PMC7086599_01
Granulomatous lesions (skin) and EBV lymphoproliferative disorder (small bowel). Right arm, cutaneous granulomatous lesion: a initial; b after 6 months progression. Histopathology, skin biopsy: c Prominent focally diffuse dermal and subcutaneous lympho-histiocytic infiltrate suggesting lymphoma; d Poorly formed granulomas, composed of epithelioid histiocytes; e Focal areas of necrosis in the subcutaneous tissue. Resected 17 cm of small bowel, EBV-LPD: f Lobulated, ulcerated, partially necrotic tumour (4 cm in diameter); g Tumorous mass: small intestine containing diffuse infiltrate/sheets of atypical large centroblastic lymphoid cells amongst which are scattered larger, more pleomorphic forms; background of small reactive lymphocytes, macrophages, scattered eosinophils and plasma cells. h High power: Hodgkin/Reed-Sternberg cells set singly in a mixed inflammatory background with numerous eosinophils. i Immunohistochemical staining: centroblastic and pleomorphic B cells (express CD20, Pax5, CD30 and MUM1), most are cyclin D1-negative but several aggregates of positive cells morphologically suggestive of atypical lymphoid cells are present throughout. EBV-EBER in situ hybridisation shows strong widespread positivity; the pleomorphic cells express EBV-LMP1. The Ki67 proliferation fraction is high (approximately 80 %). Staining for CD2, CD3 and CD5 highlights the reactive T-cell population. In situ hybridisation of immunoglobulin light chains shows the plasma cells to be polytypic. EBV-EBER EBV-encoded RNA, EBV-LMP1 EBV-latent membrane protein 1, CD cluster of differentiation
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Fig1
A 2 year 8 month female, the first child of unrelated Caucasian parents, presented with a 12 months history of initially small painless erythematous lesion affecting the right arm, gradually progressing in size (Fig. 1a-b), and a smaller lesion on the right leg. The initial skin biopsy (Fig. 1c-e) demonstrated CD3+ lymphocyte infiltrate and a T cell clone by T cell receptor (TCR) gene rearrangement analysis; EBV in-situ hybridization was negative as were mycobacterial PCR and fungal stains. Exploratory laparotomy revealed an ileal tumorous mass (Fig. 1f) which was resected and confirmed to be EBV-related diffuse large B-cell lymphoma (Fig. 1g-i).
Immunologic parameters II: TCR V-beta family pattern. Skewed usage of TCR V-beta family, with increased number of expansions seen in the CD4+ population, and increased number and size of expansions in the CD4- (CD8+) population. See Table Legend for further explanation. CD cluster of differentiation, TCR T cell receptor
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Fig2
However, she was found to have severe T cell immunodeficiency (Table I, Fig. 2) and viral infections (by PCR, EBV 5.5 x 10e4 and HHV6 2 x 10e3 (copies/ml) in blood, sapovirus in stool, adenovirus in nasal swab, and few EBV-positive cells were detected in the second skin biopsy).  
Bone radiography (age 2.8 years)
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Fig3
Based on the features of short stature since birth, severe T cell immunodeficiency and unusual granulomatous skin inflammation, in spite of normal bone radiography (Fig. 3), we searched for disease-causing mutations in the RMRP gene.