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Hindawi Case Reports in Immunology Volume 2018, Article ID 2053716, 6 pages https://doi.org/10.1155/2018/2053716 Case Report Runaway Train: A Leaky Radiosensitive SCID with Skin Lesions and Multiple Lymphomas 1,2,3 4,5 6 7 Børre Fevang , Unn Merete Fagerli, Hanne Sorte, Harald Aarset, 7,8 9 10 11 1,2,3 Håkon Hov, Marit Langmyr, Thomas Morten Keil, Ellen Bjørge, Pål Aukrust, 6 12,13 Asbjørg Stray-Pedersen, and Tobias Gedde-Dahl K.G. Jebsen Center for Cancer Immunotherapy and K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway Department of Oncology, St. Olav’s Hospital, Trondheim, Norway Department of Cancer Research and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU, Trondheim, Norway Department of Medical Genetics, Oslo University Hospital, Oslo, Norway Department of Pathology, St. Olav’s Hospital, Trondheim, Norway Department for Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine and Health Sciences, NTNU, Trondheim, Norway Department of Radiology, St. Olav’s Hospital, Trondheim, Norway Department of Nuclear Medicine, St. Olav’s Hospital, Trondheim, Norway Department of Dermatology, St. Olav’s Hospital, Oslo, Norway Department of Hematology, Oslo University Hospital, Oslo, Norway Institute for Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway Correspondence should be addressed to Børre Fevang; firstname.lastname@example.org Received 24 January 2018; Revised 21 March 2018; Accepted 1 April 2018; Published 14 May 2018 Academic Editor: Claudio Pignata Copyright © 2018 Børre Fevang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The nuclease Artemis is essential for the development of T-cell and B-cell receptors and repair of DNA double-strand breaks, and a loss of expression or function will lead to a radiosensitive severe combined immunodeficiency with no functional T-cells or B-cells (T-B-SCID). Hypomorphic mutations in the Artemis genecanleadtoafunctional,but reduced, T-cell andB-cellrepertoirewith a more indolent clinical course called “leaky” SCID. Here, we present the case of a young man who had increasingly aggressive lymphoproliferative skin lesions from 2 years of age which developed into multiple EBV+ B-cell lymphomas, where a hypomorphic mutation in the Artemis gene was found in a diagnostic race against time using whole exome sequencing. eTh patient was given a haploidentical stem cell transplant while in remission for his lymphomas and although the initial course was successful, he succumbed to a serious Pneumocystis jirovecii pneumonia 5 months aeft r the transplant. eTh case underscores the importance of next-generation sequencing in the diagnosis of patients with suspected severe immunodeficiency. 1. Introduction immunodeficiency with no or very limited expression of T-cells and B-cells (T-B-SCID) [1, 2]. However, hypomorphic The intricate enzymatic machinery needed for the recom- mutations in these genes can lead to a spectrum of less severe bination of T-cell and B-cell receptors is the basis of adaptive phenotypes with a functional but reduced T-cell and B-cell immunity and major mutations in associated genes like repertoire, including the so-called leaky SCID [3–8]. eTh se RAG and Artemis invariably lead to severe combined patients have SCID-like features but do not fill the criteria for 2 Case Reports in Immunology SCID and have, at least initially, a milder and more indolent Table 1: Hematologic and immunologic characteristics. clinical course. Before transplant Day 30 Day 150 The Artemis protein (also known as DNA cross-link Blood counts repair enzyme 1C, DCLRE1C) was first characterized as a Hemoglobin (g/dL) 12,1 7,9 10,0 part of the VDJ-recombination process in 2001 in a study of patients with radiosensitive SCID . Importantly, the Thrombocytes ( ×10 /L) 240 39 82 Artemis protein, as opposed to RAG, was found to be Leukocytes (×10 /L) 3,9 3,2 14,1 essential also for the repair of DNA double-strand breaks Lymphocytes (×10 /L) 0,8 0,5 6,7 explaining the radiosensitive nature of the immunodefi- CD4 (×10 /L) 177 ciency. It is expressed in a wide variety of tissues, including CD8 (×10 /L) 277 fibroblasts, facilitating the use of b fi roblast cultures in diag- CD19 (×10 /L) <5 nostic radiosensitivity assays. Typically, complete Artemis Immunoglobulins deficiency presents itself as T-B-SCID in early infancy with IgG (g/L) 6,1 2,8 life-threatening infections, diarrhea, and failure to thrive. eTh IgM (g/L) 0,1 <0,1 clinical presentation is similar to other forms of T-B-SCID, IgA (g/L) 0,4 <0,1 and while increased radiosensitivity heightens the suspicion ∗∗ Chimerism 99% of Artemis disease, genetic tests will be needed to distinguish it from, for example, DNA Ligase IV deficiency. Artemis Pretransplant data from first presentation at Oslo University Hospital. ∗∗ Chimerism data at day 100. deficiency has a recessive pattern of inheritance and has been found with increased frequency in certain population groups, including native Americans. Hematopoietic stem cell trans- plantation (HSCT) is the only available curative treatment, diagnosis and considering