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CME ARTICLES
Year : 2006  |  Volume : 51  |  Issue : 2  |  Page : 89-95
Childhood pemphigus


Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Correspondence Address:
Amrinder J Kanwar
Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.26926

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   Abstract 

Childhood pemphigus is a rare diasease and comprises only a minority of immunobullous diseases seen in children. Almost all variants of pemphigus in childhood have been described in literature. Pemphigus vulagaris is the most common type seen, after excluding endemic foliaceus. The clinical features are essentially similar to that of adults. Special consideration is required while treating children so as to use drugs which are less carcinogenic and do not affect fertility. We present here a review of cases of childhood pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, pemphigus erythematosus, paraneoplastic pemphigus, IgA pemphigus and neonatal pemphigus.


Keywords: Pemphigus, IgA, immunobullous


How to cite this article:
De D, Kanwar AJ. Childhood pemphigus. Indian J Dermatol 2006;51:89-95

How to cite this URL:
De D, Kanwar AJ. Childhood pemphigus. Indian J Dermatol [serial online] 2006 [cited 2019 Nov 17];51:89-95. Available from: http://www.e-ijd.org/text.asp?2006/51/2/89/26926


The term pemphigus is used to describe a group of chronic bullous disease originally named by Wichman in 1791.[1] It is a chronic intraepidermal vesicullobullous autoimmune disease involving skin and mucous membrane. It can broadly be divided into two types-pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Pemphigus vegetans is an unusual variant of pemphigus vulgaris occurring in 1-2% of cases[2] and pemphigus erythematosus is a variant of pemphigus foliaceus. The mean age of onset of pemphigus vulgaris is reported between 40 and 60 years.[2],[3],[4] Childhood pemphigus is a rare disease and of all the immunobullous disorders in childhood, pemphigus comprises a minority.[5] Except for endemic pemphigus foliaceus most patients reported till now have been as case reports. All clinical types of pemphigus have been observed in children.


   Pemphigus Vulagaris Top


Epidemiology

In chilhood disease,mean age of onset is 12 years.[6] Boys have a lower mean age of onset as compared to girls. Male to female ratio was 1:0.96 in one study[6] while in another study it was 1:1.26.[7]

Till date 46 cases of pemphigus have been reported. Cases under 10 years of age are extremely rare implying an increase in incidence during puberty.[7] The youngest female reported was 4 years old, while the youngest male was 3 years old.[6]

Certain trigger/aggravating factors have been associated with childhood PV similar to adults.This includes drugs like enalapril[8] and monteleukast[9] and vaccination with diphtheria- tetanus toxin.[10] Coexistance of pempigus vulgaris and vitiligo in a 10-year-old boy has also been reported.[11]

Clinical features

Clinical presentation in children is essentially similar to cases in adults with majority of cases presenting with flaccid vesicles on erythematous or normal skin which break easily to form erosions and crust [Figure - 1]. Blisters may exhibit Nikolsky sign, separation of the epithelium with tangential pressure on the skin surface. Involvement of mucous membrane mainly the oral mucosa has been seen in almost all cases and usually precedes the cutaneous lesions . Ocular involvement in childhood PV have been reported.[12] The characteristic ocular finding is conjunctivitis with hyperemia and mucoid discharge. Conjunctival blisters, erosions, and synechiae are rare, and long-term sequel are uncommon.

Treatment

It should be tailored for each case depending on age, drug contraindication, side effects, area involved and disease activity. Corticosteroids are the cornerstone of treatment just as in adults,[13] though there is no data to guide their optimal administration and to determine if and when adjuvant therapy should be started with them. Children have been treated with oral steroid as single oral agent with success.[14],[15] Cushing's syndrome, growth retardation and infection are the most common side effects seen in children. Bjarnason et al[6] have suggested an initial dose in range of 2-3 mg/kg/day with slow tapering to 5-8 mg/kg/day in approximately 2 weeks following alternate day schedule for further reduction. Methylprednisolone pulse[16] (1 gm/day I.V. for 5 days) and dexamethasone pulse[17] (136 mg of dexamethasone/day I.V. for 3 consecutive days) has also been used successfully in severe cases with high antibody burden. With dexamethasone pulses lesions dried faster and side effects of steroids were minimized. Topical and intralesional steroids have been used for single recalcitrant lesion to avoid escalation of systemic dose.

