The official journal of INTERNATIONAL FEDERATION OF PIGMENT CELL SOCIETIES · SOCIETY FOR MELANOMA RESEARCH
PIGMENT CELL & MELANOMA Research The biology of hyperpigmentation syndromes Reinhart Speeckaert, Mireille Van Gele, Marijn M. Speeckaert, Jo Lambert and Nanja van Geel
DOI: 10.1111/pcmr.12235 Volume 27, Issue 4, Pages 512–524 If you wish to order reprints of this article, please see the guidelines here
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REVIEW
Pigment Cell Melanoma Res. 27; 512–524
The biology of hyperpigmentation syndromes Reinhart Speeckaert*, Mireille Van Gele*, Marijn M. Speeckaert, Jo Lambert and Nanja van Geel Department of Dermatology, Ghent University Hospital, Gent, Belgium CORRESPONDENCE Reinhart Speeckaert, e-mail: [email protected] *Equally contribution.
KEYWORDS hyperpigmentation/melanin/melanocyte/pigmentation pathway/syndrome PUBLICATION DATA Received 8 September 2013, revised and accepted for publication 19 February 2014, published online 24 February 2014 doi: 10.1111/pcmr.12235
Summary Hyperpigmentation is a key feature in a variety of inherited and acquired syndromes. Nonetheless, determining the exact diagnosis only on the clinical phenotype can be challenging, and a detailed search for associated symptoms is often of crucial importance. As pigmentation pathways are regulated by complex signaling transduction cascades (e.g. MSH/cAMP, KIT signaling pathways), the underlying defects leading to elevated melanin production are numerous. With regard to treatment, limited therapeutic options exist, each with specific side effects. In acquired hyperpigmentation, the melanin deposition may, however, be reversible after adequate therapy of the underlying disorder or even disappear spontaneously. In this review, we provide an overview of the biology of hyperpigmentation syndromes classified according to the main underlying defect that deregulates physiological melanogenesis. The identification of novel genes or key players involved in hyperpigmentary disorders is becoming increasingly important in view of the development of safer and more efficient treatments.
Introduction Hyperpigmentation is a frequent reason for consultation in clinical practice. It affects quality of life of patients and remains often a persistent burden due to the sparse and limited efficacy of available treatments. Hyperpigmentation disorders range from physiological phenomena to genetic inherited disorders. In other diseases, darkening of the skin is a side phenomenon from pathologic transduction cascades coincidentally interacting with pigmentation pathways. As such, hyperpigmentation can be a first sign of an underlying genetic, metabolic, or neoplastic disorder. An increased deposition of melanin in the skin can be caused by a wide range of disorders, and especially diffuse hyperpigmentation can pose a diagnostic challenge. A detailed understanding of the underlying biological phenomena in these diseases may aid in further insights into the development of new therapies. Furthermore, the pathogenesis of these disorders sheds light on the functional biology of melanocytes. Melanocytes are specialized cells originating from a subset of multipotent stem cells at the neural crest. The precursor cells, called melanoblasts, express early specific markers such as microphthalmia-associated 512
transcription factor (MITF), paired box gene 3a (Pax3a), and Sry-related HMG-box (Sox10). MITF has been shown to be crucial for the survival of melanoblasts. Subsequently, the melanoblasts migrate from the dorsal midline of the neural tube in a dorsolateral way to their final destination at the basal layer of the epidermis, where they acquire a mature phenotype (Thomas and Erickson, 2008). Epidermal melanocytes are the exclusive pigment producing cells offering protection against DNA-damaging UV light. They produce melanin in lysosome-related organelles, called melanosomes, which are transported from the nucleus to the peripheral border of the melanocyte by a complex melanosomal transport mechanism. Ultimately, melanosomes are transferred from the dendritic tips of the melanocytes to the surrounding keratinocytes, giving the skin its natural pigmentation (Van Gele et al., 2009). This review focuses on the biology/pathogenesis of hyperpigmentary diseases with the aim to provide the reader a more detailed insight into the genetic causes leading to specific hyperpigmentary phenotypes. The disorders were classified based on affected genes involved in melanocyte development or involved in common cellular processes or pathways associated with ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Biology of hyperpigmentation syndromes
melanogenesis. However, it has become clear that in most hyperpigmentation syndromes multiple pathways that regulate melanoblast differentiation/migration, melanogenesis, and melanocyte proliferation are affected simultaneously. Nonetheless, the disorders were classified according to the presumed main deregulated factor leading to the observed hyperpigmentation. Hyperpigmentation due to benign or malignant melanocytic lesions (e.g. naevi, melanoma) are distinct entities associated with increased melanin production which were not included in this review.
Pathways influencing pigmentation Melanin synthesis is triggered by hydroxylation of L-phenylalanine to L-tyrosine or directly from L-tyrosine. Tyrosinase hydroxylates L-tyrosine, resulting in 3,4-Ldihydroxyphenylalanine (L-DOPA), which further undergoes oxidation to dopaquinone. Thereafter, two main pathways diverge leading in the end to production of black-brown eumelanin and yellow-red pheomelanin. Microphthalmia-associated transcription factor (MITF) is a central factor in melanogenesis that upregulates the expression of tyrosinase (TYR), tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2) (also called dopachrome tautomerase) (Bertolotto et al., 1998). The pivotal role of MITF is further substantiated by its role on the transport of melanosomes to the dendritic tips (Chiaverini et al., 2008). The expression of MITF is mainly controlled by the KIT and melanocyte-stimulating hormone (MSH)/ ATP to 30 ,50 -cyclic adenosine monophosphate (cAMP) signaling pathways, which will be briefly discussed below.
MSH/cAMP signaling pathway The melanocortin system involves the melanocortin peptides a-, b-, and c-MSH and adrenocorticotropic hormone (ACTH). They are formed by proteolytic cleavage of pro-opiomelanocortin (POMC) (Grantz and Fong, 2003). a-MSH exerts its effects on pigmentation by binding the melanocortin-1 receptor (MC1R) at the cell membrane of melanocytes (Figure 1) (Yang et al., 1997). The ACTH molecule shares the first 13 amino acid sequences with MSH and exerts an activity similar to MSH. Activated melanocortin 1 receptor (MC1R) is able to bind Gas proteins, which subsequently activate adenylate cyclase (AC) (Costin and Hearing, 2007). In turn, AC catalyzes the conversion of ATP to cAMP. cAMP signaling is an essential regulator of pigmentation. cAMP directly activates protein kinase A (PKA) which is then able to transfer to the nucleus. Once arrived, PKA becomes phosphorylated and upregulates cAMP-responsive element-binding proteins (CREB) (Costin and Hearing, 2007). CREB binds to the CRE domain present in the promotor of the MITF gene. As such, transcription the MITF gene becomes initiated (Im et al., 1998). cAMP is also known to improve the binding affinity of MITF to the M-box of the TYR gene (Tachibana, 2000). KIT signaling pathway The KIT signaling pathway upregulates MITF by phosphorylating mitogen-activated protein kinase (MAPK). Stem cells factor (SCF) binds to the c-KIT receptor located on the cell membrane of melanocytes (Figure 1). This triggers dimerization of two subunits followed by autophosphorylation of tyrosine. Subsequently
Figure 1. Pigmentation pathways with hyperpigmentation syndromes located according to the involved signaling cascade. AC, adenylate cyclase; ACTH, adrenocorticotropic hormone; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; MAPK, mitogen-activated protein kinase; MC1R, melanocortin 1 receptor; MSH, melanocyte-stimulating hormone; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; SCF, stem cell factor; TYR, tyrosinase; TRP-1, tyrosinase-related protein 1; TRP-2, tyrosinase-related protein 2.
