The interaction of leukocytes with vascular endothelial cells, which is mediated by several families of adhesion molecules, is crucial for their migration to the tissues (79, 80). Leukocyte adhesion deficiency (LAD) is a group of autosomal recessive (AR) PIDs due to defects in leukocyte adhesion cascade with altered extravasation into tissues. To date, three different forms have been described (79). LAD type I [>320 reported cases (81)] affects the firm adhesion of leukocytes to the endothelium (79, 82, 83). LAD type II (<10 patients reported worldwide) is characterized by a defect in the rolling adhesion phase that involves transient interactions between P- and E-selectins (expressed by endothelial cells) with their fucosylated ligands (expressed by neutrophils) (79, 82, 84, 85). Finally, LAD type III (described in about 20 patients) is due to abnormal integrin activation that is crucial to induce the immobilization of neutrophils (82, 86) (Table 4).

The general management of each form of LAD is described in Table 4.

As LAD type II and type III have been reported in less than 50 cases worldwide, the management of oral manifestations has been mainly described for LAD type I (LAD1) patients, in particular those with moderate form that is characterized by residual CD18 expression (2–30%). These patients usually survive childhood without HSCT but they present recurrent infections and immune-related lesions of the skin and mucosal surfaces (81). Oral involvement is observed in more than 50% of the patients with moderate LAD1 and includes periodontal diseases as well as recurrent and painful oral ulcers (81). Palatal ulcer with perforation has been reported in one LAD1 patient (92). Periodontitis is extremely aggressive and has a very early onset, affecting already primary teeth. It is characterized by an intense inflammation and a rapid loss of periodontal tissues including alveolar bone^* (66, 93). Periodontitis in LAD1 patients is mainly unresponsive to standard treatments (i.e., mechanical removal of tooth associated biofilm in combination with antibiotics), leading to premature tooth loss before young adulthood (66). Historically, LAD1-associated periodontitis has been attributed to defective neutrophil control of the periodontal infection. LAD subgingival microbiome is significantly different from the biofilm observed in healthy individuals and in individuals with localized aggressive periodontitis (94). Indeed, it is characterized by a reduced microbial diversity with a loss of health-associated microbial species and an over representation of periodontitis-associated species such as Parvimonas micra, Porphyromonas endodontalis, Eubacterium brachy, and Treponema species. Pseudomonas aeruginosa was also detected in LAD1 although it is a bacterial species that is not typically found in subgingival plaque (94). However, Moutsopoulos et al. have recently shown that LAD1 periodontitis does not represent a “raging infection” due to uncontrolled bacterial invasion of periodontal tissues but is rather caused by a dysregulated host inflammatory response, where the bacteria serve as initial triggers for local immunopathology (95–97). Indeed, the translocation of bacterial products such as lipopolysaccharide into the underlying tissues stimulates the local inflammatory response and the induction of IL23-mediated immunity. This leads to an excessive production of the proinflammatory and bone-resorptive cytokine IL17, implicating for the first time in humans the role of neutrophils in the regulation of IL17 responses (96). It has been shown that this cytokine is also overproduced in common forms of chronic periodontitis (98). This IL17 exaggerated response is mainly localized to the mucosal tissues. In the absence of tissue neutrophils, as in LAD1, the IL23 response fails to downregulate and continuously induces IL17 (66). Inhibition of the IL17 pathway in the murine model of LAD1 is associated with a reduction of both the inflammatory periodontal bone loss and the bacterial load. This suggests that dysregulated IL17-driven inflammation consecutive to impaired neutrophil recruitment fuels periodontal microbial overgrowth (95). Recently, the team of Moutsopoulos treated a patient with moderate form of LAD1, refractory periodontitis and non-healing cutaneous ulcers with anti-IL12/IL23 monoclonal antibody (ustekinumab) that inhibits IL23-dependent production of IL17 (87). The treatment allowed a significant reduction of oral inflammation and a complete resolution of the deep cutaneous wounds without significant adverse effect. Inhibition of IL23 and IL17 appears as a promising strategy in the management of moderate forms of LAD1, in particular for severe periodontal involvement (87), and an interventional protocol has been recently initiated (NCT03366142) (66). Indeed, despite strict oral hygiene regimen and regular periodontal treatment, most of the patients lose their teeth (99, 100). Their replacement relies on prosthetic rehabilitation with an age-specific approach. In growing patients, removable prostheses are favored and can be adapted depending on the teeth that are lost. To date, dental implants have been reported in only one patient with LAD (101).

