Bednarski, Jeffrey J

Bigley, Tarin M

Guess, Rachel

Harocopos, George

Hassmann, Lynn M

English

Digital Commons@Becker

Washington University School of Medicine Digital Commons@Becker 2020-Current year OA Pubs Open Access Publications 12-22-2023 Pediatric necrobiotic xanthogranuloma as a novel phenotype of IKAROS gain of function Rachel Guess Washington University School of Medicine in St. Louis George Harocopos Washington University School of Medicine in St. Louis Jeffrey J Bednarski Washington University School of Medicine in St. Louis Lynn M Hassmann Washington University School of Medicine in St. Louis Tarin M Bigley Washington University School of Medicine in St. Louis Follow this and additional works at: https://digitalcommons.wustl.edu/oa_4  Part of the Medicine and Health Sciences Commons Please let us know how this document benefits you. Recommended Citation Guess, Rachel; Harocopos, George; Bednarski, Jeffrey J; Hassmann, Lynn M; and Bigley, Tarin M, "Pediatric necrobiotic xanthogranuloma as a novel phenotype of IKAROS gain of function." Journal of clinical immunology. 44, 1. 19 (2023). https://digitalcommons.wustl.edu/oa_4/3855 This Open Access Publication is brought to you for free and open access by the Open Access Publications at Digital Commons@Becker. It has been accepted for inclusion in 2020-Current year OA Pubs by an authorized administrator of Digital Commons@Becker. For more information, please contact vanam@wustl.edu. / Published online: 22 December 2023 Journal of Clinical Immunology (2024) 44:19 Vol.:(0123456789) https://doi.org/10.1007/s10875-023-01622-4LETTER TO EDITORPediatric Necrobiotic Xanthogranuloma as a Novel Phenotype of IKAROS Gain of FunctionRachel Guess1 · George Harocopos2,3 · Jeffrey J. Bednarski4 · Lynn M. Hassmann2 · Tarin M. Bigley1 Received: 30 August 2023 / Accepted: 24 October 2023 © The Author(s) 2023To the Editor,The IKFZ1 (IKAROS) gene has broad roles in T and B lym-phocyte development and function. Loss of function variants in the IKAROS gene have been associated with a range of presentations including a spectrum of immunodeficiency, immune dysregulation, and hematologic malignancy [1–3]. Gain of function (GOF) variants in IKAROS were reported in patients presenting with immune dysregulation in the form of allergies, autoimmunity, increased rate of infec-tions, and lymphoproliferation, while somatic variants have been linked to multiple myeloma [4]. We describe a pedi-atric patient with IKAROS GOF presenting with immune dysregulation and necrobiotic xanthogranuloma (NXG).A 15-year-old white male presented as a transfer of care with a chronic right orbital mass resulting in right eye vision loss. He first presented at age 5 with fever, rash, and multi-organ failure requiring prolonged hospitalization. He was diagnosed with systemic juvenile idiopathic arthritis (sJIA). Treatment included corticosteroids, hydroxychloroquine, and methotrexate, which induced remission. He was off medications for several years until age 9 when he devel-oped progressive erythematous swelling of the right perio-cular tissues. Imaging showed a large right inflammatory orbital mass. Biopsy of the right orbital mass demonstrated inflammatory histiocytic infiltration including palisading around necrobiotic areas, negative cultures, negative IgG4 staining, and a CD4:CD8 T cell ratio of 9:1. He was treated with multiple immunosuppressives, including prednisone, hydroxychloroquine, methotrexate, mycophenolate mofetil, adalimumab, abatacept, tocilizumab, intravenous immuno-globulin (IVIG), and rituximab without improvement of the mass. Adalimumab and IVIG were not tolerated due to side effects. He was noted to have moderate seasonal allergies, polyarthralgia, myalgia, and recurrent supra-infections of the right orbital mass. He underwent several surgical procedures on the orbital mass. Repeat biopsies performed 3 years later exhibited xanthogranulomatous inflammation and negative microbial staining. Imaging at age 13 indicated an extensive inflammatory and sclerosing right orbital mass and a lesser involvement of the left orbit and lacrimal gland.Upon presentation to our center, he was receiving low-dose prednisone and rituximab bimonthly for a chronic orbital mass resulting in facial asymmetry and loss of right-eye vision, presumably due to a combination of com-pressive optic neuropathy and corneal scarring from prop-tosis-related exposure (Fig. 1A). His workup demonstrated a negative auto-antibody profile, normal to elevated immu-noglobulin levels (while B cell depleted), normal serum IgG4 levels, elevated muscle enzymes, abnormal T cell phenotyping with moderately increased CD4 + memory T cells, and mildly decreased memory B cells (measured after B cell reconstitution) (Supplemental Tables 1–2). The