A nonepidermolytic keratinocytic epidermal naevus associated with a postzygotic mutation in the gene encoding epidermal growth factor receptor

TY - JOUR

T1 - A nonepidermolytic keratinocytic epidermal naevus associated with a postzygotic mutation in the gene encoding epidermal growth factor receptor

AU - Umegaki-Arao, N.

AU - Ono, N.

AU - Tanaka, R.

AU - Sasaki, T.

AU - Fujita, H.

AU - Shiohama, A.

AU - Aoki, S.

AU - Amagai, M.

AU - Kubo, A.

N1 - Funding Information: N. Umegaki‐Arao N. Ono R. Tanaka T. Sasaki H.  Fujita A. Shiohama S. Aoki M. Amagai A.  Kubo akiharu@a5.keio.jp Department of Dermatology Keio University School of Medicine Tokyo Japan Department of Dermatology Tokyo Women's Medical University Medical Center East Tokyo Japan Center for Supercentenarian Medical Research Keio University School of Medicine Tokyo Japan KOSÉ Endowed Program for Skin Care and Allergy Prevention Keio University School of Medicine Tokyo Japan Practical Research Project for Rare/Intractable Diseases 16ek0109067h0003 Japan Agency for Medical Research and Development, AMED 16ek0109151h0002 Funding sources: this work was supported, in part, by the Practical Research Project for Rare/Intractable Diseases, grants 16ek0109067h0003 and 16ek0109151h0002 from the Japan Agency for Medical Research and Development, AMED. Conflicts of interest: none to declare These signal pathways are essential for cell proliferation and cell survival, suggesting that nonmalignant overgrowth of keratinocytes causes nonepidermolytic KEN. Among the growth factor receptor genes found upstream of these pathways, mutations in either D ear E ditor , Nonepidermolytic keratinocytic epidermal naevi (KEN) are benign congenital skin lesions exhibiting verrucous acanthosis and hyperkeratosis characterized by a linear distribution along the lines of Blaschko. Nonepidermolytic KEN arise as a result of prenatal postzygotic mutations in components of either the rat sarcoma (RAS)/mitogen‐activated protein kinase (MAPK) pathway or the phosphoinositide‐3‐kinase (PI3K)/AKT pathway. FGFR2 or However, mutations in the FGFR3 have been reported to cause KEN. EGFR gene, encoding epidermal growth factor receptor (EGFR), a major growth factor receptor in keratinocytes, have not been reported. Here we describe a case of nonepidermolytic KEN exhibiting characteristic clusters of velvet‐like whitish papules along the lines of Blaschko and a postzygotic mutation in EGFR . a, b). However, dermoscopic observations using gel to reduce reflection on the surface of the stratum corneum revealed a cobblestone pattern of epidermal hyperplasia within a hyperpigmented network (Fig.  c). A biopsy of the whitish papules showed acanthosis and hyperkeratosis without granular degeneration, and widespread basal melanosis, consistent with the dermoscopic findings. The rete ridges were relative flat and lacked verrucous hyperelongation. In contrast, the surface of the acanthotic epidermis was markedly uneven with squames stacked in the pits (Fig.  d). Based on these findings, the patient was diagnosed with nonepidermolytic KEN. The patient was a 6‐year‐old boy with an unremarkable family history. At the age of 3 months, his parents had noticed widespread slightly whitish skin on his trunk. The lesions lacked pruritus and were localized along the lines of Blaschko, primarily on the right side of the body. The lesions were comprised of characteristic clusters of velvet‐like whitish papules, with less pigment relative to the surrounding normal skin (Fig.  