CXCR4 WHIM syndrome is a cancer predisposition condition for virus-induced malignancies.

Warts, hypogammaglobulinaemia, infections and myelokathexis syndrome (WHIMS) is a rare combined primary immunodeficiency caused by the gain of function of the CXCR4 chemokine receptor. We present the prevalence of cancer in WHIMS patients based on data from the French Severe Chronic Neutropenia Registry and an exhaustive literature review. The median follow-up of the 14 WHIMS 'patients was 28.5 years. A central review and viral evaluation of pathological samples were organized, and we conducted a thorough literature review to identify all reports of WHIMS cases. Six French patients were diagnosed with cancer at a median age of 37.6 years. The 40-year risk of malignancy was 39% (95% confidence interval [CI]: 6%-74%). We observed two human papillomavirus (HPV)-induced vulvar carcinomas, three lymphomas (two Epstein-Barr virus [EBV]-related) and one basal cell carcinoma. Among the 155 WHIMS cases from the literature, 22 cancers were reported in 16 patients, with an overall cancer 40-year risk of 23% (95% CI: 13%-39%). Malignancies included EBV-associated lymphoproliferative disorders and HPV-positive genital and anal cancers as in the French cohort. Worldwide, nine cases of malignancy were associated with HPV and four with EBV. Immunocompromised WHIMS patients appear to be particularly susceptible to developing early malignancy, mainly HPV-induced carcinomas, followed by EBV-related lymphomas.

Does HPV biotype influence the characteristics and evolution of plantar warts?

BACKGROUND: Few studies have addressed the relationship of human papillomavirus (HPV) biotypes to patient characteristics and the clinical signs, course, and response to the treatment of plantar warts. OBJECTIVE: Analyze the HPV types associated with plantar warts and their relationship with warts characteristics, patient characteristics and response to treatment. METHODS: A total of 372 patients sampled for hyperkeratosis of a plantar wart were included. Multiplex polymerase chain reaction (PCR) was performed to detect the HPV biotype. RESULTS: The prevalence of HPV was 81.2%, and HPV1 was the most prevalent biotype (36.1%). HPV1 was the most prevalent biotype in patients < 70 years old (90.9% in < 10 years), and biotypes 2, 19 and 27 were the most prevalent in patients > 70 years old (p = 0.012). HPV1 was the most frequent in patients with one (39,9%) or two (47.1%) warts and HPV5 (33.3%) in patients with three warts (p < 0.001). Cure, spontaneous resolution, and recurrence were higher in HPV1 (p < 0.001). HPV14 warts healed the fastest (2 months quartile 1-3 (2.0-2.0)), and HPV5 (10.977 (6.0-20.0)) and HPV27 (7.5 (3.0-10.0)) warts (p = 0.033) took the longest to heal. CONCLUSIONS: HPV biotype is associated with age and the number of warts and appears to influence the natural history of warts and their response to treatment.

Flat Warts (Verrucae Planae) Confined to the Pigment of a Tattoo: A Rare Tattoo-associated Complication.

