Pediatric Dermatology Vol. 33 No.

2 e77–e81, 2016

Spectrum of Clinical Responses to Therapies

in Infantile Bullous Pemphigoid
Helene Taquin, M.D.,* Christine Chiaverini, M.D., Ph.D.,*,† and Jean Philippe Lacour, M.D.*
*Department of Dermatology, University Hospital of Nice, Nice, France, †Department of Pediatrics, Nice Centre
Hospitalier Universitaire Lenval Pediatric Hospital, Nice, France

Abstract: Infantile bullous pemphigoid (BP) is a rare autoimmune

dermatosis characterized by the presence of antibodies against basal
membrane zone proteins. Histologic and immunologic features are similar
to those of the adult disease, but its clinical features may vary in children.
We report here four cases of infantile BP whose atypical presentation or
progression shed new light on the disease.

Bullous pemphigoid (BP), an autoimmune bullous observed 48 hours earlier. He was the first child of the
dermatosis seen mainly in elderly adults, is character- couple and was born at term after an uncomplicated
ized by the presence of antibodies against basement pregnancy. Large tense bullae were predominant on
membrane zone (BMZ) proteins. Approximately 100 the palm and soles without urticarial plaques (Fig. 1).
childhood cases of BP have been reported (1). The mucous membranes were spared. There was no
Histologic and immunologic features of childhood fever or associated symptoms. Clinical examination of
BP are similar to those of adults, with some specific his mother was normal, with no blisters or pruritus.
features: frequent involvement of the palms and soles Microbiologic analyses of the bullous exudate were
in patients younger than 1 year, forms limited to sterile. Laboratory findings showed a white blood cell
mucous membranes, and vaccination as a trigger count of 14,000/lL with 5% eosinophils (700/lL).
factor (2). Childhood BP usually has a good progno- Indirect immunofluorescence (IFI) was negative.
sis, with rapid response to steroids and few reported Enzyme-linked immunosorbent assay (ELISA) was
relapses. We present four atypical cases of infantile positive for BP180 (24 U/mL) and negative for BP230.
BP, emphasizing their heterogeneity. The four cases Western blot (WB) against epidermal extract showed a
are summarized in Table 1. 180-kDa band corresponding to BP180/BPAG2. The
mother showed positive IFI with immunoglobulin G
(IgG) anti-BMZ antibodies bound to the epidermal
CASE REPORTS side of normal human skin, ELISA positive for BP230
(34 U/mL) and negative for BP180, and a negative WB
Patient 1
analysis. Histologic analysis of the child’s skin biopsy
A 9-day-old boy was transferred from the department specimen revealed a subepidermal bulla with dense
of obstetrics with a cutaneous bullous eruption first eosinophilic infiltrates in the superficial dermis and

Address correspondence to Helene Taquin, M.D., Department

of Dermatology, University Hospital of Nice, Archet 2 Hospital,
Route de Saint Antoine de Ginestiere, 06200 Nice, France, or
e-mail: helene.taquin@yahoo.fr.

DOI: 10.1111/pde.12779

© 2016 Wiley Periodicals, Inc. e77

TABLE 1. Clinical and Laboratory Features of Our Four Patients

White blood
Patient Age Sex Vaccination cell count Immunology Histology Therapy Evolution

1 9 Male No 5% eosinophils IFI: negative Subepidermal bulla Oral steroids (prednisolone Complete remission of
days (700/lL) WB: 180-kDa band with dense eosinophilic 0.5 mg/kg/day) for 48 hours lesions within 48 hours
ELISA: positive for infiltrates in superficial No relapse after 5 years
BP180 (24 U/mL), dermis of follow-up
negative for BP230 DIF: linear deposition
of IgG and C3 along
BMZ
2 3 Male Yes 5.7% eosinophils IFI: IgG class of anti- Subepidermal bulla Topical steroids (one tube of Complete remission within
months (DTaP) (500/lL) BMZ antibody at a with dense eosinophilic betamethasone dipropionate) 1 week
titer of 1:50 infiltrates in superficial for 1 week No relapse during 6 months
WB: not performed dermis of follow-up
ELISA: not performed DIF: linear deposition
of IgG and C3 along
BMZ
3 4 Male No 10% eosinophils IFI: IgG anti-BMZ Subepidermal bulla with Oral steroids (prednisolone Complete resolution of
e78 Pediatric Dermatology Vol. 33 No. 2 March/April 2016

