Diffuse Epidermolytic Epidermal Nevus and Genetic Counseling: A Case Report and Brief Review of the Topic Christa M. Tomc, DO,* Peter Malouf, DO,** Stephen Weis, DO***

*Dermatology resident, 1st year, University of North Texas Health Science Center/Texas College of Osteopathic Medicine, Fort Worth, TX **Program director, University of North Texas Health Science Center/Texas College of Osteopathic Medicine, Fort Worth, TX ***Associate program director, University of North Texas Health Science Center/ Texas College of Osteopathic Medicine, Fort Worth, TX

Disclosures: None Correspondence: Christa M. Tomc, DO; [email protected]

Abstract A 16-month-old female presented with an extensive epidermal nevus demonstrating epidermolytic hyperkeratosis on histologic evaluation. Individuals with this disorder are at increased risk of bearing children with epidermolytic ichthyosis. This occurs because the same mutations causing cutaneous somatic mosaicism may also affect the gonads. Genetic counseling is advised for individuals with extensive epidermolytic epidermal nevus, as the generalized epidermolytic hyperkeratosis carries significant morbidity and mortality.

Introduction was red and scaly with no noted blisters. It was On physical exam, the patient was an alert Epidermal nevi are a class of hamartomas derived initially treated with triamcinolone acetonide 16-month-old in no acute distress. On from ectoderm. They are relatively common, 0.1% ointment, which improved the pruritus but cutaneous examination, there were whorled affecting 1 in 1,000 individuals. They may present did not alter the morphology of the lesions. Since plaques of various morphologies in a Blaschkoid as a single plaque or be more extensive, assuming the initial appearance of the lesions, some of the arrangement distributed on her neck, bilateral a whorled appearance. This type of arrangement areas had become brown and scaly, others brown upper extremities, flanks, abdomen, and bilateral is also known as a Blaschkoid pattern, which is and warty. The mother reported an uneventful medial thighs (Figure 1). Verrucous brown frequently seen in skin conditions displaying pregnancy and birth. The patient was the youngest papules coalesced into linear plaques on the left genetic mosaicism.1 Genetic mosaicism occurs of four sisters, none of whom had similar lesions. anterior neck, bilateral axillae, and crural folds. when two genetically distinct cell populations There was no family history of consanguinity, On the flanks were digitate erythematous plaques proliferate in one organism. This can result in two and the parents denied any members of the with white scale. A hyperpigmented plaque or more phenotypically unique cutaneous lesions, extended family with similar markings. On with large, plate-like, brown scale was located as in the case of epidermal nevi.2 presentation to the clinic, the patient was being on the left lateral leg. No apparent unilateral treated with isoniazid for latent tuberculosis. She hemihypertrophy of the limbs or dysmorphic Keratinocytic epidermal nevi are those derived was otherwise a healthy, well-developed toddler. facies was appreciated. from ectoderm that goes on to differentiate Her parents denied a history of cognitive or Shave biopsies were obtained from a verrucous into keratinocytes. There are more than 10 developmental delays. They were concerned that histologically distinct types of keratinocytic nevi. lesion of the left axilla and from an eczematous the lesions were a result of a chicken pox vaccine lesion on the left flank. These were submitted One such variant demonstrates epidermolytic she received in Iraq. hyperkeratosis and is thus known as an in formalin for standard pathologic evaluation epidermolytic epidermal nevus. This entity is clinically indistinguishable from other subtypes Figure 1 within this category.3 Uniquely, this histologic finding is also seen in a generalized form, known as epidermolytic ichthyosis or bullous congenital ichthyosiform erythroderma. Generalized epidermolytic ichthyosis an autosomal- dominantly inherited condition with significant associated morbidity and mortality, resulting from a mutation in the genes that code for keratins (K) 1 and 10. These same defects have been demonstrated in epidermolytic epidermal nevi in individuals who have born offspring with epidermolytic hyperkeratosis. This indicates that this postzygotic mutation may also result in gonadal mosaicism, especially in individuals with extensive lesions. We present a case of a patient with an extensive epidermolytic epidermal nevus to highlight the importance of genetic counseling, as these patients are at heightened risk for bearing children with epidermolytic ichthyosis.

