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• W2594677291 abstract "Linear and whorled nevoid hypermelanosis (LWNH) has hitherto been considered a nonspecific manifestation of mosaicism. We performed deep-exome sequencing on skin from a patient with LWNH and identified a postzygotic mutation in KITLG, associated with increased KITLG and c-KIT epidermal expression. Because germline KITLG mutations have previously been described in a Mendelian disorder, familial progressive hyper- and hypopigmentation (FPHH), LWNH can be considered a mosaic presentation of FPHH. Linear and whorled nevoid hypermelanosis was initially described as a macular hyperpigmentation following Blaschko’s lines (Kalter et al., 1988Kalter D.C. Griffiths W.A. Atherton D.J. Linear and whorled nevoid hypermelanosis.J Am Acad Dermatol. 1988; 19: 1037-1044Abstract Full Text PDF PubMed Scopus (107) Google Scholar). Differential diagnosis includes other linear pigmentary anomalies, such as the pigmentary stage of incontinentia pigmenti, the early stage of keratinocytic epidermal nevi, or hypomelanosis of Ito, the hypopigmented counterpart of LWNH, which can be associated with streaks of hyperpigmentation (Cohen et al., 2014Cohen 3rd, J. Shahrokh K. Cohen B. Analysis of 36 cases of Blaschkoid dyspigmentation: reading between the lines of Blaschko.Pediatr Dermatol. 2014; 31: 471-476Crossref PubMed Scopus (25) Google Scholar). As for hypomelanosis of Ito, LWNH has been considered a nonspecific pigmentary manifestation of mosaicism (Happle, 2014Happle R. Mosaicism in human skin: understanding nevi, nevoid skin disorders, and cutaneous neoplasia. Springer, Berlin2014Crossref Google Scholar) rather than a specific nosological entity. Indeed, various cytogenetic anomalies have been reported in association with hypomelanosis of Ito (Sybert, 1994Sybert V.P. Hypomelanosis of Ito: a description, not a diagnosis.J Invest Dermatol. 1994; 103: 141S-143SAbstract Full Text PDF PubMed Scopus (104) Google Scholar) or LWNH, either in a mosaic or nonmosaic state. However, the molecular basis of LWNH has remained unknown. Here, we report identification of a postzygotic KITLG mutation in a sporadic case of LWNH. A 6-year-old boy previously reported in infancy (Maruani et al., 2012Maruani A. Khallouf R. Machet M.C. Lorette G. Diffuse linear and whorled nevoid hypermelanosis in a newborn.J Pediatr. 2012; 160: 171Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar) had congenital linear and mottled hyperpigmentation on his trunk and limbs, without previous rash or additional cutaneous features. He had normal psychomotor, neurosensory, and general development after a 6-year follow-up. Hyperpigmentation increased in the first days of life and then remained stable. No hypopigmentation was found. Results of an audiogram performed because of chronic otitis were normal. Complete blood count and full clinical examination results were otherwise normal. Skin biopsy showed increased keratinocytic melanin content in the lower epidermis, without pigmentary incontinence (Figure 1). We performed deep whole-exome sequencing with a mean coverage of 150.64-fold on hyperpigmented skin from the patient and blood from his unaffected parents (see Supplementary Materials and Methods online). We identified a de novo postzygotic KITLG variant (NM_000899.3:c.329A>G; encoding p.Asp110Gly) in 41 out of 145 reads (Figure 2), which we confirmed by targeted next-generation sequencing using the Nextera XT DNA Library Preparation Kit (Illumina, San Diego). The KITLG c.329A>G variant was found in 28% of reads in affected skin (mean coverage = 2279.8-fold) and in 18% of reads in blood (mean coverage = 927.2-fold). The identified substitution was absent from the COSMIC (i.e., Catalogue of Somatic Mutations in Cancer) and ExAC (i.e., Exome Aggregation Consortium) databases. It alters an evolutionarily conserved nucleotide (Genomic Evolutionary Rate Profiling score = 5.950) and is predicted to be deleterious by in silico algorithms (Combined Annotation Dependent Depletion score = 17.270, Grantham score = 94, and PolyPhen score = 1). Paraffin-embedded skin section immunostaining using anti-KITLG polyclonal antibody (anti-SCF, C19H6; Abcam, Cambridge, MA) showed intense nuclear and cytoplasmic staining of basal and spinous layer keratinocytes. In addition, c-KIT staining showed increased epidermal expression in basal keratinocytes, and HMB45 staining showed an increase in melanocytes in the basal epidermal layer (Figure 1).Figure 