months (900/lL) antibodies bound dense eosinophilic 1 mg/kg/day) for 5 months lesions within 2 weeks
to the epidermal side infiltrates in superficial and topical steroids Several small and localized
WB: 180-kDa band dermis (betamethasone dipropionate) relapses during the 3
ELISA: positive for DIF: linear deposition following years
BP180 (30U/mL), of IgG and C3 along No relapse after 4 more
negative for BP230 BMZ years of follow-up
4 4 Female Yes 50% eosinophils IFI: IgG anti-BMZ Subepidermal bulla Oral steroids (prednisolone Failure of topical steroids
months (DTaP) (6,000/lL) antibodies bound with dense eosinophilic initial dose of 0.5mg/kg/per use alone. Any improvement
to the epidermal side infiltrates in superficial day, progressively with worsening of the
WB: 180-kDa band dermis increased by 0.5mg/kg/ eruption after 1 month
ELISA: positive for DIF: linear deposition day every 2 weeks, maxium of oral and topical steroids
BP180 (>200U/mL), of IgG and C3 along dose of 2.5mg/kg/day therapy
negative for BP230 BMZ Topical steroids (betamethasone Complete remission after
dipropionate started at once the first cure of Ig
per day and progressively No relapse after 1 year of
increased at twice per day follow-up
Ig infusions (2 g/kg infused
over 2 days) at 0, 2, 4, 8,
and 16 weeks
IFI, indirect immunofluorescence; WB, Western blot; ELISA, enzyme-linked immunosorbent assay; DIF, direct immunofluorescence; BMZ, basement membrane zone; DTaP,
diphtheria-tetanus-acellular pertussis A-polio; Ig, immunoglobulin.
 Taquin et al: Atypical Infantile Bullous Pemphigoid e79

linear deposition of IgG and C3 in the BMZ on direct

immunofluorescence, confirming the diagnosis of BP.
Treatment with oral steroids (prednisolone 0.5 mg/kg/
day) was initiated, leading to complete remission of all
lesions within 48 hours. The mother and child were
discharged from hospital, at which point the mother
decided to discontinue her child’s treatment. There has
been no relapse after 5 years of follow-up. She has had
no other children since.

Patient 2
A 3-month-old boy was referred with a 7-day history of
a blistering skin eruption that had started 5 days after
his first diphtheria-tetanus-acellular pertussis A-polio
(DTaP) vaccination. He had tense blisters on the palms
and soles and herpetiform blisters in skin folds and the
umbilicus (Fig. 2). The mucous membranes were
spared. There was no urticarial plaque or fever. The
results of routine laboratory tests revealed a white
blood cell count of 8,600/lL with 5.7% eosinophils
(500/lL). Standard IFI showed IgG-class antibase-
ment membrane antibodies at a titer of 1:50. WB and
ELISA were not performed. Skin biopsy confirmed the
diagnosis of BP with typical features. In view of the
small skin area involved, topical treatment with corti- Figure 2. Blistering eruption predominant on the folds
costeroids was prescribed. After 1 week of treatment after a diphtheria-tetanus-acellular pertussis A-polio
that used only one tube of betamethasone dipropionate vaccination in a 3-month-old infant (patient 2).
cream 0.05%, complete remission was obtained, with
no relapse during the 6 months of follow-up, although a white blood cell count of 8,600/lL with 10%
he received all other scheduled vaccinations. eosinophils (900/lL). IFI revealed antibasement
membrane antibodies binding to the roof of salt-split
skin. ELISA for BP180 was positive (30 U/mL) and
Patient 3
WB against epidermal extract was positive in the
A 4-month-old boy developed an erythematous BPAG2 (180 kDa) band, consistent with a diagnosis
papular and pruritic eruption that progressed to form of BP. ELISA for BP230 was negative. Skin biopsy
blisters on the trunk, hands, and feet. The mucous confirmed the diagnosis. Because of the severity of the
membranes were spared. No precipitating factor was eruption, treatment with oral prednisolone 1 mg/kg/
identified. Routine laboratory investigations showed day combined with topical betamethasone dipropi-
onate was started, leading to complete resolution of
lesions within 2 weeks. Prednisolone was well toler-
ated and gradually tapered over a 5-month period.
During the following 3 years, the patient experienced
several small, localized relapses, particularly affecting
the gingivae and genital area (Fig. 3), that healed after
the use of a topical steroid (betamethasone dipropi-
onate) for a few days. He has had no more relapses
after further follow-up of 4 years.

