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Epidermodysplasia Verruciformis

Lewandowsky-Lutz Syndrome

Epidermodysplasia verruciformis is a rare genetic disease of cell-mediated immunity that develops due to of mutations involving the EVER1 and EVER2 genes on chromosome 17, but X-linked inheritance has also been described. These mutations lead to a life-long predisposition to cutaneous infections by human papillomavirus (HPV). Pityriasis versicolor-like macules and wart-like papules are typical lesions that develop on the upper extremities, the trunk, the neck, and the head. In a significant number of cases, these lesions transform into nonmelanotic cancers. The diagnosis rests on clinical criteria and a histopathological examination that detects distinctive features.


Presentation

The first signs of epidermodysplasia verruciformis are encountered in early childhood when the cell-mediated immunity cannot effectively fight against HPV [1] [2] [3] [4] [5] [6]. The hallmark of this condition is the appearance of macules strikingly similar to those seen in pityriasis versicolor (commonly known as Tinea) [1] [3]. They are flat, hyperpigmented, and exhibit scaling [1] [3]. The upper extremities, the trunk, and the head and neck area are the sites where macule appear [1] [3]. A wart-like papule is also a frequent cutaneous manifestation [1] [3]. Both lesions pose a marked risk for the patient due to their ability to transform into malignant tumors [1] [3]. Approximately 20-30 years is necessary for these lesions to convert into a malignant tumor and most commonly identified types are Bowen's disease and invasive squamous cell carcinoma [1] [2] [3]. Tumors develop on sun-exposed skin (the forehead is observed as the predominant location) and it is thought that prolonged exposure to ultraviolet light promotes the transformation of benign lesions into a malignant variant [1]. Fortunately, metastatic spread of neoplasias is very rare [1]. In addition to macules and warts, other notable cutaneous features are plaques that resemble seborrheic keratosis, whereas mucous membranes remain intact [1] [6]. Despite the known genetic background of epidermodysplasia verruciformis, several studies have used the term "acquired epidermodysplasia verruciformis" to illustrate the occurrence of this condition in patients who are immunocompromised from other conditions [3] [6]. Furthermore, psoriasis and human immunodeficiency virus (HIV) infection have even associated with this cutaneous disorder [3] [6].

Pallor
  • Skin biopsy of a macular lesion revealed epidermal acanthosis with vacuolated keratinocytes presenting blue-gray pallor, arranged in clusters at the granular and upper spinous layer.[ncbi.nlm.nih.gov]
  • Keratinocytes of the upper epidermal layers are enlarged with perinuclear vacuolization and a typical blue-gray pallor. HPVs can be detected in keratinocytes using in situ hybridization or immunohistochemistry with anti-HPV antibodies.[orpha.net]
  • […] transplantation ( J Cutan Pathol 2002;29:480 ) More commonly has irregular granular layer with rare perinuclear halos Microscopic (histologic) images Images hosted on other servers: Various images Characteristic enlarged keratinocytes with blue-gray pallor[pathologyoutlines.com]
  • Articles Abstract Author Information Authors The classic histologic presentation of epidermodysplasia verruciformis is a verruca plana-type lesion with minimal hyperkeratosis and acanthotic areas where the cells contain perinuclear halos and blue–gray pallor[journals.lww.com]
Increased Susceptibility to Infections
  • TEXT Epidermodysplasia verruciformis (EV) is a rare primary immunodeficiency, and EV patients have an increased susceptibility to infection with human betapapillomaviruses (beta HPVs) ( 1 , 2 ).[jvi.asm.org]
Hoarseness
  • A 3-year-old Lebanese girl presented with hoarseness, beaded papules along the eyelid margins, waxy papules and plaques on her head and neck, and lichenoid verrucous papules on the forearms and hands.[ncbi.nlm.nih.gov]
Failure to Thrive
  • As an infant, the patient had failure to thrive and a combined immunodeficiency, but was lost to follow-up for 15 years. He currently continues to have severe hypogammaglobinemia and cellular immunodeficiency.[ncbi.nlm.nih.gov]
Cutaneous Manifestation
  • A wart-like papule is also a frequent cutaneous manifestation. Both lesions pose a marked risk for the patient due to their ability to transform into malignant tumors.[symptoma.com]
  • Prose NS, von Knebel-Doeberitz C, Miller S, Milburn PB, Heilman E: Widespread flat warts associated with human papillomavirus type 5: a cutaneous manifestation of human immunodeficiency virus infection. J Am Acad Dermatol 1990;23:978–981.[karger.com]
  • Iarikov DDuke WSkiest D Extensive development of flat warts as a cutaneous manifestation of immune reconstitution syndrome. AIDS Read 2008;18 (10) 524- 527 PubMed Google Scholar 29.[jamanetwork.com]
Scaly Rash
  • A 43 year-old immunosuppressed woman presented with a widespread macular scaly rash, clinically and histologically consistent with epidermodysplasia verruciformis. She had no family history of epidermodysplasia verruciformis.[ncbi.nlm.nih.gov]
Darkly Pigmented Skin
  • We performed HPV typing of biopsied cysts with polymerase chain reaction for a patient with darkly-pigmented skin, epidermodysplasia verruciformis (EV) and more than 250 photodistributed cysts.[ncbi.nlm.nih.gov]
Neglect
  • Vinetz, A misdiagnosed infection mimicking “tree man disease”, PLOS Neglected Tropical Diseases, 11, 6, (e0005543), (2017). S.‐L. Li, L.‐N. Duo, H.‐J. Wang, W. Dai, E.‐Y.H. Zhou, Y.‐N. Xu, T. Zhao, Y.‐Y. Xiao, L. Xia, Z.‐H. Yang, L.‐T. Zheng, Y.‐Y.[doi.org]