First described in a French family by the physicians Papillon and Lefèvre (102), Papillon-Lefevre syndrome (PLS; MIM 245000) is a rare AR condition characterized by the association of aggressive early-onset periodontitis and palmoplantar hyperkeratosis. The prevalence of PLS ranges between 1 to 4 cases per million individuals (103). PLS is caused by homozygous (2/3 of the cases) or compound heterozygous (1/3 of the cases) pathogenic variants in the gene CTSC that encodes a lysosomal cysteine protease called cathepsin C (CTSC) or dipeptidyl peptidase I (103, 104). CTSC is involved in posttranslational modification and activation of many serine proteases stored primarily in azurophilic granules from neutrophils (i.e., neutrophil elastase, cathepsin G, proteinase 3) (105). CTSC plays also a role in the activation of granzymes A and B in cytotoxic T lymphocytes (106). Whereas, mature neutrophils of PLS patients lack all serine proteases' activity, the latter is normal in immature neutrophils. PLS phenotype may therefore arise from functional defects affecting mature neutrophils within tissues. For example, they are incapable of producing neutrophil extracellular traps (NETs) in response to reactive oxygen species (ROS) (107). However, despite lack of active serine proteases in neutrophils and cytotoxic T lymphocytes from PLS patients, the associated immunodeficiency is remarkably mild as an only 15 to 20% of PLS patients are predisposed to recurrent bacterial infections (108). Most of these infections are mild skin pyodermas, but occasionally, severe and/or fatal pyogenic abscesses involving internal organs (i.e., liver abscesses) do occur (109).

In addition to activation of immune cells, the proteolytic activity of CTSC has also been proposed to play a role in epithelial differentiation and desquamation (110), likely explaining the skin phenotype that is dominated by palmoplantar hyperkeratosis. The latter can vary from mild psoriasiform scaly skin to overt hyperkeratosis. Keratosis can also affect other sites such as elbows and knees, and additional clinical findings may include intracranial calcifications, hyperkeratosis of the hair follicles, nail dystrophy, and hyperhidrosis (111).

Periodontitis in PLS patients is exceptionally severe with a very early-onset and a generalized pattern resulting in premature loss of both primary and permanent teeth (Figure 1). Although it has been associated with functional defects in neutrophils, the mechanisms by which CTSC deficiency leads to periodontitis have not been fully elucidated so far (66). Aggressive periodontitis in PLS patients could be attributed, at least in part, to a dysregulated inflammatory response rather than to an inefficient control of the periodontal bacteria. Indeed, CTSC deficiency results in failure to activate neutrophil-derived serine proteases, impairing proteolytic degradation of proinflammatory chemokines and cytokines, a mechanism important for periodontal tissue homeostasis (112). The subgingival microbiota in PLS patients is diverse with many periodontal pathogens commonly associated with chronic and aggressive periodontitis (e.g., Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum). Eruption of deciduous teeth occurs at expected ages with normal structure and form (113). Extremely intense gingival inflammation (e.g., erythema, edema, pain) develop shortly after eruption of primary teeth with a rapid periodontal destruction (e.g., deep periodontal pockets with pus exudate, extensive alveolar bone resorption, tooth mobility and migration) and premature tooth loss without signs of root resorption (Figures 1A,C) (111, 113, 114). Halitosis and lymphadenopathy are frequent. After the exfoliation or the extraction of the primary teeth, inflammation resolves rapidly. However, the cycle repeats itself with the eruption of permanent teeth (Figure 1B) (113). Radiological examination shows vertical alveolar bone loss around the teeth and in advanced stages, teeth can appear to be “floating” in the bone (Figure 1C) (113). Most PLS patients lose all of their primary and permanent teeth (66, 115) and only few patients without periodontal involvement have been reported (116, 117). Third molars remain however frequently unaffected (113). Gingival inflammation disappears in the totally edentulous patient. Although palmoplantar keratoderma and aggressive periodontitis are the cardinal clinical signs of PLS and usually manifest simultaneously between the age of 6 months and 4 years, no significant correlation has been found between the severity of these two conditions (118).

