Pediatric Dermatology Vol. 32 No. 3 e74–e77, 2015
Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome Associated with Neonatal Epidermolysis Bullosa Acquisita Sabina Bis, M.D.,* Sheilagh M. Maguiness, M.D.,† Stephen E. Gellis, M.D.,† Lynda C. Schneider, M.D.,† Pui Y. Lee, M.D.,† Luigi D. Notarangelo, M.D.,† Sevgi Keles, M.D.,† Talal A. Chatila, M.D.,† Birgitta A. Schmidt, M.D.,† and Daniel D. Miller, M.D.‡ *Harvard Combined Dermatology Program, Boston, Massachusetts, †Division of Immunology, Department of Medicine, Boston Children’s Hospital, Boston, Massachusetts, ‡Department of Dermatology, School of Medicine, Boston University, Boston, Massachusetts
Abstract: We report the case of a 2-week-old boy who presented with a vesiculopustular, bullous eruption in the setting of autoimmune enteropathy, hypothyroidism, membranous nephropathy, Coombs-positive hemolytic anemia, and persistent eosinophilia. Immunologic testing revealed a deficiency of FOXP3-expressing regulatory T cells, and a diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome was made. Histologic analysis, immunofluorescence, and enzyme-linked immunosorbent assay confirmed the bullous eruption as epidermolysis bullosa acquisita with associated collagen VII autoantibody production. The skin lesions responded to systemic immunosuppressant therapy and have regressed after allogeneic bone marrow transplantation.
A 2-week-old boy was hospitalized with irritability, dark urine, and a vesiculopustular eruption on the face and trunk. He was the product of a full-term pregnancy complicated by polyhydramnios and transient respiratory distress and hypotonia at birth. Initial dermatologic examination revealed pustules, vesicles, and crusted erosions on the face and erythematous edematous plaques studded with pustules on the chest (Fig. 1). Laboratory studies demonstrated peripheral eosinophilia (31%; normal 1%–5%), an absolute eosinophil count of 5.49 (nor-
mal 0.1–0.42 K cells/lL), high serum concentrations of immunoglobulin E (IgE) (1,179 U/mL; normal 0– 30 U/mL), high creatinine, proteinuria, hypoalbuminemia, a negative rapid plasma reagin, and negative antinuclear and anti-Ro antibodies. A skin biopsy from the left chest revealed epidermal spongiosis with eosinophilic exocytosis and rare necrotic keratinocytes, predominantly eosinophilic pustules within follicular infundibulae, and a superficial dermal infiltrate of eosinophils and neutrophils (Fig. 2A, B). This constellation of findings suggested
Address correspondence to Daniel D. Miller, M.D., Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA 02118, or email:
[email protected]. DOI: 10.1111/pde.12550
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© 2015 Wiley Periodicals, Inc.
Bis et al: IPEX Syndrome Associated with Neonatal EBA
Figure 1. Clinical appearance at 2 weeks of age: erythematous edematous plaques with superimposed pustules on the chest.
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a differential diagnosis that included eosinophilic pustular folliculitis, incontinentia pigmenti, hyperIgE syndrome or other immunodeficiency, or an autoimmune bullous disease such as the urticarial phase of bullous pemphigoid. Shortly thereafter the patient developed tachypnea, peripheral edema, intermittent fevers, acute renal insufficiency, diarrhea, and failure to thrive. An immunodeficiency disorder was suspected and the patient was transferred to Boston Children’s Hospital for further evaluation. Physical examination at this time revealed numerous edematous circular plaques with bullae and erosions on the upper extremities, upper chest, back, scrotum, and perianal area, with subsequent spreading to involve the lower legs, face, neck, and axilla (Fig. 3A, B). There were no oral lesions and no nail or hair abnormalities. A repeat skin biopsy of a bulla on the right chest revealed focal interface dermatitis with basal layer vacuolization and rare dyskeratotic cells, papillary dermal edema, and a superficial perivascular and interstitial lymphocytic infiltrate with a prominent eosinophilic component
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Figure 2. Histopathology of a vesiculopustular lesion on left chest: (A) eosinophilic spongiosis and superficial dermal infiltrate of eosinophils and neutrophils (hematoxylin and eosin, 409 magnification); (B) epidermal spongiosis with eosinophilic exocystosis, eosinophilic pustules, and rare necrotic keratinocytes (1009 magnification).
Figure 3. Clinical appearance at 1 month of age: (A) erythematous papulovesicles with resultant hypopigmentation on the chest; (B) close-up of bullae and vesicles on the left ankle.
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Figure 4. Hematoxylin and eosin histology of vesicle on the chest: (A) subepidermal clefting (409 magnification) and (B) focal interface dermatitis, papillary dermal edema, and predominantly eosinophilic perivascular and interstitial infiltrate (2009 magnification).