the clinical presentation, a diag- but conditioning is complicated by increased sensitivity to nosis of sarcoidosis was given. Despite aggressive immuno- both radiation and alkylating agents. Radiosensitive SCID, suppressive therapy including corticosteroids, methotrexate, including Artemis deficiency, is thus an obvious candidate for azathioprine, and anti-TNF agents, the lesions gradually gene therapy . evolvedalthoughinaslowandundulatingmanner.In a eu Th seofadvancedgeneticmethodsindiagnosisof reevaluation of the skin biopsies, the pathologists found primary immunodeficiencies has shown us that the spectrum a diffuse lymphohistiocytic infiltrate dominated by CD8 of diseases associated with SCID genes is both wide and T-cells with several different monoclonalities as well as variable. While homozygotic null-mutations in Artemis have epithelioid cell granulomas. eTh y concluded with a T-cell a defined phenotype, multiple publications over the last years dominated lymphoproliferative state associated with a form have shown that other genetic variants in Artemis,including of primary immunodeficiency, for example, a RAG-mutation. Meanwhile the patient underwent carmustine therapy on heterozygotic and compound heterozygotic mutations, can the suspicion of mycosis fungoides without any apparent cause a range of clinical presentations. “Leaky” SCIDs are clinical effect. One year before presentation at Oslo University defined by low levels of T-cells with an impaired functional Hospital, the patient was found to have a diffuse large cell response and have been associated with hypomorphic muta- B-cell lymphoma (non-GC-B type, EBV+) in a tumor of the tions in SCID-associated genes like Artemis,which cause neck and at the same time another different B-cell lymphoma dysfunction but not absence of the related protein . eTh (unclassifiable, with features intermediate between diffuse clinical consequence of these nonclassical SCID-associated large-B cell lymphoma (DLBCL) and classical Hodgkin lym- mutations is unpredictable, but any dysfunction related to phoma) preauricularly (Figure 2). PET-CT showed a possible DNA-repair mechanisms like Artemis is likely to have a lymphoma in the right lung, and as such he was staged serious and progressive course. as IVA, aaIPI 1. He underwent chemotherapy (R-CHOEP 14x 6 + 2R) [10, 11] and radiation therapy against residual 2. Case Presentation disease and went in complete remission with a negative The patient was a 23-year-old male of Turkish/Kurdish PET-CT. His skin lesions, however, got worse throughout descent of consanguineous parents (second-cousins) who the chemotherapy and radiation therapy and continued to had 4 healthy siblings and one sister with a rare lung disease evolve with infiltration into the masseter muscle in the face not immediately associated with the patient’s condition. His and a similar histopathological picture was found in lesions parents had lost a child at a few months of age with no certain diffusely infiltrating the liver and possibly spleen. eTh patient diagnosis. had no history of recurrent infections, autoimmunity, or eTh patient had skin lesions from 2 years of age, affecting other manifestations of a primary immunodeficiency beside his face and extremities and to a lesser degree his truncus. his skin lesions and lymphoma. el Th esionsappearedaspurpleplaques oftheskinwith At presentation at Oslo University Hospital, he was variable thickness evolving into deep atrophic scars over time. immunologically characterized by a slight hypogammaglob- There had been numerous biopsies over the years showing ulinemia (IgG 6,1 g/L) and absence of B-cells in peripheral an uncharacteristic massive lymphoid infiltration dominated blood considered to be secondary to rituximab treatment by CD8+ lymphocytes and histiocytes and with some granu- (Table 1). However, low numbers but not absence of B-cells lomas (Figure 1). In lack of a more precise histopathological in previous bone marrow biopsies had been noted. He did Case Reports in Immunology 3 (a) (b) (c) (d) Figure 1: Skin lesions. (a) multiple scar-like bluish-red lesions on both arms. (b) indurated, erythematous scar-like lesion on the left cheek. (c, d) Skin biopsy showing massive lymphohistiocytic infiltration focally with formation of granulomas (H&E, 100x and 400x, resp.). eTh re was a dominance of CD8+ T-cells and also an increased proportion of CD4/CD8 double-negative T-cells. not receive any immunoglobulin therapy. He was slightly There was a strong clinical suspicion of an underlying immunodeficiency but DNA-sequencing covering exons and lymphopenic (0,8× 10 /L) and had low levels of CD4+ cells introns to the RAG1/RAG2 gene did not reveal any muta- (177× 10 /L) with an inversed CD4/CD8 ratio of 0,63. There ¨ tions. Samples were taken for whole-exome sequencing, but was an absence of naıveCD4+T-cellsandrecentthymic emigrants. His CD8+ cell pool was expanded but had a whilewaiting forthe results, thepatient hadaDLCBL-like normal phenotype. He had normal levels of double-negative relapse in the gastroventricular mucosa engaging pancreas