Verruciform epidermodysplasia B07.x

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 31.05.2022

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generalized verrucosis; Lewandowsky-Lutz syndrome

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Lewandowsky and Lutz, 1922

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Rare, hereditary, HPV-induced (oncogenic and non-oncogenic human papillomaviruses) genodermatosis with a tendency to form generalized wart infections and non-melanoma skin cancers in about 50% of patients.

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Human papilloma viruses, especially HPV types 5, 8, 9, 12, 14, 15, 17, 19, 20, 21-25, 36, 38, 47, 50.

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The cause is discussed to be the autosomal recessive (X-linked recessive) inherited mutation of the EVER1 gene (TMC6 gene/transmembrane channel-like protein 6) (EVER = acronym for Epidermodysplasia Verruciformis Endoplasmatic Reticulum Gene) or the EVER2 gene(TMC8 gene/transmembrane channel-like protein 8), both of which are located next to each other at gene locus 17q25. These mutations lead to disruption of integral membrane proteins of the endoplasmic reticulum and increase susceptibility to human papillomavirus infection.

TMC6 encodes "transmembrane channel-like protein 6", TMC8 encodes "transmembrane channel-like protein 8". Both proteins cooperatively form a complex with zinc transporter 1 (SLC30A1). This complex is localized in the endoplasmic reticulum, but also in the Golgi apparatus. Evidence suggests that zinc is a necessary cofactor for many viral proteins and that the biological activity of the transcription products of TMC6/TMC8 can reduce the availability of zinc to foreign proteins (i.e., viral proteins) and thus prevent viral growth and spread. The mutations lead to inactivation of these integral membrane proteins and increase susceptibility to human papillomavirus infection (types 3, 5a, 5b, 8-10, 12, 14, 15, 17, 19-21, 23-26, 37, 38, 47, and others). Familial clustering has been described in about 30% of cases.

The extent to which polymorphisms of the interleukin 10 gene promoter, leading to decreased production of this cytokine, are etiopathogenetically significant remains unclear. Interleukin 10 induces downregulation of proinflammatory cytokines such as TNF-alpha, IL-1, IL-6 (possible explanation for the specific tolerance to HPV viruses in EV).

Mutations in the RASGRP1 gene are also associated with epidermodysplasia verruciformis (Platt CD et al. 2017).

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Congenital (8-10%), in infancy or childhood (50-70%), during puberty (10-25%).

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Skin areas exposed to light, such as the forehead, ears, back of the hands, but also palms of the hands and soles of the feet.

Clinical features
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Disseminated sowing up to 1.0 cm in size, yellowish or yellow-brown, smooth or warty, papular or plaque-like papillomas which occur in localized or beet-like aggregation. They are often combined with(pityriasis versicolor-like) pigment spots. Diagnostic criteria:

  • Occurrence of disseminated skin lesions on the trunk, extremities and face, resembling mainly verrucae planae but also flat verrucae seborrhoicae.
  • In 25-30% of cases, mainly in the light-exposed areas, malignant transformation and development of Bowen's disease or Bowen's carcinoma occurs (Shruti F et al. 2017).
  • The general condition of the patients is good.

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Depending on the bioptate localization and the duration of the disease, different histological images may be available. In advanced stages, irregularly configured acanthotic surface epithelium with different hypergranulosis and distinct orthhyperkeratosis are visible. Sometimes swollen keratinocytes with fine-vacuolar cytoplasm, cell nuclei of different sizes, sometimes also blistered. In the dermis unspecific, mostly perivascular round cell infiltrates.

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Carcinomatous degeneration (often from the age of 30) depending on the HPV type and other factors (UV exposure, underlying diseases). In larger studies (147 patients) about 1/3 of the patients developed carcinomas after 24 years of illness.

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A causal therapy is not known. Careful clinical monitoring is mandatory. Regular removal of suspicious lesions by curettage, laser or cryosurgery.

Consistent light protection is required to avoid the additive carcinogenic UV effect.

Positive therapeutic effects could be achieved by long-term therapy with isotretinoin (initial 70mg/day, permanent 0.3mg/kgKG) (Troyanova-Slavkova S et al. 2018).

External therapy
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External therapy attempts with ointments containing vitamin A acid, also under occlusion, are usually unsuccessful.

In a single case study a good effect could be achieved with Imiquimod (5% Imiqimod cream 2-3 times/week for 12 weeks).

Radiation therapy
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Successful therapy trials with photodynamic therapy (off-label use) are described on the basis of individual case reports.

Internal therapy
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Therapy trials with retinoids such as acitretin (neotigason) starting with 0.5-1 mg/kg bw/day and after improvement with 0.3-0.5 mg/kg bw/day and interferons ( interferon alfa-2a 1-3 times/week 1-3 million IU s.c. or peginterferon alfa-2b 1 μg/kg bw/week s.c.) are described and lead to an improvement of the clinical picture, but not to a complete healing. Remissions after discontinuation of therapy.

Temporary success according to case studies: trial with cimetidine (Tagamet) 40 mg/day/kg bw.

Operative therapie
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Excision for suspected carcinoma.

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Regular dermatological checks, as malignant degeneration can occur.

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Currently unanswered is the question of the extent to which the combination with primary lymphedema represents a separate entity.

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  8. López-Ramírez S et al (2020) Next-generation sequencing identifies a homozygous nonsense p.Tyr370* mutation of the TMC6 gene in a Mexican pedigree with Epidermodysplasia Verruciformis. Rev Invest Clin doi: 10.24875/RIC.20000415.
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  11. Majewski S et al (2002) Do epidermodysplasia verruciformis human papillomaviruses contribute to malignant and benign epidermal proliferations? Arch Dermatol 138: 649-654
  12. Platt CD et al (2017) Combined immunodeficiency with EBV positive B cell lymphoma and epidermodysplasia verruciformis due to a novel homozygous mutation in RASGRP1. (Letter) Clin Immun 183: 142-144.

  13. Ramoz N et al (2002) Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet 32: 579-581
  14. Roncalli W et al (2003) Polymorphisms of the interleukin 10 gene promoter in patients from Brazil with epidermodysplasia verruciformis. J Am Acad 49: 639-643.
  15. Shruti S et al.(2017) Epidermodysplasia verruciformis: three case reports and a brief review.
    Acta Dermatovenerol Alp Pannonica Adriat 26:59-61.
  16. Szeimies RM et al (2002) Non-oncologic indications for ALA-PDT. J Dermatolog Treat 13(Suppl 1): S13-18
  17. Troyanova-Slavkova S et al. (2018) Low-dose prophylactic oral isotretinoin treatment for 18 years in a patient with epidermodysplasia verruciformis and numerous squamous cell carcinomas Hautarzt 69):1033-1038 .


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Last updated on: 31.05.2022