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Assiya El Kettani
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Kettani, A.E.;  Ailal, F.;  Bakkouri, J.E.;  Zerouali, K.;  Béziat, V.;  Jouanguy, E.;  Casanova, J.;  Bousfiha, A.A. HPV-Related Skin Phenotypes in Inborn Errors of Immunity. Encyclopedia. Available online: https://encyclopedia.pub/entry/25740 (accessed on 07 July 2025).
Kettani AE,  Ailal F,  Bakkouri JE,  Zerouali K,  Béziat V,  Jouanguy E, et al. HPV-Related Skin Phenotypes in Inborn Errors of Immunity. Encyclopedia. Available at: https://encyclopedia.pub/entry/25740. Accessed July 07, 2025.
Kettani, Assiya El, Fatima Ailal, Jalila El Bakkouri, Khalid Zerouali, Vivien Béziat, Emmanuelle Jouanguy, Jean-Laurent Casanova, Ahmed Aziz Bousfiha. "HPV-Related Skin Phenotypes in Inborn Errors of Immunity" Encyclopedia, https://encyclopedia.pub/entry/25740 (accessed July 07, 2025).
Kettani, A.E.,  Ailal, F.,  Bakkouri, J.E.,  Zerouali, K.,  Béziat, V.,  Jouanguy, E.,  Casanova, J., & Bousfiha, A.A. (2022, August 01). HPV-Related Skin Phenotypes in Inborn Errors of Immunity. In Encyclopedia. https://encyclopedia.pub/entry/25740
Kettani, Assiya El, et al. "HPV-Related Skin Phenotypes in Inborn Errors of Immunity." Encyclopedia. Web. 01 August, 2022.
HPV-Related Skin Phenotypes in Inborn Errors of Immunity
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This entry is adapted from the peer-reviewed paper 10.3390/pathogens11080857

Patients with inborn errors of immunity (IEI) are prone to develop infections, either due to a broad spectrum of pathogens or to only one microbe. Since skin is a major barrier tissue, cutaneous infections are among the most prevalent in patients with IEI due to high exposures to many microbes. In the general population, human papillomaviruses (HPVs) cause asymptomatic or self-healing infections, but, in patients with IEI, unusual clinical expression of HPV infection is observed ranging from epidermodysplasia verruciformis (EV) (a rare disease due to β-HPVs) to profuse, persistent, and recalcitrant warts (due to α-, γ-, and μ-HPVs) or even tree man syndrome (due to HPV2). Mutations in EVER1, EVER2, and CIB1 are associated with EV phenotype; GATA2, CXCR4, and DOCK8 mutations are typically associated with extensive HPV infections, but there are several other IEI that are less frequently associated with severe HPV lesions.

HPV skin inborn errors of immunity

1. Introduction

Human papillomaviruses (HPVs) are DNA viruses with a specific tropism to keratinocytes, which are the main component of stratified epithelia, including skin, genital, and laryngeal mucosa. There are more than 200 different genotypes of HPVs classified in five (α-, β-, γ-, μ-, and ν-) genera. HPV subtypes of all genera infect the skin, and only some HPVs of α-genus infect the mucosal epithelia. Some α- and β-HPV types are oncogenic and are associated with benign genital condyloma, cervical and anogenital cancers, and non-melanoma skin cancers, respectively [1][2].
In the general population, HPVs cause asymptomatic or self-healing infections, with spontaneous clearances reported: 23% at 2 months and 66% by 2 years [3][4]. The transmission is from skin-to-skin or mucous-to-mucous contact. Seroprevalence is variable, depending on the HPV genus, age, and screening policy of each country. However, it is estimated to be <40% and 20–65% for oncogenic α-HPV and β-HPVs, respectively. Cervical cancer is the main clinical concern following HPV infection, as it is the fourth most frequent female cancer, with a death rate around 7.5%. In addition, more than 85% of deaths due to cervical cancer are in developing countries. The incidence of cutaneous warts varies with age, with a range from 1 to 12% in the adult general population, but could be over 24% in school age children [5].
Inborn errors of immunity (IEI) are characterized by an impaired immune response, affecting tissue-intrinsic immunity that is either, innate, adaptive, or both. IEI could be associated with higher susceptibility to infections, auto-inflammation, and/or autoimmunity. Unusual clinical expression of HPV infection is frequently observed in patients with IEI. The spectrum of the clinical phenotype is large from epidermodysplasis verruciformis (EV) (a rare disease due to β-HPV) to profuse, persistent and recalcitrant warts (due to α-, γ-, and μ-genera) [6]. Very rare individuals develop tree man syndrome (TMS) due to HPV2 [7].

