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A novel childhood pemphigus vegetans variant of intraepidermal neutrophilic IgA dermatosis
Journal of the American Academy of Dermatology Volume 38, Number 4
Brief communications 635
A novel childhood pemphigus vegetans variant of intraepidermal neutrophilic IgA dermatosis William L. Weston, MD,a Marti Friednash, MD,a Takashi Hashimoto, MD,b Peter Seline, MD,a J. Clark Huff, MD,a and Joseph G. Morelli, MDa Denver, Colorado, and Fukuoka, Japan We describe a child in whom a pemphigus vegetans variant of intraepidermal neutrophilic IgA dermatosis occurred while he was taking immunosuppressive drugs. The IgA autoantibody from the patient showed an intercellular pattern on human skin substrates at a titer of 1:5 but did not react with desmogleins or desmocollins. We believe this to be the first report of this condition.1-15 CASE REPORT A 7-year-old boy had oozing areas in both axillae and in the left groin for 2 weeks. The patient also had homozygous α1-antitrypsin deficiency and had experienced liver failure by 5 months of age. When he was 6 months old he received a liver transplant that failed and a second liver transplant that was successful. He was maintained on a regimen of cyclosporine and prednisone. For the past 2 years he had experienced generalized itching that worsened the month before axillary lesions appeared. From the Department of Dermatology, University of Colorado School of Medicine, Denver,a and the Department of Dermatology, Kurume University School of Medicine, Fukuoka.b Reprint requests: William L. Weston, MD, Professor and Chairman, Department of Dermatology, University of Colorado School of Medicine, 4200 E. Ninth Ave. B-153, Denver, CO 80262. J Am Acad Dermatol 1998;38:635-8. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/54/88867
Examination revealed oozing, verrucous plaques in both axillae (Fig. 1), the left inguinal area, and the left side of the scrotum. Three biopsy specimens of the left axillary lesion were obtained. Tissue culture of one grew Staphylococcus aureus but no mycobacteria, fungi, or anaerobic bacteria. He was treated with cephalexin at 50 mg/kg per day for 4 weeks, but the lesions continued to spread. Acantholysis of the midepidermis with extension down hair follicles, and neutrophilic abscesses, were observed on histologic examination; no organisms were seen on special stains (Fig. 2). Direct immunofluorescence examination of skin revealed 2+ IgA intercellular staining of the epidermis in a pemphigus-like pattern with all other immunoreactants negative (Fig. 3). Indirect immunofluorescence from his serum was negative on monkey esophagus, but showed IgA intercellular space deposits in the lower epidermis of both EDTA-split human skin and normal human skin at a titer of 1:5. The child had normal serum immunoglobulins without elevation of IgA. Because he experienced the condition while receiving cyclosporine and prednisone, and because he had exclusively IgA deposits with neutrophilic abscesses, we reasoned that dapsone might be effective. He received dapsone 25 mg daily and, after 1 week, the pruritus and crusting were reduced. The axillary and inguinal vegetative lesions completely cleared after 3 weeks and dapsone was discontinued after 1 month. Eighteen months later, his skin remains clear.
Journal of the American Academy of Dermatology April 1998
636 Brief communications
Fig. 1. Oozing verrucous plaques in left axilla.
Fig. 2. Pseudoepitheliomatous hyperplasia with neutrophilic microabscess. (Hematoxylin-eosin stain; original magnification ×200.)
Immunoblotting examination by means of extracts of EDTA-separated normal human epidermis tested against the patient’s serum was performed as previously described.16 With this technique all pemphigus vulgaris sera react with desmoglein 3, and a third of pemphigus foliaceus sera react with desmoglein I. The patient’s serum reacted with neither for both IgG and IgA. Serum was also examined for reaction with
desmocollins as has been described in IgA pemphigus of the subcorneal pustular dermatosis type in which IgA autoantibodies react with desmocollin I.17 Sera were tested on COS cells transfected with cDNAs for either desmocollin 1, 2, or 3 by the immunofluorescence method previously described.15-17 The sera did not react with any of the cell surface–expressed desmocollins.