To date, therapeutic strategies remain limited and the management of both skin and oral manifestations is known to be difficult.

Regarding periodontal treatment, the main goal is to eradicate the reservoirs of periodontopathogens and to limit the destruction of periodontal tissues. The management of periodontitis includes careful plaque control with professional and individual oral hygiene regimens, the possible use of antiseptic mouth rinses (e.g., 0.2% chlorhexidine), conventional mechanical periodontal treatment to remove tooth-associated biofilm (scaling and root planing) along with courses of systemic antibiotics, followed by regular supportive periodontal therapy. The treatment of teeth with deep periodontal pockets may require flap surgical procedures (113, 119, 120). The commonly used systemic antibiotics are tetracyclines (that should be avoided in pediatric patients under 8 years of age due to the risk of teeth discoloration and enamel hypoplasia), erythromycin, amoxicillin plus metronidazole, or clavulanic acid (113, 119, 120). Extraction of primary teeth with poor prognosis, in combination with the eradication of the periodontal pathogens, creates a safe environment for the eruption of permanent teeth (113). However, despite regular and appropriate periodontal and antibiotic treatment regimens, the majority of the PLS patients lose all of their teeth. Nickles et al. analyzed long-term results (≥10 years follow-up) of periodontal treatment in eight patients with PLS and the teeth were maintained in only two of them (120). The replacement of lost teeth relies on prosthetic rehabilitation with an age-specific approach in a similar way than for LAD patients. Implants have been used by several authors in adult patients to improve stability and support of the prostheses (120–124). However, in PLS patients, implant placement is often complicated by the severe alveolar bone resorption due to early tooth loss. Although bone augmentation techniques and the use of short implants can possibly be considered (125), PLS patients are at high risk of peri-implantitis and implants loss. In Nickles et al. study, implants have been placed in four patients but three of them showed peri-implantitis only 4 years after their insertion (120). A very regular maintenance is therefore required to avoid early implant loss (120).

Treatment of dermatological manifestations relies on topical applications of emollients, keratolytic agents containing salicylic or lactic acid, and topical steroids to reduce skin inflammation. Several authors have suggested that oral retinoids such as acitretin, etretinate, and isotretinoin (analogs of vitamin A), which are effectively used in the treatment of various types of keratinizing disorders (by decreasing the keratin content of keratinocytes), may be beneficial in the management of cutaneous lesions of PLS, but also useful to prevent the loss of permanent teeth in children with PLS (126–131). Whereas, palmoplantar keratoderma usually improves rapidly in patients receiving oral retinoids, periodontal disease requires longer periods of treatment (128). The safety of oral retinoids in children remains however controversial due to their side-effects, in particular on skeletal development (132). Recently, an enzyme replacement therapy with recombinant CTSC has been developed and allowed to correct pathophysiologic markers in fibroblasts from PLS patients. It can therefore be a promising therapeutic approach for the future treatment of CTSC deficiency (133). A multidisciplinary team including dermatologists, pediatricians and dentists (periodontology, pediatric dentistry, oral surgery, prosthodontics) is important for the overall care of PLS patients.

Homozygous and heterozygous pathogenic variants in WDR1 gene that encodes an actin-interacting protein alter the regulation of neutrophil cytoskeleton, causing neutrophil dysfunction with abnormal morphology (herniation of nuclear lobes), chemotaxis and survival (140, 141). A more recent study also identified defects in the T- and B-cell compartments (aberrant assembly of immunological synapses) (141). Patients present recurrent infections and varying clinical manifestations including mild neutropenia, skin ulceration, impaired wound healing, and moderate intellectual disability (140, 141).

Patients with WDR1 deficiency can suffer from severe aphthous stomatitis^* leading to oral stenosis, and from candidiasis. Facial dysmorphia has been observed in some patients (frontal bossing, hypertelorism, wide nasal nostrils) (141).