Case Report A 16-month-old Iraqi immigrant presented to the clinic with her parents for evaluation of a skin eruption. The lesions appeared when she was Figure 1. Physical exam revealed various morphologies, including digitate erythematous plaques 3 weeks old and developed on her neck, arms, with white scale on the flank and whorled brown verrucous plaques in the axilla. flanks, abdomen, and legs. The rash initially Page 30 DIFFUSE EPIDERMOLYTIC EPIDERMAL NEVUS AND GENETIC COUNSELING: A CASE REPORT AND BRIEF REVIEW OF THE TOPIC via hematoxylin and eosin stain (H&E). Lesions may appear macerated at birth, but tend inflammatory linear verrucous epidermal nevus Both biopsies demonstrated mild epidermal to become more verrucous with age. ILVEN, a refers to the clinical appearance of the lesion, hyperplasia associated with hypergranulosis and variant of epidermal nevi, is a verrucous and as an inflammatory infiltrate is not typically hyperkeratosis with papillomatosis. There was erythematous lesion that can occur at any site characteristic on histologic observation.10 Other pallor of superficial epidermal keratinocytes but is most often seen on the limbs or perineum findings, such as epidermolytic hyperkeratosis, as in at irregular intervals. Clumped eosinophilic in females.7 Characteristic of epidermal nevi is our patient, may also be seen. This is characterized tonofilaments were present adjacent to nuclei the linear or whorled arrangement, which tends by perinuclear vacuolization of keratinocytes with alteration of the granular layer, consistent to follow the lines of Blaschko. This Blaschkoid and increased numbers of enlarged keratohyalin with epidermolytic hyperkeratosis. No significant pattern is thought to be due to the clonal granules with overlying hyperkeratosis. inflammatory infiltrate or eosinophils were proliferation of two genetically distinct cell lines In patients with epidermolytic epidermal nevus, present (Figure 2). The pathological findings, that arise from a postzygotic mutation during 2 evaluation of affected tissue with epidermolysis when considered with the clinical findings, were embryogenesis, referred to as genetic mosaicism. has demonstrated mutations in KRT1 and consistent with epidermolytic epidermal nevus. A genetic mosaic is an organism composed of two KRT10, the genes that code for keratins 1 and 10 or more genetically different populations of cells (K1 and K10). These abnormal keratins are found Discussion that originate from one genetically homogeneous in the spinous and granular layer of the epidermis, Epidermal nevi represent a heterogenous group zygote. There are two major categories of mosaic where the epidermolysis occurs. Mutations in of hamartomas of ectodermal origin. Skin phenotypes: functional mosaicism, resulting K1 and K10 are also seen in individuals with from the Lyon effect of X inactivation, which structures arising from ectoderm include the 8 generalized epidermolytic hyperkeratosis. adnexa (hair follicles, sebaceous, and apocrine can be transmitted from mother to daughter, Generalized epidermolytic hyperkeratosis is glands) as well as keratinocytes.4 Epidermal nevi and genomic mosaicism, which is caused by usually transmitted as an autosomal-dominant are subdivided into organoid and nonorganoid postzygotic autosomal mutations. This latter trait.11 However, instances of individuals with nevi. An organoid nevus is a hamartoma category is the type of mosaicism observed in extensive epidermolytic epidermal nevi bearing consisting of more than one type of tissue, or in epidermal nevi. The degree of clonal proliferation offspring with generalized epidermolysis have which identification of a single tissue of origin and the point at which the mutation occurred been observed.12,13 Studies of three unrelated is not possible. Organoid nevi include nevus during embryogenesis determine the extent and persons