2. Clinical Phenotypes

2.1. Epidermodysplasia Verruciformis

With less than 250 cases reported worldwide, epidermodysplasia verruciformis (EV) is a rare disease that appears at young ages: infancy (7.5% of cases), childhood (61.5% of cases), and adolescence (22% of cases). Lesions are characterized by progressive onset hyperpigmented or achromic flat verrucous lesions, irregular patches of a reddish-brown color, keratotic seborrheic lesions, and pityriasis versicolor-like macules. The lesions are found mainly on sun-exposed areas, such as the face, trunk, neck, forearms, hands, and feet. Although various genotypes of β-HPVs are detected in EV lesions, HPV5 and -8 are found in 80% of cases. Histologic features of an EV lesion are characterized by a flat wart and showing mild to moderate hyperkeratosis, hypergranulosis, and acanthosis of the epidermis. The keratinocytes in the upper layer of the epidermis are enlarged and exhibit a vacuolated nucleus and a pale blue-gray color [8].
EV can be isolated (typical EV) or syndromic (atypical EV) associated with other clinical manifestations, infectious, or not. [9]. Among 40–50-year-old patients, 30 to 60% of EV patients develop non-melanoma skin cancer, particularly squamous cell carcinoma, occurring in sun-exposed areas. People with black skin have a much lower incidence of skin cancer. Most squamous cell carcinomas remain localized. Metastases are not frequent [8][10].

2.2. Profuse Warts (PWs)

Profuse warts (PWs) are defined as more than 20 lesions in more than one area of the body. If they do not disappear after 6 months of treatment, they are also classified as recalcitrant [11]. PW cauliflower-like papules have a rough, hyperkeratotic surface but they can be flat depending on the HPV involved. PWs are the consequence of an infection with α- or γ-HPV, and less frequently with μ- and ν-HPVs [12]. Histologic analyses of PWs have shown markedly papillomatous epidermis with hypergranulomatosis and overlying tiers of parakeratosis. The upper epidermis may contain large pink inclusions, particularly in cases arising on acral skin. Other lesions have shown smaller basophilic granules. Classically, in the upper epidermis, koilocytes or vacuolated keratinocytes which have a small shrunken nucleus surrounded by a perinuclear halos are observed [13].

2.3. Tree Man Syndrome

In exceptional cases, the warts can also transform into exophytic cutaneous lesions and giant horns, resulting in tree man syndrome [7]. TMS presents with the most extensive warts developing into cutaneous horns, which can be giant and generalized. These lesions start as cutaneous warts, slowly spreading over the hands and feet before transforming into cutaneous horns, characteristic of the TMS phenotype. This condition is extremely rare, with less than 10 cases reported so far. All cases were sporadic with no family history. Due to the paucity of reported cases, it is unclear whether these lesions in TMS have malignant potential [7].

3. Immunological Phenotypes and Inborn Errors of Immunity

3.1. No immunological Phenotype in Blood (Skin-Intrinsic Immunity Disorder)

Isolated EV is due to autosomal recessive (AR) mutations in TMC6 and TMC8, which encode EVER1 and EVER2, two endoplasmic reticulum plasma membrane proteins, respectively, and in CIB1, which encodes calcium and integrin binding protein [9][14]. Patients with isolated EV did not show any major leukocyte abnormalities, neither quantitative nor qualitative, in terms of proliferation or antibodies production. The HPV proteins, E5 and E8, targeted the EVER1–EVER2–CIB1 complex, strongly suggesting that this complex is acting as a restriction factor to HPVs in keratinocytes. In terms of the physiological mechanism, the dominant hypothesis is that isolated EV is the consequence of IEI affecting the keratinocyte-intrinsic immune response [14].

