Naoki Oiso, M.D., Ph.D, Departments of Dermatology and Patient Safety and Management, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan. E-mail: email@example.com
Piebaldism is an uncommon autosomal dominantly inherited pigment anomaly characterized by a congenital white forelock and leukoderma on the frontal scalp, forehead, ventral trunk and extremities. It is caused by a loss-of-function mutation in the KIT gene. Genetic analyses reveal a consistent genotype–phenotype relationship in piebaldism. However, recently reported cases of piebaldism that are milder or severer than genetically expected indicate that other factors, such as a modifier gene of MC1R, influence skin and hair color. The KIT ligand/KIT that triggers the Ras/mitogen-activated protein kinase signaling pathway play essential functions in the migration, proliferation, survival, melanogenesis and melanosome transfer of the melanocytes. We summarize current research progress in piebaldism and related disorders.
More than 800 phenotypic alleles currently are recognized in mice models of pigment disorders.1 This clearly shows that multiple genes regulate skin, hair and eye color. The color is determined by a multistep process: (i) melanoblast migration to skin of the embryo; (ii) proliferation and survival of the melanocytes in the basal layer of the epidermis; (iii) biogenesis of the melanosomes in the melanocytes; (iv) production of melanin granules in the melanosomes in the melanocytes; (v) translocation of melanosomes from the perinuclear region to the peripheral region of the melanocytes; (vi) transfer of the melanosomes from the melanocytes to the keratinocytes; and (vii) translocation of the transferred melanin granules from the peripheral region to the supranuclear region of the keratinocytes.2
Damage during the initial step brings aberrant migration of the melanoblasts in embryo and induces most or all of the loss of the melanocytes in the ventral skin and hair after birth. This is because the melanoblasts originated in the neural crest located in the dorsal area and migrate towards the ventral area. The genetic disorders of aberrant migration of melanoblasts in embryo include non-syndromic piebaldism,3 syndromic Waardenburg syndrome (WS), and a severe PCWH syndrome (characterized by peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS and Hirschsprung disease).4–18 Piebaldism is caused by a mutation in the KIT protooncogene encoding the transmembrane receptor tyrosine kinase (TK), KIT.3 Piebaldism, WS and PCWH syndrome and their responsible genes are summarized in Table 1.3–18
Table 1. Piebaldism, Waardenburg syndrome and related disorders
AD, autosomal dominant; AR, autosomal recessive; FPH, familial progressive hyperpigmentation; FPHH, familial progressive hyper- and hypopigmentation; LS1, LEOPARD syndrome type 1; LS2, LEOPARD syndrome type 2; LS3, LEOPARD syndrome type 3; NF1, neurofibromatosis type 1; PCWHS, peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease syndrome; WS1, Waardenburg syndrome type 1; WS2A, Waardenburg syndrome type 2A; WS2B, Waardenburg syndrome type 2B; WS2C, Waardenburg syndrome type 2C; WS2D, Waardenburg syndrome type 2D; WS2E, Waardenburg syndrome type 2E; WS3, Waardenburg syndrome type 3; WS4A, Waardenburg syndrome type 4A; WS4B, Waardenburg syndrome type 4B; WS4C, Waardenburg syndrome type 4C.
A complex melanogenic paracrine network between the mesenchymal and epithelial cells regulates skin color via the survival and proliferation of the melanocytes, and via melanogenesis in the melanosomes in the melanocytes after birth.19 Among the melanogenic growth factors, the KIT ligand (KITLG) (stem cell factor, steel factor or mast cell growth factor) and its receptor KIT that triggers the Ras/mitogen-activated protein kinase (MAPK) signaling pathway play crucial roles in the control of physiological and pathological skin pigmentation.19 Familial progressive hyper- and hypopigmentation (FPHH)20 and familial progressive hyperpigmentation (FPH)20,21 are caused by a mutation in KITLG. A mutation in the proteins involving the Ras/MAPK signaling pathway causes neurofibromatosis type 1 (NF1), NF1-like syndrome (Legius syndrome), LEOPARD syndrome, Noonan syndrome, Costello syndrome or cardiofaciocutaneous (CFC) syndrome.22 The causative genes of the pigment anomalies of NF1, Legius syndrome and LEOPARD syndrome are summarized in Table 1.23–27
Here, we focus on non-syndromic piebaldism in clinical features, genetic analyses in KIT, the genotype–phenotype relationship, modifier genes, differential diagnosis, treatment and KITLG/KIT mediating signaling.