T-cells and gamma-delta T-cells. Overall the T-cells seemed and spleen with infiltration of irregularly shaped histiocytic to be strongly activated with half being HLA-DR+. We have cells and T-cells monoclonal for the TCR-gamma chain. no data on proliferative response to mitogens or specific Dose-reduced chemotherapy was initiated (isophosphamide, antigens. methotrexate, and etoposide), but aer ft 3 days of therapy, 4 Case Reports in Immunology (a) (b) (c) (d) Figure 2: Aeff ction of facial muscles and internal organs. (a) MR of the neck showing a large ulcerating tumor on the left side with infiltration into nearby muscles. (b) CT of the abdomen showing massive thickening of the ventricular wall due to lymphoma with infiltration also into the spleen and left adrenal gland. (c, d) Skin biopsy from the neck lesion showing sheets of lymphoid cells throughout dermis, with large pale gray nuclei with prominent nucleoli (H&E, 100x and 400x, resp.). On immunohistochemistry, the cells were positive for CD20, Pax5, Bcl-2, MUM1, and EBERISH and negative for CD3, CD4, CD5, CD8, CD30, CD10, Bcl-6, and cyclin D1. Ki-67 showed a proliferative fraction of 70–80% of tumor cells. eTh lesion was classified as diffuse large B-cell lymphoma. a near catastrophic gastrointestinal bleeding occurred from conserved both between species and in members of the𝛽- the tumor. He went through extensive surgery and we CASP domain. received report of a homozygous missense mutation in exon eTh patient was again evaluated by PET-CT and con- 8 of the Artemis-coding gene DCLRE1C (NM 001033855.2: sidered in complete remission aer ft surgery and referred c.632G>T, p.G211V), while he was still in the intensive forHSCT. He hadnoseverecomorbidity,andthenow care unit. Sanger sequencing confirmed homozygosity in increasingly aggressive nature of his immunodeficiency made patient DNA and heterozygosity in his father and one of the case for HSCT well founded. None of his siblings his siblings, while his mother was not tested. Fibroblastic were HLA identical and no matched unrelated donor could culture furthermore revealed radiosensitivity consistent with be identified. For practical reasons, availability as well as identical ABO type, we decided to choose his haploidenti- an Artemis defect. The genetic variant has previously been reported as disease-causing in a patient from a patient cohort cal father as the preferred haploidentical stem cell donor. eTh parents’ heterozygosity for the Artemis mutation was with radiosensitive SCID and Omenn syndrome . It has not been observed in databases for normal variation (ExAC considered irrelevant due to the recessive nature of the trait and their apparently normal immune function. Artemis and gnomAD) . mutated immunodeficiencies in general are likely to toler- eTh affected amino acid is located in the 𝛽-CASP domain of DCLRE1C . Predicted secondary structure suggests ate myeloablative conditioning, which gives the best long- term immune reconstitution with thymopoiesis and B-cell that the amino acid is located in a six-amino-acid-sized stretch between a helix and a strand. eTh amino acid is highly function. eTh options of (A) conditioning with alemtuzumab, Case Reports in Immunology 5 treosulfan, uda fl rabine, and thiotepa using a TCR-alpha and while being generally in good health and with no apparent -beta depleted graft versus (B) using a T-cell replete marrow immunodeficiency. graft aer ft cyclophosphamide 14, 5 mg/kg days −6and−5, The patient had unique skin manifestations and even if sarcoidosis of the skin can present itself with a wide flu 30 mg/m days−6to−2 (5 days), and 200 cGy TBI day range of lesion from papules to plaques and scarring, it is −1  with the addition of busulfan 3.2 mg/kg/day, days−4 unusual in small children. eTh histopathological pattern with and−3 to achieve myeloablation  as conditioning and lymphohistiocytic skin infiltrates with or without granulomas posttransplant cyclophosphamide 50 mg/kg days +3 and +4 is unspecific but is reported in several different primary and tacrolimus and mycophenolate mofetil as gra-v ft ersus- immunodeficiencies, including deficiencies of Artemis , host-disease (GVHD) prophylaxis  were discussed. We and can be an early n fi ding. This patient later developed chose the latter option for our patient, and he received overt B-cell lymphomas of different subtypes. eTh y were BMSC, only 1,7 × 10 NC/Kg, and stable engraftment was achieved at day +18. Donor chimerism was >99% at day all EBV-positive, similar to what is oeft n seen in immun- odeficient patients in the posttransplant situation. Both 100. The posttransplant course was uncomplicated except histopathological settings could therefore alert the observant for two episodes of CMV reactivation that was preemptively pathologist in cooperation with clinicians in the direction treated. of immunodeficiency as an underlying cause. At the time On Day 150, however, the patient was referred to hospital an immunodeficiency was suspected he had already been with fever and lung symptoms with CT scans demonstrating through massive medical treatment