Chronic granulomatous disease (CGD) is a PID [~1 case in 200 000 to 250 000 live births (142, 143)] due to functional impairment of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in all phagocytes (neutrophils, monocytes, macrophages and dendritic cells [DCs]) (144). NADPH oxidase (NOX) is a multiprotein enzyme complex comprising both membrane-bound (cytochrome b558: gp91^phox and p22^phox) and cytosolic (p40^phox, p47^phox, and p67^phox) proteins that assemble upon phagocytes' activation. It catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide ions that are used for the generation of ROS (e.g., hydrogen peroxide, hypochlorous acid). ROS production, called respiratory or oxidative burst, is a powerful antimicrobial mechanism essential for the destruction of phagocytosed bacteria and fungi (145). Pathogenic variants in the genes encoding any of the five structural subunits of NOX result in defective ROS production and in the development of CGD (144) (Table 5). More recently, it has been shown that homozygous germline mutations in CYBC1 abolish the expression of EROS, a chaperone protein required for stable expression of membrane-bound components of NOX, and represent therefore a novel cause of CGD (148–150). Two thirds of CGD patients have an X-linked form with various germline mutations in CYBB (Table 5) (144, 151) and the majority of the patients are diagnosed during early childhood (151). Survival is associated with residual ROS production independently of the gene that is mutated (152). CGD patients suffer from a variety of severe and recurrent bacterial and fungal infections, in particular due to Aspergillus species, Staphylococcus aureus, Burkholderia cepatia species, Serratia marcescens, and Nocardia species (153, 154). The lungs (pneumonia), skin (abscesses, granulomas…), lymph nodes (lymphadenitis), and the liver (abscesses) are the most common affected sites (144, 151). In developing countries, BCG (Bacille-Calmette-Guérin) and Mycobacterium tuberculosis are also important pathogens (155). CGD is associated with a very high prevalence of invasive fungal infections that affect up to 40% of the patients and can be life-threatening (156). “Mulch pneumonitis,” due to an intense inflammatory response to fungal elements in aerosolized decayed organic matter, is almost pathognomonic of CGD (144, 151). In addition to severe infections, CGD patients also suffer from dysregulated inflammation, in particular in the gastrointestinal [inflammatory bowel disease (IBD)-like] and genitourinary tracts, and can develop granulomatous obstructive disorders (157). Inflammatory and autoimmune manifestations (e.g., arthritis, discoid lupus, systemic lupus erythematosus, vasculitis, immune thrombocytopenia) are observed in respectively 70 and 10% of the cases, with the highest frequency in X-linked CGD patients (142, 143, 157). As NOX is active in other cell types than phagocytes, the clinical picture of CGD may even be more complex (144).

Diagnosis of CGD is made by functional evaluation of NADPH activity after phagocytes activation and by molecular confirmation. Conventional management predominantly relies on lifelong prophylactic antibiotics (trimethoprim-sulfamethoxazole) and antifungals (itraconazole), interferon (IFN)-γ therapy that can correct metabolic defects in phagocytes (158), along with the treatment of acute infections (144, 151). CGD-associated IBD is difficult to manage, in particular due to the combination with the inherent susceptibility to infections. The treatment of gastrointestinal (GI) tract inflammation frequently relies on corticosteroids although they remain controversial as they increase the growth retardation and the infectious risk (159). Allogeneic HSCT is currently the only curative treatment of CGD and may reverse both infectious and inflammatory manifestations (160).

Several factors predispose CGD patients to oral manifestations. They include neutrophil dysfunction, but also the use of immunosuppressive therapies to manage inflammatory complications, as well as malnutrition due to GI complications. Indeed, GI tract inflammation is very frequent, with a reported incidence ranging from 30 to 60% (157, 159, 161, 162). Recent findings have demonstrated a crucial role of NOX complex in the regulation of gut immunity, regardless the susceptibility to infections (163). Although it remains a distinct entity, GI involvement in CGD mimics IBD with overlapping features of both ulcerative colitis and Crohn's disease (159). Every part of the GI tract can be affected from the oral cavity to the anus. In a series of 98 patients, the most frequent reported GI manifestation was non-infectious diarrhea, followed by oral ulcerations and anal fistulae (157). In an important cohort of 459 European CGD patients, oral ulcers have been observed in 11% of the cases (142) and in a long-term follow-up study on 39 patients, they have been reported in 26% of the cases, along with stomatitis (164). Oral ulcers are similar clinically to aphthae with frequent recurrences. Granulomatous inflammation of the oral mucosa with a nodular and cobblestoning aspect, which is typically observed in patients with Crohn's disease (orofacial granulomatosis), has however been rarely described in CGD patients (165). Most of CGD patients present very early-onset forms of IBD (159). Importantly, GI manifestations may precede the diagnosis of CGD as well as the development of infectious complications (166). CGD should be considered in all patients who present early-onset IBD. Recurrent oral ulceration can therefore represent one of the inaugural signs of the disease. To our knowledge, no cases of severe oral infection have been reported (167, 168). In the CGD cohort of Liese et al., only 5% of the patients had one episode of parotid glands infection during the 22-year follow-up (164). In addition, although some studies show that gingivitis is common in CGD patients, with a prevalence ranging from 11% (142) to 35% (169), severe periodontitis has been rarely observed (65, 165, 170). In a large survey on 368 CGD patients, severe gingival or periodontal inflammation has been found in only 2% of the cases (143). This is in contrast with other PIDs due to a defective function of neutrophils such as LAD1. One hypothesis of the reduced prevalence of periodontitis associated with this PID could be the absence of a respiratory burst in neutrophils, despite its importance in periodontal pathogens' destruction (65, 168). Indeed, enhanced ROS generation has been clearly involved in the pathophysiology of periodontal disease (168).