Piebaldism is a rare, autosomal dominant disorder characterized by congenital white skin (leukoderma) and white hair (poliosis) on the frontal scalp, forehead, ventral trunk and extremities (Fig. 1).3 The white patches are commonly stable throughout life, even though pigmented dots or macules can develop at the margins or within the macules.28,29 The severe form shows a typical white forelock on the frontal scalp and relatively larger leukoderma on the chest, abdomen, arms and legs. The mild type may only show relatively smaller leukoderma on the ventral trunk and/or an extremity without a white forelock. Importantly, patients with piebaldism may develop café-au-lait spots. They may be misdiagnosed as concurrently having NF1 and piebaldism.30
Genetic analyses in KIT
The significant or complete loss of melanocytes in the ventral white patches and white hair is caused by improper migration of melanoblasts in embryo. Therefore, a severe phenotype showing larger leukoderma is associated with severely damaged migration in embryo. After identification of a missense mutation in the KIT gene on the chromosome 4q12 in a large family,3 32 missense mutations,3,29,31–47 17 deletions,31,34,40,41,43,48–54 four insertions,31,34,35,43 seven nucleotide splice-site mutations,31,34,39,41,43 two nonsense mutations39,41 and one pericentric chromosomal inversion55 have been identified in the KIT gene or in the chromosomal region of the KIT gene. These genetic studies indicate that the clinical features and phenotypic severity of piebaldism clearly correlate with the site and the type of mutation in the KIT gene.56
The receptor KIT is a member of the type III group of transmembrane receptor tyrosine kinase (Fig. 2),56 and is composed of an amino-terminal extracellular ligand-binding domain, a single transmembrane domain, and a cytoplasmic region.57,58 The cytoplasmic region contains a juxtamembrane domain and a TK domain that is subdivided into a TK domain 1 (TK1) (amino acid residues, 582–684), a kinase insert domain (amino acid residues, 685–761) and a TK domain 2 (TK2) (amino acid residues, 762–973).58,59 The TK2 contains the highly conserved enzymatic site of the TK2 activation loop (amino acid residues, 810–839).58,59 The binding of KITLG to the extracellular domain leads to receptor dimerization, intracellular autophosphorylation and tyrosine kinase activation.58,59 The binding of KITLG to KIT regulates the migration of melanocytes, cell proliferation, differentiation, survival, melanogenesis and melanosome transfer.20,60
The mild piebald phenotype is associated with haploinsufficiency in a missense mutation in the extracellular ligand-binding domain (Figs 2,3a) or in a mutation of complete elimination of the production of KIT by the defective allele (Figs 2,3b). These mutations preserve approximately 50% of the KIT function, resulting in a mild phenotype.40,41 The wide range of piebald phenotypes, from mild to severe, correlates with haploinsufficiency or dominant-negative effect caused by a truncated mutation in the TK domain (Fig. 2). Severe piebaldism has an association with dominant-negative inhibition caused by a missense mutation in the TK domain (Figs 2,3c). These mutations preserve approximately 25% of the KIT function, resulting in a characteristically severe phenotype.40,41,56
Recently, Chong et al. described an Indian family with a mild piebald phenotype caused by a dominant-negative mutation, Leu611Phe, in the TK domain of the KIT gene.46 Subsequently, we reported two children with milder than expected piebaldism and a father with café-au-lait spots and no leukoderma in a family with the same recurrent mutation Phe584Leu in the TK domain of the KIT gene (Fig. 4).47 The father’s condition indicates that a main feature of leukoderma in piebaldism may be an incomplete penetration of KIT by the mutation,47 even though leukoderma has been thought to involve a complete penetration of KIT by the mutation.3,31,34,35,37,40–42,48,51 There are three possibilities for the milder piebald phenotype: (i) the presence of a modifier gene upregulating or compensating the function;47 (ii) decreased KIT expression in the mutated allele by another polymorphism, mutation or epigenetic modification;47 and (iii) a minor disturbance of the protein by a substitution for a similar amino acid.46
A modifier gene downregulating the function of KIT was detected in a Japanese patient with a peculiar combination of piebald characteristics – a white forelock, auburn hair on the scalp except the frontal area, leukoderma on the ventral trunk, fair skin on the dorsal trunk, and multiple café-au-lait spots on the entire body – caused by a novel missense mutation Pro832Leu in the KIT gene and a homozygous dysfunctional variant Ile120Thr in the MC1R gene encoding the melanocortin-1 receptor for melanocortins.44 A very exceptional point was the auburn hair on the scalp. The red hair color phenotype and fair skin of Caucasians are caused by non-functional variants of an amino acid substitution in the MC1R gene. The possibility of the presence of the homozygous variant Thr120 in the Japanese population is 0.000441 (one person per 2268 people).61 The homozygous variant Thr120 by itself could not cause auburn hair in the Japanese population, because red or auburn hair color is extremely rare.44 Statistics suggest that KITLG/KIT and melanocortins/MC1R signaling are both involved in determining the hair color.44 Therefore, it may be possible to conclude that auburn hair is caused by the missense mutation in the TK domain of the KIT gene in conjunction with the homozygous non-functional variants in the MC1R gene.
