As this case demonstrates, PG is a challenging and urgent diagnosis that many clinicians mistake for infection. PG usually occurs in middle aged adults, with an average age of presentation around 51 [8]. PG is rare in children, accounting for only 4% of all cases [3]. There are several sub-classifications of PG, including classic/ulcerative, pustular, bullous/atypical, and vegetative variants [9]. The case described here represents the bullous subtype, which is characterized by rapidly evolving painful vesicles that enlarge into hemorrhagic bullae [9]. To our knowledge, eight cases of pediatric bullous pyoderma gangrenosum have been reported since 1994. A recent systematic review of pediatric PG cases found that only seven cases of pediatric bullous PG were reported between 1994 and 2016 [7], and we are aware of only one additional case since 2016 [10]. Additionally, we are not aware of any other reported cases of pediatric bullous PG occurring in a Native American patient.
Association with Other Diseases
To date, no other disease was found to be associated with the case above. However, greater than 50% of PG cases in pediatric patients are associated with systemic disease [7]. Inflammatory bowel disease (IBD), equally split between Crohn’s and ulcerative colitis, is most frequently associated with PG in children [7]. Other commonly associated conditions in children include hematologic malignancies, immune deficiencies, vasculitis, and PAPA syndrome [7]. The bullous subtype is most often idiopathic in pediatric patients, but at least one case has been associated with Crohn’s disease, one with myelodysplastic syndrome [7], and one with acute myeloid leukemia [10]. In the adult population, bullous PG is highly associated with hematologic malignancy, which is present in greater than 70% of cases [9, 11].
Pathogenesis
PG can be thought of as a neutrophilic dermatosis because pathology exhibits significant neutrophilic infiltration of the dermis without evidence of infection [2]. The pathogenesis of PG is not fully understood but is currently thought to involve overactivation of neutrophils due to intrinsic neutrophil dysfunction, and abnormal production of inflammatory cytokines [12]. Recent studies have shown that PG neutrophils are dysfunctional in a variety of domains - abnormal chemotaxis, migration, phagocytosis, hyperactivity, and bactericidal ability [2, 3]. Studies have also found that several inflammatory cytokines are overproduced in PG lesions, including IL-8, and IL-1β [13]. IL-8 is a known neutrophil chemokine, and exposure of human skin xenografts to high levels of IL-8 has been shown to cause formation of PG like lesions [14]. The association of PG with other inflammatory diseases and improvement of the disease with agents that inhibit neutrophil function such as dapsone, and colchicine also support an etiology of underlying neutrophil dysfunction [2]. Interestingly, there are many reports of PG occurring in patients with leukocyte adhesion deficiency type 1, a disorder wherein neutrophils are unable to extravasate into surrounding tissue [12, 7]. This finding suggests that development of PG is likely not solely due to neutrophils [12].
Genetic Syndromes
Several genetic syndromes and individual genetic mutations are associated with the development of PG. PAPA syndrome is characterized by the triad of pyogenic sterile arthritis, cystic acne, and PG [12, 15]. This syndrome has been found to originate from a mutation in the PSTPIP-1 gene, which leads to increased production of the inflammatory cytokines IL-1β, and IL-16 [1]. A different mutation of the same gene results in PAPASH syndrome – characterized by a tetrad of pyogenic sterile arthritis, PG, cystic acne, and hidradenitis suppurativa [12, 15]. These syndromes follow an autosomal dominant inheritance pattern [15]. Although these conditions cannot be ruled out without official genetic testing, they are unlikely in patients, such as the patient presented above, who do not have a family history of these conditions. PG has also been found to share several gene mutations with IBD - including IL-8RA, and tissue inhibitor of metalloproteinase 3 [12, 15]. Additionally, in patients with associated polycythemia vera, mutations in the JAK/STAT pathway are thought to contribute to development of PG. [2, 4, 12].
