Sporadic Pemphigus Foliaceus in a 3-Year-Old Vietnamese Girl: A Case Report and Literature Review

Pemphigus foliaceus is an uncommon autoimmune intraepidermal blistering disease characterized by immunoglobulin (Ig) G autoantibodies that attack desmoglein-1 in the epidermis. There are two predominant forms of pemphigus foliaceus, sporadic and endemic. Sporadic pemphigus foliaceus is known to be more prevalent in middle-aged and elderly people and to be extremely rare in children. Less than 40 nonendemic pediatric pemphigus foliaceus cases have been documented in the literature. This report documents a case of sporadic pemphigus foliaceus in a 3-year-old Vietnamese girl who presented with generalized scaling and crusted erosions over the body.


Introduction
Pemphigus belongs to a heterogeneous group of immunobullous diseases where pathogenic autoantibodies attack the cell surface of keratinocytes, resulting in the disruption of cell-cell adhesion in the epidermis.Based on the levels of intraepidermal detachment and the types of antigens under attack, pemphigus is divided into pemphigus foliaceus (PF) or pemphigus vulgaris (PV).PF, characterized by more superfcial blisters and lack of mucosal involvement, is milder than PV.Te peak age of onset for both types of pemphigus is 40-60 years, yet it may also occur in younger patients, including infants.Childhood pemphigus remains rare, with an apparent preponderance of PV [1].Due to the paucity of pediatric PF cases, misdiagnosis and diagnostic delays are common that may lead to serious complications [2,3].Moreover, data on treatment, long-term follow-up, and overall prognosis are still limited.Herein, we report a unique case of pediatric PF and review the currently available literature in an efort to elucidate the characteristics, clinical course, and treatment options for this condition.
Pemphigus erythematosus, with characteristics overlapping PF and lupus erythematosus attributes, is considered a separate condition rather than a variant of PF, and is thereby not included in this review [4].

Case Report
A 42-month-old Vietnamese girl was transferred to our hospital with extensive scaling and reddening of the skin.Te skin lesions had erupted 8 weeks prior, initially appearing as scaly and crusted erythematous macules on her face.Te patient was not taking any medications before these skin lesions developed, and her medical history was unremarkable.She was initially misdiagnosed with infected eczema and treated with various antibiotics for 6 weeks without improvement.Subsequently, faccid blisters developed on the trunk and extremities, which promptly ruptured into difuse crusted erosions.Te patient was admitted to a pediatric hospital for severe skin infection and sepsis and was treated for 2 weeks before being transferred to our hospital.On examination, the facial skin was covered with large faky scales in the background of difuse erythema, and its tightness caused mild ectropion (Figure 1).Generalized scaling and crusted erythematous patches were interspersed with moist, eroded areas on the trunk and extremities (Figure 2).Skin lesions caused severe pain, leading to limited mobility.Nikolsky's sign was positive.No evidence of mucosal or nail involvement was found.
Microscopic examination of the scaly erythematous lesions showed multiple focal splits at the level of the subcorneal layer, with some superfcial acantholysis, which supported the diagnosis of PF (Figure 3).In addition, direct immunofuorescence (DIF) of the perilesional skin yielded intercellular immunoglobulin (Ig) G and C3 deposits in the superfcial epidermis (Figure 4).Hematological and biochemical test results and coagulation profles were all within normal ranges.Furthermore, tests for antinuclear antibodies (ANA) and anti-dsDNA were negative.C3 and C4 levels were not reduced.Te Dsg1 and Dsg3 tests were not done.
Prednisolone (15 mg/day) treatment was initiated but was increased to 20 mg/day after 2 weeks because of the slow healing of established lesions.Te new dose resulted in only partial improvement.Terefore, we intended to add dapsone because of its corticosteroid-sparing efect.Unfortunately, the patient's glucose-6-phosphate dehydrogenase (G6PD) level was low, and we decided to maintain the previous prednisolone dosage.After 4 weeks, this treatment was effective in reducing desquamation, redness, and healing of the old erosions (Figures S1 and S2).Te prednisolone dosage of 20 mg/day lasted for more than 3 weeks before being tapered by 2.5 mg every 2 weeks to eventually reach 5 mg/day.From the third month onward, all skin lesions healed (Figures S3 and S4), and no new blisters or erythema was observed.At the eighth month of the follow-up, the administration of systemic corticosteroids had been discontinued for 1 month and the patient had achieved complete remission.

