Pediatrics and Neonatology (2016) 57, 338e342

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CASE REPORT

Oral Ulcers as an Initial Presentation ofJuvenile Pemphigus: A Case Report

I-Hsuan Chen a, Shu-Chi Mu a, Dino Tsai b, Yuh-Yu Chou c,Li-Fang Wang d, Ling-Jen Wang a,*

aDepartment of Pediatrics, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, TaiwanbDepartment of Dermatology, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, TaiwancDepartment of Pathology, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, TaiwandDepartment of Dermatology, National Taiwan University, Taipei, Taiwan

Received Apr 22, 2013; received in revised form Jul 9, 2013; accepted Aug 1, 2013Available online 2 December 2013

Key Wordsoral ulcers;paraneoplasticpemphigus;

pemphigus vulgaris;rituximab

* Corresponding author. No. 95, WenCity 111, Taiwan. Tel.: þ886 2 2833 2

E-mail address: jpcantw@yahoo.co

http://dx.doi.org/10.1016/j.pedneo.21875-9572/Copyright ª 2013, TaiwanCC BY-NC-ND license (http://creative

Pemphigus vulgaris (PV) is an autoimmune disease in which the autoantibody, immunoglobulinG, is directed against the keratinocytes in the epidermis. The classic presentations of PV areflaccid vesicles or bullae over the oral mucosa, trunk, groin, and extremities. The age of onsetis usually between 40 and 60 years, and cases of PV in children or adolescent patients are rare.Here, we present a 17-year-old boy who had painful oral ulcers for 3 months initially and bullaespreading to the whole body in the following days. Paraneoplastic pemphigus was another dif-ferential diagnosis due to the atypical appearance of the skin lesion. However, PV wasconfirmed by hematoxylin and eosin staining and immunofluorescence examination of the skinbiopsy specimens. The patient had a good response to corticosteroid treatment and the immu-nosuppressive agent, rituximab.Copyright ª 2013, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is anopen access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Pemphigus vulgaris (PV) is an autoimmune blistering diseaseof the skin and mucous membranes. Autoantibodiesdirected against the surface of keratinocytes leads to the

chang Rd., Shilin Dist., Taipei211x2695.m.tw (L.-J. Wang).

013.08.008Pediatric Association. Publishedcommons.org/licenses/by-nc-nd

loss of cell-to-cell adhesion in the epidermis. The age ofonset is usually between 40 and 60 years. The disease rarelyaffects children and adolescent patients.1e4 PV is treatedwith high doses of systemic corticosteroids to control thepainful and spreading lesions during the acute phase. Oncethe acute phase is controlled, immunosuppressive agents(ISAs) are used for the steroid-sparing effect and to reducethe production of pathogenic autoantibody. We hereinreport the case of a 17-year-old adolescent who had

by Elsevier Taiwan LLC. This is an open access article under the/4.0/).

Oral ulcers as an initial presentation 339

chronic oral ulcers initially and was diagnosed with PVbased on the histopathologic and direct immunofluores-cence (DIF) findings.

2. Case report

A 17-year-old, previously healthy, Taiwanese boy presentedwith a 3-month history of painful oral ulcers. Initially, hehad been diagnosed with handefootemouth disease. Hereceived some supportive treatments such as analgesicdrugs and local anesthetic spray but the effect was limitedand the oral ulcers persisted. He denied any recent medi-cation use or infections. There was no family history ofautoimmune disease.

He had regular follow-up at the outpatient departmentof ears, nose, and throat. The oral ulcers persisted andrefractory mucositis was impressed; therefore, predniso-lone (0.35 mg/kg/day) was prescribed 1 month before thisadmission. However, its effect was limited. Furthermore,multiple vesicles arose from the lip, neck, hands, trunk,extremities, and groin to the buttocks. Because of theseproblems, he was referred to our outpatient clinic.

He had cough for 6e8 weeks, fatigue, and weight loss(4 kg), which were attributed to painful oral ulcers. He wasunderweight (body mass index: 16 kg/m2) with pallidappearance. Facial examination revealed multiple oral ul-cers with crust and necrotic tissue distributed from theouter lip to the soft and hard palate (Figure 1).

Figure 1 Oral ulcers with necrotic tissue on the top.

Furthermore, round vesicles and bullae with serouscontent, slightly tensed, were scattered across the trunkand four limbs (Figure 2). The initial differential diagnosisincluded herpes virus infection, human immunodeficiencyvirus (HIV) infection, Behcet’s disease, and immune defi-ciency (Table 1). The Tzanck smear test was performed,which revealed a multinucleated giant cell.