3.2. Immunological Phenotype with Qualitative or/and Quantitative T Cells Defects Only

In contrast to isolated EV, syndromic EV is related to IEI affecting T cells. Some of these IEI are also associated with PW phenotype. For some of them, warts are a major clinical symptom [6]. For instance, in AR DOCK8 deficiency, warts were reported in >40% of patients that were characterized by T and NK cell lymphopenia, and some patients developed α-HPV-induced malignancies [15]. Furthermore, AR mutations in the serine/threonine kinase 4 (STK4) gene are primarily characterized by a reduced amount and survival of circulating naïve T cells. Progressive CD4 T cell lymphopenia with profoundly low naïve CD4 T cell counts is hallmark, while CD8 T cells and NK cells are within normal range. T cell proliferation responses to both antigens and mitogens are markedly impaired. B cell counts are mildly low with hypergammaglobulinemia of IgG and variable increases in IgA and IgE [16].
More recently, patients with CARMIL2 and CD28 deficiencies were associated with HPV susceptibility [7][17]. These IEI both affect the CD28 signaling pathway, which is the major costimulatory pathway of TCR. Patients with CARMIL2 deficiency developed disseminated warts among other infectious manifestations, and they also had decreased memory B cells [17], whereas CD28 deficiency was associated with PW only. Interestingly, one of the CD28 patients developed TMS [7].

3.3. Immunological Phenotype with Several Impaired Leukocyte Subsets

This category includes warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, and classical CID and SCID syndromes. The warts are also due to α-HPV and the immunological phenotypes of these diseases are variable but qualitative or/and quantitative T cell defects are common to all of them [18]. For example, in WHIM syndrome, between 60 and 80% of patients develop warts after α-HPV infection, and about 16% of these patients develop HPV-related cancers. This disease is associated with mutations in the CXCR4 gene, encoding a chemokine receptor. The immunological phenotype is characterized by neutropenia, low counts of dendritic cells (DC), memory B cells, and naïve CD4+ and CD8+ T cells [19]. In GATA2 haploinsufficiency, α-HPV infections occur in more than 50% of the cases, and genital cancers are frequent. Low monocyte, DC, B cell, CD4+ T cell, and NK cell counts are the most common immunological features of the patients [18][20].