The differential diagnosis includes WS, vitiligo, nevus depigmentosus, oculocutaneous albinism (OCA), pigmentary mosaicism and NF1. WS is characterized by piebald-like leukoderma (a white forelock and leukoderma in WS types 1–4), pigmentary changes of the iris (heterochromatic irises and a brilliant blue eye in types 1 and 2), syndromic features of sensorineural hearing loss in types 1–4, dystopia canthorum (an outward displacement of the inner canthus of the eyes) in types 1 and 3, musculoskeletal abnormalities of the upper limbs in type 3 and Hirschsprung disease in type 4.62 PCWH syndrome is a more severe phenotype with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS and Hirschsprung disease.18 Vitiligo is a depigmented skin disorder showing acquired, progressive leukoderma on the skin, mucosa and hair.63 Nevus depigmentosus is a congenital demarcated hypopigmented macule with a serrated and irregular border. It is commonly present at birth and changes little thereafter.64 It includes three clinical variants: the solitary (isolated), segmental and systematized (unilateral whorls and streaks) forms. OCA comprises inherited disorders characterized by complete leukoderma or hypopigmented macules on the entire skin, hair and eyes.65 OCA includes non-syndromic OCA, syndromic Hermansky–Pudlak syndrome, Chediak–Higashi syndrome and Griscelli syndrome. Pigmentary mosaicism of the hypopigmented type (hypomelanosis of Ito) is characterized by unilateral or bilateral hypopigmented whorls and streaks following the Blaschko lines and commonly accompanied by neurological deficit and/or asymmetrical abnormalities in other organs.66 Multiple café-au-lait spots are not uncommon in piebaldism.30 The coexistence of NF1 in piebaldism should be based on neurofibromas or a demonstration of an NF1 gene mutation by DNA testing, because more than six café-au-lait spots and axial freckles may be present in piebald patients.30
The white patches in piebaldism are usually stable. Patients with piebaldism have undergone camouflaging67 or grafting.43,68–71 The grafting includes suction blister epidermal grafting,68 autologous punch grafting,69 non-cultured epidermal cellular grafting,70 cultured epidermal autografts43 and a combination of neodymium:yttrium–aluminum–garnet laser treatment and autologous cultured epidermis grafting.71 Further progress is necessary to improve the quality of life for affected individuals.
KIT and signaling
A complex melanogenic paracrine network between mesenchymal and epithelial cells includes KITLG/KIT, melanocortins/MC1R, endothelin-1 (ET-1)/endothelin B receptor (ETBR), basic fibroblast growth factor (b-FGF)/fibroblast growth factor receptor 2 (FGFR2), and hepatocyte growth factor (HGF)/receptor for HGF (c-Met).20 KITLG/KIT that triggers the Ras/MARK signaling pathway plays crucial functions in melanin synthesis (Fig. 5).20 Imatinib mesylate, a multi-tyrosine kinase inhibitor targeting the BCR-ABL protein in CML, KIT and platelet-derived growth factor receptors, can induce skin hypopigmentation as a benign side-effect.72–74
A gain-of-function mutation in the KITLG gene produces two phenotypes: FPH and FPHH. FPHH is characterized by progressive hypo- and hyperpigmentation, café-au-lait spots and macules, and lentigines.19 FPH is characterized by progressive hyperpigmented macules and lentigines with no hypopigmentation.19 The loss-of-function mutation in the KIT gene causes piebaldism, whereas the gain-of-function mutation in the KIT gene induces mastocytosis, mast cell leukemia and gastrointestinal stromal tumors. Aberrant regulation of the Ras/MARK signaling pathway is associated with pigment anomalies of NF1, Legius syndrome and LEOPARD syndrome.23–27
Piebaldism, a genetic congenital pigment anomaly caused by a mutation in KIT, is characterized by leukoderma and poliosis by aberrant migration of neural crest-derived melanoblasts in the embryo. Genetic studies identified distinct genotype–phenotype relationships via a dominant-negative effect for the severe form, or via haploinsufficiency for the mild form. Recently reported cases of piebald phenotypes that are milder or severer than genetically expected indicate that the size of leukoderma and the white forelock can be modified by other factors. Current identification of the causative genes in various pigment anomalies involved in KITLG/KIT interaction and the subsequent Ras/MARK signaling pathway brings us the opportunity to elucidate more precise mechanisms not only for migration, proliferation and survival of melanocytes, but also for the melanogenesis and melanosome transfer.20 Further scientific investigation would offer the strategies for novel treatments for piebaldism as well as pigmentary disorders in general.
We would like to thank the parents of the patient and Honorary Professor Toshio Hamada, Osaka City University Graduate School of Medicine for allowing us to show a clinical figure.