feature is the development of cutaneous, mucosal, and/or cardiac myxomas. 
- Bandler syndrome, a rare genodermatosis, also presents with hyperpigmented macules in the hands, nails, and oral mucosa during infancy. Patients can manifest significant gastrointestinal bleeding due to intestinal vascular malformations. 
- Patients with Cronkhite-Canada syndrome have mucocutaneous hyperpigmented macules, uniform darkening of the skin, alopecia, gastrointestinal polyposis, and onychodystrophy.  This syndrome, which presents in adulthood, often begins with complaints of hypogeusia and diarrhea, later followed by the ectodermal changes.
Palmar and plantar hyperpigmented macules
In darkly skinned individuals, hyperpigmented macules, also referred to as melanotic macules, are common and appear to increase in the incidence with age.  They have not been identified in infants. These lesions can be solitary but are usually multiple small, round, dark brown macules on the palms and soles.  Hyperpigmentation is a result of increased deposition of melanin in all epidermal layers, hyperpigmented solitary dendritic melanocytes scattered along the basal layer and melanophages in the dermis.  Dermoscopy of these lesions may show a parallel ridge pattern, which is similar to the pattern observed in the pigmented macules of Peutz-Jegher and Laugier-Hunziker.  Some cases of Laugier-Hunziker showing a parallel furrow pattern have also been reported. Parallel ridge pattern is band-like pigmentation located on the ridges of the skin markings. , This dermoscopy finding is usually found in acral melanomas;  however, the clinical history and presence of multiple volar macules should signal that these findings are not representative of a malignant process. Focal acral hyperpigmented macules may also be drug-induced. It is most commonly observed with chemotherapy agents. 
Melanonychia is the black, brown or gray pigmentation of the normal nail plate that usually presents as a longitudinal band (longitudinal melanonychia).  This is a common and normal finding in dark skinned individuals. , Bands of longitudinal pigmentation with a grayish background and thin regular gray lines under dermoscopy on multiple fingers and/or toenails usually characterize pigmentation in this population.  It has been reported in 77-96% of black persons and 11% of Asians.  It is also present in white adults with a prevalence of 1.4-12.6 in 100, but it is rare in white children. , The incidence of melanonychia increases with age. Despite the rare occurrence in children, its presence is usually benign.  Only a handful of pediatric cases have been reported of malignant melanoma occurring in the nail matrix.  In children (and adults), despite the rare incidence of melanoma of the nail bed, any rapidly changing pigmented lesion should be further evaluated.
A single longitudinal band of melanonychia, particularly on the thumb or great toe, is more concerning and should be carefully evaluated for signs of melanoma, which include adult onset, polychrome lesion, increasing width, Hutchinson sign (pigmentation of the cuticle), or irregular pattern of pigmentation, thickness, and spacing under dermoscopy. 
Other causes of melanonychia include drugs, trauma, infection, nail apparatus nevus or lentigo, or it may be idiopathic. The most commonly reported drugs causing melanonychia include zidovudine, hydroxyurea, and minocycline.  Secondary causes of longitudinal melanonychia should be excluded prior to attributing longitudinal melanonychia to physiologic pigmentation [Table 4].
Other causes of hyperpigmentation
There are several pathologic conditions that give rise to hyperpigmentation of the face and body. It is important to be aware of these conditions prior to attributing hyperpigmentation to normal physiologic changes. Identification of the morphology of hyperpigmentation, which includes assessing the pattern of pigmentation, color of pigmentation, and distribution, along with obtaining a proper history of present illness should readily allow for proper diagnosis with little need for skin biopsy. It is important to ascertain from the patient if any local symptoms or inflammation preceded hyperpigmentation, which suggests that hyperpigmentation is a secondary process known as post-inflammatory hyperpigmentation. Physical examination should look for additional skin findings in locations other than the face that are suggestive of other acquired dermatoses characterized by hyperpigmentation, such as erythema dyschromicum perstans. It is important to evaluate for prior use of bleaching agents that can cause exogenous ochronosis. A proper medication history should be obtained to rule out drug-induced melanosis, including intake of alternative medicines such as colloidal silver preparations. The presence of co-morbidities such as insulin resistance and/or obesity is more suggestive of a diagnosis of acanthosis nigricans than physiologic hyperpigmentation.
| Summary|| |
There is an increasing demand for even skin complexion. In particular, among nationally representative data from the United States, dyschromia is one of the leading diagnoses in the skin of color population amongst dermatologists. , Differences in the structure and function of richly pigmented skin contribute to the variations seen in clinical presentations of pigmentation.
Darker skin phenotypes are typified by late stage melanosomes, which are larger, non-aggregated, and degraded at lower rates, higher content of melanin, higher eumelanin to pheomelanin ratio, and more effective distribution of melanin that confers protection against UV light. The amount, density, and distribution of melanin within the melanosome and melanocyte activity lead to differences in clinically perceived skin color.
Physiologic pigmentation refers to the normal variation of the skin, which occurs by definition in the absence of inherited or acquired disorders of pigmentation. Our review summarizes the diverse patterns of the physiologic pigmentation that are especially common in richly pigmented individuals. These include PDL, maturational pigmentation, mucosal melanosis, palmar and plantar hyperpigmented macules and forms of periorbital hyperpigmentation and longitudinal melanonychia. In order to properly diagnose and manage disorders of pigmentation, one must be aware of the normal variations in skin pigmentation. Furthermore, understanding the molecular pathways that are responsible for pigmentation provides the foundation to understand associated disorders and the treatments that target these pathways. When treating patients with the physiologic pigmentation, counseling is of utmost importance. Although aggressive treatment for physiologic pigmentation is not necessary or beneficial, all patients with increased melanin production and deposition will benefit from sun avoidance and photoprotection. This involves avoiding the peak hours of sunlight, seeking shade, wearing protective clothing and using a broad-spectrum sunscreen with reapplication.
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[Table 1], [Table 2], [Table 3], [Table 4]