LOF heterozygous pathogenic variants in GATA2 (guanine-adenine-thymine-adenine 2), a zinc finger transcription factor regulating early hematopoietic differentiation as well as lymphatic and vascular development, cause GATA2 haploinsufficiency (GATA2 deficiency: MIM 137295). Germline mutations arise spontaneously (de novo) but are then transmitted with autosomal dominant (AD) inheritance. The age of clinical presentation ranges from early childhood to late adulthood, with most of the cases occurring during adolescence and early adulthood. GATA2 deficiency is a protean disorder with a broad phenotype encompassing (I) multi-lineage cytopenia [DCs, monocytes, NK (natural killer) cells, B cells], (II) immunodeficiency with increased susceptibility to human papillomavirus (HPV), invasive non-tuberculous mycobacterial (NTM) and fungal infections, (III) high risk of developing hematologic malignancies (MDS/AML), (IV) pulmonary alveolar proteinosis (pulmonary disease), and (V) congenital lymphedema (vascular/lymphatic dysfunction) (171, 172). However, GATA2 deficiency has a variety of presentations and offers a challenge in any classification system. Indeed, a small proportion of patients present with only asymptomatic mild neutropenia and no other discernible hematological abnormalities except monocytopenia or macrocytosis, but with high risk of hematologic transformation (173).

Allogeneic HSCT remains currently the best therapeutic option to prevent or treat hematologic malignancies and life-threatening opportunistic infections (174, 175).

Oral manifestations associated with GATA2 deficiency have not been reviewed extensively yet. Authors report infectious oral lesions mainly caused by HPV (i.e., warts, condylomas) but also by herpes simplex virus 1 (HSV-1). A close monitoring of these lesions is strongly required, in particular due to their high risk of HPV-related malignant transformation (i.e., squamous intra-epithelial lesions, Bowenoid papulosis^*, invasive squamous cell carcinoma) (176, 177). Other oral features have been described and include recurrent ulcerations and blistering, gingival hyperplasia and inflammation, as well as glossitis (177, 178).

The most common genetic etiology of MSMD is AR complete IL12 receptor β1 (IL12Rβ1) deficiency. The latter is due to germline mutations in IL12RB1 gene that encodes one of the chains of IL12 and IL23 receptors (185). Mild forms of chronic mucocutaneous candidiasis (CMC) have been reported in about 25% of the patients (197–199). Whereas, IL12 is a key cytokine for IFNγ production, IL23 plays a role in the maintenance of IL17 producing T cells (Th17 cells) that are important effectors in host defense against fungi, in particular Candida albicans (200). Indeed, PID patients with impaired IL17 immunity [see “predisposition to mucocutaneous candidiasis (CMC)” section] are susceptible to Candida species and develop CMC (201). Ouederni et al. reported the clinical features of candidiasis in 35 patients with IL12Rβ1 deficiency and observed that recurrent oropharyngeal candidiasis was by far the most common presentation (in 34 patients). Although it was less severe than in patients with defects of IL17 axis, it tends to persist despite antifungal therapy (202). CMC is also observed in patients with pathogenic variants in IL12B gene, but not in other genetic etiologies of MSMD, as it is related to IL23-dependent impaired IL17 immunity. Indeed, IL12B encodes IL12p40, which is a common subunit of both IL12 and IL23 cytokines (179). However, patients with AR complete IL-12Rβ2 or IL23R deficiency that have been described more recently display mycobacteriosis without increased susceptibility to candidiasis (189). Bi-allelic germline mutations in RORC, which encodes RORγ and RORγT transcription factors, have been associated with impaired systemic IFNγ response to mycobacteria but also with defective IL-17 mucocutaneous immunity to Candida. RORγ- and RORγT-deficient individuals can therefore display both mycobacteriosis and mucocutaneous candidiasis (recurrent or persistent oral candidiasis in 70% of the cases) (191). MSMD must therefore been investigated in patients with CMC or persistent oropharyngeal candidiasis.