Laboratory investigations revealed eosinophilia (9.2%)and lymphocyte-predominant white blood cell differentia-tion (50.4%), elevated erythrocyte sedimentation rate(18 mm/hour), elevated C-reactive protein (1.08 mg/dL),decreased immunoglobulin G (IgG) level (623 mg/dL), andnegative titers for HIV screen, antinuclear antibodies,blood culture, herpes simplex virus-1 (HSV-1) IgM, HSV-2IgM, and VZV IgM, but positive titer for varicella-zoster virusIgG. A chest X-ray showed increasing bilateral lunginfiltration.

He received acyclovir (1500 mg/m2/day) for the initialimpression (chicken pox infection). Oxacillin (93 mg/kg/day) was also infused to cover the secondary bacterialinfection. Intravenous Ig (IVIG; 976 mg/kg/day) was injec-ted for 2 days for the low IgG level, which we consideredmight be related to the poor nutritional status over thepast 3 months. However, the result was not so satisfactory.

Figure 2 Vesicles and bullae spread to the trunk.

Table 1 Summary of the differential diagnosis of oral ulcers.

Disease Clinical presentation Treatment Side effect

Laboratory data

InfectionHIV Generalized lymphadenopathy,

weight loss, opportunistic infectionHighly activeantiretroviraltherapy

Vary by drugs,opportunisticinfectionHIV screen, Western blot

Herpes simplex virus Vesicular lesions on the tongue,buccal mucosa, and vermilion border

Acyclovir Nausea, vomiting

Tzanck smear, culture, PCRVaricella-zoster virus Papules, vesicles, pustules,

crusts simultaneouslyAcyclovir Nausea, vomiting

Tzanck smear, culture, PCRHandefootemouthdisease

Vesicles at the soft palate ortonsil pillars

Symptomatictreatment

d

Virus culture, PCROral candidiasis White to creamy plaque Nystatin Abdominal pain,

nausea, vomitingFungus cultureMalignancySquamous cellcarcinoma

Sharply demarcarated,hyperkeratotic macules or plaque

Topicalchemotherapy,cryotherapy,surgical excision

d

Biopsy

Melanoma Brown macules with irregular border Surgical excision d

BiopsyAutoimmune diseaseSystemic lupus erythematosus

Butterfly rash, scaly plaque Prednisolone,immunosuppressivedrugs

Infection, renal orhepatotoxicityPathology, ANAs, dsDNA

Behcet’s disease Recurrent aphthous ulcers, genitalulcers, eye (uveitis) or skin lesion(erythema nodosum)

Glucocorticoid,colchicines,azathioprine

Cushing syndrome,osteoporosis

No pathognomonic laboratory testsReiter’s disease Arthritis, enthesitis, dysuria, urethritis,

oral ulcersNSAID,glucocorticoid

Dyspepsia, renaltoxicity

HLA-B27, rheumatoid factorCutaneous diseasePemphigus Flaccid blister, mucosa involvement Prednisolone,

immunosuppressant,methotrexate

Cushing syndrome,osteoporosis,opportunisticinfection

Pathology, DIF

Pemphigoid Tense bullae, pruritus Prednisolone,immunosuppressant

Cushing syndrome,osteoporosis,opportunisticinfection

Pathology, DIF

Erythema multiforme Target lesions, involvement of mucusmembranes (oral ulcers, erythema)

Symptomatictreatment

d

No specific laboratory tests indicatedLichen planus Pruritus, purple, polygonal, planar,

papules, plaquesTopical steroid,antihistamine, topicalretinoid

d

Clinical diagnosis, pathologyAphthous stomatitis One or multiple round-to-ovoid, shallow,

painful oral ulcersCorticosteroids,chlorhexidinegluconate

d

CBC, chemistry panel, nutritional workup

ANAs Z antinuclear antibodies; CBC Z complete blood count; DIF Z direct immunofluorescence; dsDNA Z double-stranded DNA;HIV Z human immunodeficiency virus; HLA-B27 Z human leukocyte antigen B27; NSAID Z nonsteroidal anti-inflammatory drug;PCR Z polymerase chain reaction.