with epidermolytic epidermal nevi sebaceus, syringocystadenoma papilliferum, distribution of an epidermal nevus, which may demonstrated mutations in one of the two K10 nevus comedonicus, porokeratotic eccrine and present as an isolated plaque or diffusely. They alleles in keratinocytes cultured from lesional ostial dermal duct nevus (PEODDN, also known can involve an entire limb, half of the body in skin but not from nonlesional epidermis. Each as porokeratotic eccrine nevus).5,6 Nonorganoid a unilateral distribution (nevus unius lateris) of the patients had offspring with generalized nevi are also referred to as keratinocytic nevi, or both sides of the trunk, limbs, and face in a epidermolytic hyperkeratosis, all with the denoting their ectodermal tissue of derivation. symmetric pattern with demarcation at the same K10 mutations isolated from the parents’ This group includes inflammatory linear midline (ichthyosis hystrix). epidermolytic EN.1 verrucous nevus (ILVEN), linear porokeratosis, At least 10 histologic variants of epidermal It is crucial that persons with epidermolytic non-epidermolytic verrucous nevus, and, as in our nevi have been delineated. Virtually all are verrucous nevi who are planning pregnancy be patient, epidermolytic verrucous nevus. characterized by hyperkeratosis, epidermal aware of the possibility of bearing offspring with hyperplasia, acanthosis, papillomatosis, and Epidermal nevi appear at or shortly after birth 9 epidermolytic hyperkeratosis. Epidermolytic as localized lines of epidermal thickening. variable parakeratosis. The inflammation of an hyperkeratosis is also known as epidermolytic ichthyosis, bullous congenital ichthyosiform Figure 2 erythroderma of Brocq, or bullous ichthyosis. It presents at birth with erythroderma, erosions, and peeling, with widespread areas of denuded skin. Skin fragility and blistering decrease over time, and marked hyperkeratosis supersedes. Epidermolytic ichthyosis can be severely disfiguring and have a tremendous impact on patient quality of life. Neonates are at high risk for sepsis as well as fluid and electrolyte imbalances. Later in life, issues with secondary skin infections, in addition to postural and gait abnormalities secondary to the severe hyperkeratosis, may develop. Awareness of these issues is essential for family planning. The risk of recurrence of epidermolytic ichthyosis in future offspring is 50% if one parent is affected with generalized EHK. It is difficult to estimate the risk of a parent with an epidermolytic epidermal nevus producing a child with the generalized form. According to the mosaic hypothesis, the risk depends on the percentage of gonadal cells that are involved, ranging from 50% if all the cells were involved to 0% if no cells were involved. A correlation between the extent of cutaneous involvement and the likelihood of gonadal mosaicism may exist.12 Postzygotic Figure 2. (H&E, 200x) Biopsy of the flank lesion demonstrated the perinuclear vacuolization of mutations that occur very early in embryonic keratinocytes and enlarged keratohyalin granules with overlying hyperkeratosis characteristic of development may lead to more extensive epidermolytic hyperkeratosis. epidermal nevus and may affect organ systems other than the skin, such as the gonads.4 At this TOMC, MALOUF, WEIS Page 31 time, it is not possible to accurately predict if a References person with an epidermolytic epidermal nevus 1. Paller AS, Syder AJ, Chan YM, Yu QC, Hutton will have a child with generalized epidermolytic E, Tadini G, Fuchs E. Genetic and clinical hyperkeratosis. mosaicism in a type of epidermal nevus. N Engl J Prenatal diagnosis of epidermolytic ichthyosis Med. 1994 Nov 24;331(21):1408-15. was initially performed by ultrastructural analysis 2. Happle R. Mosaicism in human skin. of fetal skin biopsies and amniotic fluid cells. The Understanding the patterns and mechanisms. presence of keratin filament aggregates within Arch Dermatol. 