Journal of the American Academy of Dermatology Volume 38, Number 4
Brief communications 637
Fig. 3. Direct immunofluorescence examination demonstrates IgA deposits in a pemphigus-like pattern. (Original magnification ×200.) DISCUSSION
Immunobullous diseases in children are uncommon. We have seen only 24 cases over 16 years in a referral population of 4 million.1 This is similar to the experience of others.2,3 We could not find reports of pemphigus vegetans in childhood 2-12 or of IgA pemphigus vegetans pattern at any age.2-15 We believe this to represent a pemphigus vegetans variant of intraepidermal neutrophilic IgA dermatosis because of the histology compatible with pemphigus vegetans, the absence of IgG binding on both direct and indirect immunofluorescence, the presence of IgA antikeratinocyte surface antibodies at a titer of 1:5, the presence of neutrophilic intraepidermal microabscesses, and a clinical response to dapsone. Unfortunately, although direct and indirect immunofluorescence revealed an intercellular pattern with IgA but not IgG, we could not detect binding with some of the known antigens implicated in pemphigus, the desmogleins, or those implicated in the IgA neutrophilic dermatoses, the desmocollins.14-17 The pemphigus vegetans presentation in our patient is a distinct clinical and histologic pattern, different from other reported patients with intraepidermal neutrophilic IgA dermatosis. It is of interest that his condition appeared while taking immunosuppressive drugs (cyclo-
sporine, prednisone) commonly used to treat pemphigus. These agents have not proved to be effective in IgA neutrophilic dermatoses.13-15 Although pemphigus vegetans in adults may have a benign course and spontaneous remissions may occur after several months,6,11 we attributed the prompt clearing of the lesions to dapsone therapy. The presence of neutrophils and the dramatic response to dapsone would be more characteristic of other IgA immunobullous disorders13-15 than classic pemphigus vegetans. Of the IgA pemphigus-like disorders, only two cases have been described in children.18,19 Unlike our patient, both had the subcorneal pustular dermatosis type.18,19 Thus we believe our patient to be unique. It is important to note that his serum did not react with monkey esophagus, which is a standard used to screen for pemphigus autoantibodies.10,15 Thus other such patients may have been overlooked unless human substrates were used. We are uncertain as to the effect of the liver transplant or the α1-antitrypsin deficiency in this child. Whether a second transplant generated a unique autoantibody response is unknown. We believe that the S. aureus cultured from the skin surface simply colonized a vegetative lesion. The lack of response to systemic antistaphylococcal antibiotics would support this concept.
Journal of the American Academy of Dermatology April 1998
638 Brief communications REFERENCES 1. Weston WL, Huff JC, Morelli JG. Misdiagnosis, treatments, and outcomes in the immunobullous diseases in children. Pediatr Dermatol 1997;14:264-72. 2. Rico MJ. Autoimmune blistering diseases in children. Semin Dermatol 1995;14:54-9. 3. Rabinowitz LG, Esterly NB. Inflammatory bullous diseases in children. Dermatol Clin 1993;11:565-7. 4. von Hebra F. On diseases of the skin including the exanthemata. London: New Sydenham Society; 1866. p. 2867. 5. Mintzer IJ, Rubin Z. Pemphigus vulgaris in a thirteenyear-old girl. NY State Med J 1907;55:1903. 6. Lever WF. Pemphigus and pemphigoid. Springfield (IL): Charles C. Thomas; 1965. 7. Jordon RE, Ihrig JJ, Perry HO. Childhood pemphigus vulgaris. Arch Dermatol 1969;99:176-9. 8. Murphy PJ, Harrell ER, Arbor A. Pemphigus vulgaris in childhood. Am J Dis Child 1972;123:70-1. 9. Smitt JHS. Pemphigus vulgaris in childhood: clinical features, treatment and prognosis. Pediatr Dermatol 1985;2:185-7. 10. Martins CR, Squiquera HL, Diaz LA. Pemphigus vulgaris and pemphigus foliaceus. In: Provost T, Weston WL, editors. Bullous diseases. St. Louis: Mosby–Year Book; 1993. p. 17-61. 11. Director W. Pemphigus vegetans: a clinicopathological correlation. Arch Dermatol 1953;66:343. 12. Kanwar AJ, Dhar S, Kaur S. Further experience with
13. 14.