Tattoos are a form of decorative body art in which pigment dyes of different colors are inoculated into the skin. It is estimated that 15-25% of general population has one or more tattoos (1), and the reasons for the popularity of this procedure may include greater social acceptance, aesthetic appeal, or perhaps the option of using laser removal techniques to eliminate unwanted tattoos. Even though modern professional tattoos are usually performed in sterile conditions, complications still occur, and with increasing numbers of people getting tattoos, the incidence of tattoo-associated side-effects presenting to dermatologists, which may be as high as 2%, is likely to increase (2). Herein we present a case of a 43-year-old male patient with multiple HPV-associated flat warts (verrucae planae) confined to the black pigment of a tattoo done 15 years ago. A 43-year-old patient presented to our clinic due to eczema on the trunk. However, during skin examination, we observed asymptomatic verrucous papules confined to the black ink of a tattoo done 15 years ago on the lateral side of his right lower leg (Figure 1a). Clinical examination showed multiple, discrete, skin-colored, verrucous papules disseminated exclusively within the lines of the black-colored tattoo. Full skin examination did not reveal any similar lesions anywhere else on the body. Dermoscopically, papules showed a discretely papillomatous surface and sharp borders (Figure 1b). The patient had another black tattoo on his trunk, in which no similar lesions were found. All his tattoos had been done more than 15 years ago in a professional tattoo salon and with no previous history of cutaneous lesions within tattoos. The patient had no other medical conditions and was not taking any medications. Additionally, no history of warts or other HPV-related lesions of the skin or mucosal membranes could be established. A biopsy of an individual papule was taken and sent for a histopathological analysis, which subsequently showed hyperkeratotic, orthokeratotic, and parakeratotic acanthotic epidermis with hypergranulosis and rare cells with perinuclear halo indicative of koilocytes (Figure 3b). Immunohistochemical analysis showed negative reaction for p16 and p53, while Ki67 was positive only in rare basal and suprabasal cells. These findings were indicative of low-risk HPV, and the diagnosis of HPV-induced verruca plana was ultimately established. The patient was then successfully treated with cautious curettage of the lesions, leaving no scars. Due to the growing popularity of tattoos, especially among younger populations, it is necessary to emphasize the possibility of various tattoo-related side-effects that can still occur due to improper preparation of the tattoo location, contamination of ink products, improperly sterilized instruments, or due to insufficient personal hygiene following tattooing (3). In the past, tattoo-associated infections were significantly more frequent, with the highest prevalence of Staphylococcus and Streptococcus infections causing impetigo, folliculitis, cellulitis, erysipelas, or sepsis (2), but recent improvement and efforts in using sterile techniques in tattooing has led to a significant drop in the number of tattoo-related infections. In this short report, we present a case of a different and a relatively rare type of tattoo-associated infection - flat warts i.e., verrucae planae. Flat warts are usually caused by HPV-3, -6B, -10, -28, and -49. Typical predilection sites are the face, dorsal sides of the hands or feet, arms, and legs, and they usually appear as skin-colored, pink, or brown, flat-topped discrete papules. It is believed that HPV can be inoculated through contaminated ink, instruments, the artist's saliva, or that it may be a pre-existing unnoticed wart in the tattooed area (4-6). The latency period between tattooing and HPV infection can range from several months to 10 years, with a mean period of 5 years (3). This may suggest that the immune system can control the infection for some time, and that some form of immune suppression may result in the development of a clinical disease. In our case, the latency period could not be established due to the patient's unawareness of the lesions, and no potential trigger could be identified. The occurrence of lesions on only one of the patient's tattoos as well as their confinement to the black pigmented ink may indicate a correlation to this specific pigment. Ramey et al. (6) conducted a study in which they assessed the localization of warts in differently colored tattoos. The results showed that black ink tattoos had a seven times higher risk of developing warts when compared with colored ink. At first it was thought that this was due to HPV inoculation via contaminated instruments, ink, or autoinoculation of the patient's own warts, but some evidence indicates that it is unlikely for HPV to survive in ink and that if the warts were inoculated they would occur equally in all ink colors. A different theory by Ruocco et al. (7) explains this phenomenon through an "immunocompromised district" mechanism, in which polycyclic aromatic hydrocarbons found in black ink produce reactive oxygen species (ROS) that can damage cellular structures and consequently increase the risk of a variety of infections, including HPV. Moreover, black ink contains almost pure nanoparticles, which are associated with greater ROS production than the larger particles found in colored ink (7,8). There are several treatment options for verrucae planae, such as liquid nitrogen cryotherapy, topical 5% fluorouracil, topical 5% imiquimod, 0.025-0.050% tretinoin, 10% salicylic acid, or 10-30% glycolic acid. These treatments have differing success rates. Destructive modalities, such as surgical excision, curetting, or laser ablation may significantly damage the tattoo and cause scarring, and are thus not regularly performed. It's necessary to emphasize that despite today's sterile methods of tattooing, complications may still occur and medical professionals, namely dermatologists, should be aware of them. A person who wishes to get a tattoo should be advised to visit a licensed tattoo artist at a licensed tattoo parlour only. Patients with pre-existing dermatoses characterized by an isomorphic phenomenon, such as psoriasis or lichen planus, are particularly prone to developing a tattoo-associated adverse reaction, and those with severe dermatoses should be advised to avoid tattooing. Additionally, people with a previous history of warts should be aware of the possibility of warts occurrence, even years or decades after tattooing. Even though most of tattoo-related side effects are merely inconveniences, there is a potential for serious complications and patients should be advised as such.

