When diagnosing external genital ulcers in women, both endo- and exogenous causes should be considered. Numerous factors like inflammatory, immunological, neoplastic, traumatic, or medication-induced causes need to be taken into account.10.
PFAPA SYNDROME
A thorough physical examination and detailed history-taking should be taken, because the patient’s childhood diseases can have a significant impact on current health problems. Our patient has been diagnosed with PFAPA syndrome in the past. This disease is a complex auto-inflammatory disorder diagnosed based on the clinical symptoms, which are: periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis. This disease is characterized by recurrent attacks with asymptomatic periods between episodes. Gastrointestinal disorders often accompany these symptoms.11. In addition to the main complaint, our patient presented abdominal pain, nausea, and vomiting. PFAPA syndrome is associated with a polygenic predisposition to impaired functioning of the innate immune system. The interaction of genetic susceptibility and environmental factors, probably infections, predisposes to the manifestation of the disease and its recurrence in the autoimmune mechanism.11., 12. People suffering from PFAPA have increased activation of CD4Th1 and Th17 lymphocytes.13. These molecular susceptibility results in dysfunction of antigen-presenting cells like monocytes and dysregulation of T cells. Monocytes produce higher levels of pro-inflamamtory cytokine IL-12, which stimulates CD4 and CD8 lymphocytes to produce excessive amounts of IFN-γ and lipopolisacharide (LPS).14. Moreover, the expression of the IL-10 gene decreases, resulting in a reduction of anti-inflammatory IL-10 cytokine.13. In addition, down regulation (Chemokine (C-C motif) receptor 1) CCR1 predisposes to reduce migration of monocytes.15. Depletion of these cells in inflammatory diseases may predispose to the increased migration of microorganisms through the permeable mucous membrane and ulcerations appears.14. In PFAPA the classical pathway of complement is activated, however the alternative pathway remains unchanged. During PFAPA flare-ups levels T-cell chemokines (IP-10/CXCL10, MIG/CXCL9), G-CSF (granulocyte colony-stimulating factor) and pro-inflammatory cytokines: IL-1β, IL-6, IL-12, IL-18 are increased as well as activation of the complement system. 11., 12. PFAPA is a consequence of excessive intracellular protein complexes response with the participation of pro-inflammatory factors such as caspase-1, IL-6, IP-10 (interferon gamma-induced protein 10) and interleukin 1 receptor antagonist (IL1Ra), but the level of the other pro-inflammatory factors, such as TNF ɑ (tumor necrosis factor) and MCP-1 (monocyte chemoattractant protein-1) remains relatively constant.
During PFAPA attacks, the complete blood count reveals leukocytosis with an increased level of neutrophils and monocytes with lymphopenia and eosinopenia.12.,16. The disease usually responds to treatment with corticosteroids.11. antibiotics are not justified due to the autoimmune basis of the disease. Tonsillectomy provides 70–97% long-term remission of the PFAPA syndrome.17.
PFAPA syndrome may predispose to the occurrence of AGU.13.,18. However, AGU are a very rare and atypical manifestation of PFAPA. Decreased levels of IL-10, which is an anti-inflammatory cytokine and CCR1 play an important role in the development of vulvar ulcers in patients with concomitant PFAPA syndrome.13., 14. According Scattoni et al. it should evaluate this atypical symptom as a possible and useful indication of PFAPA.18.
We considered the possible influence of PFAPA syndrome on the development of labia ulceration in our patient. The patient presented the same result of the leukocyte, neutrophil and eosinophil in the early stages of the disease. The vulvar lesions were accompanied by fever episodes, abdominal pain, nausea, and vomiting. Our patient did not undergo a tonsillectomy.
Moreover, the researchers emphasize that, during the COVID-19 pandemic, the incidence of PFAPA syndrome increased.14.