15.
16.
17.
18.
19.
pemphigus in children. Pediatr Dermatol 1994;11: 107-11. Huff JC, Golitz LE, Kunke KS. Intraepidermal neutrophilic IgA dermatosis. N Engl J Med 1985;313:1643. Iwatsuki K, Hashimoto T, Ebihara T, Teraki Y, Hishikawa T, Kaneko F. Intercellular IgA vesiculo-pustular dermatoses and related disorders: diversity of IgA anti-intercellular autoantibodies. Eur J Immunol 1993;3:7-16. Hashimoto T, Ebihara T, Dmochowski M, Kawamura K, Suzuki T, Tsurufuji S, et al. IgA antikeratinocyte surface autoantibodies from two types of intercellular IgA vesiculopustular dermatosis recognize distinct isoforms of desmocollin. Arch Dermatol Res 1996;288:447-51. Hashimoto T, Ogawa MM, Konohana A, Nishikawa T. Detection of pemphigus vulgaris and pemphigus foliaceus antigens by immunoblot analysis using different antigen sources. J Invest Dermatol 1990;94:327-31. Hashimoto T, Kiyokawa C, Mori O, Miyasato M, Chidgey MAJ, et al. Human desmocollin 1 (Dsc I) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus. J Invest Dermatol 1997;109:127-31. Saurat J-H, Merot Y, Saloimon D, Didierjean L. Pemphigus-like IgA deposits and vesiculopustular dermatosis in a 10-year-old girl. Dermatologica 1987; 175:96. Teraki Y, Amagai N, Hashimoto T, Kusunoki T, Nishikawa T. Intercellular IgA dermatosis of childhood. Selective deposition of monomer IgA1 in the intercellular space of the epidermis. Arch Dermatol 1991;127: 221-4.
Brief communications 635
A novel childhood pemphigus vegetans variant of intraepidermal neutrophilic IgA dermatosis William L. Weston, MD,a Marti Friednash, MD,a Takashi Hashimoto, MD,b Peter Seline, MD,a J. Clark Huff, MD,a and Joseph G. Morelli, MDa Denver, Colorado, and Fukuoka, Japan We describe a child in whom a pemphigus vegetans variant of intraepidermal neutrophilic IgA dermatosis occurred while he was taking immunosuppressive drugs. The IgA autoantibody from the patient showed an intercellular pattern on human skin substrates at a titer of 1:5 but did not react with desmogleins or desmocollins. We believe this to be the first report of this condition.1-15 CASE REPORT A 7-year-old boy had oozing areas in both axillae and in the left groin for 2 weeks. The patient also had homozygous α1-antitrypsin deficiency and had experienced liver failure by 5 months of age. When he was 6 months old he received a liver transplant that failed and a second liver transplant that was successful. He was maintained on a regimen of cyclosporine and prednisone. For the past 2 years he had experienced generalized itching that worsened the month before axillary lesions appeared. From the Department of Dermatology, University of Colorado School of Medicine, Denver,a and the Department of Dermatology, Kurume University School of Medicine, Fukuoka.b Reprint requests: William L. Weston, MD, Professor and Chairman, Department of Dermatology, University of Colorado School of Medicine, 4200 E. Ninth Ave. B-153, Denver, CO 80262. J Am Acad Dermatol 1998;38:635-8. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/54/88867
Examination revealed oozing, verrucous plaques in both axillae (Fig. 1), the left inguinal area, and the left side of the scrotum. Three biopsy specimens of the left axillary lesion were obtained. Tissue culture of one grew Staphylococcus aureus but no mycobacteria, fungi, or anaerobic bacteria. He was treated with cephalexin at 50 mg/kg per day for 4 weeks, but the lesions continued to spread. Acantholysis of the midepidermis with extension down hair follicles, and neutrophilic abscesses, were observed on histologic examination; no organisms were seen on special stains (Fig. 2). Direct immunofluorescence examination of skin revealed 2+ IgA intercellular staining of the epidermis in a pemphigus-like pattern with all other immunoreactants negative (Fig. 3). Indirect immunofluorescence from his serum was negative on monkey esophagus, but showed IgA intercellular space deposits in the lower epidermis of both EDTA-split human skin and normal human skin at a titer of 1:5. The child had normal serum immunoglobulins without elevation of IgA. Because he experienced the condition while receiving cyclosporine and prednisone, and because he had exclusively IgA deposits with neutrophilic abscesses, we reasoned that dapsone might be effective. He received dapsone 25 mg daily and, after 1 week, the pruritus and crusting were reduced. The axillary and inguinal vegetative lesions completely cleared after 3 weeks and dapsone was discontinued after 1 month. Eighteen months later, his skin remains clear.