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a variety of signal transduction cascades are initiated. In melanocytes, phosphorylated c-KIT receptor recruits adapter proteins such as GRB2 (growth factor receptor-bound protein 2), SHC (Src homology 2 domaincontaining transforming protein 1), SOS (son of sevenless), and SHP2 (SH2 domain-containing protein tyrosine phosphatase), followed by activation of the Ras-MAPK pathway that stimulates MITF (Vance and Goding, 2004). Wnt signaling pathway The Wnt signaling pathway has besides important functions in embryogenesis and cancer development also a role in melanogenesis. Wnt proteins bind to the frizzled family cell surface receptors. As a result, the dishevelled family protein is activated, which inhibits a multiprotein complex consisting of axin, adenomatous polyposis coli (APC), casein kinase Ia (CKIa), and glycogen synthase kinase-3b (GSK3b). Normally this protein complex stimulates the degradation of b-catenin (Rubinfeld et al., 1996). During embryogenesis, optimal levels of b-catenin have a crucial role in the development of mature melanocytes. Moreover, activated GSK3b synergizes with MITF to enhance the expression of TYR (Khaled et al., 2002).
gene. NEMO (Xq28) is expressed in epidermal cells, and the transcribed protein offers protection against tumor necrosis factor alpha (TNF-a)-triggered apoptosis. NEMO is a part of the regulatory subunit of the IjB kinase (IKK) complex. IKK dephosphylates IjB proteins which normally inhibit NF-jB signaling. IP is characterized by a blaschkoid hyperpigmentation due to highly skewed patterns of X-chromosome inactivation (lyonization). Four stages have been identified: during the first months of life a vesiculobullous stage is observed which is most marked on the extremities. The second stage is verrucous, followed by a hyperpigmented phase which is typically localized on the trunk and intertriginous areas. This stage takes from 3 months of age until adolescence. The last phase involves hypopigmented and atrophic lesions on the calves (Jabbari et al., 2010). This clinical phenotype can be explained by inflammatory lesions, which heal into hyperpigmented lesions resulting from melanin incontinence. Thereafter, melanin is taken up by macrophages which explains the final hypopigmented atrophic stage (Ehrenreich et al., 2007).
Dyschromatosis symmetrica hereditaria Patients with dyschromatosis symmetrica hereditaria (DSH) (reticulate acropigmentation of Dohi) have small hyper- and hypopigmented macules on the dorsal side of hands and feet. In a number of cases, it extends to the dorsal sides of the limbs. The disturbed skin pigmentation develops in most cases (73%) before the age of 6. The hyperpigmented macules tend to progress until adolescence. DSH is inherited by autosomal-dominant mutations in the adenosine deaminase RNA-specific (ADAR) gene (Table 1). It has been put forward that an aberrant editing of RNA during the migration of melanoblasts results in areas of hyperactive and hypoactive melanocytes with different capacity of melanin production (Cui et al., 2005; Miyamura et al., 2003). On histological examination, the melanocytes in the hyperpigmented macules are increased in size but not in number (Kono and Akiyama, 2013).
Linear and whorled nevoid hypermelanosis Linear and whorled nevoid hypermelanosis (LWNH) is an uncommon sporadic skin disorder. LWNH patients have multiple swirls and whorls of hyperpigmented macules organized along the Blaschko lines. The macules have a reticulated pattern and can be segmental or diffuse. LWNH is mostly detected from birth or during the first 2 yrs and stabilizes beyond the age of 2. It has been associated with several congenital problems including neurodevelopmental delay, skeletal malformations, growth retardation, cardiac defects, and ocular abnormalities (Mehta et al., 2011). It can be differentiated from IP by the absence of an inflammatory phase with blister formation or verrucous lesions. A genetic mosaicism has been proposed as the underlying mechanism leading to areas of melanocytes with a different capacity to produce melanin (Maruani et al., 2012). A variety of chromosomal abnormalities (e.g. trisomy 7, 14, 18, 20, X-chromosome mosaicism) have been detected in patients with LWNH, especially when associated with extracutaneous symptoms (Hong et al., 2008). The large majority of documented chromosomal defects overlap with at least one gene involved in pigmentation although in a subset of cases the responsible genetic locus remains to be elucidated (Taibjee et al., 2004).
Incontinentia pigmenti Incontinentia pigmenti (IP) is an X-linked, dominant genetic disorder which is almost only observed in females as being lethal in males before birth. It affects ectodermal structures (skin, teeth, eyes, nails) and the nervous system caused by mutations in the nuclear factor kappa-B (NF-jB) essential modulator (NEMO)
Neurofibromatosis type 1 Neurofibromatosis type 1 (NF1) is a well-known genetic disorder caused by mutations in the NF1 gene. Typical symptoms of NF1 are neurofibromas, pigmented lesions, lisch nodules, neurological abnormalities, development delay, and skeletal deformations. An increased risk for malignant peripheral nerve sheat tumors and other
Hyperpigmentation due to gene defects affecting early melanocyte development and function
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Biology of hyperpigmentation syndromes Table 1. Overview of affected genes in genetic hyperpigmentary syndromes
Disease
Gene(s)
Gene locus
Genes involved in early melanocyte development and function Dyschromatosis symmetrica ADAR 1q21.3 hereditaria (DSH, OMIM #127400)
Gene function
Caused defect
Catalyzing the deamination of adenosine to inosine in dsRNA substrates
Failure of correct RNA editing during melanoblast migration: irregular distribution of hyperor hypoactive melanocytes in the skin Mutations or deletions: abnormal self-destruction (apoptosis) of MCs Disruption of NF1-dynein heavy chain 1 interaction: increased trafficking of melanosomes in au-lait melanocytes of cafe macules
Incontinentia pigmenti (IP, OMIM #308300)
NEMO
Xq28
Essential for NF-ΚB activation
Neurofibromatosis type I (NF1, OMIM # 162200)
NF1
17q11.2
Gene involved in melanosome localization
12q22
Melanogenesis
Gain-of-function mutations: increased TYR activity
17q24.2
Crucial signaling factor in cAMP pathway a-subunit of Gs protein (GTPase)
Mutated PRKAR1A: increased cAMP activity Gain-of-function mutations: increased cAMP activity
16q24.3 Xp22.2 9q22.32 13q13.1 3p25.3 6p21.31
DNA repair maintenance of chromosomal integrity
Overactivation of TYR activity due to reduced thioredoxin levels
17q21.2
Melanosome uptake in keratinocytes
Abnormal melanin distribution in keratinocytes
12q13.13
Melanosome uptake in keratinocytes Organelle transport Serine/threonine kinase regulates cell polarity and tumor suppressor function Tyrosine phosphatase
Deficient melanin aggregation in keratinocytes
Genes involved in pigmentation and related pathways Familial progressive KITLG hyperpigmentation (FPH, OMIM #145250) Carney complex (CNC1, OMIM PRKAR1A #160980) McCune–Albright syndrome GNAS1 (MAS, OMIM #174800) Deregulation of the tyrosinase gene Fanconi’s anemia (FANCA, OMIM #227650) FANCA (FANCB, OMIM #300514) FANCB (FANCC, OMIM #227645) FANCC (FANCD1, OMIM #605724) BRCA2 (FANCD2, OMIM #227646) FANCD2 (FANCE, OMIM #600901) FANCE Genes involved in cell structure and metabolism Naegeli–Franceschetti– KRT14 Jadassohn syndrome (NFJ, OMIM #161000) Dowling–Degos syndrome (DGS, KRT5 OMIM #179850) Peutz–Jeghers syndrome (PJS, OMIN #175200)
STK11
LEOPARD syndrome (LS, OMIM PTPN11 #151100) Genes involved in DNA repair or senescence Xeroderma pigmentosum (XPA, OMIM #278700) XPA (XPB, OMIM #610651) ERCC3 (XPC, OMIM #278720) XPC (XPD, OMIM #278730) ERCC2 (XPE, OMIM #278740) DDB2 (XPF, OMIM #278760) ERCC4 (XPG, OMIM #278780) ERCC5 Dyskeratosis congenita (DKCX, OMIM #305000) DKC1 (DKCA1, OMIM #127550) TERC (DKCA2, OMIM #613989) TERT
20q13.32
19p13.3
12q24.13
Dysregulation of mTOR pathway Dysregulation of Wnt pathway Dysregulation of mTOR pathway increased RAS activity
9q22.33 2q14.3 3p25.1 19q13.32 11p11.2 16p13.12 13q33.1
DNA repair gene
Failure of nucleotide excision repair machinery
Xq28 3q26.2 5p15.3
Components of the telomerase complex
Accumulation of DNA damage increased melanin synthesis in senescent melanocytes
cancer types (gliomas, leukemia) has also been observed -au-lait macules (CALMs) are a hallmark (Korf, 2000). Cafe feature of this disorder being present in almost all ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
patients with NF1. Second-hit NF1 mutations in NF1 have been proposed in lesional melanocytes (Boyd et al., 2010). However, haploinsufficiency for neurofibromin 515
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may already affect melanocytes in a specific stage of early development. This can lead to elevated presence of melanocytes derived from schwann cell precursors (Deo et al., 2013). Moreover, NF1-mutant melanocytes have an increased survival capacity in absence of growth factors such as mast cell growth factor (Wehrle-Haller et al., 2001). CALMs in NF1 patients have been shown to exhibit an increased epidermal melanization and increased amount of melanocytes (De Schepper et al., 2006). Axillary and inguinal freckling is another key feature of NF1. The NF1 gene encodes neurofibromin which is a tumor suppressor gene. Differences in melanosome size and distribution of melanocytes have been found in patients with NF1. As NF1 is a regulating factor in the Ras signaling pathway an enhanced Ras activation in melanocytes seems an obvious explanation for increased melanin production in the melanocytes of CALMs. However, normal levels of Ras-GTP have been found in these melanocytes (Griesser et al., 2000). Neurofibromin has also a regulatory capacity on the MAPK and cAMP pathway (Busca and Balotti, 2000). In absence of NF1, NF1-dynein heavy chain 1 (DHC) interaction is lost. This results in increased trafficking of melanosomes to the tips of melanocytes whereby the transfer of melanin to the surrounding keratinocytes is enhanced (Arun et al., 2013). In addition, neurofibromin colocalizes with amyloid precursor protein in melanosomes. Amyloid precursor protein functions as a kinesin1 cargo receptor probably involved in the anterograde migration of melanosomes. In patients with NF1, this complex is lost, which may impair melanosome transport or result in formation of macromelanosomes (De Schepper et al., 2006).