The clinicopathological appearance and genetic features of the epidermal naevi with a somatic c.2582T>A, (p.L861Q) mutation. (a, b) Whitish scaly plaques and macules were scattered along the lines of Blaschko on the right lower extremity (a) and right torso (b). (c) Dermoscopic findings from the boundary of affected (lower part) and adjacent normal skin (upper part). (d) Haematoxylin and eosin staining, scale bar = 50 μm. (e) Sanger sequencing chromatogram of (upper panels) and digital polymerase chain reaction ( and the c.2582T>A variant (lower panels) using genomic EGFR EGFR PCR ) detecting wild‐type EGFR DNA obtained from peripheral blood leucocytes, lesional epidermis and lesional dermis as templates. Digital PCR data are available from the authors. (f) Immunohistochemical staining of affected skin (left panel) and epidermolytic keratinocytic epidermal naevi bearing the KRT 10 p.R156H mutation (right panel) using a rabbit polyclonal anti‐epidermal growth factor receptor (phosphor‐Y1068) antibody at 1 : 200 dilution. Scale bars = 100 μm. Exome sequencing was performed using genomic DNA purified from the epidermis after obtaining written informed consent in accordance with the guidelines of the institutional review board of the Keio University School of Medicine. A heterozygous c.2582T>A (p.L861Q) variant was detected in including The distribution along the lines of Blaschko indicates a genetic basis underlying the lesional keratinocytes. To understand the nature of these lesions, lesional biopsies were taken and separated into epidermis and dermis using dispase. EGFR (NM_005228·3), with no variants identified in any of the genes previously implicated in KEN, HRAS , KRAS , NRAS , PIK3CA , FGFR2 , FGFR3 , BRAF and PTEN . Sanger sequencing revealed the heterozygous e), as confirmed by digital polymerase chain reaction (Fig.  e). EGFR c.2582T>A (p.L861Q) variant specifically in the affected epidermis, but not from the affected dermis or white blood cells (Fig.  Immunohistochemical staining using an anti‐phospho‐Y1068 EGFR antibody (ab40815; Abcam, Cambridge, U.K.) revealed aberrant EGFR activation in the basal layer of the naevus, unlike what was observed in epidermolytic KEN naevi bearing the f). We conclude that the The p.L861Q variant has been reported as an activating mutation of EGFR kinase in malignant tumours. KRT10 mutation (Fig.  de novo occurrence of the constitutive‐active EGFR variant caused the nonepidermolytic KEN. While EGFR mutations have been identified in seborrhoeic keratosis, a common benign epidermal tumour in adults, to the best of our knowledge this is the first report of a somatic EGFR mutation in nonepidermolytic KEN. Seborrhoeic keratosis has been associated with a variety of mutations in the RAS/MAPK and PI3K/AKT pathways, among which mutations in PIK3CA and FGFR3 are the most common disease‐causing mutations, with less common mutations observed in EGFR , HRAS and A lower incidence of EGFR mutations was also reported in cutaneous squamous cell carcinoma. To date, various cases of nonepidermolytic KEN have been associated with mutations in KRAS . HRAS , KRAS , PIK3CA , FGFR2 and FGFR3 , but not in EGFR . Thus, EGFR is likely a minor causative gene not only for seborrhoeic keratosis and squamous cell carcinoma, but also for KEN. Further research will be necessary to understand how EGFR can act as a minor causative gene in both benign and malignant epidermal tumours. The distinctive clinical features of this case were the whitish appearance of the KEN instead of basal melanosis, combined with the hyperpigmented network appearance by dermoscopy. Histological analyses revealed skin lesions with acanthotic bumps and massive accumulation of hyperkeratotic plugs between the bumps, suggesting that the irregular reflection of visible light at the surface of the hyperkeratotic stratum corneum may have produced the whitish appearance. Further study would be needed to elucidate whether the distinctive clinical appearance of this case is a specific feature of KEN caused by the EGFR mutation.

PY - 2020/5/1

Y1 - 2020/5/1

UR - http://www.scopus.com/inward/record.url?scp=85077147107&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85077147107&partnerID=8YFLogxK

U2 - 10.1111/bjd.18729

DO - 10.1111/bjd.18729

M3 - Letter

C2 - 31745974

AN - SCOPUS:85077147107

SN - 0007-0963

VL - 182

SP - 1303

EP - 1305

JO - British Journal of Dermatology

JF - British Journal of Dermatology

IS - 5

ER -