VACCINATION AGAINST SARS-COV-2
An effective vaccination against SARS-CoV-2 is a vital tool to halt the spread of the current pandemic, however, some predisposed people may have adverse effects of the vaccination. Several cutaneous side effects were observed e.g. delayed large local reactions and eruptions.
Recently, cases of AGU associated with COVID-19 vaccinations have been reported.2., 5., 19. Of the 94 cases of vulvovaginal ulceration reported in the female adolescent age group, there was evidence that at least 37 were AGUs. In addition, up to December 2022, there are approximately 12 case reports published in the scientific literature for genital ulcerations after COVID-19 vaccine administration in non-sexually active adolescent patients. In majority, the events occurred after the second dose, usually within 1 week. Common symptoms included pain-related difficulty in urination, defecation, sitting and walking. Fever, vulvar swelling and fatigue were also described. Despite a different approach, the ulcers are usually self-limiting and heals between 2 to 6 weeks.20.
The most reported altered effects of vaccines are pain and swelling. Mucosal changes (bleeding gums, oral sores and ulcers) may occur after administration of diphtheria, tetanus, acellular pertussis and polio vaccines.19. Incidences of Lichen Planus, an chronic inflammatory disease, which affects the stratified squamous epithelium and frequently involves the oral and genital mucosa, have been reported after Hepatitis B vaccination. It is likely that the immune system recognizes similar/identical epitopes to protein of the virus on keratinocytes and induce immunological response and apoptosis of these cells.21.
Once, mRNA vaccine is administered, the spike protein, a viral receptor-binding protein, is produced by ribosomes in muscle cells. Subsequently, it binds to the host receptor angiotensin-converting enzyme 2 and triggers a robust of CD8 + and CD4 + cell mediated response inducing the production of neutralizing antibodies and memory B and T-cells. The mechanisms through COVID-19 vaccines provoke autoimmune response includes the particular autoantibodies production, the effects of certain vaccine adjuvants and molecular mimicry. 22.
The SARS-CoV-2 spike protein and lung surfactant proteins share 13 of 24 pentapeptides and the respiratory system is the most frequently attacked system in case of COVID-19 infection. Similar mechanism of cross-reactions between virus’ proteins and a variety of human antigens could lead to autoimmunity against other organs, including mucosal and skin lesion, invaded by the coronavirus as well as induced by COVID-19 vaccines22 The side effects of vaccination might as well be due to transient bursts of IFN-I expression, effective antibody production, oxidative stress and DNA-damage which may stimulate hyperinflammatory conditions. Another possible mechanism indicates that in case of mRNA vaccines, mRNA presents as both antigen and adjuvant, which might be identified by Toll-like receptors triggering inflammation and immunity.22. Nevertheless, the pathophysiology of AGUs after vaccination remains poorly understood.
A rare problem following COVID-19 vaccination described in the literature is Behcet's disease, and it is also possible that AGU after vaccination are the first manifestation of this condition and consistent monitoring of the possible clinical symptoms of these conditions is necessary.23.
BEHCET’S DISEASE
Behcet’s disease (BD) also should be evaluated in our patient’s history of aphthous skin lesions in the mouth and genital ulcerations. Behcet’s disease is a rare, inflammatory disorder which diagnosis is based on the clinical symptoms and specific criteria.24. According to the new criteria a patient who scores ≥ 4 points is classified as having BD. Characteristic signs and symptoms are: ocular lesions (2), genital aphthosis (2), oral aphthosis (2), skin lesions (1), neurological manifestations (1) vascular manifestations (1) and optional positive pathergy test (1).24. In addition, BD is often associated with Neutrophil to Lymphocyte Ratio (NLR) increased while the Hemoglobin (HB) level is decreased. Moreover, ESR erythrocyte sedimentation rate and C reactive protein CRP are increased and human leukocyte antigens HLA-B51- positive.25.