Genes involved in pigmentation and related pathways Deregulation of the KIT pathway Familial progressive hyperpigmentation Familial progressive hyperpigmentation (FPH) represents a rare congenital disorder displaying a congenital diffuse hyperpigmentation. It is inherited in an autosomal-dominant or recessive manner. At birth or early in life, hyperpigmented patches become apparent, which enhance in size and number during life leading to a substantial amount of hyperpigmented skin over time including the face, neck, trunk, limbs, lips, oral mucosa, palms, and soles. On microscopic examination, an increased amount of melanin pigment can be detected in the epidermis, in particular in the stratum corneum. Outside of the skin, no other organs are affected. FPH is probably a heterogeneous disease from which most underlying molecular defects remain still to be discovered (Rojek and Niedziela, 2013). Gain-of-function mutations of kit ligand (KITL) have been found in families with FPH. KIT and KITLG genes play a crucial role in the
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development, survival, and proliferation of the melanocyte and melanin synthesis. KITLG is produced in the human epidermis by keratinocytes and endothelial cells (Wang et al., 2009). Interestingly, overexpression of kit ligand a (Kitla), binding to the Kita receptor, in wild-type zebrafish embryos resulted in hyperpigmented embryos with more and larger melanocytes (Hultman et al., 2007). Although the exact mechanism leading to increased numbers of melanocytes is currently not known, the authors concluded that during normal embryonic development Kitla is rate-limiting, and a correct amount of its expression is needed to produce the wild-type pigment pattern. Further studies are warranted to gain more insight into the role of Kitla/Kita signaling in cell number, cell size control, and directing melanocyte migration. Hyperactivation of the cAMP pathway Carney complex Carney complex is a rare dominant inherited disorder consisting of a combination of hyperpigmented spots -au-lait spots), (lentigines, freckling, blue nevi and cafe schwannomas, myxomas, endocrine overactivity, and endocrine tumors. Lentigines are typically situated bilateral at the medial side of the canthi and genital mucosa. Mutations in the protein kinase, cAMP-dependent, regulatory, type I, alpha (PRKAR1A) gene have been identified as the causal factor. PRKAR1A encodes the subunit type 1-a of protein kinase A (PKA). PKA is a crucial signaling factor in the cAMP pathway, and loss of PRKAR1A function leads to an increased cAMP activity. No increased prevalence of melanoma has been observed in these patients (Lodisch and Stratakis, 2011). McCune–Albright syndrome -auMcCune–Albright syndrome is characterized by cafe lait spots, fibrous dysplasia, sexual precocity, and hyperfunction of multiple endocrine glands. The cAMP pathway is activated by a somatic mutation explaining the symptoms of the McCune–Albright syndrome. This overactive cAMP activity stimulates several cell types including melanocytes (Weinstein et al., 1991). Mutations in the GNAS gene, which encodes the alpha subunit of the G protein, have been found in patients with McCune– Albright. A constitutive activation of the cAMP pathway is caused by a missense mutation which impairs the GTPase activity of the stimulatory G protein (GSa). The phenotype of the disease is believed to be dependent on varying degrees of mosaicism. Somatic mutations in G protein signaling cascades modulate cell proliferation -au-lait patches or linear (Parma et al., 1994). Cafe epidermal naevi are typical dermatological signs. A marked pigmentation on the nape of the neck is also frequently observed (Millington, 2006). The hyperpigmented areas are unilateral with a sharp lining bordering the midline of the body which is a sign of hyperpigmen-
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tation caused by somatic mosaicism. Melanocytes migrate during embryogenesis from the dorsal edge of the neural crest in a ventrolateral way. The migration pathway of melanoblasts ends at the midline of the body. This results in hyperpigmentary diseases due to somatic mosaicism with a sharp midline demarcation. Elevated stimulation of MC1R Endocrine disorders Addison’s disease or primary adrenal insufficiency results from a deficiency to synthesize glucocorticoid and mineralocorticoid hormones. In response, adrenocorticotropin hormone (ACTH) is increased in an attempt to reactivate the adrenal gland production (Tsatmali et al., 2000). It is characterized by a diffuse hyperpigmentation especially on sun-exposed areas which is due to the elevated levels of ACTH and a-MSH. The hyperpigmentation is more pronounced on flexural areas, skin folds, areas of friction, recent scars, the vermillion border of the lips and the genital skin (Nieman and Chanco Turner, 2006). A similar mechanism takes place in Cushing’s syndrome, where an overproduction of ACTH can be explained by a pituitary corticotroph adenoma or an ectopic non-pituitary tumor (Bertagna et al., 2009). Hyperpigmentation is a feature of hyperthyroidism. The pigmentation can only be apparent on the face and sun-exposed areas or be generalized, similar to Addison’s disease (Stefanato and Bhawan, 1997). Excessive pigmentation in patients with hyperthyroidism is caused by increased ACTH secretion. Depigmented areas are also frequently found in patients with thyroid disease, but are mostly a sign of associated vitiligo, which has a high prevalence in patients with thyroid disorders (van Geel et al., 2013a). Phaeochromocytoma is another cause of hyper-ACTH production, which can be associated with hyperpigmentation. Dark skin can be a paraneoplastic phenomenon by release of a-MSH or analogues that bind on MC1 receptors (Zawar and Walvekar, 2004). Melasma Local or diffuse hyperpigmentation can be seen in a subset of women probably due to hormonal factors. Melasma is the most common presentation with hyperpigmented macules on the face which become more pronounced after sun exposure. The number of melanocytes is not increased but they become enlarged and more dendritic, suggesting a hypermetabolic state. This is highlighted by increased melanin deposition in the epidermis and dermis (Grimes et al., 2005; Kosmadaki and Kontochristopoulos, 2011). Pregnancy and oral contraceptives have been linked to increased skin pigmentation. It has been speculated that this is due to increased levels of estrogen and progesterone stimulating the activity of melanocytes (Wong and Ellis, 1984). In third-trimester pregnancy, increased levels of estrogen,
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progesterone, and MSH have been associated with melasma. Melanocytes express estrogen receptors and increased levels of estradiol stimulate enzymes involved in melanogenesis, in particular TYR, TRP1, and TRP2 (Kippenberger et al., 1998). In lesional skin, a-MSH is elevated compared to perilesional skin. It has been speculated that persistent overexpression of a-MSH following UV exposure plays an important role in the development of melasma (Im et al., 2007). Nonetheless, the exact pathogenesis remains to be elucidated. Other proposed hypotheses include upregulation of Wnt pathway modulator genes and prostaglandins (Kang et al., 2011). Even non-coding RNA (H19 gene) could be involved in the pathogenesis of melasma (Kim et al., 2010). UV-mediated elevations in inducible nitric oxide synthase (iNOS) levels is another plausible option which can activate the AKT-NFjB pathway (Jo et al., 2009; Passeron, 2013). Renal failure A diffuse, brown color of the skin can be found in patients with renal failure. The duration and severity of kidney disease has been linked to the development of pigmentation (Khanna et al., 2010). Most prominent areas include the face, the palms, and soles (Pico et al., 1992). This seems more pronounced in patients with hepatitis C (Choi et al., 2003). High levels of b-MSH have been found in patients with hyperpigmentation and renal failure. b-MSH becomes accumulated due to decreased renal clearance (Smith et al., 1975). This eventually results in an increased activation of MC1R, followed by elevated levels of cAMP inducing an excessive production of melanin. Deposition of lipochromes and carotenoids in the skin may also contribute to its appearance. Hyperpigmentation as a result of tyrosinase deregulation Fanconi’s anemia Fanconi’s anemia (FA) is a rare autosomal recessive disorder with a progressive pancytopenia, an increased risk of cancer, several congenital defects, a mottled -au-lait spots. A reduced hyperpigmentation, and cafe antioxidative capacity is believed to be the underlying cause of FA. FA cells have an increased sensitivity for TNF-a induced apoptosis. FA cells have decreased levels of thioredoxin (Kontou and Adelfalk, 2002). Thioredoxin regulates an adequate activity of ribonucleotide reductase inside cells. Low thioredoxin levels lead to a decreased function of ribonucleotide reductase. This ultimately results in an increased chromosomal breakage, which is typical in FA. Beside an antioxidative capacity, thioredoxin is also involved in the pigmentation pathway. Thioredoxin regulates the function of TYR, a key enzyme in melanin synthesis. Reduced thioredoxin levels will lead to an aberrantly increased activity of TYR, resulting in hyper-