Skin surface material for detecting human papillomavirus infection of skin warts.

Warts, caused by human papillomavirus (HPV) infection, have various clinical presentations, making them difficult to differentiate from clavus, callus, and sometimes, squamous cell carcinoma. Although skin biopsies are the gold standard, a less-invasive method of examining these lesions is desired. Ninety patients with warts and related diseases, such as clavus and callus, were recruited to explore new differentiation methods using the surface of the warts. DNA was extracted from three types of specimens in each case: surface swab, shaved hyperkeratotic scale, and post-shaved surface swab. Total DNA was successfully extracted from these three specimens and was sufficient for subsequent HPV DNA detection. We analyzed samples for the HPV type and HPV viral load using polymerase chain reaction (PCR). Fifty-five cases were PCR-positive, and HPV1a, 2a, 4, 27, 57, and 65 were detected. The amount of HPV1a DNA produced was significantly greater than that of other HPV types. Regarding the correlation between the clinical diagnosis and HPV detection, the positive agreement rate was 90.9%, the negative agreement rate was 40.0%, and the overall agreement rate was 71.1%. Ten of the 21 cases clinically diagnosed as plantar warts were PCR-negative, especially in elderly patients. This suggests that it is difficult to distinguish plantar warts from clavus and callus in clinical practice. Although the amount of HPV DNA in the removed keratinization scale was highest for all HPV types, HPV detection by swabbing before and after shaving is also useful for follow-up as well as for differential diagnosis.

[Early detection of WHIM symdrome. A case report]. / Identificación temprana de síndrome de WHIM. Informe de un caso.

BACKGROUND: WHIM syndrome corresponds to an inborn error of innate and intrinsic immunity, characterized by: warts (Warts), Hypogammaglobulinemia, Infections and Myelocathexis, for its acronym in English. CASE REPORT: 4-year-old male, with severe neutropenia and B-cell lymphopenia from birth, without severe infections or warts; the panel genetic sequencing study of primary immunodeficiencies with the CXCR4 c.1000C>T (p.Arg334*) variant, which is associated with WHIM syndrome. CONCLUSIONS: The diagnosis of severe neutropenia from birth should include the search for inborn errors of immunity, through genetic sequencing studies, especially in asymptomatic or oligosymptomatic patients.

ANTECEDENTES: El síndrome WHIM corresponde a un error innato de la inmunidad innata e intrínseca, caracterizada por verrugas (Warts), hipogammaglobulinemia, infecciones y mielocatexis, por sus siglas en inglés. REPORTE DE CASO: Paciente masculino de 4 años, con neutropenia severa y linfopenia de células B desde el nacimiento, sin infecciones severas ni verrugas. El estudio de secuenciación genética informó la variante CXCR4 c.1000C>T (p.Arg334*), relacionada con el síndrome de WHIM. CONCLUSIÓN: El diagnóstico de neutropenia severa desde el nacimiento debe incluir la búsqueda de errores innatos de la inmunidad, mediante estudios de secuenciación genética, especialmente en pacientes asintomáticos u oligosintomáticos.

Comparative Study Among CO 2 Laser, Intralesional Vitamin D3, and Combined Intralesional Vitamin D3 and CO 2 Laser in Treatment of Palmoplantar Warts.

BACKGROUND: Many therapeutic modalities are used for palmoplantar warts; whether destructive, such as chemical cautery, electrocautery, cryocautery, surgical removal, and laser ablation, or immunotherapeutic, stimulating the immune system against the virus such as intralesional vitamin D3 injection. OBJECTIVE: To compare the efficacy of intralesional vitamin D injection combined with CO 2 laser to the efficacy of either modality alone. PATIENT AND METHODS: Eighty age- and sex-matched patients with palmoplantar warts were divided into 4 groups: Group A received intralesional vitamin D3 injections, group B received ablative CO 2 laser, group C received CO 2 laser and intralesional vitamin D3 injection, and group D (control group) were injected intralesionally with normal saline. Assessment was performed clinically, photographically, and dermoscopically before and after treatment to evaluate the response, and then, another assessment was performed after 3 months to detect any recurrence. RESULTS: Complete clearance was seen in 90% of cases in group C, in 80% in group A, and in 75% in group B with no statistically significant difference. CONCLUSION: Intralesional vitamin D, CO 2 laser, and the combination show comparable efficacy and recurrence rates. Intralesional vitamin D maybe a better option for people with a relative contraindication to CO 2 laser.