1993 Nov;129(11):1460-70. these cells confirms the diagnosis. However, analysis of amniotic cells is not sufficient to 3. Su WP. Histopathologic varieties of epidermal exclude epidermolytic ichthyosis, as tonofilament nevus. A study of 160 cases. Am J Dermatopathol. clumping may not be uniformly present. 14 The 1982 Apr;4(2):161-70. sensitivity of ultrastructural fetal skin analysis is 4. Gonzalez ME, Jabbari A, Tlougan BE, Mandal improved by multiple fetal skin biopsies. Biopsies R, Schaffer JV. Epidermal nevus. Dermatol must be performed after 14 weeks gestational Online J. 2010 Nov 15;16(11):12. age, the earliest point at which K1 and K10 are expressed in the suprabasal layer.15 Rothnagel 5. Solomon LM, Esterly NB. Epidermal and et al. demonstrated that direct gene sequencing other congenital organoid nevi. Curr Probl of DNA from a parent with generalized Pediatr. 1975 Nov;6(1):1-56. epidermolytic hyperkeratosis could be performed 6. Patterson JW, Straka BF, Wick MR. Linear to isolate the K1 and K10 mutations. Subsequent syringocystadenoma papilliferum of the thigh. J analysis of chorionic villus DNA sampled at Am Acad Dermatol. 2001 Jul;45(1):139-41. 15 weeks could then be performed as a means 7. Happle R, Rogers M. Epidermal nevi. Adv of prenatal diagnosis.16 This method has also Dermatol. 2002;18:175-201. been used in prenatal testing for epidermolytic ichthyosis in parents with extensive epidermolytic 8. Lyon MF. The William Allan memorial award epidermal nevi.1 address: X-chromosome inactivation and the location and expression of X-linked genes. Am J Given the extent of our patient’s lesions, she Hum Genet. 1988 Jan;42(1):8-16. and her family were advised to seek genetic counseling were she to become pregnant in 9. Su WP. Histopathologic varieties of epidermal the future. Genetic sequencing of lesional skin nevus. A study of 160 cases. Am J Dermatopathol. could be performed to isolate the specific gene 1982 Apr;4(2):161-70. mutation, which could then be compared to 10. Altman J, Mehregan AH. Inflammatory linear fetal DNA. This case is presented as a reminder verrucous epidermal nevus. Arch Dermatol. 1971 that cutaneous postzygotic mosaicism can have Oct;104(4):385-9. an increased risk for gonadal involvement, resulting in offspring with generalized disease. 11. Reddy BS, Thadeus J, Kumar SK, Jaishanker Epidermolytic ichthyosis results in significant T, Garg BR. Generalized epidermolytic morbidity, further emphasizing the importance hyperkeratosis in a child born to a parent with of early patient education in patients with systematized epidermolytic linear epidermal epidermolytic epidermal nevi. nevus. Int J Dermatol. 1997 Mar;36(3):198-200. 12. Nazzaro V, Ermacora E, Santucci B, Caputo R. Acknowledgements Epidermolytic hyperkeratosis: Generalized form We would like to thank Dr. Ryan Hick of in children from parents with systematized linear Propath Laboratory of Dallas, TX, for reviewing form. Br J Dermatol. 1990 Mar;122(3):417-22. and discussing the pathology in this case. 13. Cheng J, Syder AJ, Yu QC, Letai A, Paller AS, Fuchs E. The genetic basis of epidermolytic hyperkeratosis: A disorder of differentiation- specific epidermal keratin genes. Cell. 1992 Sep 4;70(5):811-9. 14. Sybert VP, Holbrook KA, Levy M. Prenatal diagnosis of severe dermatologic diseases. Adv Dermatol. 1992;7:179,209; discussion 210. 15. Dale BA, Holbrook KA, Kimball JR, Hoff M, Sun TT. Expression of epidermal keratins and filaggrin during human fetal skin development. J Cell Biol. 1985 Oct;101(4):1257-69. 16. Rothnagel JA, Longley MA, Holder RA, Kuster W, Roop DR. Prenatal diagnosis of epidermolytic hyperkeratosis by direct gene sequencing. J Invest Dermatol. 1994 Jan;102(1):13-6.

Page 32 DIFFUSE EPIDERMOLYTIC EPIDERMAL NEVUS AND GENETIC COUNSELING: A CASE REPORT AND BRIEF REVIEW OF THE TOPIC