Patient 4

Figure 1. Large tense bullae predominant on the palm A 4-month-old girl presented with a 14-day history of
and soles in newborn of 9 days (patient 1). a blistering eruption on her hands and feet that
e80 Pediatric Dermatology Vol. 33 No. 2 March/April 2016

in association with applications of betamethasone

dipropionate twice a day without any improvement
in her condition after 1 month. By this time, her
eosinophil count was 6,000/lL and she had hyperten-
sion, growth delay, and Cushingoid facies.
Immunoglobulin infusions (2 g/kg infused over
2 days) were initiated. A total of five infusions were
given at 0, 2, 4, 8, and 16 weeks. The bullae resolved
dramatically after the first infusion, permitting the
tapering and discontinuation of steroids over
4 months. No relapse has occurred after 1 year of
follow-up.
Figure 3. Tardive relapse in the gingival mucous after
oral corticotherapy in a 36-month-old boy (patient 3).
DISCUSSION
Childhood BP is a rare autoimmune disease with
usually characteristic clinical, biologic, and histologic
features (3). Whereas in adulthood two hemidesmo-
some-associated proteins (BP230 and BP180) have
been identified as targets of autoantibodies (4), only
anti-BP180 antibodies have been reported in children
in a few case reports, similar to those of our patients
(5,6). All of the patients discussed herein presented in
infancy with typical bullous eruptions of the extrem-
ities, urticarial plaques in one case, and no mucosal
involvement. All fulfilled the diagnostic criteria of
Nemeth et al (7). Vaccination seems to be a frequent
trigger factor in childhood BP, as in patients 2 and 4.
Approximately 20 cases of childhood BP reported in
the literature occurred after vaccination. The tetanus,
diphtheria, pertussis, and polio vaccine was adminis-
tered in all cases, although in some patients, vaccina-
tions against pneumococcus, Hemophilus influenzae B,
hepatitis B, and Meningococcus were also adminis-
Figure 4. Generalized and erythematous eruption with
large bullae on his hands and feet in a 4-month-old girl tered and cannot be excluded as triggering factors (8).
(patient 4). Even with similar initial clinical, immunologic,
histologic, and trigger factors, the course of the
disease and its response to treatment varied greatly
occurred a few days after she had received a DTaP among our patients. The first patient did not have
vaccination. The blisters were associated with urticar- stricto sensu childhood BP, but neonatal BP. Passive
ial and pruriginous plaques (Fig. 4). There was no transfer of maternal IgG autoantibodies to BMZ
mucosal involvement. Skin biopsy favored the diag- proteins across the placenta causes this rare condition.
nosis of BP. IFI on 1 mol/L sodium chloride– The diagnosis is generally straightforward with a
separated unaffected skin showed IgG anti-BMZ bullous eruption occurring in a newborn infant of a
antibodies bound to the epidermal side. ELISA was mother with gestational pemphigoid (9). Surprisingly,
positive for BP180 (>200 U/mL) and negative for the patient’s mother had no history of bullous
BP230. WB against epidermal extract was positive in eruption or pruritus and had different antibodies than
the BPAG2 (180 kDa) band. Because of the small skin her son. We believe this case to be unique in the
area involved, topical treatment with betamethasone literature. It is possible that the mother had subclin-
dipropionate was initiated but was ineffective after ical asymptomatic gestational pemphigoid, because of
1 month. Oral steroids were then started at 0.5 mg/ the low level of her antibodies.
kg/day, but the eruption worsened. The prednisone Childhood BP has a good prognosis and responds
dosage was progressively increased to 2.5 mg/kg/day well to conventional treatment with topical or oral
 Taquin et al: Atypical Infantile Bullous Pemphigoid e81