(Fig. 4A, B). Perilesional direct immunofluorescence revealed linear IgG and IgM deposition at the dermoepidermal junction. To better characterize the nature of this bullous disorder, indirect immunofluorescence was performed, revealing a positive IgG titer at 1:20,480 (normal A) that disrupts the splice donor site between exon 1 and intron 1. The diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome was consistent with the constellation of clinical findings, including autoimmune enteropathy leading to failure to thrive, membranous nephropathy (confirmed according to renal biopsy and immunofluorescence studies), hypothyroidism, Coombs-positive hemolytic anemia, and eosinophilia. His symptoms, and in particular his skin eruption, improved on topical steroids and methylprednisolone, which was only started after full immunologic evaluation was first undertaken. The patient was subsequently transitioned to systemic tacrolimus becuase renal function was most severely affected and then slowly weaned off of oral steroids. Despite initial dermatologic response to immunosuppressant medications, the patient was readmitted at 5 months of age for a flare of eczematous dermatitis, which responded to pulse methylprednisolone and topical steroids. The patient ultimately underwent a human leukocyte antigen (HLA)–matched allogeneic bone marrow transplant at 6 months of age, with complete remission of EBA and his eczematous lesions. DISCUSSION IPEX syndrome is a rare X-linked recessive disorder characterized by mutations in the FOXP3 gene or associated regions. Approximately 30% of males with IPEX syndrome have defects in noncoding regions including promoter or enhancer regulatory elements of FOXP3, thus sequencing of the coding regions of the gene itself may be normal (1). The FOXP3 gene encodes a DNA-binding protein that controls the development and function of CD4+/CD25+ regulatory T (Treg) cells. These FOXP3+-expressing Treg cells are essential for suppression of T-cell activation and proliferation and play an integral role in maintenance of self-tolerance (2). In IPEX syndrome, FOXP3 dysfunction results in absent or dysfunctional Tregs and disrupts immune homeostasis, leading to
Bis et al: IPEX Syndrome Associated with Neonatal EBA
early-onset autoimmunity. Clinical manifestations of this immune dysregulation include autoimmune enteropathy, diabetes mellitus, thyroiditis, nephropathy, Coombs-positive hemolytic anemia, and thrombocytopenia. Patients also frequently have high IgE levels, food allergies, recurrent infections, and associated dermatitis (3). Cutaneous manifestations of IPEX syndrome are frequently observed and were documented in 22 of 55 patients in a literature review (4). Furthermore, a recent retrospective study of patients with IPEX syndrome revealed cutaneous involvement in 7 of 10 boys. These affected children initially presented with diffuse and severe atopic dermatitis–like lesions between 0 and 4 months of age, and two of these boys eventually evolved to erythroderma (1). Additional cutaneous manifestations include psoriasiform or ichthyosiform lesions, severe fissuring cheilitis, perioral edema and urticaria secondary to food allergies, and onychodystrophy (1,5). High serum IgE and hypereosinophilia are also frequently seen in individuals with IPEX. Affected patients typically improve with topical corticosteroids, but no consistent improvement was seen with immunosuppressive agents (1). Unusual cutaneous presentations of IPEX previously documented in the literature include a 5-yearold boy with chronic dermatitis who initially developed papulovesicles followed by widespread bullae and prurigo nodularis–like nodules. Direct immunofluorescence demonstrated linear C3 and IgG staining of the dermoepidermal junction, and ELISA was positive for BP180, confirming the diagnosis of pemphigoid nodularis (6). Another case of biopsyproven bullous pemphigoid has been reported in a 7year-old boy with neonatal enteropathy, chronic dermatitis, and frequent bacterial and viral infections. A perilesional biopsy revealed subepidermal separation and granular C3 deposition at the roof and the floor of the subepidermal blister consistent with bullous pemphigoid, although no ELISA testing was performed for confirmation of the diagnosis (7). In this report we describe the first reported case of EBA associated with IPEX syndrome presenting in a neonate with associated autoimmune enteropathy, hypothyroidism, membranous glomerulonephritis, and Coombs-positive hemolytic anemia. The patient also initially demonstrated clinical and pathologic
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findings of an eosinophilic pustular folliculitis, similar to the early presentation of many patients with hyperIgE syndrome (8). This case highlights the spectrum of dermatologic conditions associated with IPEX, including EBA, and emphasizes the importance of full immunologic evaluation before beginning immunosuppressant medication. Autoimmune bullous diseases should be considered in children with immunodeficiency and bullous lesions. ACKNOWLEDGMENT The authors would like to acknowledge Drs. Kelly Cordoro and Ilona Frieden for their clinical input in this case. REFERENCES 1. Halabi-Tawil M, Ruemmele FM, Fraitag S, et al. Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Br J Dermatol 2009;160:645–651. 2. Verbsky JW, Chatila TA. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr 2013;25:708– 714. 3. d’Hennezel E, Bin Dhuban K, Torgerson T, et al. The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 2012;49:291–302. 4. Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 2002;39:537–545. 5. Nieves DS, Phipps RP, Pollock SJ, et al. Dermatologic immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Arch Dermatol 2004;140:466–472. 6. McGinness JL, Bivens MMC, Greer KE, et al. Immune dysregulation, polyendocrinopathy, enteropathy, Xlinked syndrome (IPEX) associated with pemphigoid nodularis: a case report and review of the literature. J Am Acad Dermatol 2006;55:143–148. 7. Ferguson PJ, Blanton SH, Saulsbury FT, et al. Manifestations and linkage analysis in X-linked autoimmunity-immunodeficiency syndrome. Am J Med Genet 2000;90:390–397. 8. Olaiwan A, Chandesris MO, Fraitag S, et al. Cutaneous findings in sporadic and familial autosomal dominant hyper-IgE syndrome: a retrospective, single-center study of 21 patients diagnosed using molecular analysis. J Am Acad Dermatol 2011;65:1167–1172.