NEMO (NF-κB essential modulator), also called IKBKG (inhibitor of NF-κB kinase regulatory subunit gamma) is an essential component of NF-κB (nuclear factor kappa B) signaling pathway. It is the regulatory subunit of the inhibitor of IκB kinase (IKK) complex, which activates NF-κB. Germline mutations in NEMO gene have long been known to cause different ectodermal dysplasia^* (EDA) syndromes i.e., incontinentia pigmenti (IP) and anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (Table 6). In its classical form, EDA is characterized by abnormalities of ectodermal structures including anodontia^* or oligodontia^* with cone shaped teeth, hypotrichosis, and hypohidrosis with heat intolerance (206, 207).

In the 2017 IUIS classification (2), hypomorphic mutations in NEMO gene were classified in MSMD disease category as they were previously shown to cause also X-linked recessive (XR; MIM 300636) MSMD (type 1) (208). These pathogenic variants interfere selectively with the CD40-NEMO-NF-κB signaling pathway, leading to an impaired T-cell dependent production of IL12 by monocytes and monocyte-derived DCs in response to CD40 (194). As a result of impaired IFNγ-mediated immunity, infections are mostly limited to mycobacterial diseases, in particular due to Mycobacterium avium complex. Unlike other patients with germline NEMO mutations, most of XR-MSMD type 1 patients lack the developmental features typical of EDA. Only some cases have been reported to have hypodontia^* or conic shaped teeth, but to date, none of them has been described with oligo- or anodontia (180, 194, 208). In the most recent 2019 IUIS classification, NEMO mutations have however been removed from MSMD disease category and classified only as combined immunodeficiencies (CIDs) with syndromic features [disease category 2 (3)].

As discussed before (see section on CGD), germline mutations in CYBB are responsible for the most common form of CGD (MIM 306400) (143, 144). More recently, specific pathogenic variants in CYBB have been associated with X-linked MSMD (type 2) in male subjects suffering from recurrent mycobacterial diseases. The MSMD-causing mutations in CYBB selectively affect the respiratory burst in macrophages that is crucial for protective immunity to mycobacteria. Unlike CGD patients, NADPH activity is normal in neutrophils and monocytes (195, 209). To our knowledge, no specific oral manifestations have been reported in these patients.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by a selective susceptibility to keratinocyte-tropic HPV infections (subgroup B1) and that typically presents in early childhood (210, 211). Disseminated, flat, wart-like hypo-, or hyper-pigmented papules develop on the trunk, the neck, the face, the head as well as the extremities and are mainly benign. Lesions with greater malignant potential present as verrucous or seborrheic keratosis-like lesions and occur more frequently on sun exposed surfaces. Indeed, patients with EV have a higher risk to develop actinic keratosis and non-melanoma skin cancers, in particular cutaneous squamous cell carcinomas (210, 211). Homozygous LOF pathogenic variants in EVER1 (MIM 226400) and EVER2 (MIM 618231) genes, also named TMC6 and TMC8, respectively, have been reported in ~75% of patients with EV (210, 211). More recently, biallelic germline mutations in CIB1 gene (calcium- and integrin-binding protein-1) have also been described (212). CIB protein forms a complex with EVER1 and 2 and it has been suggested that the disruption of the CIB1–EVER1–EVER2-dependent keratinocyte-intrinsic immunity may underly the selective susceptibility to beta-HPVs of EV patients (212).

The development of EV lesions cannot be prevented, but regular monitoring and appropriate treatment of skin lesions (e.g., surgical excision, cryotherapy) that might transform into skin cancers are recommended (210).