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pigmentation of the skin (Rupptisch et al., 1998). To date, FA has been divided into 14 groups according to the affected genes. Most patients (85%) carry defects in FANC, FANCC or FANCG genes (Table 1) (Kaddar and Carreau, 2012). Post-inflammatory hyperpigmentation Post-inflammatory hyperpigmentation (PIH) is a very common observed entity especially in patients of darker skin type. It can develop after a wide range of endogenous or exogenous inflammatory conditions. A subset with only epidermal elevations of melanin and a subset with both epidermal and dermal melanin deposition due to pigment accumulation in melanophages located in the superficial dermis have been identified (Pandya and Guevara, 2000). Arachidonic acid-derived mediators are believed to play a central etiologic role in this condition, ultimately elevating melanin production and transfer. Especially prostaglandins (PGE2 and PGF2alpha), leukotrienes (e.g LTC4 and LTD4), and thromboxanes (TXs) have been discovered as the main inducers of tyrosinase (Yamaguchi and Hearing, 2009). In vitro stimulation of melanocytes with prostaglandins and leukotrienes leads to a swollen and dendritic aspect of melanocytes which is more suited for melanin transfer. Melanocytes express multiple types of PG receptors, such as the prostaglandin F (FP) receptors which bind PGF2a and subsequently stimulate the mitogen-activated protein kinase (MAPK)/ protein kinase C (PKC) pathway and activate phospholipase C-induced phosphoinositide turnover (Breyer et al., 1996; Costin and Hearing, 2007). Vitamin B12 deficiency Vitamin B12 deficiency may be associated with anemia and can cause hyperpigmentation. The brown spots are most marked on the hands and feet, in particular on the interphalangeal joints and nails. It is more commonly found in patients of dark-skinned origin (Baker et al., 1963). The exact mechanism causing hyperpigmentation is still unknown, although it is believed that vitamin B12 deprivation decreases intracellular-reduced glutathione. This leads to an increased tyrosinase activity (Hoffman et al., 2003; Mori et al., 2001).
Hyperpigmentation due to gene defects involved in cell structure and metabolism Defects in keratin genes Dowling–Degos syndrome Dowling–Degos syndrome (DGS) presents with multiple pigmented reticulated macules on the flexural areas. In some patients dark, plugged follicles are visible and atrophic pits around the perioral area. Loss-of-function mutations (haploinsufficiency) in keratin 5 (KRT5) are the underlying cause of the Dowling–Degos syndrome 518
(Batycka-Baran et al., 2010; Pickup and Mutasim, 2011). As explained above, keratins are believed to play an important role in melanosome uptake into keratinocytes. Mutations in KRT5 have also been found in patients with EBS-MP. These mutations have been suggested to cause a deficient melanin granule aggregation explaining the clinical hyperpigmentation (Garcia et al., 2011). Recently, involvement of the Notch pathway has been demonstrated in DDS. A mutation in the POFUT1 gene was found. POFUT1 acts by supplementing O-linked fucose to epidermal growth factor-like repeats of Notch receptors. As a result, Notch ligands bind to Notch receptors and the Notch Intracellular Domain (NICD) is released. Knockdown of POFUT1 leads to reduced expression of NOTCH1, NOTCH2, HES1, and KRT5. The Notch pathway plays a key role in the early development of melanocytes (Stahl et al., 2008; Yao et al., 2001). Loss of POFUT1 leads to decreased levels of TYR and MITF, explaining the hypopigmented macules, whereas the reticular hyperpigmentation results from an abnormal melanin distribution in the epidermis (Li et al., 2013). Naegeli–Franceschetti–Jadassohn syndrome Naegeli–Franceschetti–Jadassohn syndrome (NFJ) is a rare genetic syndrome which affects skin pigmentation, sweat glands (resulting in hypohidrosis), nails, hair, and teeth. The genetic defect lies in the KRT14 gene and is inherited in a dominant way. A reticular hyperpigmentation can be observed, and dermatoglyphs are absent. Diffuse palmoplantar keratoderma can also be present. The hyperpigmentation starts at an early age and is, in contrast to incontinentia pigmenti, not preceded by an inflammatory phase. The hyperpigmentation is situated on the trunk, proximal extremities, skin folds, and periocular and perioral regions. The hyperpigmented areas become more pronounced until approximately the age of 10. They fade again from 15 yrs of age leaving in the aged NFJ patients almost no clear hyperpigmented areas (Itin and Burger, 2010). Dermatopathia pigmentosa reticularis (DPR) is another dominantly inherited disorder closely related to NFJ and also linked to mutations in KRT14. Goh et al. (2009) reported a patient with a KRT14 mutation. DPR has a reticulate pigmentation combined with alopecia, nail changes, palmoplantar hyperkeratosis, and loss of dermatoglyphics. Interestingly, a missense mutation has also been detected in the a-helical rod domain of KRT14 in a patient with a rare subtype of epidermolysis bullosa, namely epidermolysis bullosa showing mottled pigmentation (EBS-MP) (Harel et al., 2006). Genetic studies with mouse models provided supporting evidence for a novel role of keratins in regulating skin pigmentation (Gu and Coulombe, 2007). Although the exact mechanisms remain to be elucidated, it is proposed that, besides KRT5, KRT14 is also involved in the regulation of melanosome import and melanin distribution in ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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keratinocytes explaining the reticulate or mottled hyperpigmentation of the skin. The group of Barsh performed some interesting studies on mice with dark skin. Mutations in a keratin gene were one of the few nonmelanocyte-restricted genetic events involved in hyperpigmentation. A particular mutation was discovered in Keratin 2e (Thr500Pro), which is presumed to impair intermediate filament assembly. Interestingly, in these mice, the hyperkeratosis precedes the epidermal melanocytosis, suggesting a role of paracrine secretion from keratinocytes that stimulate melanocyte proliferation (Fitch et al., 2003). To further elucidate this topic, it would be interesting in future experiments to investigate the role of paracrine factors on melanocytes secreted by keratinocyte cell lines overexpressing keratin genes. Aberrant regulation of the Ras pathway (RASopathies) Lentiginosis Lentigines are small (
PIGMENT CELL & MELANOMA Research The biology of hyperpigmentation syndromes Reinhart Speeckaert, Mireille Van Gele, Marijn M. Speeckaert, Jo Lambert and Nanja van Geel
DOI: 10.1111/pcmr.12235 Volume 27, Issue 4, Pages 512–524 If you wish to order reprints of this article, please see the guidelines here
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REVIEW
Pigment Cell Melanoma Res. 27; 512–524
The biology of hyperpigmentation syndromes Reinhart Speeckaert*, Mireille Van Gele*, Marijn M. Speeckaert, Jo Lambert and Nanja van Geel Department of Dermatology, Ghent University Hospital, Gent, Belgium CORRESPONDENCE Reinhart Speeckaert, e-mail: [email protected] *Equally contribution.