Workup

Although epidermodysplasia verruciformis is very rarely encountered in the general population, a presumptive diagnosis can be made solely on clinical criteria. For this reason, it is necessary to perform a detailed physical examination and obtain a thorough patient history. During the examination, the typical localization of lesions, their appearance, and characteristics may significantly narrow the differential diagnosis. Conversely, the onset of cutaneous lesions and the presence of similar complaints in parents or close relatives should be covered during the interview. As soon as clinical criteria are met, examination with a dermatoscope and subsequent histopathological studies should be sought [1] [6]. Enlarged keratinocytes with a pale blue cytoplasm in stratum spinosum is a somewhat specific findings in epidermodysplasia verruciformis, while the presence of keratohyalin granules in stratum granulosum and parakeratosis of stratum corneum may also be noted [1]. A definitive diagnosis is made if mutation of EVER1 and EVER2 genes on chromosome 17 are identified, with up to 75% of patients yielding a positive result [1].

Antinuclear Autoantibodies
  • This progressed to a lupuslike syndrome with lichenoid, violaceous, flat-topped papules in a malar distribution and positive antinuclear autoantibodies.[ncbi.nlm.nih.gov]

Treatment

  • Bajandar’s condition returned after he interrupted treatments in May 2018. His doctors requested that he return for treatment many times.[en.wikipedia.org]
  • After two rounds of the PDT treatment, the skin lesion disappeared and a skin biopsy confirmed the efficacy of the treatment. This method was simple, less invasive than other treatments, and achieved a satisfactory cosmetic result.[ncbi.nlm.nih.gov]
  • Management and treatment Although permanent cure of EV cannot be achieved by any therapy at present, described treatment modalities include cryotherapy, topical imiquimod and 5-fluorouracil, systemic retinoids, interferon alpha, and 5-aminolevulinic acid[orpha.net]
  • With regard to management, there are no randomized controlled trials in either immunocompetent or immunocompromised patients, and only a limited number of anecdotal treatment options.[ncbi.nlm.nih.gov]
  • Data from the literature show that a standardized approach to this condition is lacking; the combination treatment chosen in our case may be proposed because it led to an excellent clinical outcome and a long-lasting remission.[ncbi.nlm.nih.gov]

Prognosis

  • Prognosis Prognosis is favorable since skin tumors appear progressively and metastases are uncommon. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • Diagnosis - Epidermodysplasia verruciformis Prognosis - Epidermodysplasia verruciformis Not supplied. Treatment - Epidermodysplasia verruciformis Resources - Epidermodysplasia verruciformis Not supplied.[checkorphan.org]
  • PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Squamous cell carcinoma develops in 30-50% of cases TREATMENT Treatment of epidermodysplasia verruciformis with a combination of acitretin and interferon alfa-2a Rana Anadolu, MD, etal J Am Acad Dermatol[thedoctorsdoctor.com]