Journal of the American Academy of Dermatology April 1998
636 Brief communications
Fig. 1. Oozing verrucous plaques in left axilla.
Fig. 2. Pseudoepitheliomatous hyperplasia with neutrophilic microabscess. (Hematoxylin-eosin stain; original magnification ×200.)
Immunoblotting examination by means of extracts of EDTA-separated normal human epidermis tested against the patient’s serum was performed as previously described.16 With this technique all pemphigus vulgaris sera react with desmoglein 3, and a third of pemphigus foliaceus sera react with desmoglein I. The patient’s serum reacted with neither for both IgG and IgA. Serum was also examined for reaction with
desmocollins as has been described in IgA pemphigus of the subcorneal pustular dermatosis type in which IgA autoantibodies react with desmocollin I.17 Sera were tested on COS cells transfected with cDNAs for either desmocollin 1, 2, or 3 by the immunofluorescence method previously described.15-17 The sera did not react with any of the cell surface–expressed desmocollins.
Journal of the American Academy of Dermatology Volume 38, Number 4
Brief communications 637
Fig. 3. Direct immunofluorescence examination demonstrates IgA deposits in a pemphigus-like pattern. (Original magnification ×200.) DISCUSSION
Immunobullous diseases in children are uncommon. We have seen only 24 cases over 16 years in a referral population of 4 million.1 This is similar to the experience of others.2,3 We could not find reports of pemphigus vegetans in childhood 2-12 or of IgA pemphigus vegetans pattern at any age.2-15 We believe this to represent a pemphigus vegetans variant of intraepidermal neutrophilic IgA dermatosis because of the histology compatible with pemphigus vegetans, the absence of IgG binding on both direct and indirect immunofluorescence, the presence of IgA antikeratinocyte surface antibodies at a titer of 1:5, the presence of neutrophilic intraepidermal microabscesses, and a clinical response to dapsone. Unfortunately, although direct and indirect immunofluorescence revealed an intercellular pattern with IgA but not IgG, we could not detect binding with some of the known antigens implicated in pemphigus, the desmogleins, or those implicated in the IgA neutrophilic dermatoses, the desmocollins.14-17 The pemphigus vegetans presentation in our patient is a distinct clinical and histologic pattern, different from other reported patients with intraepidermal neutrophilic IgA dermatosis. It is of interest that his condition appeared while taking immunosuppressive drugs (cyclo-
sporine, prednisone) commonly used to treat pemphigus. These agents have not proved to be effective in IgA neutrophilic dermatoses.13-15 Although pemphigus vegetans in adults may have a benign course and spontaneous remissions may occur after several months,6,11 we attributed the prompt clearing of the lesions to dapsone therapy. The presence of neutrophils and the dramatic response to dapsone would be more characteristic of other IgA immunobullous disorders13-15 than classic pemphigus vegetans. Of the IgA pemphigus-like disorders, only two cases have been described in children.18,19 Unlike our patient, both had the subcorneal pustular dermatosis type.18,19 Thus we believe our patient to be unique. It is important to note that his serum did not react with monkey esophagus, which is a standard used to screen for pemphigus autoantibodies.10,15 Thus other such patients may have been overlooked unless human substrates were used. We are uncertain as to the effect of the liver transplant or the α1-antitrypsin deficiency in this child. Whether a second transplant generated a unique autoantibody response is unknown. We believe that the S. aureus cultured from the skin surface simply colonized a vegetative lesion. The lack of response to systemic antistaphylococcal antibiotics would support this concept.
