15251470, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pde.15116 by Readcube (Labtiva Inc.), Wiley Online Library on [01/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Received: 28 April 2022 Accepted: 31 July 2022 DOI: 10.1111/pde.15116 Pediatric Dermatology Verrucous epidermal nevus as a manifestation of a type 2 mosaic PTEN mutation in Cowden syndrome Adrià Plana-Pla MD1,2 | Laura Condal MD1,2 | Ane Jaka PhD1,2 | Ignacio Blanco PhD3,4 | Elisabeth Castellanos PhD4,5 | Isabel Bielsa PhD1,2 1 Dermatology Department, Hospital Universitari Germans Trias I Pujol (HUGTiP), Abstract Badalona, Barcelona, Spain Linear Cowden nevus, also known as linear PTEN nevus, is a type of epidermal nevus, 2 Departament de Medicina, Universitat Autònoma de Barcelona. Badalona, Barcelona, first described in 2007, which is seen in patients with PTEN hamartoma tumor syn- Spain drome. It is considered to be a type 2 form of segmental mosaicism, and we suggest 3 Clinical Genetics and Genetic Counseling that it has certain clinical features that distinguish it from epidermal nevi seen in simi- Unit, Clinical Genetics Service, Northern Metropolitan Clinical Laboratory, Germans lar conditions, such as Proteus syndrome. We present a case of linear Cowden nevus Trias i Pujol University Hospital (HUGTiP), in a 4-year-old boy and review the literature. Badalona, Barcelona, Spain 4 Clinical Genomics Research Unit, Germans KEYWORDS Trias i Pujol Research Institute (IGTP-PMPPC), Badalona, Barcelona, Spain Cowden syndrome, epidermal nevus, lipoma, macrocephaly, mosaicism type 2, PTEN 5 Clinical Genomics Unit, Clinical Genetics Service, Northern Metropolitan Clinical Laboratory, Germans Trias i Pujol University Hospital (HUGTiP), Badalona, Barcelona, Spain Correspondence Isabel Bielsa, Departament de Medicina, Universitat Autònoma de Barcelona, Badalona, Carretera del Canyet s/n, Badalona, Barcelona CP 08916, Spain. Email: ibielsa.germanstrias@gencat.cat 1 | I N T RO DU CT I O N associated with intellectual disability, overgrowth, and predisposi- tion to tumors. These manifestations often overlap and the condi- PTEN is a tumor suppressor gene involved in the regulation of apo- tions are grouped under the umbrella term PTEN hamartoma tumor ptosis and cycle arrest in the mammalian target of rapamycin syndrome (PHTS). Therefore, these patients can be diagnosed using (mTOR) pathway. Under normal conditions, it decreases the growth the PTEN hamartoma syndrome clinical diagnostic criteria revised and survival of cells.1 Numerous diseases have been linked to germ- by Pilarsky et al in 2013,3 although the diagnosis is usually subse- line PTEN mutations in recent decades, including Cowden syn- quently confirmed by genetic testing. No clear genotype– drome, Bannayan–Riley–Ruvalcaba syndrome, Lhermitte–Duclos phenotype correlations have yet been described.1 1 disease in adults, macrocephaly/autism syndrome, and SOLAMEN Happle4 coined the term linear Cowden nevus (also called linear syndrome (segmental overgrowth, lipomatosis, arteriovenous mal- PTEN nevus)4 to refer to a new clinical-genetic entity within the 2 formation, and epidermal nevus syndrome). Cowden syndrome is group of keratinocytic epidermal nevi.4 He described it as a type 2 seg- the most common phenotypic manifestation within this spectrum. mental manifestation (produced by the loss of the corresponding Although each syndrome has characteristic features, they are all wild-type allele resulting in a pronounced segmental involvement This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors. Pediatric Dermatology published by Wiley Periodicals LLC. Pediatric Dermatology. 2023;40:179–181. wileyonlinelibrary.com/journal/pde 179 15251470, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pde.15116 by Readcube (Labtiva Inc.), Wiley Online Library on [01/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 180 Pediatric PLANA-PLA ET AL. Dermatology We present the case of a patient diagnosed with PHTS manifest- ing a germline PTEN mutation and an epidermal nevus in which loss of heterozygosity was detected in DNA extracted from the lesion. We also review the literature. 