KEYWORDS hyperpigmentation/melanin/melanocyte/pigmentation pathway/syndrome PUBLICATION DATA Received 8 September 2013, revised and accepted for publication 19 February 2014, published online 24 February 2014 doi: 10.1111/pcmr.12235
Summary Hyperpigmentation is a key feature in a variety of inherited and acquired syndromes. Nonetheless, determining the exact diagnosis only on the clinical phenotype can be challenging, and a detailed search for associated symptoms is often of crucial importance. As pigmentation pathways are regulated by complex signaling transduction cascades (e.g. MSH/cAMP, KIT signaling pathways), the underlying defects leading to elevated melanin production are numerous. With regard to treatment, limited therapeutic options exist, each with specific side effects. In acquired hyperpigmentation, the melanin deposition may, however, be reversible after adequate therapy of the underlying disorder or even disappear spontaneously. In this review, we provide an overview of the biology of hyperpigmentation syndromes classified according to the main underlying defect that deregulates physiological melanogenesis. The identification of novel genes or key players involved in hyperpigmentary disorders is becoming increasingly important in view of the development of safer and more efficient treatments.
Introduction Hyperpigmentation is a frequent reason for consultation in clinical practice. It affects quality of life of patients and remains often a persistent burden due to the sparse and limited efficacy of available treatments. Hyperpigmentation disorders range from physiological phenomena to genetic inherited disorders. In other diseases, darkening of the skin is a side phenomenon from pathologic transduction cascades coincidentally interacting with pigmentation pathways. As such, hyperpigmentation can be a first sign of an underlying genetic, metabolic, or neoplastic disorder. An increased deposition of melanin in the skin can be caused by a wide range of disorders, and especially diffuse hyperpigmentation can pose a diagnostic challenge. A detailed understanding of the underlying biological phenomena in these diseases may aid in further insights into the development of new therapies. Furthermore, the pathogenesis of these disorders sheds light on the functional biology of melanocytes. Melanocytes are specialized cells originating from a subset of multipotent stem cells at the neural crest. The precursor cells, called melanoblasts, express early specific markers such as microphthalmia-associated 512
transcription factor (MITF), paired box gene 3a (Pax3a), and Sry-related HMG-box (Sox10). MITF has been shown to be crucial for the survival of melanoblasts. Subsequently, the melanoblasts migrate from the dorsal midline of the neural tube in a dorsolateral way to their final destination at the basal layer of the epidermis, where they acquire a mature phenotype (Thomas and Erickson, 2008). Epidermal melanocytes are the exclusive pigment producing cells offering protection against DNA-damaging UV light. They produce melanin in lysosome-related organelles, called melanosomes, which are transported from the nucleus to the peripheral border of the melanocyte by a complex melanosomal transport mechanism. Ultimately, melanosomes are transferred from the dendritic tips of the melanocytes to the surrounding keratinocytes, giving the skin its natural pigmentation (Van Gele et al., 2009). This review focuses on the biology/pathogenesis of hyperpigmentary diseases with the aim to provide the reader a more detailed insight into the genetic causes leading to specific hyperpigmentary phenotypes. The disorders were classified based on affected genes involved in melanocyte development or involved in common cellular processes or pathways associated with ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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melanogenesis. However, it has become clear that in most hyperpigmentation syndromes multiple pathways that regulate melanoblast differentiation/migration, melanogenesis, and melanocyte proliferation are affected simultaneously. Nonetheless, the disorders were classified according to the presumed main deregulated factor leading to the observed hyperpigmentation. Hyperpigmentation due to benign or malignant melanocytic lesions (e.g. naevi, melanoma) are distinct entities associated with increased melanin production which were not included in this review.
Pathways influencing pigmentation Melanin synthesis is triggered by hydroxylation of L-phenylalanine to L-tyrosine or directly from L-tyrosine. Tyrosinase hydroxylates L-tyrosine, resulting in 3,4-Ldihydroxyphenylalanine (L-DOPA), which further undergoes oxidation to dopaquinone. Thereafter, two main pathways diverge leading in the end to production of black-brown eumelanin and yellow-red pheomelanin. Microphthalmia-associated transcription factor (MITF) is a central factor in melanogenesis that upregulates the expression of tyrosinase (TYR), tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2) (also called dopachrome tautomerase) (Bertolotto et al., 1998). The pivotal role of MITF is further substantiated by its role on the transport of melanosomes to the dendritic tips (Chiaverini et al., 2008). The expression of MITF is mainly controlled by the KIT and melanocyte-stimulating hormone (MSH)/ ATP to 30 ,50 -cyclic adenosine monophosphate (cAMP) signaling pathways, which will be briefly discussed below.
MSH/cAMP signaling pathway The melanocortin system involves the melanocortin peptides a-, b-, and c-MSH and adrenocorticotropic hormone (ACTH). They are formed by proteolytic cleavage of pro-opiomelanocortin (POMC) (Grantz and Fong, 2003). a-MSH exerts its effects on pigmentation by binding the melanocortin-1 receptor (MC1R) at the cell membrane of melanocytes (Figure 1) (Yang et al., 1997). The ACTH molecule shares the first 13 amino acid sequences with MSH and exerts an activity similar to MSH. Activated melanocortin 1 receptor (MC1R) is able to bind Gas proteins, which subsequently activate adenylate cyclase (AC) (Costin and Hearing, 2007). In turn, AC catalyzes the conversion of ATP to cAMP. cAMP signaling is an essential regulator of pigmentation. cAMP directly activates protein kinase A (PKA) which is then able to transfer to the nucleus. Once arrived, PKA becomes phosphorylated and upregulates cAMP-responsive element-binding proteins (CREB) (Costin and Hearing, 2007). CREB binds to the CRE domain present in the promotor of the MITF gene. As such, transcription the MITF gene becomes initiated (Im et al., 1998). cAMP is also known to improve the binding affinity of MITF to the M-box of the TYR gene (Tachibana, 2000). KIT signaling pathway The KIT signaling pathway upregulates MITF by phosphorylating mitogen-activated protein kinase (MAPK). Stem cells factor (SCF) binds to the c-KIT receptor located on the cell membrane of melanocytes (Figure 1). This triggers dimerization of two subunits followed by autophosphorylation of tyrosine. Subsequently
Figure 1. Pigmentation pathways with hyperpigmentation syndromes located according to the involved signaling cascade. AC, adenylate cyclase; ACTH, adrenocorticotropic hormone; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; MAPK, mitogen-activated protein kinase; MC1R, melanocortin 1 receptor; MSH, melanocyte-stimulating hormone; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; SCF, stem cell factor; TYR, tyrosinase; TRP-1, tyrosinase-related protein 1; TRP-2, tyrosinase-related protein 2.