The pathomechanism of BD may depend on the neutrophil-mediated mechanisms. Neutrophil hyperactivation via both a massive reactive oxygen species (ROS) production and neutrophil extracellular traps (NETs) release. Serum concentrations of sTNFR, leptin, sCD40L and IL-6 are higher in BD patients. Tumor necrosis factor alpha (TNF-alpha), leading neutrophils to disrupt the oral mucosa is elevated in patients with recurrent aphthae and affects endothelial cell adhesion and neutrophil chemotaxis. It is believed to be one of the molecular factors that is responsible for aphthous ulcers. It was observed as source of aphthous ulcers the rare side effect of Covid-19 vaccination mentioned earlier in this article, as well as high Serum concentrations of sTNFR in BD.26.
Such as PFAPA syndrome and Behcet’s disease are characterized by similar pathomechanisms, for this reason, they are often considered in the differential diagnosis.10.,13. It is postulated that the same HLA type like HLA-B5 and HLA-B51 is involved in the development of both diseases.13., 14. Thus, ulcerations in the vaginal area can be a symptom of PFAPA syndrome and Behcet’s disease.
INFECTIOUS ETIOLOGY
The vulva can be affected by a variety of microorganisms including bacteria, viral, fungal and parasitic. Commonly those infections are transmitted by sexual contact. However, in non-sexually active adolescents genital infections might develop as well. AGU is commonly described as associated with a variety of infections including Cytomegalovirus (CMV), Herpes Zoster Virus (HZV), influenza type A and B, mumps virus, salmonella, mycoplasma and the most common - Epstein-Barr virus (EBV).4.
EBV causing infectious mononucleosis syndrome (IMS) has been reported as a most common cause of AGU. Serologic testing for EBV in patients with vulvar ulcer demonstrated evidence of acute as well as prior infections.3. Most patients develop systemic symptoms of IMS and lymphadenopathy distant from the site of ulceration is also common, however in the presented case enlargement of lymph nodes has not been described. Acute CMV infection has been also detected in cases of patients with AGU and CMV inclusions found in cells of the vulva and cervix.3., 27. HZV infection of the vulva is rare and pain or burning sensation are common symptoms and lesions characteristically present in dermatomal distribution.
Herpes Simplex Virus (HSV) causing genital herpes remains the most common factor of genital ulcers among sexually active female. However, it might also be responsible for ulcers in non-sexually active adolescents.4., 28. There are two types of HSV, HSV-2 is considered as the main cause of AGU, whilst HSV-1 is mostly linked to oral cavity lesions.
American Pediatric and Adolescent Gynecology Care Providers suspect an 80% of HSV etiology at the onset of AGU diagnosis, therefore aggressive diagnosis of lesions should be delayed.29.
Since there is no single infectious agent identified as a cause of AGU, clinical examination and detection of viral genetic material or serologic tests play a pivotal role in the diagnostic process.
CANCER
We also considered the possibility of vulvar cancer, although the incidence of genital cancers are rare in young girls.30. However, the macroscopic appearance of the vulvar lesion as an ulcer, raised suspicions of oncological concern. There are two types of vulvar intraepithelial neoplasia (VIN). The former, defined as differentiated (dVIN) is often associated with lichen sclerosus. The second is vulvar high-grade squamous intraepithelial lesions (vH-SIL).31. It is an HPV-related oncology condition that is specific to younger women and refers to intraepithelial neoplasia and squamous cell vulvar carcinoma (SVC).32. Moreover, given the increase in HPV infections and an early age of sexual initiation, there is a significant risk of vulvar cancer in younger age groups.33. However, biopsy from vulvar lesions in children is debatable among many researchers, unless there is a recurrence or a non-infectious etiology is suspected.29. Most cases of vulvar ulceration in young women are self-limiting and respond to topical and systemic corticosteroid therapy. For this reasons, some authors recommend reducing extensive diagnostics.34. Due to the extensive area of necrosis, as well as the specificity of a hospital also providing oncological treatment, it was decided to collect material for histopathological examination. Biopsy excluded neoplastic invasion, therefore we ruled out vulvar cancer.