HPV-Related Skin Phenotypes in Patients with Inborn Errors of Immunity

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. In this review, we describe clinical, immunological, and genetic patterns of IEI related to severe HPV cutaneous infections and propose an algorithm for diagnosis of IEI with severe warts associated, or not, with lymphopenia.


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 αand 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, Pathogens 2022, 11, 857 2 of 10 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].
There are some published reviews and case reports that describe clinical, immunological, and genetic patterns of IEI related to severe HPV cutaneous infections, but there are too many aspects of these issues that are still unknown and are being discovered continuously. Here, we present an up-to-date review of the major clinical, immunological, and genetic patterns of IEI related to severe HPV cutaneous infections, and we propose an algorithm for diagnosis of IEI with severe warts in order to help clinicians who may encounter patients with recurrent and recalcitrant warts due to an underlying inherited immunodeficiency.

Clinical Phenotypes
Depending on the HPV genera, there are different characteristics of HPV skin lesions. Macroscopy and histology analyses could help with an appropriate diagnosis.

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 ( Figure 1). 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].

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 ( Figure 2). PWs are the consequence of an infection with αor γ-HPV, and less frequently with µand 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

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 ( Figure 2). 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].

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 ( Figure 2). 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].

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 ( Figure 3). 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]. 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 ( Figure 3). 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].

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] (Table  1). 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].

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] (Table 1). 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].

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 (Table 2) [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].

Immunological Phenotype with Several Impaired Leukocyte Subsets
This category includes warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, and classical CID and SCID syndromes ( Table 3). 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 [24]. 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 [26]. 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 [18,24].

Conclusions
HPV skin lesions are a common symptom during infancy to childhood. Although recalcitrant warts, or even EV, are a rare clinical manifestation, physicians, including dermatologists and pediatricians, should consider IEI for a patient with recurrent or disseminated HPV skin lesions. The diagnosis strategy is crucial for a prompt and appropriate treatment of those patients. Furthermore, investigations of patients with EV or PW will increase our understanding of skin-intrinsic host immunity against HPVs.