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a variety of signal transduction cascades are initiated. In melanocytes, phosphorylated c-KIT receptor recruits adapter proteins such as GRB2 (growth factor receptor-bound protein 2), SHC (Src homology 2 domaincontaining transforming protein 1), SOS (son of sevenless), and SHP2 (SH2 domain-containing protein tyrosine phosphatase), followed by activation of the Ras-MAPK pathway that stimulates MITF (Vance and Goding, 2004). Wnt signaling pathway The Wnt signaling pathway has besides important functions in embryogenesis and cancer development also a role in melanogenesis. Wnt proteins bind to the frizzled family cell surface receptors. As a result, the dishevelled family protein is activated, which inhibits a multiprotein complex consisting of axin, adenomatous polyposis coli (APC), casein kinase Ia (CKIa), and glycogen synthase kinase-3b (GSK3b). Normally this protein complex stimulates the degradation of b-catenin (Rubinfeld et al., 1996). During embryogenesis, optimal levels of b-catenin have a crucial role in the development of mature melanocytes. Moreover, activated GSK3b synergizes with MITF to enhance the expression of TYR (Khaled et al., 2002).
gene. NEMO (Xq28) is expressed in epidermal cells, and the transcribed protein offers protection against tumor necrosis factor alpha (TNF-a)-triggered apoptosis. NEMO is a part of the regulatory subunit of the IjB kinase (IKK) complex. IKK dephosphylates IjB proteins which normally inhibit NF-jB signaling. IP is characterized by a blaschkoid hyperpigmentation due to highly skewed patterns of X-chromosome inactivation (lyonization). Four stages have been identified: during the first months of life a vesiculobullous stage is observed which is most marked on the extremities. The second stage is verrucous, followed by a hyperpigmented phase which is typically localized on the trunk and intertriginous areas. This stage takes from 3 months of age until adolescence. The last phase involves hypopigmented and atrophic lesions on the calves (Jabbari et al., 2010). This clinical phenotype can be explained by inflammatory lesions, which heal into hyperpigmented lesions resulting from melanin incontinence. Thereafter, melanin is taken up by macrophages which explains the final hypopigmented atrophic stage (Ehrenreich et al., 2007).
Dyschromatosis symmetrica hereditaria Patients with dyschromatosis symmetrica hereditaria (DSH) (reticulate acropigmentation of Dohi) have small hyper- and hypopigmented macules on the dorsal side of hands and feet. In a number of cases, it extends to the dorsal sides of the limbs. The disturbed skin pigmentation develops in most cases (73%) before the age of 6. The hyperpigmented macules tend to progress until adolescence. DSH is inherited by autosomal-dominant mutations in the adenosine deaminase RNA-specific (ADAR) gene (Table 1). It has been put forward that an aberrant editing of RNA during the migration of melanoblasts results in areas of hyperactive and hypoactive melanocytes with different capacity of melanin production (Cui et al., 2005; Miyamura et al., 2003). On histological examination, the melanocytes in the hyperpigmented macules are increased in size but not in number (Kono and Akiyama, 2013).
Linear and whorled nevoid hypermelanosis Linear and whorled nevoid hypermelanosis (LWNH) is an uncommon sporadic skin disorder. LWNH patients have multiple swirls and whorls of hyperpigmented macules organized along the Blaschko lines. The macules have a reticulated pattern and can be segmental or diffuse. LWNH is mostly detected from birth or during the first 2 yrs and stabilizes beyond the age of 2. It has been associated with several congenital problems including neurodevelopmental delay, skeletal malformations, growth retardation, cardiac defects, and ocular abnormalities (Mehta et al., 2011). It can be differentiated from IP by the absence of an inflammatory phase with blister formation or verrucous lesions. A genetic mosaicism has been proposed as the underlying mechanism leading to areas of melanocytes with a different capacity to produce melanin (Maruani et al., 2012). A variety of chromosomal abnormalities (e.g. trisomy 7, 14, 18, 20, X-chromosome mosaicism) have been detected in patients with LWNH, especially when associated with extracutaneous symptoms (Hong et al., 2008). The large majority of documented chromosomal defects overlap with at least one gene involved in pigmentation although in a subset of cases the responsible genetic locus remains to be elucidated (Taibjee et al., 2004).
Incontinentia pigmenti Incontinentia pigmenti (IP) is an X-linked, dominant genetic disorder which is almost only observed in females as being lethal in males before birth. It affects ectodermal structures (skin, teeth, eyes, nails) and the nervous system caused by mutations in the nuclear factor kappa-B (NF-jB) essential modulator (NEMO)
Neurofibromatosis type 1 Neurofibromatosis type 1 (NF1) is a well-known genetic disorder caused by mutations in the NF1 gene. Typical symptoms of NF1 are neurofibromas, pigmented lesions, lisch nodules, neurological abnormalities, development delay, and skeletal deformations. An increased risk for malignant peripheral nerve sheat tumors and other
Hyperpigmentation due to gene defects affecting early melanocyte development and function
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Biology of hyperpigmentation syndromes Table 1. Overview of affected genes in genetic hyperpigmentary syndromes
Disease
Gene(s)
Gene locus
Genes involved in early melanocyte development and function Dyschromatosis symmetrica ADAR 1q21.3 hereditaria (DSH, OMIM #127400)
Gene function
Caused defect
Catalyzing the deamination of adenosine to inosine in dsRNA substrates
Failure of correct RNA editing during melanoblast migration: irregular distribution of hyperor hypoactive melanocytes in the skin Mutations or deletions: abnormal self-destruction (apoptosis) of MCs Disruption of NF1-dynein heavy chain 1 interaction: increased trafficking of melanosomes in au-lait melanocytes of cafe macules
Incontinentia pigmenti (IP, OMIM #308300)
NEMO
Xq28
Essential for NF-ΚB activation
Neurofibromatosis type I (NF1, OMIM # 162200)
NF1
17q11.2
Gene involved in melanosome localization
12q22
Melanogenesis
Gain-of-function mutations: increased TYR activity
17q24.2
Crucial signaling factor in cAMP pathway a-subunit of Gs protein (GTPase)
Mutated PRKAR1A: increased cAMP activity Gain-of-function mutations: increased cAMP activity
16q24.3 Xp22.2 9q22.32 13q13.1 3p25.3 6p21.31
DNA repair maintenance of chromosomal integrity
Overactivation of TYR activity due to reduced thioredoxin levels
17q21.2
Melanosome uptake in keratinocytes
Abnormal melanin distribution in keratinocytes
12q13.13
Melanosome uptake in keratinocytes Organelle transport Serine/threonine kinase regulates cell polarity and tumor suppressor function Tyrosine phosphatase
Deficient melanin aggregation in keratinocytes
Genes involved in pigmentation and related pathways Familial progressive KITLG hyperpigmentation (FPH, OMIM #145250) Carney complex (CNC1, OMIM PRKAR1A #160980) McCune–Albright syndrome GNAS1 (MAS, OMIM #174800) Deregulation of the tyrosinase gene Fanconi’s anemia (FANCA, OMIM #227650) FANCA (FANCB, OMIM #300514) FANCB (FANCC, OMIM #227645) FANCC (FANCD1, OMIM #605724) BRCA2 (FANCD2, OMIM #227646) FANCD2 (FANCE, OMIM #600901) FANCE Genes involved in cell structure and metabolism Naegeli–Franceschetti– KRT14 Jadassohn syndrome (NFJ, OMIM #161000) Dowling–Degos syndrome (DGS, KRT5 OMIM #179850) Peutz–Jeghers syndrome (PJS, OMIN #175200)
STK11
LEOPARD syndrome (LS, OMIM PTPN11 #151100) Genes involved in DNA repair or senescence Xeroderma pigmentosum (XPA, OMIM #278700) XPA (XPB, OMIM #610651) ERCC3 (XPC, OMIM #278720) XPC (XPD, OMIM #278730) ERCC2 (XPE, OMIM #278740) DDB2 (XPF, OMIM #278760) ERCC4 (XPG, OMIM #278780) ERCC5 Dyskeratosis congenita (DKCX, OMIM #305000) DKC1 (DKCA1, OMIM #127550) TERC (DKCA2, OMIM #613989) TERT
20q13.32
19p13.3
12q24.13
Dysregulation of mTOR pathway Dysregulation of Wnt pathway Dysregulation of mTOR pathway increased RAS activity
9q22.33 2q14.3 3p25.1 19q13.32 11p11.2 16p13.12 13q33.1
DNA repair gene
Failure of nucleotide excision repair machinery
Xq28 3q26.2 5p15.3
Components of the telomerase complex
Accumulation of DNA damage increased melanin synthesis in senescent melanocytes
cancer types (gliomas, leukemia) has also been observed -au-lait macules (CALMs) are a hallmark (Korf, 2000). Cafe feature of this disorder being present in almost all ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
patients with NF1. Second-hit NF1 mutations in NF1 have been proposed in lesional melanocytes (Boyd et al., 2010). However, haploinsufficiency for neurofibromin 515
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may already affect melanocytes in a specific stage of early development. This can lead to elevated presence of melanocytes derived from schwann cell precursors (Deo et al., 2013). Moreover, NF1-mutant melanocytes have an increased survival capacity in absence of growth factors such as mast cell growth factor (Wehrle-Haller et al., 2001). CALMs in NF1 patients have been shown to exhibit an increased epidermal melanization and increased amount of melanocytes (De Schepper et al., 2006). Axillary and inguinal freckling is another key feature of NF1. The NF1 gene encodes neurofibromin which is a tumor suppressor gene. Differences in melanosome size and distribution of melanocytes have been found in patients with NF1. As NF1 is a regulating factor in the Ras signaling pathway an enhanced Ras activation in melanocytes seems an obvious explanation for increased melanin production in the melanocytes of CALMs. However, normal levels of Ras-GTP have been found in these melanocytes (Griesser et al., 2000). Neurofibromin has also a regulatory capacity on the MAPK and cAMP pathway (Busca and Balotti, 2000). In absence of NF1, NF1-dynein heavy chain 1 (DHC) interaction is lost. This results in increased trafficking of melanosomes to the tips of melanocytes whereby the transfer of melanin to the surrounding keratinocytes is enhanced (Arun et al., 2013). In addition, neurofibromin colocalizes with amyloid precursor protein in melanosomes. Amyloid precursor protein functions as a kinesin1 cargo receptor probably involved in the anterograde migration of melanosomes. In patients with NF1, this complex is lost, which may impair melanosome transport or result in formation of macromelanosomes (De Schepper et al., 2006).