When a high dose prednisolone is required to control the disease or when repeated attempts to taper steroid doses are associated with recurrence of disease, addition of an adjuvant becomes prudent. Multiple adjuvants have been used in children, amongst which azathioprine has been best studied.[16],[18],[19]

Azathioprine is a purine antagonist derived from 6 -mercaptopurine. It inhibits formation of purine bases, hence inhibiting DNA and RNA synthesis. In the studies using azathioprine, children were treated initially with 50 mg twice daily and 100 mg prednisolone once daily. Tapering of azathioprine to 50 mg and 10 mg prednisolone daily successfully controlled the disease. Bjarnason et al[6] suggested 2 mg/kg/day to be used initially in two divided doses followed by maintenance dose of 1 mg/kg/day. Due to relatively lower toxicity, lower risk of sterility and lower life time risk of malignancy especially as compared to cyclophosphamide, it is well recommended in children.

Gold can be used in intramuscular form as aurothioglucose or aurothiomalate or in oral form as auronofin which is easier to use and less toxic. It was used by Paltzik et al[20] in children in dose of 15 mg/week for 32 weeks.

Since it shows no carcinogenic or infertility effect it is preferable in children and in patients in reproductive age group. But 25% patients of JRA treated with gold exhibit toxic. Most common serious side effects are renal toxicity, hematologic abnormality and allergic cutaneous reaction. Onset of action is slow and effect is usually seen 6 months after starting treatment.

Cyclosporine has been reported to induce prolonged remission in 2 cases of childhood pemphigus vulgaris.[21]

Methotrexate was used by Faure et al in dose of 20 mg i.m./ week.[22] Associated side effects are increase incidence of infections and delayed healing.

Other adjuvants that have been used are dapsone 100-200 mg per day,[23] cyclophosphamide in dose of 50 mg/day[24] and plasmapheresis.[16] Recently a 17 year old female with 10 year history of PV refractory to azathiopurine, mycophenolate mofetil (2 gm/day), prednisolone (2 mg/kg/day), IVIg (1 gm/kg) and plasmapheresis was treated successfully with anti CD 20 antibody Rituximab (375 mg/m 2sub ) with decline in circulating anti Dsg 1 and Dsg 3.[25]

Prognosis

It is not possible to predict the long term prognosis of childhood pemphigus vulgaris because the fate of cases after publication is not documented. Initial reports suggested that the course of PV is similar to that observed in adults, [17] but Wananukul et al[26] stated the prognosis to be better than adult cases. One fatal case was reported by Jorden et al .[5] Mortality is mainly due to infections (pneumonia and septicemia).[5]

Early diagnosis and therapy influence course of the disease towards better prognosis.[23]

Pemphigus vulgaris, as in adults, may remain localized throughout,[7] initially localized and subsequently generalized or rapidly progressive from the initial stage itself.[27]

Pemphigus foliaceus

Pemphigus foliaceus is also known as superficial pemphigus. It is a cutaneous immunobullous disease with recognized autoantigen as Dsg1. Two major categories of pemphigus foliaceus occur-endemic and sporadic. Endemic PF is also called fogo selvagem and is prevalent in rural areas of Brazil. It spreads by bite of black fly, Simulium nigrimanum .


   Epidemiology Top


Fogo selvagem is primarily a disease of children and young adults while sporadic PF occurs primarily in middle aged and elderly. Till date, 29 cases of sporadic PF in children have been reported. Pemphigus foliaceus is rarer than pemphigus vulgaris in childhood just as the case in adults.[28]

In review data of 28 cases of PF and PE by Metry et al[29] in 2002 the average age at presentation was 7.7 years. The youngest child reported is 18 months old.[30]

Childhood PF is slightly more common in boys with M:F ratio of 1.33:1 but gender does not correlate with age at presentation. Among the trigger factors sunlight[31] and drugs[32] have been identified similar to adults. Other trigger factors that have been reported are bacterial infection,[33] cytomegalovirus infection[34] and otitis.[28]


   Clinical features Top


In the review by Metry et al ,[29] crusted plaques and erosions were the most commonly described primary lesions [Figure - 2]. Superficial flaccid vesiculobullae were less frequent. Intact vesiculobullae were less typical and when present tended to occur in lower legs in a grouped[34] or linear arrangement.[35] Patients presenting initially with erythroderma have also been reported.[26] An unusual circinate/arcuate/polycyclic pattern has been described in few patients. This pattern appears to be a unique and specific presentation in children.[28],[30]

The face, scalp or both are the sites most commonly involved initially. followed by trunk or upper extremities. Lesions of groin and pubis have been reported rarely.[36] No case has been reported involvement of mucous membranes.