To our knowledge, no HPV-related lesions or cancers have been described in the oral cavity, but they can develop on the facial skin.

WHIM syndrome (MIM 193670) is a rare AD condition whose incidence is estimated to be about 1 in 4.3 millions live births (213, 214). The term “WHIM” is an acronym of the main clinical manifestations including warts, hypogammaglobulinemia, infections, and myelokathexis (i.e., bone marrow retention). WHIM is caused by dominant heterozygous GOF pathogenic variants in the gene encoding the CX chemokine receptor 4 (CXCR4). Since CXCR4 is involved in the retention of neutrophils in the bone marrow, GOF germline mutations will exaggerate this process, thereby retarding neutrophil egress, leading to neutropenia (214). WHIM is mainly characterized by susceptibility to extensive HPV infection, which causes multiple cutaneous, plantar, anogenital, and oral warts. Warts can also occur in atypical locations such as the limbs, chest and face, and are unusually resistant to destructive treatments such as cryotherapy or surgery. HPV-driven squamous cell carcinomas constitute a significant cause of morbidity. A regular monitoring of HPV lesions, especially in the mouth and anogenital regions, is therefore strongly required and must include frequent biopsies (211, 214). Patients present severe neutropenia, but also often lymphopenia and monocytopenia, as well as moderate hypogammaglobulinemia, and suffer from frequent oto-sinopulmonary infections. Recurrent lung infections can lead to bronchiectasis and be associated with colonization by Pseudomonas aeruginosa and Stenotrophomonas maltophilia. Nasal and skin infections due to Staphylococcus aureus or Streptococcus sp. are also reported and can lead to skin abscesses, cellulitis or even septicemia (arthritis, osteomyelitis) (214).

The management of WHIM syndrome includes HPV vaccination (although WHIM patients respond less robustly than healthy individuals), prophylactic antibiotics, intravenous or subcutaneous immunoglobulins (IV Igs/SC Igs) substitution to prevent oto-sinopulmonary infections, as well as G-CSF injections to enhance the release of neutrophils from the bone marrow (214). More recently, some patients have been treated with low-dose plerixafor, a CXCR4 antagonist, with encouraging results (NCT02231879) (215).

In addition to oral warts and HPV-related oral squamous cell carcinomas described above (216), patients with WHIM syndrome can present severe pyogenic bacterial infections (e.g., cellulitis, recurrent acute and chronic sinusitis), or viral (e.g., HSV-1, VZV) infections (217, 218). The development of early-onset periodontitis has also been reported in several WHIM patients with rapid progression leading to early tooth-loss (219). Aphthous ulcers can be observed but they are less common than in individuals with SCN (214, 220). Rarely, odontogenic infections may disseminate and cause brain abscess or endocarditis, in particular in cases of associated congenital cardiopathies (e.g., tetralogy of Fallot) that are common in WHIM patients (214). The impact of G-CSF or plerixafor treatment on periodontitis evolution has however not been assessed yet (66).

IFN signaling is crucial for the defense against viral infections. Several gene defects affecting this pathway have been described (Table 7) and predispose to severe, even life-threatening, viral infections (e.g., encephalitis, pneumonitis), in particular due to herpes (e.g., HSV-1, VZV [varicella-zoster virus], CMV) and influenza viruses. As IFN signaling is also a central aspect of the response to other intracellular pathogens in macrophages and neutrophils, patients may in addition be susceptible to mycobacterial infections (239).

Viral infections, in particular due to herpes viruses, can manifest in the oral cavity. However, considering the severity of the infections affecting the patients with pathogenic variants in IFN signaling pathway, their oral localization is rarely mentioned. HSV-1 gingivostomatitis has been described in STAT2 deficient patients (225, 226) but to our knowledge, specific oral features have been reported neither in IFNAR1/2, IRF7/9, MDA5, nor in RNA polymerase III-deficient patients.

FcγRIIIA (CD16) is a low-affinity receptor for IgG Fc that is expressed by NK cells. Homozygous pathogenic variants in the FCGR3A gene lead to CD16 deficiency (MIM 615707) characterized by functional deficiency of NK cells with defective cytotoxic activity but retained antibody-dependent cellular cytotoxicity. Patients typically present early in childhood with severe herpes viral infections, in particular due to Epstein Barr Virus (EBV), VZV, and HPV (240–242).