Discussion
In contrast to endemic PF, prevalent among inhabitants of the river valleys of rural Brazil that mostly afects children and young adults, sporadic PF rarely develops in childhood.Among the nonendemic pediatric cases of pemphigus, PF seems to be rarer than PV [1].Less than 40 pediatric PF cases, confrmed by immunofuorescent tests, have been presented in the literature.Some of these patients were neonates, all of whom experienced a transient course of PF over the frst few days of life, followed by spontaneous recovery [5,6].Placental transfer of maternal antidesmoglein-1 antibodies may play a causative role in neonatal acantholysis.Gradual elimination of these maternal autoantibodies from the neonatal blood circulation promotes the natural remission of pemphigus foliaceus in these newborns.Terefore, neonatal PF should be considered a phenomenon of passive immunity instead of true childhood PF.To better describe the nature of pediatric PF, we recommend further categorizing the condition into the following three subtypes: (1) newborn PF, the cause of which is related to the passive maternal transmission of maternal antibodies; (2) childhood PF (patients aged ≤12 years); and (3) juvenile PF (patients aged 13-18 years).
We conducted a comprehensive literature search of the PubMed database.Te keyword "pemphigus foliaceus" was used in combination with "pediatric," "children," "child,"   Case Reports in Dermatological Medicine "childhood," "neonate," "infant," "juvenile," or "adolescent."Endemic patients were excluded from this study.Our search yielded 31 related articles with a total of 32 pediatric PF patients, three of which did not have a full text and were excluded from this review.Te 29 remaining cases included four newborns, sixteen child patients, and nine juvenile patients.Excluding the neonatal cases, the youngest PF patient was an 18-months-old girl [7].Pediatric PF was equally prevalent in both boys and girls (Table 1).Te median time between the onset of skin lesions and defnitive diagnosis was 3 months, ranging from a few days to 5 years.Te patients were frequently misdiagnosed with impetigo [8], tinea [3,21], eczema [3], or psoriasis [1,21], and treatment with neither empirical treatment antibiotics nor antifungal agents proved efective.Te cutaneous manifestations of PF in children are similar to those in adults, with fragile, faccid blisters that quickly rupture into superfcial erosions and form crusting plaques.Annular (polycyclic) [3], follicular [27], and erythrodermic [19,24] variants have been reported in pediatric-onset disease.Mucous membranes are rarely involved in PF, except for mild conjunctivitis in one case [25].Interestingly, photoinduced PF has also been described in the literature, with four out of 29 patients reporting exacerbation of skin lesions after exposure to sunlight [2,4,8,27].
Previous studies have shown that PF is associated with myasthenia gravis and thymoma in adults.Although this connection was not observed in pediatric patients, concurrent occurrences of PF and Graves' disease have been reported in two juvenile cases [10,26].In addition, other autoimmune diseases including dermatomyositis [18] and neuromyelitis optica [22] have also been reported to be possible comorbidities.PF is an autoimmune condition, and the relationship between PF and the potentially higher prevalence of other autoimmune diseases requires further research.
Subcorneal blisters containing acantholytic cells in the blister cavity are pathognomonic for PF.However, the histological features of pediatric PF are sometimes indistinguishable from those of Hailey-Hailey disease [7], psoriasiform dermatitis [4], or toxic epidermal necrolysis [19].Terefore, DIF remains the gold standard for diagnosis.Te DIF test of perilesional skin in the 29 reviewed cases detected IgG, with or without C3, in the intercellular space of the superfcial epidermis.Target antigens were searched in 10 of the 29 reviewed cases.Desmoglein-1 was the principal but not the only target.Geller et al. have reported a unique PF case where intercellular IgG deposits attacked desmocollin-1 [2].Unfortunately, neither immunoblots nor ELISA results for these 10 cases were available for further analysis.
Corticosteroids remain the most efective frst-line treatment of PF in current guidelines.As mentioned above, PF in newborns generally resolves without specifc treatment.Although localized PF can be successfully treated with topical and/or sublesional injections of corticosteroids, generalized PF requires systemic corticosteroids to induce a clinical response.Te optimal corticosteroid dose in pediatric patients with PF has not been established, but prednisone (0.5-2 mg/kg/day), or its equivalents, has proven to be efective in the majority of cases.In our patient, prednisone at a dosage of 1 mg/kg/day showed a slow clinical Case Reports in Dermatological Medicine response.Dapsone was the most commonly prescribed adjuvant therapy in pediatric patients (fve cases) but was sometimes inefective [12].Other corticosteroid-sparing agents included azathioprine, mycophenolate mofetil, hydroxychloroquine, niacinamide, intravenous (IV) IG, methotrexate, cyclophosphamide, and minocycline.Treatment failure with a combination of systemic corticosteroids and other adjuvant therapies was observed in two children, whose condition then dramatically improved with rituximab infusion.Rituximab, a monoclonal antibody against CD20positive B cells, is the frst FDA-approved biologic agent for the treatment of pemphigus vulgaris in adult patients.Recently, rituximab has proved its safety and efcacy in childhood/juvenile pemphigus patients (both PF and PV) and can be used as frst-line therapy in this group [28].
Pediatric PF generally follows a chronic yet benign trajectory.No deaths have been reported in children with PF, and the lesions heal without scarring.Nine children remained free of lesions and required no further treatment for 2 months to more than 3 years.Unfortunately, the others were unable to discontinue systemic drugs, and the majority needed 5-20 mg of prednisone on alternate days.Future case reports are warranted to gain a better understanding of the efective treatment and long-term prognosis for PF in pediatric patients.

Figure 1 :
Figure 1: Large faky scales in the background of difuse erythema on the face of a pemphigus foliaceus patient.

Figure 2 :
Figure 2: Difuse scaly and crusted lesions on the trunk and extremities of a pemphigus foliaceus patient.

Figure 3 :
Figure 3: Skin biopsy of a pemphigus foliaceus patient with H&E staining shows a cleft within the subcorneal layer and superfcial acantholysis.H&E, hematoxylin and eosin.