and an assessment of his extensive lung infiltrates. Bronchoscopy with bronchoalveo- “na¨ıve” immunological state is hard to make. eTh patient larlavagewasperformedshowingapositivePCR reaction had a mild hypogammaglobulinemia that could have been for Pneumocystis jirovecii, and while the immunou fl orescence secondary to both his previous treatment and his immun- test was negative, a Pneumocystis jirovecii pneumonia (PCP) odeficiency. B-cells can be absent from peripheral blood washighlysuspected.PCPprophylaxiswithtrimethoprim- for several years aer ft treatment with rituximab but are not sulfamethoxazole had been prescribed but the patient had always accompanied by significant hypogammaglobuline- for unknown reasons only taken this on and o.ff Further mia. tests showed a positive Herpes simplex virus PCR reaction The diagnosis of SCID is transforming as more and more in plasma, and Staphylococcus aureus and Candida albicans centers introduce screening methods that will detect major T- were found in blood cultures. eTh patient was extensively cell defects even before clinical symptoms become apparent, treated with antibiotics including high-dose trimethoprim- as is possible in this case. sulfamethoxazole as well as corticosteroids and acyclovir. eTh introduction of whole-exome sequencing to clinical Sadly, however, he did not respond to this treatment and died on day 167. Autopsy was unfortunately not done. immunology has transformed not only the diagnostics but also the treatment of primary immunodeficiencies. In our 3. Discussion case, the strong suspicion of a recombination defect was con- rfi med and made the decision to proceed with a transplant This case of a hypomorphic Artemis mutation highlights the easier, even without a matching donor. Furthermore, even if progressive nature of this disease, gradually presenting new theclinicalbasis foratransplantcouldbeconsideredclear complications as the clinicians strive to keep clinical control. without the exact diagnosis, the finding of a recombination Mutations in the Artemis/DCLRE1C gene have traditionally defect and the subsequent radiosensitivity assay had a major been associated with SCID and Omenn syndrome, but influence on the choice of protocol and conditioning needed. recently various mutations have been shown to be associated Time was of the essence, and the value of a prompt diagnosis also with milder forms of immunodeficiencies, including in this setting cannot be overestimated. hypogammaglobulinemia [3, 4]. While dysfunction of the Datafromourcenterindicatethatwhole-exomesequenc- Artemis gene is less destructive to the recombination of T-cell ing leads to revision of the clinical diagnosis in more and B-cell receptors than RAG deficiencies, the ubiquitous than half of the patients and management was directly distribution of the protein in all cells of the body makes the altered in nearly a quarter of families based on molec- clinical consequences both wider and less predictable . The ular findings . The major obstacles for the wide mutation found in our patient has previously been reported as implementation of high-throughput sequencing in diag- causing SCID-like disease but the clinical and immunological nosis of primary immunodeficiencies are the high price characteristics of these patients are not known . There and limited capacity for sequencing and interpretation. is a known association between Artemis deficiency and Both continue to improve, but the immense value of lymphomas, as demonstrated by early reports of aggressive this diagnostic tool in the care of these highly com- B-cell lymphomas in patients with hypomorphic Artemis plex patients should make this happen sooner rather than mutations, as well as mutations in DNA-repair genes in B-cell later. lymphomas [8, 17, 18]. Leaky SCIDs and other forms of combined immunode- Data Availability ficiencies with an indolent but severe prognosis represent a special challenge to geneticists, immunologists, and clinicians All available data is included in the manuscript. The full involved in the care of these patients. In our case, the patient transcript of the genomic analyses cannot be published due had more than 20 years of slowly progressing skin lesions to legislative regulations. 6 Case Reports in Immunology Conflicts of Interest Nordic lymphoma group study,” Annals of Oncology,vol.24,no. 5, Article ID mds621, pp. 1385–1392, 2013. eTh authors declare that there are no conflicts of interest  U. Pannicke, M. Honig ¨ , I. Schulze et al., “eTh most frequent regarding the publication of this paper. DCLRE1C (ARTEMIS) mutations are based on homologous recombination events,” Human Mutation,vol.31,no.2,pp. 197– 207, 2010. Acknowledgments  M.Lek,K.J.Karczewski,andE. V.Minikel,“Analysisofprotein- The authors thank Dr. Andrew Gennery, Great North’s coding genetic variation in 60,706 humans,” Nature,vol.536,no. Children Hospital, Newcastle, UK, and Dr. Dennis Hichstein, 7616, pp. 285–291, 2016. National Institutes of Health, Bethesda, USA, for valuable  I. Callebaut, D. Moshous, J.-P. 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