Etiology

  • Epidermoid inclusion cysts are common lesions with unclear etiology. We sought to examine evidence for human papillomavirus (HPV) infection and ultraviolet light (UV) exposure as risk factors in the formation of epidermoid inclusion cysts.[ncbi.nlm.nih.gov]
  • As squamous cell cancer (SCC) is the most common malignancy in organ transplant recipients, a viral etiology has been proposed.[ncbi.nlm.nih.gov]
  • We aim to decipher novel genetic etiologies of EV following hypothesis-free, genome-wide approaches, which may reveal new aspects of the molecular and cellular mechanisms underlying cutaneous immunity against EV-HPVs.[grantome.com]
  • PATHOGENESIS Environmental Exposure • HPV infection is established as etiologic agent Only gold members can continue reading.[basicmedicalkey.com]
  • Etiology EV can be caused by loss-of-function mutations in either of the 2 adjacent genes EVER1/TMC6 or EVER2/TMC8 (17q25.3) coding for membrane proteins that form a complex with the Zinc transporter protein ZnT-1 in the endoplasmic reticulum (ER) membrane[orpha.net]

Epidemiology

  • The epidemiology, virology, and natural history of HPV infection are discussed separately. (See "Human papillomavirus infections: Epidemiology and disease associations" .) (See "Virology of human papillomavirus infections and the link to cancer" .)[uptodate.com]
  • The epidemiological and clinical features of seven cases with EV that have been followed up for 5 years were included in the study. Seven cases consisted of four males and three females. All seven cases were working outdoors.[ncbi.nlm.nih.gov]
  • MATERIALS AND METHODS: We describe clinical and epidemiological features of 10 cases of EV during a 5-year period.[ncbi.nlm.nih.gov]
  • Epidemiologic studies in the general population seem to suggest that beta HPV plays a role in the formation of SCC, both for invasive and in situ lesions. Copyright 2012 S. Karger AG, Basel.[ncbi.nlm.nih.gov]
  • We focused on the epidemiologic, clinical, virologic, and immunologic features of EV in human immunodeficiency virus (HIV)-positive patients.[ncbi.nlm.nih.gov]
Sex distribution
Age distribution

Pathophysiology

  • We describe a case of EV in a patient with LP and discuss the pathophysiology.[ncbi.nlm.nih.gov]
  • The pathophysiology of epidermodysplasia verruciformis is linked to defective cell-mediated immunity, with elucidation of mutations in EVER1 ( TMC6 ) and EVER2 ( TMC8 ) genes (band 17q25). [2, 7] Their gene products are integral membrane proteins localized[emedicine.medscape.com]
  • There is a genetic component in the etiology, but the inheritance pattern is uncertain at present.The pathophysiology of epidermodysplasia verruciformis (EV) is linked to defective cell-mediated immunity with elucidation of mutations in EVER1 and EVER2[medigoo.com]

Prevention

  • Although there is no standardized treatment for acquired EV, prevention and surveillance for transformation to squamous cell carcinoma are primary concerns.[ncbi.nlm.nih.gov]
  • We report a case of an HIV-positive patient with acquired EDV who achieved sustained clinical resolution even after discontinuation of oral acitretin by applying topical imiquimod to prevent recurrence of his lesions.[ncbi.nlm.nih.gov]
  • Preventive measures, in particular sun exposure avoidance and photoprotection, are crucial for proper management. Prognosis Prognosis is favorable since skin tumors appear progressively and metastases are uncommon.[orpha.net]
  • This method has shown promising results in prevention of further carcinomas.[allhealthsite.com]

References

Article

  1. Emsen IM, Kabalar ME. Epidermodysplasia verruciformis: An early and unusual presentation. Can J Plast Surg. 2010;18(1):21-24.
  2. McDermott DH, Gammon B, Snijders PJ, et al. Autosomal dominant epidermodysplasia verruciformis lacking a known EVER1 or EVER2 mutation. Pediatr Dermatol. 2009;26(3):306-310.
  3. Rogers HD, Macgregor JL, Nord KM, et al. Acquired epidermodysplasia verruciformis. J Am Acad Dermatol. 2009;60(2):315-320.
  4. Gül U, Kiliç A, Gönül M, Cakmak SK, Bayis SS. Clinical aspects of epidermodysplasia verruciformis and review of the literature. Int J Dermatol. 2007;46(10):1069-1072.
  5. Sá NB, Guerini MB, Barbato MT, Di Giunta G, Nunes DH. Epidermodysplasia verruciformis: clinical presentation with varied forms of lesions. An Bras Dermatol. 2011;86(4 Suppl 1):S57-60.
  6. Segura S, Carrera C, Ferrando J, et al. Dermoscopy in epidermodysplasia verruciformis. Dermatol Surg. 2006;32(1):103-106.

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Last updated: 2019-06-28 09:36