References

  1. Bernard, H.-U.; Burk, R.D.; Chen, Z.; van Doorslaer, K.; zur Hausen, H.; de Villiers, E.-M. Classification of Papillomaviruses (PVs) Based on 189 PV Types and Proposal of Taxonomic Amendments. Virology 2010, 401, 70–79.
  2. PaVE: Papilloma Virus Genome Database. Available online: https://pave.niaid.nih.gov/#home (accessed on 22 October 2021).
  3. Massing, A.M.; Epstein, W.L. Natural History of Warts. A Two-Year Study. Arch. Dermatol. 1963, 87, 306–310.
  4. Kainz, J.T.; Kozel, G.; Haidvogl, M.; Smolle, J. Homoeopathic versus Placebo Therapy of Children with Warts on the Hands: A Randomized, Double-Blind Clinical Trial. Dermatology 1996, 193, 318–320.
  5. Loo, S.K.; Tang, W.Y. Warts (Non-Genital). BMJ Clin. Evid. 2009, 2009, 1710.
  6. Béziat, V. Human genetic dissection of papillomavirus-driven diseases: New insight into their pathogenesis. Hum. Genet. 2020, 139, 919–939.
  7. Béziat, V.; Rapaport, F.; Hu, J.; Titeux, M.; Bonnet des Claustres, M.; Bourgey, M.; Griffin, H.; Bandet, É.; Ma, C.S.; Sherkat, R.; et al. Humans with Inherited T Cell CD28 Deficiency Are Susceptible to Skin Papillomaviruses but Are Otherwise Healthy. Cell 2021, 184, 3812–3828.e30.
  8. Zambruno, G. Epidermodysplasie Verruciforme, Orpha.Net. Available online: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=FR&data_id=8531&MISSING%20CONTENT=Epidermodisplasia-verruciforme&search=Disease_Search_Simple&title=Epidermodisplasia-verruciforme (accessed on 11 July 2022).
  9. de Jong, S.J.; Imahorn, E.; Itin, P.; Uitto, J.; Orth, G.; Jouanguy, E.; Casanova, J.-L.; Burger, B. Epidermodysplasia Verruciformis: Inborn Errors of Immunity to Human Beta-Papillomaviruses. Front. Microbiol. 2018, 9, 1222.
  10. Orth, G. Génétique et Sensibilité Aux Papillomavirus: Le Modèle de l’épidermodysplasie Verruciforme. Bull. Acad. Natl. Méd. 2010, 194, 923–941.
  11. Leung, L. Recalcitrant Nongenital Warts. Aust. Fam. Physician 2011, 40, 40–42.
  12. Uitto, J.; Saeidian, A.H.; Youssefian, L.; Saffarian, Z.; Casanova, J.-L.; Béziat, V.; Jouanguy, E.; Vahidnezhad, H. Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes. J. Invest. Dermatol. 2022, 142, 1265–1269.
  13. Emanuel, P. Verruca Vulgaris Pathology. Available online: https://dermnetnz.org/topics/verruca-vulgaris-pathology (accessed on 11 June 2022).
  14. de Jong, S.J.; Créquer, A.; Matos, I.; Hum, D.; Gunasekharan, V.; Lorenzo, L.; Jabot-Hanin, F.; Imahorn, E.; Arias, A.A.; Vahidnezhad, H.; et al. The Human CIB1–EVER1–EVER2 Complex Governs Keratinocyte-Intrinsic Immunity to β-Papillomaviruses. J. Exp. Med. 2018, 215, 2289–2310.
  15. Aydin, S.E.; Kilic, S.S.; Aytekin, C.; Kumar, A.; Porras, O.; Kainulainen, L.; Kostyuchenko, L.; Genel, F.; Kütükcüler, N.; Karaca, N.; et al. DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options—A Review of 136 Patients. J. Clin. Immunol. 2015, 35, 189–198.
  16. Abdollahpour, H.; Appaswamy, G.; Kotlarz, D.; Diestelhorst, J.; Beier, R.; Schäffer, A.A.; Gertz, E.M.; Schambach, A.; Kreipe, H.H.; Pfeifer, D.; et al. The phenotype of human STK4 deficiency. Blood 2012, 119, 3450–3457.
  17. Alazami, A.M.; Al-Helale, M.; Alhissi, S.; Al-Saud, B.; Alajlan, H.; Monies, D.; Shah, Z.; Abouelhoda, M.; Arnaout, R.; Al-Dhekri, H.; et al. Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency. Front. Immunol. 2018, 9, 203.
  18. Béziat, V.; Jouanguy, E. Human inborn errors of immunity to oncogenic viruses. Curr. Opin. Immunol. 2021, 72, 277–285.
  19. Dotta, L.; Notarangelo, L.D.; Moratto, D.; Kumar, R.; Porta, F.; Soresina, A.; Lougaris, V.; Plebani, A.; Smith, C.E.; Norlin, A.C.; et al. Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies. J. Allergy Clin. Immunol. Pract. 2019, 7, 1568–1577.
  20. Bousfiha, A.; Jeddane, L.; Picard, C.; Al-Herz, W.; Ailal, F.; Chatila, T.; Cunningham-Rundles, C.; Etzioni, A.; Franco, J.L.; Holland, S.M.; et al. Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification. J. Clin. Immunol. 2020, 40, 66–81.
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Subjects: Microbiology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Assiya El Kettani
,
Fatima Ailal
,
Jalila El Bakkouri
,
Khalid Zerouali
,
Vivien Béziat
,
Emmanuelle Jouanguy
,
Jean-Laurent Casanova
,
Ahmed Aziz Bousfiha
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Revisions: 2 times (View History)
Update Date: 02 Aug 2022
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