Genes involved in pigmentation and related pathways Deregulation of the KIT pathway Familial progressive hyperpigmentation Familial progressive hyperpigmentation (FPH) represents a rare congenital disorder displaying a congenital diffuse hyperpigmentation. It is inherited in an autosomal-dominant or recessive manner. At birth or early in life, hyperpigmented patches become apparent, which enhance in size and number during life leading to a substantial amount of hyperpigmented skin over time including the face, neck, trunk, limbs, lips, oral mucosa, palms, and soles. On microscopic examination, an increased amount of melanin pigment can be detected in the epidermis, in particular in the stratum corneum. Outside of the skin, no other organs are affected. FPH is probably a heterogeneous disease from which most underlying molecular defects remain still to be discovered (Rojek and Niedziela, 2013). Gain-of-function mutations of kit ligand (KITL) have been found in families with FPH. KIT and KITLG genes play a crucial role in the
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development, survival, and proliferation of the melanocyte and melanin synthesis. KITLG is produced in the human epidermis by keratinocytes and endothelial cells (Wang et al., 2009). Interestingly, overexpression of kit ligand a (Kitla), binding to the Kita receptor, in wild-type zebrafish embryos resulted in hyperpigmented embryos with more and larger melanocytes (Hultman et al., 2007). Although the exact mechanism leading to increased numbers of melanocytes is currently not known, the authors concluded that during normal embryonic development Kitla is rate-limiting, and a correct amount of its expression is needed to produce the wild-type pigment pattern. Further studies are warranted to gain more insight into the role of Kitla/Kita signaling in cell number, cell size control, and directing melanocyte migration. Hyperactivation of the cAMP pathway Carney complex Carney complex is a rare dominant inherited disorder consisting of a combination of hyperpigmented spots -au-lait spots), (lentigines, freckling, blue nevi and cafe schwannomas, myxomas, endocrine overactivity, and endocrine tumors. Lentigines are typically situated bilateral at the medial side of the canthi and genital mucosa. Mutations in the protein kinase, cAMP-dependent, regulatory, type I, alpha (PRKAR1A) gene have been identified as the causal factor. PRKAR1A encodes the subunit type 1-a of protein kinase A (PKA). PKA is a crucial signaling factor in the cAMP pathway, and loss of PRKAR1A function leads to an increased cAMP activity. No increased prevalence of melanoma has been observed in these patients (Lodisch and Stratakis, 2011). McCune–Albright syndrome -auMcCune–Albright syndrome is characterized by cafe lait spots, fibrous dysplasia, sexual precocity, and hyperfunction of multiple endocrine glands. The cAMP pathway is activated by a somatic mutation explaining the symptoms of the McCune–Albright syndrome. This overactive cAMP activity stimulates several cell types including melanocytes (Weinstein et al., 1991). Mutations in the GNAS gene, which encodes the alpha subunit of the G protein, have been found in patients with McCune– Albright. A constitutive activation of the cAMP pathway is caused by a missense mutation which impairs the GTPase activity of the stimulatory G protein (GSa). The phenotype of the disease is believed to be dependent on varying degrees of mosaicism. Somatic mutations in G protein signaling cascades modulate cell proliferation -au-lait patches or linear (Parma et al., 1994). Cafe epidermal naevi are typical dermatological signs. A marked pigmentation on the nape of the neck is also frequently observed (Millington, 2006). The hyperpigmented areas are unilateral with a sharp lining bordering the midline of the body which is a sign of hyperpigmen-
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Biology of hyperpigmentation syndromes
tation caused by somatic mosaicism. Melanocytes migrate during embryogenesis from the dorsal edge of the neural crest in a ventrolateral way. The migration pathway of melanoblasts ends at the midline of the body. This results in hyperpigmentary diseases due to somatic mosaicism with a sharp midline demarcation. Elevated stimulation of MC1R Endocrine disorders Addison’s disease or primary adrenal insufficiency results from a deficiency to synthesize glucocorticoid and mineralocorticoid hormones. In response, adrenocorticotropin hormone (ACTH) is increased in an attempt to reactivate the adrenal gland production (Tsatmali et al., 2000). It is characterized by a diffuse hyperpigmentation especially on sun-exposed areas which is due to the elevated levels of ACTH and a-MSH. The hyperpigmentation is more pronounced on flexural areas, skin folds, areas of friction, recent scars, the vermillion border of the lips and the genital skin (Nieman and Chanco Turner, 2006). A similar mechanism takes place in Cushing’s syndrome, where an overproduction of ACTH can be explained by a pituitary corticotroph adenoma or an ectopic non-pituitary tumor (Bertagna et al., 2009). Hyperpigmentation is a feature of hyperthyroidism. The pigmentation can only be apparent on the face and sun-exposed areas or be generalized, similar to Addison’s disease (Stefanato and Bhawan, 1997). Excessive pigmentation in patients with hyperthyroidism is caused by increased ACTH secretion. Depigmented areas are also frequently found in patients with thyroid disease, but are mostly a sign of associated vitiligo, which has a high prevalence in patients with thyroid disorders (van Geel et al., 2013a). Phaeochromocytoma is another cause of hyper-ACTH production, which can be associated with hyperpigmentation. Dark skin can be a paraneoplastic phenomenon by release of a-MSH or analogues that bind on MC1 receptors (Zawar and Walvekar, 2004). Melasma Local or diffuse hyperpigmentation can be seen in a subset of women probably due to hormonal factors. Melasma is the most common presentation with hyperpigmented macules on the face which become more pronounced after sun exposure. The number of melanocytes is not increased but they become enlarged and more dendritic, suggesting a hypermetabolic state. This is highlighted by increased melanin deposition in the epidermis and dermis (Grimes et al., 2005; Kosmadaki and Kontochristopoulos, 2011). Pregnancy and oral contraceptives have been linked to increased skin pigmentation. It has been speculated that this is due to increased levels of estrogen and progesterone stimulating the activity of melanocytes (Wong and Ellis, 1984). In third-trimester pregnancy, increased levels of estrogen,
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progesterone, and MSH have been associated with melasma. Melanocytes express estrogen receptors and increased levels of estradiol stimulate enzymes involved in melanogenesis, in particular TYR, TRP1, and TRP2 (Kippenberger et al., 1998). In lesional skin, a-MSH is elevated compared to perilesional skin. It has been speculated that persistent overexpression of a-MSH following UV exposure plays an important role in the development of melasma (Im et al., 2007). Nonetheless, the exact pathogenesis remains to be elucidated. Other proposed hypotheses include upregulation of Wnt pathway modulator genes and prostaglandins (Kang et al., 2011). Even non-coding RNA (H19 gene) could be involved in the pathogenesis of melasma (Kim et al., 2010). UV-mediated elevations in inducible nitric oxide synthase (iNOS) levels is another plausible option which can activate the AKT-NFjB pathway (Jo et al., 2009; Passeron, 2013). Renal failure A diffuse, brown color of the skin can be found in patients with renal failure. The duration and severity of kidney disease has been linked to the development of pigmentation (Khanna et al., 2010). Most prominent areas include the face, the palms, and soles (Pico et al., 1992). This seems more pronounced in patients