Majority of children are asymptomatic. Pruritus is reported uncommonly.[34] In majority of reported cases initial histopathology was consistent with PF. Initial DIF results were also positive in majority. However one fourth of initial IIF results were negative.[28],[37] The antibody titre did not correlate with the severity and extent of skin disease.

Treatment

Regarding treatment, in majority of cases systemic steroids alone were used. Steroids were also used topically[30] and sublesionally.[38] Dapsone was the most commonly used adjuvant. Other therapies included erythromycin,[39] chloroquine,[40] methotrexate,[26] sulfapyridine,[35] azathioprine[41] and hydroxychloroquine.[29] Relative effectiveness among the various agents was difficult to assess because of frequent overlapping of agents, difference in disease severity, total duration of therapy, time to clear disease etc. The majority of those children reviewed (88%) were clear of disease either off medication or low maintenance dose within 1 year regardless of the type of therapeutic intervention.

Prognosis

Though the mortality is less as compared to pemphigus vulgaris morbidity is still significant. One death due to skin disease has been reported.[39] Most patients follow a benign course of relatively short duration as compared to childhood PV. However long term follow up data is lacking and the longest follow up period available in literature is 4 years.[23] Patients respond to lesser dose of steroid than pemphigus vulgaris and mild cases may be controlled by topical steroids only. Many cases don't require adjuvant.

Pemphigus vegetans

Three cases of pemphigus vegetans have been reported till 2004.[26],[42],[43]

There are two main types - Neumann and Hallopeau. The mechanism by which pemphigus vulgaris and pemphigus vegetans develop different clinical manifestations are unknown, though they have indistinguishable immunologic findings. Course of Neumann type is similar to pemphigus vulgaris with high dose steroid requirement. The clinical presentation, histopathology and immunological findings were similar to adults in the reported cases.


   Pemphigus Erythematosus Top


It is also known as Senear-Usher syndrome and is used to describe PF localized to malar and seborrhoeic areas. Many patients with PE have characteristic lupus band on DIF (IgG and C3 at the basement membrane)and show serology suggestive of SLE. Otherwise, PE has similar histology to PF and involves same target antigen. Furthermore patients initially diagnosed as PE often progress to more widespread classic PF.[44] Hence PE is considered a variant of PF rather than a distinct entity. Four cases of PE have been reported till date.[33],[40],[45]

A case of 7-year-old male child was reported by Gupta et al[46] in 2004 with erythematous scaly lesions on nose and cheeks in butterfly distribution and photosensitivity and characteristic DIF findings {IgG, C3 and fibrin antibodies in intercellular space pattern (ICS) (fishnet) and granular deposit of IgG and C3 at the basement membrane}. He was treated initially with prednisolone 2.5 mg/kg/day and dapsone 50 mg once daily while relapse was treated by similar prednisolone dose and azathioprine 25 mg once daily.

Paraneoplastic pemphigus

Paraneoplastic pemphigus (PNP) was first described by Anhalt et al in 1990.[47] Certain key features of the seminal description that have remained constant are intractable stomatitis, presence of antiplakin antibodies, association with a specific group of B cell lymphoproliferative disease and progressive disease refractory to treatment with fatal outcome in most cases. New contributions include recognition of additional antigens- plectin, desmoglein-3 (Dsg3), Dsg1, respiratory injury evolving to bronchiolitis obliterans[48] and prominent lichenoid mucositis or dermatitis.[49]


   Epidemiology Top


Although adult patients are more commonly affected there has been an increasing number of individual reports in the child and adolescent population. PNP affects children and adolescent aged 8-18 years with no gender preference.


   Clinical features Top


In the study of 14 child and adolescent PNP patients by Mimouni et al ,[50] a constant clinical finding in all patients was debilitating painful stomatitis . The majority of patients (8/14) had lichenoid lesions of skin and oral mucosa. Extensive and refractory mucositis involving labial mucosa was a constant feature but unlike adult cases mucocutaneous disease was most often lichenoid and not blistering. Associated Castleman's disease was seen in 12/14, respiratory involvement in 10/14, a fatal outcome in 10/14 and Hispanic background in 8/14. The underlying neoplasm was unsuspected in majority of cases (10/14).

Histologically, 3 patterns of involvement were identified:

1. Sulli

2. lichenoid infiltrate with cell necrosis

3. Intraepithelial acantholysis

4. combination of both.