2 | CASE REPORT A 4-year-old boy was noted at birth to have a thick, linear, yellowish- white lesion with a verrucous surface on the posterior aspect of his left thigh and buttock diagnosed as an epidermal nevus (Figure 1). The child was born at 40 weeks gestation and had a history of macrocephaly with normal brain magnetic resonance imaging (MRI) findings. He has had delayed development and altered tooth morphology. Three subcutane- ous tumors with an elastic consistency were observed in the trunk and groin areas between the ages of 2 and 4 years; both clinical and ultra- sound findings were consistent with lipoma. Phimosis and bilateral crypt- orchidism were also observed. Biopsy of the verrucous plaque on the left thigh (Figure 2) and one of the subcutaneous tumors confirmed the respective clinical diagnoses of epidermal keratinocytic nevus and lipoma. Given the history of macrocephaly and developmental delays, F I G U R E 1 Brown lesion with a verrucous surface on the posterior aspect of the left thigh and buttock Cowden syndrome was suspected. This tentative diagnosis was con- firmed genetically by next-generation sequencing of peripheral blood using a customized gene panel.5 The results showed the heterozygous pathogenic PTEN variant c.367C>G (NM_000314.6), which causes a change in the protein without altering the reading frame (p.(His123Asp)). This variant has been described as pathogenic in other patients with clin- ical manifestations suggestive of PHTS, and has been found to inactivate the phosphatase function of PTEN (ClinVara: RCV000693998) in in vitro assays. Subsequent analysis of DNA extracted from the epidermal nevus showed loss of heterozygosity following detection of the c.367C>G variant in heterozygosity in the affected tissue, confirming a diagnosis of linear Cowden (or PTEN) nevus. 3 | DI SCU SSION Linear Cowden (or PTEN) nevus was first described in 2007 in a 3-year-old boy with hydrocephalus, lipomas, limb asymmetry, unilat- eral macrodactyly and epidermal nevus. The boy was a carrier of a germline PTEN mutation and investigation of DNA extracted from the epidermal nevus showed loss of heterozygosity for this mutation.4,6 Although the lesion was initially diagnosed as an epidermal nevus in the context of Proteus syndrome, Happle indicated that the patient F I G U R E 2 Biopsy from the epidermal nevus (H&E 40) showing probably had Cowden syndrome and that the nevus was a type 2 form epidermal hyperplasia with marked acanthosis, hyperkeratosis, and of mosaicism.4 Proteus syndrome was frequently confused with PHTS papillomatosis at this time as its genetic basis had not yet been discovered. In addi- tion, approximately 50% of patients with Proteus syndrome have an being superimposed on the ordinary nonsegmental phenotype) of epidermal nevus. It is now known, however, that Proteus syndrome is Cowden disease in patients harboring a germline PTEN pathogenic caused by lethal AKT mutations that survive in mosaic forms.7 Accord- variant and a second-hit mutation, usually a loss of heterozygosity ingly, patients with clinical features of Proteus syndrome and a PTEN early in embryonic development.4 mutation described in early reports probably had PHTS. 15251470, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pde.15116 by Readcube (Labtiva Inc.), Wiley Online Library on [01/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License PLANA-PLA ET AL. Pediatric 181 Dermatology In our review of the literature, we identified three additional cases DATA AVAILABILITY STAT EMEN T of congenital epidermal nevi in which identification of a heterozygous The data that support the findings of this study are available from the germline pathogenic variant in the PTEN gene led to the detection of corresponding author upon reasonable request. a second-hit mutation affecting the wild-type allele in DNA extracted from the lesions.2,8,9 The first of these cases was described in 2000 OR CID by Zhou et al.8 in a patient with hypertrophy of the lower right Adrià Plana-Pla https://orcid.org/0000-0003-2241-5664 extremity, arteriovenous malformations, macrocephaly, lipomas, and epidermal nevi. The second-hit mutation was observed in DNA RE FE RE NCE S extracted not only from the epidermal nevus but also from a lipoma 1. Macken WL, Tischkowitz M, Lachlan KL. PTEN hamartoma tumor and an arteriovenous malformation. The second case was published syndrome in childhood: a review of the clinical literature. Am J Med Genet Part C Semin Med Genet. 