Clinical Presentation
The clinical presentation of bullous PG involves formation of pustules or vesicles, that rapidly expand into hemorrhagic bullae that eventually develop into painful ulcerations. Lesions are usually associated with severe pain, which is often out of proportion to ulcer size [3]. Adults usually have less than three ulcers [8], with the classic form preferentially affecting the lower extremities, and the bullous form affecting the upper extremities [3, 6]. In contrast, children most commonly exhibit widespread disease, with ulcers affecting multiple anatomical locations [7]. PG lesions often demonstrate pathergy, with formation after minor trauma to the skin [8]. There have been many reports of the disease presenting or worsening after surgery due to pathergy [8]. Systemic symptoms such as fever, joint pain, malaise, and myalgia are also often present [3]. The case presented above followed a relatively classic presentation for bullous PG in children. Of note, the patient developed wide-spread ulcerations that were extremely painful. The deep severe ulceration in the axilla may have been due to pathergy, as this is an area exposed to significant friction and disturbance with arm movement. Additionally, the patient had intermittent fevers that made it especially difficult to differentiate PG from an infectious etiology.
The presentation of PG mimics that of several other more common diseases, which often delays diagnosis. The differential diagnosis often includes infection of any cause, insect bites, sweet syndrome, systemic lupus erythematosus, granulomatosis with polyangiitis, cutaneous lymphoma, and Behcet disease, to name a few [4]. The median time from symptom onset to diagnosis of PG in pediatric patients has been reported to be around 2 months [7]. With a diagnosis made just 12 days after symptom onset, the PG case presented here was identified much quicker than most cases reported in the literature. This may be due to the severity of the presentation in this case.
Diagnosis
The diagnosis of PG is made based on the clinical manifestations, and progression, along with histologic findings, and exclusion of other disease processes. In 2018, a study by Maverakis et al. set out to determine a set of diagnostic criteria to help physicians identify this disease [4]. The current consensus is that a biopsy demonstrating neutrophilic invasion into the dermis is a major criterion [4]. In addition, 4 out of 8 minor criteria must be present: histological exclusion of infection, pathergy, history of IBD, papules or pustules that rapidly ulcerates, multiple ulcers with at least one in the lower extremities, cribriform scars at healed sites, erythematous ulcers with undermining borders, and a decrease in ulcer size following immune suppression therapy [4]. Additionally, to determine the PG classification subtype, two separate minor and major criteria must be met [11]. For bullous PG, the major criteria include painful inflammatory bullae that rapidly enlarge and coalesce with the exclusion of any other cause of bullae formation [11]. The minor criteria include pathology demonstrating neutrophils in the subepidermal bullae with or without necrosis, associated hematological malignancy, pathergy, and a positive response to steroids [11].
Treatment
Management of PG involves inflammation suppressing medications, wound care, pain management, and identification and treatment of any underlying systemic conditions [1]. Small, localized lesions can often be managed with locally acting immune suppression agents such as topical corticosteroids, or topical tacrolimus [1]. Diffuse, rapidly progressive PG is most often treated with systemic corticosteroids, cyclosporine, or biologic immunomodulators [1]. As reported in the case above, patients generally have rapid improvement when treated with these agents [8]. However, wounds that are refractory to traditional treatments can be treated with IVIg or alkylating agents [1]. Due to a lack of large randomized controlled trials on the treatment of PG, the optimum pharmacotherapy is currently unknown. Proper wound care is required to prevent superinfection and promote healing. This usually involves gentle cleaning of ulcers with normal saline. Harsh cleansing or dressing techniques such as the use of wet to dry dressings or silver nitrate should be avoided as these may lead to pathergy [1]. Because the disease is so often associated with severe pain, opiates, NSAIDs, and other pain medications are often needed. With the widespread ulcerations in the case above, pain control was especially challenging, and even necessitated long term sedation. It is crucial to identify and promptly treat any underlying conditions, as some associated conditions, such as hematologic malignancy, and immunodeficiency, have high mortality if not managed appropriately [7]. PG may be the first sign of one of these underlying conditions, so prompt investigation is imperative [7, 10].
Long Term Prognosis
The long-term outcomes of PG have not been well studied, but it appears that most cases resolve over time with appropriate treatment. Based on a few small case series, around 50 to 70% of cases will have complete healing within 6 months [5, 16], and up to 95% of cases will resolve within 3 years [5]. The patient in the case presented here had complete healing at 6-month follow-up. However, as shown in Fig. 4, healing of PG lesions often results in significant scarring and deformity. Recurrence of disease is common and can occur in 45 to 55% of cases [17, 18], which necessitates long term treatment [17]. Interestingly, recurrence of PG does not usually align with progression of the underlying systemic condition [9]. PG can rarely lead to death due to severe infection of diffuse lesions [17]. Mortality of patients with PG, especially pediatric patients, are most often due to underlying hematologic malignancy, immunodeficiency, or vasculitis [7, 17, 19].