Pattern 3 was found to be most common. DIF of perilesional tissue showed IgG and C3 deposition in ICS in 10/14 and variable immunostaining at BMZ IN 6/10 patients. IIF with monkey oesophagus showed circulating IgG in all cases while 12 patients showed antibodies binding to BMZ as well. IIF using murine bladder revealed antibodies binding to transitional epithelium in all cases. Immunoprecipitation studies showed IgG autoantibody against desmoplakin1, envoplakin and periplakin in all cases. Most patients had anti-Dsg3 antibodies while 3 patients in addition had anti-Dsg 1 antibody. All these 3 patients had cutaneous disease, but 7/11 patients negative for anti-DsG 1 had cutaneous disease. 13/14 patients had antiplectin antibody demonstrable by immunoblotting.

Treatment

Several immunosuppressive agents were used to treat PNP but none was consistently effective.

Prognosis

Progression and death occurred despite treatment of the neoplasm and PNP. Respiratory involvement commonly complicated the course and was a major factor in high mortality. Unlike adult cases where NHL is the most commonly associated neoplasm, in children striking association with Castleman's disease was seen . Other tumors that have been associated with childhood PNP are inflammatory myofibroblastic tumor[13] and T-cell lymphoblastic lymphoma.[51]

Lichenoid dermatitis with or without acantholysis is the most common histologic pattern. A predominance of a Tcell mediated response on the skin despite presence of circulating antibodies may explain a higher incidence of negative DIF in these patients.

Some patients do not even have circulating anti Dsg1 and anti-Dsg3 despite severe mucosal disease. Since DIF is occasionally negative and anti-Dsg are not always present the most reliable serological and confirmatory tool is detection of serum antiplakin antibodies. There is also no correlation between anti-plakin antibodies and any specific clinical or immunopathologic feature. It is unclear if these antibodies play a pathogenic role or are just surrogate marker of the syndrome. In contrast to both PV and PF there is no correlation between the anti Dsg profiles and clinical pattern of disease.[52]

IgA Pemphigus

IgA pemphigus is a group of autoimmune intraepidermal blistering diseases with tissue bound and circulating IgA autoantibody against cell surface component. It was first described by Wallach et al .[53] Two distinct varieties exist- subcorneal pustular dermatosis (SCPD, IgA pemphigus foliaceus) and intra epidermal neutrophilic type (IEN). The average age of onset is 48 years. It is rarely seen in children and eight cases have been reported in children till date including a 1 month old infant.[54],[55],[56],[57],[58],[59],[60],[61] Majority of cases reported were IEN type. Clinical presentation is similar in both types with flaccid vesicles or pustules on normal or erythematous base which coalesce to form circinate or annular pattern with central crust mainly in axilla and groin area. Some patients present with vesiculopustular lesions on head and neck,[55],[61] while one each had impetigo like lesion on head and neck,[56] purulent generalized bullae ,[54] and vegetating plaques in groins.[58] Mucous membranes were affected. in 3 patients.[54],[60],[61] Colonic involvement presenting as bloody diarrhea and ICS IgA on DIF done on colon was reported by Brukner et al .[61]

Dapsone was the first choice of therapy and 2 patients obtained complete remission while 3 patient required additional systemic steroids/immunosuppressive agent.[55],[56],[60]

Presence of neutrophils was a consistent feature on histology while acantholysis was present in 3/6 cases. Level of cleavage was found to be intraepidermal, subcorneal and subepidermal in different studies. On DIF, IgA1 is diffusely distributed in intercellular space in all patients while additional linear IgG was seen in 2 cases.[60],[61] IgA was present in IIF in majority of patients. It was negative in 1 case[56] while IgG was present in addition in 2 cases.[60],[61]

Based on the reports in which outcome was indicated the overall prognosis for children with IgA pemphigus seems benign.