340 I.-H. Chen et al

Oral ulcers as an initial presentation 341

Uveitis was checked by an ophthalmologist for Behcet’sdisease but the finding was negative. However, more flaccidbullae emerged over the bilateral medial side of the thighduring the hospitalization. Hence, skin biopsy was per-formed. Histopathologic findings included acantholysis andsuprabasal keratinocyte. The DIF assessment showedintercellular IgG and C3 staining mostly in the suprabasallayer of the epidermis (Figure 3). Thus, pemphigus groupwas diagnosed. Because of the younger age of presentationand tense bullae on the neck and ankle, abdomencomputed tomography was performed to rule out para-neoplastic pemphigus (PNP). The results indicated noenlarged lymph nodes at the mediastinum, para-aortic re-gion, or bilateral iliac chains. Therefore, we discontinuedacyclovir and instead prescribed intravenous methylpred-nisolone (1.2 mg/kg/day).

After the steroid therapy, the patient’s conditionimproved dramatically. The oral ulcers and vesicles healedand his appetite improved. He was referred to a PVspecialist at the National Taiwan University Hospital (NTUH)for further treatment. Even with high-dose prednisoloneusage, some vesicles persisted. Thus, after obtaininginformed consent, we prescribed intravenous rituximab(500 mg) weekly for four doses as a unique protocol beforeusing other medications in treating PV at the dermatolog-ical department of NTUH. Now, the disease is under controlwithout oral medications.

3. Discussion

Pemphigus is a group of autoimmune blistering skin diseasescharacterized by blister formation that occurs within theepidermis caused by acantholysis, that is, the loss ofcohesion between epidermal cells. PV often starts in theoropharynx and then spreads to areas that involve thetrunk, head, and intertriginous regions. Pemphigus is rarelyseen in childhood, with a mean age of 12 years atpresentation.5

Stomatitis is the presenting symptom in more than 50%of cases. Epistaxis and hoarseness are also seen owing to

Figure 3 Direct immunofluorescence showed immunoglob-ulin G deposited in the intercellular substance of theepidermis.

involvement of the nose, pharynx, and larynx.5 Most pa-tients present with painful oral erosions, and for some, thisis the only clinical manifestation.6 Months elapse beforeskin lesions occur. These presentations fit the pattern ofthis case. The diagnosis of PV is often delayed when orallesions are the only manifestation, and the index of suspi-cion may be even lower in a young patient because of theinfrequent incidence of PV in children.5,7

The skin lesions on this patient were different from thetypical flaccid bullae developing in PV. The vesicles andbullae were relatively tense. Therefore, PNP was suspecteddue to its mimicking PV.8 In PNP, tense blisters with sur-rounding erythema are more frequently seen on extremitiesthan on other areas.9 PNP has been associated with non-Hodgkin lymphomas, thymomas, Castleman’s disease, andchronic lymphocytic lymphoma. This young boy had neithervacuolar interface dermatitis in the histopathologic exam-ination nor IgG and complement deposition along thebasement membrane zone (BMZ) in the DIF finding. Thus,PV was presumed.

Systemic corticosteroids, alone or in conjunction withother ISA, are the mainstay of treatment for PV in child-hood. These medications reduce the synthesis of anti-bodies. Prednisolone is the first-line agent in doses of1e2 mg/kg/day. In our case, methylprednisolone (1.2 mg/kg/day) was used and the effect was promising. The ulcersand bullae started to heal. IVIG (1 g/kg/day � 2 days) wasgiven before the administration of steroid. However, theskin lesion did not regress and newly formed bullae devel-oped instead. The dose of IVIG used for PV was 2 g/kg/cyclein the previous study.10 The frequency of the infusion wasmonthly until satisfactory clinical response was achieved.The total number of cycles varied from 19 to 61 months(mean: 28.5 months).10 The indication for IVIG was lack ofresponse to prednisolone or the presence of side effects.We suspect that one cycle of IVIG may not be enough toachieve the clinical improvement. By contrast, the highcost of IVIG and possibility of cardiovascular events due tohyperviscosity syndrome make IVIG a choice for patientswho have corticosteroid-refractory PV.11 Based on therationale that pemphigus is primarily an autoantibody-driven autoimmune disorder, therapies that depleteautoreactive B-cell clones have been investigated for thetreatment of pemphigus. Rituximab, a monoclonal antibodydirected against the CD20 antigen on B lymphocytes, hasdemonstrated efficacy for PV and pemphigus foliaceus.

We report a case of juvenile PV that presented withsevere oral ulcers and generalized vesicles. The diagnosiswas delayed due to the infrequency and inexperience ofthe disease in children. Learning from this case, autoim-mune bullae disease must be included in the differentialdiagnosis when a child has severe or refractory oral lesions.PNP must be ruled out if there are atypical vesicles and thepossibility of undiscovered malignancy. Steroid is the first-line medication of PV and rituximab is promising in re-fractory cases or steroid-sparing effect.

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