Squamous Cell Carcinoma of the Foot Occurring in a Wart.

Verrucous carcinoma is a rare form squamous cell carcinoma which appears similar to a wart. When it occurs in the feet, it can be easily misdiagnosed. It rarely metastasizes or recurs posttreatment. We report a case of a septuagenarian with recurrence of verrucous carcinoma diagnosed within 6 months at the site of previous treatment. Unique features in our patient's clinical presentation include his advanced age, being nondiabetic, and the rapid recurrence of carcinoma.Level of Evidence: Level IV: Case report.

Redefining WILD syndrome: a primary lymphatic dysplasia with congenital multisegmental lymphoedema, cutaneous lymphovascular malformation, CD4 lymphopaenia and warts.

BACKGROUND: Primary lymphoedema (PL) syndromes are increasingly recognised as presentations of complex genetic disease, with at least 20 identified causative genes. Recognition of clinical patterns is key to diagnosis, research and therapeutics. The defining criteria for one such clinical syndrome, 'WILD syndrome' (Warts, Immunodeficiency, Lymphoedema and anogenital Dysplasia), have previously depended on a single case report. METHODS AND RESULTS: We present 21 patients (including the first described case) with similar clinical and immunological phenotypes. All had PL affecting multiple segments, with systemic involvement (intestinal lymphangiectasia/pleural or pericardial effusions) in 70% (n=14/20). Most (n=20, 95%) had a distinctive cutaneous lymphovascular malformation on the upper anterior chest wall. Some (n=10, 48%) also had hyperpigmented lesions resembling epidermal naevi (but probably lymphatic in origin). Warts were common (n=17, 81%) and often refractory. In contrast to the previous case report, anogenital dysplasia was uncommon-only found in two further cases (total n=3, 14%). Low CD4 counts and CD4:CD8 ratios typified the syndrome (17 of 19, 89%), but monocyte counts were universally normal, unlike GATA2 deficiency. CONCLUSION: WILD syndrome is a previously unrecognised, underdiagnosed generalised PL syndrome. Based on this case series, we redefine WILD as 'Warts, Immunodeficiency, andLymphatic Dysplasia' and suggest specific diagnostic criteria. The essential criterion is congenital multisegmental PL in a 'mosaic' distribution. The major diagnostic features are recurrent warts, cutaneous lymphovascular malformations, systemic involvement (lymphatic dysplasia), genital swelling and CD4 lymphopaenia with normal monocyte counts. The absence of family history suggests a sporadic condition, and the random distribution of swelling implicates mosaic postzygotic mutation as the cause.

High versus low dose oral isotretinoin in the treatment of cutaneous and genital warts.

Although oral isotretinoin has been considered as a potential therapeutic option for the treatment of different types of warts, the optimum dosage regimen is not yet well-established. To evaluate the efficacy and adverse effects of high versus low doses of oral isotretinoin in the treatment of cutaneous and genital warts. The study included 100 patients who were randomly assigned to two groups, 50 patients in each. Group 1 received 0.6 mg/kg/day (high dose isotretinoin) and Group 2 received 0.3 mg/kg/day (low dose isotretinoin). In both groups, therapy was given daily until resolution was achieved or for a maximum of 3 months. Complete clearance of warts was observed in 76% of the high dose isotretinoin group and in 46% of the low dose isotretinoin group. There was a statistically significant difference in the therapeutic response between the two groups. Recurrence was higher in the low dose group (26%) than the high dose group (7.8%). Adverse effects were mild and tolerable. High dose of systemic isotretinoin is more effective than low dose and seems to be a promising well-tolerated and effective therapeutic option for the treatment of cutaneous and genital warts.