Patients are prone to HSV-1 gingivostomatitis and require regular monitoring of the oral mucosa (240–242).

CARD9 (caspase recruitment domain-containing protein 9) is an adaptor molecule expressed principally in myeloid cells downstream from C-type lectin receptors activation (e.g., Dectin-1) by fungal ligands. Activated CARD9 couples with BCL10 and MALT1, resulting in NF-κB and mitogen-activated protein kinases (MAPK) activation. This signaling pathway promotes the production of key cytokines (e.g., IL1β, IL6, IL23) for antifungal immune responses (246, 247). CARD9 deficiency (MIM 212050) is characterized by the spontaneous development of invasive fungal infections due to fungi belonging the phylum Ascomycota. They include CMC (see “predisposition to CMC” section), invasive Candida infections (in particular of the CNS but also of the eyes, the colon and the bones), extensive and/or deep dermatophytosis, subcutaneous and invasive phaeohyphomycosis, as well as extrapulmonary invasive aspergillosis (248–250). CARD9 deficiency is the consequence of homozygous or compound heterozygous LOF germline mutations in CARD9 that induce impaired cytokine production in response to fungal ligands, altered neutrophil killing and/or diapedesis, and defects of Th17 immunity. To date, more than 60 cases have been described with a very heterogeneous age of disease-onset ranging from childhood to adulthood (248–250).

The treatment of patients with CARD9 deficiency is empirical, mainly based on antifungal therapies (e.g., azole agents, echinocandins) and on the surgical removal of fungal masses. In addition, CARD9-deficient patients should be given secondary prophylaxis with oral azole agents after the first episode of invasive fungal disease. In cases of persistent or relapsing Candida albicans infections of the CNS, adjuvant GM-CSF/G-CSF therapy can be considered. The potential value of HSCT still remains unclear due to the lack of available data (249).

Oral candidiasis (that is part of CMC due to Candida albicans) is very frequently associated to CARD9 deficiency and may reveal the disease (249, 251). It affects almost 30% of the patients as reported in a recent review (249). The use of oral fluconazole prophylaxis should also prevent the occurrence of CMC. In addition, frequent rigorous screening of the oral mucosa is required in order to diagnose CMC occurrence and/or relapse (249).

AR IRAK-4 (IL-1 receptor-associated kinase-4) and MyD88 (myeloid differentiation factor 88) deficiencies selectively impair the signaling via the TLR and IL1 receptor pathway (267, 268). To date, more than 80 patients have been diagnosed worldwide [reviewed in (268)]. IRAK-4 (MIM 607676) and MyD88 (MIM 612260) deficiencies, which are phenocopies in term of clinical and immunological abnormalities, are characterized by a selective predisposition to pyogenic bacterial infections (267–270). Patients are highly susceptible to invasive bacterial infections caused by Streptococcus pneumoniae and, to a lesser extent, Staphylococcus aureus, as well as to non-invasive bacterial infections mainly restricted to the skin (Staphylococcus aureus) and the upper respiratory tract (Pseudomonas aeruginosa). Despite a large impact of these genetic defects on immune responses, affected individuals however present a normal resistance to common viruses, fungi, parasites and to many bacteria (270).

In addition to vaccinations, in particular against Streptococcus pneumoniae, prophylactic antibiotic treatment (cotrimoxazole plus penicillin V) should be taken throughout the life. IV or SC Igs administrations during infancy seem to decrease the incidence of invasive bacterial infections (268). Empirical parenteral antibiotic treatment against Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa must be initiated as soon as an infection is suspected, considering the high mortality risk due to invasive bacterial infections. Secondary adaptation of the treatment should then be done once the causal bacteria has been evidenced (270).

Bacterial infections involving the orofacial region such as maxillary sinusitis, necrotizing palate infection, cellulitis, and periodontal diseases have been reported in some patients with IRAK-4 and MyD88 deficiencies (268). Four patients also presented oral candidiasis (268). The treatment relies on appropriate systemic antibiotics and systemic/topic antifungal agents, respectively. Into et al. have shown in a murine model that MyD88 deficiency has an impact on the expression of several antimicrobial factors, which could also influence the susceptibility to oral infections (271).