with hepatitis C (Choi et al., 2003). High levels of b-MSH have been found in patients with hyperpigmentation and renal failure. b-MSH becomes accumulated due to decreased renal clearance (Smith et al., 1975). This eventually results in an increased activation of MC1R, followed by elevated levels of cAMP inducing an excessive production of melanin. Deposition of lipochromes and carotenoids in the skin may also contribute to its appearance. Hyperpigmentation as a result of tyrosinase deregulation Fanconi’s anemia Fanconi’s anemia (FA) is a rare autosomal recessive disorder with a progressive pancytopenia, an increased risk of cancer, several congenital defects, a mottled -au-lait spots. A reduced hyperpigmentation, and cafe antioxidative capacity is believed to be the underlying cause of FA. FA cells have an increased sensitivity for TNF-a induced apoptosis. FA cells have decreased levels of thioredoxin (Kontou and Adelfalk, 2002). Thioredoxin regulates an adequate activity of ribonucleotide reductase inside cells. Low thioredoxin levels lead to a decreased function of ribonucleotide reductase. This ultimately results in an increased chromosomal breakage, which is typical in FA. Beside an antioxidative capacity, thioredoxin is also involved in the pigmentation pathway. Thioredoxin regulates the function of TYR, a key enzyme in melanin synthesis. Reduced thioredoxin levels will lead to an aberrantly increased activity of TYR, resulting in hyper-
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pigmentation of the skin (Rupptisch et al., 1998). To date, FA has been divided into 14 groups according to the affected genes. Most patients (85%) carry defects in FANC, FANCC or FANCG genes (Table 1) (Kaddar and Carreau, 2012). Post-inflammatory hyperpigmentation Post-inflammatory hyperpigmentation (PIH) is a very common observed entity especially in patients of darker skin type. It can develop after a wide range of endogenous or exogenous inflammatory conditions. A subset with only epidermal elevations of melanin and a subset with both epidermal and dermal melanin deposition due to pigment accumulation in melanophages located in the superficial dermis have been identified (Pandya and Guevara, 2000). Arachidonic acid-derived mediators are believed to play a central etiologic role in this condition, ultimately elevating melanin production and transfer. Especially prostaglandins (PGE2 and PGF2alpha), leukotrienes (e.g LTC4 and LTD4), and thromboxanes (TXs) have been discovered as the main inducers of tyrosinase (Yamaguchi and Hearing, 2009). In vitro stimulation of melanocytes with prostaglandins and leukotrienes leads to a swollen and dendritic aspect of melanocytes which is more suited for melanin transfer. Melanocytes express multiple types of PG receptors, such as the prostaglandin F (FP) receptors which bind PGF2a and subsequently stimulate the mitogen-activated protein kinase (MAPK)/ protein kinase C (PKC) pathway and activate phospholipase C-induced phosphoinositide turnover (Breyer et al., 1996; Costin and Hearing, 2007). Vitamin B12 deficiency Vitamin B12 deficiency may be associated with anemia and can cause hyperpigmentation. The brown spots are most marked on the hands and feet, in particular on the interphalangeal joints and nails. It is more commonly found in patients of dark-skinned origin (Baker et al., 1963). The exact mechanism causing hyperpigmentation is still unknown, although it is believed that vitamin B12 deprivation decreases intracellular-reduced glutathione. This leads to an increased tyrosinase activity (Hoffman et al., 2003; Mori et al., 2001).
Hyperpigmentation due to gene defects involved in cell structure and metabolism Defects in keratin genes Dowling–Degos syndrome Dowling–Degos syndrome (DGS) presents with multiple pigmented reticulated macules on the flexural areas. In some patients dark, plugged follicles are visible and atrophic pits around the perioral area. Loss-of-function mutations (haploinsufficiency) in keratin 5 (KRT5) are the underlying cause of the Dowling–Degos syndrome 518
(Batycka-Baran et al., 2010; Pickup and Mutasim, 2011). As explained above, keratins are believed to play an important role in melanosome uptake into keratinocytes. Mutations in KRT5 have also been found in patients with EBS-MP. These mutations have been suggested to cause a deficient melanin granule aggregation explaining the clinical hyperpigmentation (Garcia et al., 2011). Recently, involvement of the Notch pathway has been demonstrated in DDS. A mutation in the POFUT1 gene was found. POFUT1 acts by supplementing O-linked fucose to epidermal growth factor-like repeats of Notch receptors. As a result, Notch ligands bind to Notch receptors and the Notch Intracellular Domain (NICD) is released. Knockdown of POFUT1 leads to reduced expression of NOTCH1, NOTCH2, HES1, and KRT5. The Notch pathway plays a key role in the early development of melanocytes (Stahl et al., 2008; Yao et al., 2001). Loss of POFUT1 leads to decreased levels of TYR and MITF, explaining the hypopigmented macules, whereas the reticular hyperpigmentation results from an abnormal melanin distribution in the epidermis (Li et al., 2013). Naegeli–Franceschetti–Jadassohn syndrome Naegeli–Franceschetti–Jadassohn syndrome (NFJ) is a rare genetic syndrome which affects skin pigmentation, sweat glands (resulting in hypohidrosis), nails, hair, and teeth. The genetic defect lies in the KRT14 gene and is inherited in a dominant way. A reticular hyperpigmentation can be observed, and dermatoglyphs are absent. Diffuse palmoplantar keratoderma can also be present. The hyperpigmentation starts at an early age and is, in contrast to incontinentia pigmenti, not preceded by an inflammatory phase. The hyperpigmentation is situated on the trunk, proximal extremities, skin folds, and periocular and perioral regions. The hyperpigmented areas become more pronounced until approximately the age of 10. They fade again from 15 yrs of age leaving in the aged NFJ patients almost no clear hyperpigmented areas (Itin and Burger, 2010). Dermatopathia pigmentosa reticularis (DPR) is another dominantly inherited disorder closely related to NFJ and also linked to mutations in KRT14. Goh et al. (2009) reported a patient with a KRT14 mutation. DPR has a reticulate pigmentation combined with alopecia, nail changes, palmoplantar hyperkeratosis, and loss of dermatoglyphics. Interestingly, a missense mutation has also been detected in the a-helical rod domain of KRT14 in a patient with a rare subtype of epidermolysis bullosa, namely epidermolysis bullosa showing mottled pigmentation (EBS-MP) (Harel et al., 2006). Genetic studies with mouse models provided supporting evidence for a novel role of keratins in regulating skin pigmentation (Gu and Coulombe, 2007). Although the exact mechanisms remain to be elucidated, it is proposed that, besides KRT5, KRT14 is also involved in the regulation of melanosome import and melanin distribution in ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Biology of hyperpigmentation syndromes
keratinocytes explaining the reticulate or mottled hyperpigmentation of the skin. The group of Barsh performed some interesting studies on mice with dark skin. Mutations in a keratin gene were one of the few nonmelanocyte-restricted genetic events involved in hyperpigmentation. A particular mutation was discovered in Keratin 2e (Thr500Pro), which is presumed to impair intermediate filament assembly. Interestingly, in these mice, the hyperkeratosis precedes the epidermal melanocytosis, suggesting a role of paracrine secretion from keratinocytes that stimulate melanocyte proliferation (Fitch et al., 2003). To further elucidate this topic, it would be interesting in future experiments to investigate the role of paracrine factors on melanocytes secreted by keratinocyte cell lines overexpressing keratin genes. Aberrant regulation of the Ras pathway (RASopathies) Lentiginosis Lentigines are small (