Journal of the American Academy of Dermatology April 1998
638 Brief communications REFERENCES 1. Weston WL, Huff JC, Morelli JG. Misdiagnosis, treatments, and outcomes in the immunobullous diseases in children. Pediatr Dermatol 1997;14:264-72. 2. Rico MJ. Autoimmune blistering diseases in children. Semin Dermatol 1995;14:54-9. 3. Rabinowitz LG, Esterly NB. Inflammatory bullous diseases in children. Dermatol Clin 1993;11:565-7. 4. von Hebra F. On diseases of the skin including the exanthemata. London: New Sydenham Society; 1866. p. 2867. 5. Mintzer IJ, Rubin Z. Pemphigus vulgaris in a thirteenyear-old girl. NY State Med J 1907;55:1903. 6. Lever WF. Pemphigus and pemphigoid. Springfield (IL): Charles C. Thomas; 1965. 7. Jordon RE, Ihrig JJ, Perry HO. Childhood pemphigus vulgaris. Arch Dermatol 1969;99:176-9. 8. Murphy PJ, Harrell ER, Arbor A. Pemphigus vulgaris in childhood. Am J Dis Child 1972;123:70-1. 9. Smitt JHS. Pemphigus vulgaris in childhood: clinical features, treatment and prognosis. Pediatr Dermatol 1985;2:185-7. 10. Martins CR, Squiquera HL, Diaz LA. Pemphigus vulgaris and pemphigus foliaceus. In: Provost T, Weston WL, editors. Bullous diseases. St. Louis: Mosby–Year Book; 1993. p. 17-61. 11. Director W. Pemphigus vegetans: a clinicopathological correlation. Arch Dermatol 1953;66:343. 12. Kanwar AJ, Dhar S, Kaur S. Further experience with
13. 14.
15.
16.
17.
18.
19.
pemphigus in children. Pediatr Dermatol 1994;11: 107-11. Huff JC, Golitz LE, Kunke KS. Intraepidermal neutrophilic IgA dermatosis. N Engl J Med 1985;313:1643. Iwatsuki K, Hashimoto T, Ebihara T, Teraki Y, Hishikawa T, Kaneko F. Intercellular IgA vesiculo-pustular dermatoses and related disorders: diversity of IgA anti-intercellular autoantibodies. Eur J Immunol 1993;3:7-16. Hashimoto T, Ebihara T, Dmochowski M, Kawamura K, Suzuki T, Tsurufuji S, et al. IgA antikeratinocyte surface autoantibodies from two types of intercellular IgA vesiculopustular dermatosis recognize distinct isoforms of desmocollin. Arch Dermatol Res 1996;288:447-51. Hashimoto T, Ogawa MM, Konohana A, Nishikawa T. Detection of pemphigus vulgaris and pemphigus foliaceus antigens by immunoblot analysis using different antigen sources. J Invest Dermatol 1990;94:327-31. Hashimoto T, Kiyokawa C, Mori O, Miyasato M, Chidgey MAJ, et al. Human desmocollin 1 (Dsc I) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus. J Invest Dermatol 1997;109:127-31. Saurat J-H, Merot Y, Saloimon D, Didierjean L. Pemphigus-like IgA deposits and vesiculopustular dermatosis in a 10-year-old girl. Dermatologica 1987; 175:96. Teraki Y, Amagai N, Hashimoto T, Kusunoki T, Nishikawa T. Intercellular IgA dermatosis of childhood. Selective deposition of monomer IgA1 in the intercellular space of the epidermis. Arch Dermatol 1991;127: 221-4.