Intralesional combined furosemide and digoxin in cutaneous warts treatment: A randomized controlled clinical trial.

Although being a benign lesion, Warts can affect the quality of life by causing discomfort, disfigurement, and social embarrassment besides the tendency to spread. Cutaneous wart treatment faces many challenges as the development of an antiviral drug that can eradicate the human papilloma virus (HPV) is difficult. This clinical study aimed to assess the efficacy and safety of intralesional combined furosemide and digoxin in the treatment of multiple cutaneous warts. This double blinded randomized clinical trial included 80 adult patients with multiple cutaneous warts (≥2 warts) who were randomized into two groups, Group I (40 patients) treated with intralesional combined furosemide and digoxin and Group II (40 patients) who were treated with intralesional normal saline solution as a control group, weekly till improvement or for maximum five sessions. Clinical and dermoscopic evaluation at baseline, every session, and monthly for 6 months after the last session to detect any recurrence was performed. Complete wart clearance was observed in 92.5% of patients in the intralesional combined furosemide and digoxin group (Group I) compared with 10.0% in saline group (Group II), with highly statistically significant difference (P-value = 0.000). Pain during injection in 95.0% and 45.0% of patients in Group I and Group II respectively, treatment group was superior compared to control group. Intralesional injection of combined furosemide and digoxin can be a safe and effective treatment option in multiple cutaneous warts with minimal side effects in this study.

Clinical guideline for the diagnosis and treatment of cutaneous warts (2022).

AIM: Cutaneous warts caused by human papillomavirus are benign proliferative lesions that occur at any ages in human lives. Updated, comprehensive and systematic evidence-based guidelines to guide clinical practice are urgently needed. METHODS: We collaborated with multidisciplinary experts to formulate this guideline based on evidences of already published literature, focusing on 13 clinical questions elected by a panel of experts. We adopted Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to form classification of recommendations as well as the improved Delphi method to retain respective recommendations with a consensus degree of over 80%. RESULTS: Our guideline covered aspects of the diagnosis and treatment of cutaneous warts such as diagnostic gold standard, transmission routes, laboratory tests, treatment principle, clinical cure criterion, definitions, and treatments of common warts, flat warts, plantar warts, condyloma acuminatum, and epidermodysplasia verruciformis. Recommendations about special population such as children and pregnant women are also listed. In total, 49 recommendations have been obtained. CONCLUSIONS: It is a comprehensive and systematic evidence-based guideline and we hope this guideline could systematically and effectively guide the clinical practice of cutaneous warts and improve the overall levels of medical services.

Intralesional full-concentration (25 mg/ml) methotrexate in the treatment of plantar warts: A pilot study.

Plantar warts continue to represent a therapeutic challenge due to treatment resistance and high recurrence rates. Intralesional methotrexate, a cytotoxic chemotherapeutic agent with in-vitro anti-viral properties has been used for many dermatological indications. Two previous studies evaluated intralesional injection of diluted methotrexate (in 0.5, 1, and 2 mg/ml dilutions) in the treatment of warts and found it poorly effective. The concentrations used in these studies were much lower than those used for other indications. The current, open-label, prospective, pilot study aimed to evaluate the safety and efficacy of the intralesional injection of full concentration (25 mg/ml) methotrexate in the treatment of plantar warts. Twenty patients with plantar warts, 10 (50%) males, and 10 (50%) females, with mean ± SD age of 28.45 ± 8.66 years (range, 18-46 years) received biweekly sessions of intralesional methotrexate (25 mg/ml) until complete clearance or for a maximum of 6 sessions. Complete clearance of warts was achieved in 2 (10%), 6 (30%), and 7 (35%) patients after 4, 5, and 6 sessions, respectively. Another 8 (40%) patients showed partial improvement after 6 sessions. The response rate did not correlate significantly with the number of warts. Nine (45%) patients did not report any side effects. Pain and bruises were reported by 8 (40%) and 6 (30%) patients, respectively. These findings suggest that biweekly sessions of full (25 mg/ml) concentration of methotrexate are a safe and effective treatment for plantar warts. It may be considered an alternative line of treatment for resistant cases.

Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.