steroids. In most patients, remission is usually achieved 2. Merida C, Martinez-Escriban JA, Frias JF et al.
within a few weeks to a few months of treatment, and Bullous pemphigoid in an infant after vaccination.
Actas Dermosifiliogr 2005;96:255–257.
relapses are rare, however, patients 2 and 3 exhibited
3. Fisler RE, Saeb M, Liang MG et al. Childhood
an unusual response to steroids. Patient 2 responded bullous pemphigoid: a clinicopathologic study and
very quickly (within 1 week of the initiation of review of the literature. Am J Dermatopathol 2003;25:
treatment), whereas patient 3 endured a prolonged 183–189.
course, with several relapses over 3 years. The prompt 4. Izumi H, Hosokawa H. Molecular heterogeneity of the
bullous pemphigoid antigens as detected by
response in patient 2 after only 1 week’s treatment with
immunoblotting. J Immunol 1986;136:1231–1235.
topical corticosteroids, with no further recurrence, has 5. Chiaverini C, Hamel-Teillac D, Gilbert D et al.
been reported on only one other occasion in the Absence of anti-BP180 antibodies in mothers of infants
literature (10) and suggests that BP in infants may be with bullous pemphigoid. Br J Dermatol 2006;154:
underdiagnosed. Several cases in which recurrence 839–843.
6. Chimanovitch I, Hamm H, Georgi M et al. Bullous
occurred despite the completion of a full course of
pemphigoid of childhood: autoantibodies target the
steroids have been reported (2,11) but, to our knowl- same epitopes within the NC16A domain of BP180 as
edge, the duration of disease of 3 years after diagnosis autoantibodies in bullous pemphigoid of adulthood.
is the longest ever reported. Topical or oral steroids are Arch Dermatol 2000;136:527–532.
the first choice of treatment of childhood BP, with few 7. Nemeth AJ, Klein AD, Gould EW et al. Childhood
bullous pemphigoid: clinical and immunologic features,
treatment failures reported in the literature. The use of
treatment and prognosis. Arch Dermatol 1991;127:
second-line treatments such as disulone, sulfapyridine, 378–386.
or mycophenolate mofetil, alone or in combination 8. de la Fuente S, Hern  de Lucas R et al.
andez-Martın A,
with steroids, has been suggested in these cases (12–14). Postvaccination bullous pemphigoid in infancy: report
Intravenous immunoglobulins have been rarely used, of three new cases and literature review. Pediatr
Dermatol 2013;30:741–744.
perhaps because they are costly (12,13,15). Patient 4’s
9. Al-Mutairi N, Sharma AK, Zaki A et al. Maternal and
dramatic response to intravenous immunoglobulins, neonatal pemphigoid gestationis. Clin Exp Dermatol
which were well tolerated, is interesting and constitutes 2004;29:202–204.
evidence for consideration of their use. 10. Toyama T, Nakamura K, Kuramochi A et al. Two
cases of childhood bullous pemphigoid. Eur J Dermatol
2009;19:368–371.
CONCLUSION 11. Singalavanija S, Limpongsanurak W. Immunobullous
diseases in Thai children: report of 24 cases. J Med
Childhood BP is a stereotypic rare autoimmune Assoc Thai 2003;86:681–688.
disorder usually due to anti-BP180 antibodies trig- 12. Nobuyuki S, Yayoi N, Yoichiro M et al. Infantile
bullous pemphigoid treated with intravenous
gered by immunologic stimulations such as vaccina- immunoglobulin therapy. J Am Acad Dermatol
tion, with a variable course and response to treatment. 2007;57:1084–1089.
The reasons for these variations between patients are 13. Marcus KA, Halbertsma FJ, Van Steensel MA. A case
not known. of juvenile bullous pemphigoid—successful treatment
with diaminodiphenylsulfone and prednisone. Pediatr
Dermatol 2009;26:55–58.
14. Schwieger-Briel A, Moellmann C, Mattulat B et al.
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