Neonatal and stillborn cases

Neonatal pemphigus vulgaris is caused by transplacental transfer of IgG antibodies from a mother suffering from pemphigus vulgaris to her fetus. These antibodies bind to neonatal skin after crossing the placenta and may cause blisters. As pemphigus vulgaris is uncommon in young or middle aged women, neonatal pemphigus vulgaris is also uncommon. The total number of cases of neonatal PV reported in literature has not clearly been established as many cases were published before immunofluorescence techniques were available to confirm this diagnosis. Twenty three cases of neonatal pemphigus have been reported since then, the first in 1975.[62]

In 1979 a case was reported where a stillborn and it's mother had IgG deposition in ICS of epidermis in DIF.[63] Since then pemphigus antibodies were detected in two other stillborns till 1999.[64],[65]

Due to meager number of neonatal and stillborn cases no conclusion can be drawn regarding sex distribution though cases of both sexes have been reported. Of the 3 cases DIF was positive in all cases, fetal IIF was negative in one, maternal antibodies were high in 2 while data was not available in 1. Time of stillbirth varied from 28 weeks to 34 weeks. Disease was active in all mothers. Two were female fetus while one was male.

Of the 23 cases 20 mothers had PV, [63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80] two cases had pemphigus foliaceus[81],[82] one had pemphigus vegetans.[83]

Neonatal pemphigus vulgaris has shown many clinical presentations from widespread denuded skin to only oral involvement which are observed at birth. Premature deliveries have also been reported in some mothers with PV.

Antibody titer of mother or newborn or clinical presentation of mother at the time of delivery do not predict the severity of neonatal PV. There are reports of neonatal PV in newborns from mothers with no active disease[65],[73] and cases of non affected neonates born from mothers with highly active disease.[74],[75],[76],[77]

Neonates with neonatal PV usually improve spontaneously within 3 weeks thus requiring only careful handling and topical antibiotics if clinically indicated.. No progression to adult PV has been described till now. It is controversial whether therapy with corticosteroid, azathioprine or plasmapheresis in affected pregnant women is of benefit to the neonate.[72]

Pathogenesis of pemphigus with emphasis on neonatal pemphigus

The target of pemphigus antibodies are transmembrane glycoproteins of cadherin family called as desmogleins. The main Dsgs expressed in the epidermis are Dsg1, the antigen recognized by all PF sera and 50-60% of PF sera.[84] and Dsg3, the antigen recognized by all PV sera. Dsg1 is present throughout the epidermis in adult skin and much less in mucous membrane that too more in the superficial layers. In contrast, Dsg 3 is only present in basal and suprabasal layers in adult skin whereas it appears throughout all layers of adult oral mucosa. According to Dsg compensation theory,[85] pemphigus blisters form only when both Dsg1 and Dsg3 are absent In PF, anti-Dsg1 autoantibodies can only induce blisters in the superficial layers of the epidermis because this is the only area in which Dsg1 is present without co-expressed Dsg3. Mucous membrane is not affected as Dsg3 compensates throughout the epidermis. In first stages of PV only antibodies against Dsg3 are present. These induce lesions in mucosa particularly the deeper layers where much less Dsg1 is present. Later 50-60% of PV patients develop Dsg1 antibodies in addition which then produces deep blisters in both skin and mucosa due to loss of both Dsg.

In neonatal PV anti-Dsg3 antibodies alone are able to produce skin lesions in neonate as they do in oral mucosa. This explains why neonatal pemphigus is more prevalent in pregnant women with PV than in those with PF and why mothers with PV with only anti-Dsg3 antibodies and therefore with limited oral disease can give birth to babies with extensive neonatal PV. Moreover Parlowsky et al[86] showed that the neonate's antibody to Dsg3 in neonatal PV was predominantly IgG 4 subclass.

In pregnant females with pemphigus foliaceus autoantibodies cross placenta and bind fetal epidermis but rarely cause blister in neonates.[84]

This has been explained by extended compensation theory which states that expression of Dsg 3 in superficial epidermis in neonates is similar to mucous membrane and not like adult epidermis. Presence of Dsg 3 in upper epidermis in neonate protects against loss of Dsg 1 function induced by pemphigus foliaceus antibodies. This hypothesis was tested to be true in transgenic mice experiment by Wu Hong et al .[87]

Differential diagnosis of childhood pemphigus:

1. Other immunobullous diseases.

2. Impetigo, impetigenous eczema- most patients of pemphigus foliaceus in literature were initially diagnosed as impetigo

3. Erythroderma- patients of pemphigus foliaceus initially presenting as erythroderma have been reported. In such cases, other causes of erythroderma in children like atopic dermatitis, seborrhoeic dermatitis, pityriasis rubra pilaris, staphylococcal scalded skin syndrome need to be ruled out.

4. Other dermatoses like seborrheic dermatitis, psoriasis, dermatitis herpetiformis, etc.

 
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    Pemphigus Vulagaris
    Epidemiology
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    Pemphigus Erythe...
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