Paraneoplastic pemphigus associated with post- transplant lymphoproliferative disorder after small bowel transplantation

Background: PNP is a malignancy- associated autoimmune mucocutaneous syndrome due to autoantibodies against plakins, desmogleins, and other components of the epidermis and basement membrane of epithelial tissues. PNP- causing malignancies comprise mainly lymphoproliferative and hematologic neoplasms. PNP is extremely rare, especially in children. Methods: Here, we present the first case of a child who developed PNP on a PTLD after small bowel transplantation because of a severe genetic protein- losing enteropathy. Results: The patient in this case report had a severe stomatitis, striate palmoplantar keratoderma, and lichenoid skin lesions. In addition, she had marked esophageal involvement. She had lung pathology due to recurrent pulmonary infections and venti-lator injury. Although we found no evidence of BO, she died from severe pneumonia and respiratory failure at the age of 12 years. Conclusion: It is exceptional that, despite effective treatment of the PTLD, the girl survived 5 years after her diagnosis of PNP. We hypothesize that the girl survived


| INTRODUC TI ON
PNP is a severe autoimmune mucocutaneous syndrome characterized by severe stomatitis and mainly lichenoid skin involvement due to antibodies against plakins, desmogleins, and other components of the epidermis or basement membrane ( Figure 1). PNP is also described with the more inclusive term PAMS, since multiple organs may be involved. PNP in children is most commonly induced by several lymphoproliferative and hematologic neoplasms. 1 However, there are no case reports of PNP after solid organ transplantation. This is the first case of PNP in a child after solid organ transplantation associated malignancy PTLD.

| PATIENT
We present a case of a girl that was born prematurely at 35 weeks of gestation. She was one of a monochorionic-monoamniotic twin.
From birth, both girls had a severe intestinal failure with proteinlosing enteropathy and were fully dependent on parenteral nutrition. Due to recurrent central venous catheter-related infections, one of the twins presented in this case underwent a small bowel transplantation at the age of 3.5 years. The post-operative period was uncomplicated, within 2 weeks she achieved complete enteral nutrition. Only years later, at the age of 9, both were found to have a DGAT-1 mutation, as was previous described by Van Rijn et al. 2 Ten months after her transplantation our patient developed an EBV associated PTLD despite tapering down immune suppression (tacrolimus). The PTLD was classified as monomorphic plasmacytomalike PTLD (according to the WHO classification). 3 Within 6 months, she achieved complete remission after Rituximab and chemotherapy (Cyclophosphamide, Vincristine, and Prednisone). At the age of 7 years, she developed an AIHA and she increasingly suffered from painful red lesions on her tongue. At that moment, her maintenance therapy was tacrolimus at trough levels between 2.3 and 5.1 µg/L and low-dose prednisolone 7.5 mg/day (0.3 mg/kg/day).
Dermatological examination revealed an erosive cheilitis, ulcerations on the oral mucosae with white plaques and a lichenoid appearance on the buccal mucosae (Figure 2A showed binding to the urothelium ( Figure 3C). IgG enzyme-linked immunoassays (ELISA) detected IgG antibodies to Dsg-3 (index 142; cut off >19, MESACUP-2 test, MBL Nagoya Japan), but not F I G U R E 1 Proposed pathophysiology of PNP. Neoplasms (mostly lymphoid) cause immune dysregulation and formation of autoantibody formation against self-antigens. Antigen-presenting cells (APC's, i.e., dendritic cells) process tumor antigens (neoantigens) that are crossreactive with epidermal cell surface antigens, and provide co-activating signals to auto-reactive naïve T cells. Autoreactive T cells can escape energy. These autoreactive T cells induce both humoral en cell-mediated immunity. Activated B cells differentiate into plasma cells. Plasma cells produce autoantibodies against Dsg-3 and plakins in the BMZ. Humoral autoimmunity contributes to BO and acantholysis presenting as blisters. In cell-mediated immunity, autoreactive CD4+ and CD8+ T cells produce IFNγ and autoreactive CD8+ T cells secrete cytotoxic molecules, such as granzyme and perforin. These immune reactions induce BO and lichenoid dermatitis. Original illustration from reference 14 to Dsg-1 (MESACU-2 test, MBL Nagoya Japan). IgA against Dgs-1 and Dsg-3 was negative. Immunoblotting was negative for EP, PP, BP230, BP180, desmoplakin I and II, plectin, plakophilin 3, laminin-332, and desmocollin 1-3 (for the methodology see reference 4 ).
Immunoprecipitation did not reveal antibodies to the protease inhibitor alpha-2-macroglobulin-like-1 (for the methodology see refer-

| DISCUSS ION
This is the first report of a pediatric case of PNP associated with lymphoproliferative disease after solid organ (small bowel) transplantation. After solid organ transplantation, PTLD is the most frequently seen lymphoproliferative and hematologic neoplasms (5-year incidence 0.2%-2.3% in adults, 2.2%-15% in children). 6 However, an association between PNP and PTLD has not been described thus far.
PNP in children is very rare and is in the majority of cases caused by CD of which 32 cases are described between 1997 and 2016. 7 In addition, other PNP-associated tumors were inflammatory fibrosarcoma, 8,9 Hodgkin lymphoma, 10 and T-cell lymphoblastic lymphoma. 11 Based on 163 cases, PNP in adults is most frequently (84%) asso- Our case met two of three major criteria of (1) polymorphic mucocutaneous eruption and (2)  Four of these children had a biopsy-based diagnosis of BO. 7 This is supported by other studies which report a high mortality (71%-79%) due to respiratory failure and/or BO in pediatric PNP patients. [25][26][27] It was not possible to perform a bronchoscopy with biopsy or an expiratory hrCT to confirm the diagnosis of BO in our patient due to her compromised condition. Normal CT imaging showed bronchiectasis with a clear image of ventilator-induced lung injury, thus, we cannot fully exclude the presence of BO. However, the bronchiectasis was already present at an earlier age (at the age of 6 years) than pemphigus and the recurring infections can also be the cause of these radiological abnormalities. In addition, our patient had a relatively long survival, namely 5 years after the diagnosis of PNP, since most children with BO show a maximum survival of 3 years in the literature. 7 We have two hypotheses for this finding.
The first hypothesis is that the PNP phenotype associated with and CD8+ T-cell infiltration are frequently observed in the epidermis of PNP. Also in BO, it is very likely that this cellular immunity plays a crucial role in the pathogenesis. 14,29 Therefore, T-cell targeted therapy may add a new dimension to the current approach.
Despite both unsupported hypotheses, we presented a patient with a unique combination of PNP and other autoimmune phenomena after solid organ transplantation.

| CON CLUS ION
This article describes a unique case of PNP with skin and oral, an esophageal involvement, in association with a PTLD after solid organ transplantation. To our knowledge, this has never been described in adult and pediatric literature. Our patient survived for 5 years after the diagnosis PNP, which is exceptionally long because mortality rates are extremely high (70-80%) and mainly due to BO. We hypothesize that the strong T-cell suppressive treatment for her small bowel transplantation plays a role in this.

CO N FLI C T O F I NTE R E S T
The authors have no conflict of interest related to this work.