2019;181:591-610. by Tekin et al.9 in 2006 and involved a 4-year-old boy with a germline 2. Caux F, Plauchu H, Chibon F, et al. Segmental overgrowth, lipomato- PTEN mutation and a large congenital epidermal nevus; the authors sis, arteriovenous malformation and epidermal nevus (SOLAMEN) detected a second somatic PTEN mutation within a lipoma (they did syndrome is related to mosaic PTEN nullizygosity. Eur J Hum Genet. not investigate the epidermal nevus). The third and most recent case 2007;15:767-773. 3. Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cow- was published in 2007 by Caux et al.,2 who described a 30-year-old den syndrome and the PTEN hamartoma tumor syndrome: systematic woman with a germline PTEN mutation and left thigh overgrowth, review and revised diagnostic criteria. J Natl Cancer Inst. 2013;105: lymphatic vascular malformations, macrocephaly, lipomas, and an epi- 1607-1616. dermal nevus. Genetic evaluation demonstrated loss of heterozygosity 4. Happle R. Linear Cowden nevus: a new distinct epidermal nevus. Eur J Dermatol. 2007;17:133-136. in the second allele in epidermal nevus tissue and also in a lipoma. 5. Castellanos E, Gel B, Rosas I, et al. A comprehensive custom panel In all the cases of PHTS reported the epidermal nevi are described desing for routine hereditary cancer testing: preserving control, as thick, markedly papillomatous lesions with a significant hyperkera- improving diagnostics and revealing a complex variation landscape. totic component. We propose that these clinical features could be Sci Rep. 2017;4(7):39348. doi:10.1038/srep39348 useful for distinguishing PHTS-associated nevi from the flatter, softer, 6. Loffeld A, McLellan NJ, Cole T, Payne SJ, Fricker D, Moss C. Epider- mal naevus in Proteus syndrome showing loss of heterozygosity for and more velvety nevi seen in Proteus syndrome. In addition, the his- an inherited PTEN mutation. Br J Dermatol. 2006;154(6):1194-1198. topathological changes seen in these lesions (epidermal hyperplasia 7. Lindhurst MJ, Sapp JC, Teer JK. A mosaic activating mutation in AKT1 with hyperkeratosis, acanthosis and papillomatosis) are probably more associated with the Proteus syndrome. N Engl J Med. 2011;365:611-619. evident if we compare them with those of the Proteus syndrome. It is 8. Zhou X-P. Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asym- also important to keep in mind that some PIK3A-related overgrowth metry, arteriovenous malformations and lipomatosis. Hum Mol Genet. spectrum syndromes may also present with epidermal nevi. Epidermal 2000;9(5):765-768. nevi may thus be early markers of syndromes with multiple 9. Tekin M, Ozturk Hismi B, Fitoz S, et al. A germline PTEN mutation malformations. with manifestations of prenatal onset and verrucous epidermal nevus. Am J Med Genet. 2006;140:1472-1475. Regarding treatment, although there are a few reports of non- 10. Zhou AG, Antaya RJ. Topical sirolimus therapy for nevus sebaceus and syndromic epidermal nevi treated with topical rapamycin,10 this has epidermal nevus: a case series. J Am Acad Dermatol. 2022;87:407-409. not been used to treat PHTS-associated nevi. Nevertheless, it could be a treatment to consider as these syndromes are caused by alter- ations in the mTOR pathway. In conclusion, observation of a hyperkeratotic epidermal nevus in How to cite this article: Plana-Pla A, Condal L, Jaka A, a patient with macrocephaly, intellectual disability, overgrowth, or Blanco I, Castellanos E, Bielsa I. Verrucous epidermal nevus as tumors should raise suspicion for PHTS. a manifestation of a type 2 mosaic PTEN mutation in Cowden syndrome. Pediatr Dermatol. 2023;40(1):179‐181. doi:10. CONF LICT OF IN TE RE ST 1111/pde.15116 The authors declare no conflict of interest.