2Integrative Genomics Viewer (Broad Institute, Cambridge, MA) screenshot of whole-exome sequencing for KITLG variant and summary of all known KITLG mutations in human disorders. (a) KITLG c.329A>G (p.Asp110Gly) variant was present in 28% of reads in the proband’s skin and absent in parents’ blood. (b) Genomic structure of KITLG. Membrane-bound and soluble KITLG isoforms result from alternative splicing of exon 6, which contains a cleavage site (red line). Protein domains: AA 1–25 (black), signal peptide; 26–214 (grey), extracellular domain; 215–237 (black), transmembrane domain; 238–273 (grey), cytoplasmic domain. (c) KITLG p.Asp110Gly variant (red) and sKITLG domain mutations identified in FPHH (top) and nonsyndromic unilateral and asymmetric hearing loss/Waardenburg Syndrome type 2 (bottom), localized near KIT-binding sites (black) (Yuzawa et al., 2007Yuzawa S. Opatowsky Y. Zhang Z. Mandiyan V. Lax I. Schlessinger J. Structural basis for activation of the receptor tyrosine kinase KIT by Stem Cell Factor.Cell. 2007; 130: 323-334Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). FPHH, familial progressive hyper- and hypopigmentation.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Germline missense KITLG mutations in exon 2 have previously been found in patients with familial progressive hyper- and hypopigmentation (FPHH, OMIM 145250), who exhibit progressive early-onset diffuse hyperpigmentation with lentigines, hypopigmented macules, and larger café-au-lait macules (Amyere et al., 2011Amyere M. Vogt T. Hoo J. Brandrup F. Bygum A. Boon L. et al.KITLG mutations cause familial progressive hyper- and hypopigmentation.J Invest Dermatol. 2011; 131: 1234-1239Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar; Cuell et al., 2015Cuell A. Bansal N. Cole T. Kaur M.R. Lee J. Loffeld A. et al.Familial progressive hyper- and hypopigmentation and malignancy in two families with new mutations in KITLG.Clin Exp Dermatol. 2015; 40: 860-864Crossref PubMed Scopus (14) Google Scholar; Wang et al., 2009Wang Z.Q. Si L. Tang Q. Lin D. Fu Z. Zhang J. et al.Gain-of-function mutation of KIT ligand on melanin synthesis causes familial progressive hyperpigmentation.Am J Hum Genet. 2009; 84: 672-677Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar; Zanardo et al., 2004Zanardo L. Stolz W. Schmitz G. Kaminski W. Vikkula M. Landthaler M. et al.Progressive hyperpigmentation and generalized lentiginosis without associated systemic symptoms: a rare hereditary pigmentation disorder in south-east Germany.Acta Derm Venereol. 2004; 84: 57-60Crossref PubMed Scopus (20) Google Scholar; Zhang et al., 2016Zhang J. Cheng R. Liang J. Ni C. Li M. Yao Z. Report of a sporadic familial progressive hyper- and hypopigmentation child caused by a novel KITLG mutation.Br J Dermatol. 2016; 175: 1369-1371Crossref PubMed Scopus (11) Google Scholar). LWNH is, therefore, a mosaic presentation of FPHH, as previously described for other Mendelian disorders. KITLG, also known as SCF, encodes the sole activating ligand for the tyrosine kinase c-KIT receptor, which acts exclusively in a melanocyte-autonomous manner (Aoki et al., 2015Aoki H. Tomita H. Hara A. Kunisada T. Conditional deletion of Kit in melanocytes: white spotting phenotype is cell autonomous.J Invest Dermatol. 2015; 135: 1829-1838Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). KITLG controls melanocyte migration, proliferation, and survival, as well as melanin synthesis (Wehrle-Haller, 2003Wehrle-Haller B. The role of Kit-ligand in melanocyte development and epidermal homeostasis.Pigment Cell Res. 2003; 16: 287-296Crossref PubMed Scopus (184) Google Scholar). All known KITLG mutations, including the one we identified, are predicted to affect both its soluble and transmembrane isoforms. They are located near KIT binding sites and may alter binding with c-KIT (Figure 2) (Yuzawa et al., 2007Yuzawa S. Opatowsky Y. Zhang Z. Mandiyan V. Lax I. Schlessinger J. Structural basis for activation of the receptor tyrosine kinase KIT by Stem Cell Factor.Cell. 2007; 130: 323-334Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). Previously reported KITLG mutations in FPHH are clustered in exon 2 on binding site III, which interacts with the c-KIT D3 domain. These mutations are presumed to result in a gain of function, because injection of the mutant recombinant protein increases tyrosinase activity and melanin content in melanoma cell lines (Wang et al., 2009Wang Z.Q. Si L. Tang Q. Lin D. Fu Z. Zhang J. et al.Gain-of-function mutation of KIT ligand on melanin synthesis causes familial progressive hyperpigmentation.Am J Hum Genet. 2009; 84: 672-677Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). Although no functional analyses were performed on keratinocytes from our patient, immunohistochemistry suggests that the variant encoding p.Asp110Gly in exon 4 results in increased epidermal expression of KITLG and an increased number of epidermal melanocytes (Figure 1). This is consistent with previous findings on epidermal KITLG expression in FPHH (Zhang et al., 2016Zhang J. Cheng R. Liang J. Ni C. Li M. Yao Z. Report of a sporadic familial progressive hyper- and hypopigmentation child caused by a novel KITLG mutation.Br J Dermatol. 2016; 175: 1369-1371Crossref PubMed Scopus (11) Google Scholar), solar lentigo (Hattori et al., 2004Hattori H. Kawashima M. Ichikawa Y. Imokawa G. The epidermal stem cell factor is over-expressed in lentigo senilis: implication for the mechanism of hyperpigmentation.J Invest Dermatol. 2004; 122: 1256-1265Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar), or UV-induced hyperpigmentation (Hachiya et al., 2001Hachiya A. Kobayashi A. Ohuchi A. Takema Y. Imokawa G. The paracrine role of stem cell factor/c-kit signaling in the activation of human melanocytes in ultraviolet-B-induced pigmentation.J Invest Dermatol. 2001; 116: 578-586Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). Hence, hyperpigmentation associated with KITLG mutations appears to result from primary functional alteration of keratinocytes rather than melanocytes. Associated increased epidermal expression of c-KIT had not been reported in FPHH. This suggests that expression of the p.Asp110Gly variant in keratinocytes causes autocrine and paracrine up-regulation of c-KIT, resulting in increased melanogenesis in melanocytes (Wehrle-Haller, 2003Wehrle-Haller B. The role of Kit-ligand in melanocyte development and epidermal homeostasis.Pigment Cell Res. 2003; 16: 287-296Crossref PubMed Scopus (184) Google Scholar). Previously described KITLG mutations in exon 4 (near the KIT D2 binding site) have been reported in patients with nonsyndromic unilateral and asymmetric hearing loss or Waardenburg syndrome type 2, where hypopigmentation without hyperpigmentation is present (Zazo Seco et al., 2015Zazo Seco C. Serrão de Castro L. van Nierop J.W. Morín M. Jhangiani S. Verver E.J. et al.Allelic mutations of KITLG, encoding KIT ligand, cause asymmetric and unilateral hearing loss and Waardenburg syndrome type 2.Am J Hum Genet. 2015; 97: 647-660Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). Our patient had normal audition and no hypopigmentation. To conclude, this report of a molecular basis for LWNH as a mosaic presentation of FPHH due to KITLG mutations expands the spectrum of nonlethal gene mutations involved in both constitutive and mosaic disorders. However, because we have not yet studied additional patients with LWNH, we cannot exclude involvement of other genes in this pigmentary phenotype. Nevertheless, identification of a previously unreported KITLG mutation in a mosaic state in LWNH extends the clinical spectrum of KITLG-related pigmentation anomalies and may ultimately provide new insight into pigmentation regulation. Written informed consent for genomic analysis and authorization for publication of photographs were obtained from parents. The study was approved by our regional institutional review board (CPP Est I) and registered as NCT01950975. Pierre Vabres: http://orcid.org/0000-0001-8693-3183 The authors state no conflict of interest. We wish to thank the subject and his family involved in the study and the Centre de Calcul de l’université de Bourgogne (CCuB, https:// haydn2005.u-bourgogne.fr/dsi-ccub/) for technical support and management of the information technology platform. This work was supported by the Conseil Régional de Bourgogne, Centre Hospitalier Universitaire Dijon-Bourgogne, Ministère des Affaires Sociales et de la Santé, Direction Générale de l’Offre de Soins (DGOS), through the Programme Hospitalier de Recherche Clinique (PHRC), Société Française de Dermatologie (SFD), and Agence Nationale de la Recherche (ANR-13-PDOC-0029). Download .pdf (.1 MB) Help with pdf files Supplementary Materials and Methods" @default.
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• W2594677291 title "Mosaicism for a KITLG Mutation in Linear and Whorled Nevoid Hypermelanosis" @default.
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