auto-antibody testing may have been affected by ritux-imab treatment, although was similar prior to treatment apart from an ANA of 1:80. MRI of the right orbital mass revealed diffuse pre- and post-septal enhancing inflam-mation involving the extraocular muscles, with enhance-ment and stretching of the optic nerve, and prominent exophthalmos (Fig. 1B). Genetic testing with a primary immunodeficiency panel (Invitae) revealed a pathogenic variant in IKZF1 on exon 5 at c.548G > A (p.Arg183His), previously documented as a gain of function, as well as a  * Tarin M. Bigley  bigley@wustl.edu1 Division of Rheumatology/Immunology, Department of Pediatrics, Washington University School of Medicine in St Louis, St. Louis, MO, USA2 Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA3 Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA4 Division or Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USAJournal of Clinical Immunology (2024) 44:19 1 3variant of uncertain significance in ITGAM (c.1459C > T (p.Arg487*)) [4]. His sister (age 13) and father were tested, and his sister had the same pathogenic variant in IKZF1. On her evaluation, she was found to have seasonal allergies, mildly decreased CD8 + T cells, and increased IgA and IgE (Supplemental Table 3). The family history included multiple females spanning three generations who had arthritis and lung disease resulting in early death, the 19 Page 2 of 4Journal of Clinical Immunology (2024) 44:19 1 3youngest being his mother at age 34 who had been diag-nosed with autoimmune connective tissue disease and right optic neuritis (Fig. 1C).Our patient was initiated on sirolimus; however, he had progression of the bilateral orbital masses following a COVID infection. MRI also demonstrated enhancing, infil-trative tissue advancing into the right parotid gland, right cervical lymph nodes, and right soft palate (Fig. 1D). Due to concern for malignant transformation, a PET scan was obtained (Fig. 1E). This revealed a hypermetabolic infiltra-tive mass with a maximum standardized uptake value (SUV) of 13, favoring an inflammatory process over malignancy. Biopsies of the right orbital mass, right parotid gland, and lymph node were consistent with NXG, characterized by granulomatous inflammation with “foamy” histiocytes and Touton giant cells (Fig. 1F), and palisading histiocytes sur-rounding areas of necrobiosis (Fig. 1 G and H). There was also a mixed lymphoplasmacytic inflammation including some lymphoid follicles, along with scattered eosinophils. No vasculitis was seen. The abundant histiocytes were high-lighted by CD163 immunostain (Fig. 1I). The lesion was plasma cell–rich as evidenced by CD138 immunostaining (Fig. 1J) with increased IgG4 expression (Fig. 1K). Immu-nostaining for CD1a and BRAF V600E mutation were nega-tive (Supplemental Fig. 1A and 1B), as was microbial stain-ing and culture. The histo-morphology did not demonstrate any evidence of lymphoma, nor did any of the additional immunohistochemical markers that were obtained for lym-phoma work-up, while kappa and lambda in situ hybridiza-tion confirmed a polytypic mixture of plasma cells, in a 2:1 ratio. Bone marrow biopsy showed hypocellular trilineage hematopoiesis with no blasts. Lymph node flow cytometry was negative for malignancy. Serum protein electrophoresis was normal.NXG is classified as a non-Langerhans cell histiocyto-sis. NXG is an inflammatory mass typically spurred by an underlying immune dysregulation such as malignancy or autoimmunity [5–7]. It often presents as a slowly progres-sive anterior orbital mass bilaterally [5]. As described above for our patient, NXG histology is characterized by necrobi-otic zones with palisading histiocytes, Touton giant cells, cholesterol clefts, and lymphoplasmacytic infiltrate [5]. It most commonly occurs in older individuals, with average age of diagnosis being 61. NXG is often seen in associa-tion with paraproteinemia or multiple myeloma [5]. NXG is typically responsive to immunosuppression and treatment of underlying disease. In a systemic review of 175 patients, the most common therapies were IVIG, corticosteroids, alkylat-ing agents, and corticosteroid combination therapies [6]. We therefore started our patient on a combination therapy of cyclophosphamide (500 mg oral once weekly × 4 weeks), dexamethasone (20 mg twice daily on days 1 to 4 and 12 to 15), and high-dose IVIG (1 g/kg monthly). After two cycles of therapy, he had clinical improvement of the lesion and a small reduction in size based on MRI (Supplemental Fig. 1C&D). He will proceed to hematopoietic stem cell transplant after a reduction in the size of his NXG.In summary, we describe a pediatric case of IKAROS GOF resulting in immune dysregulation with multiple phe-notypic expressions including allergies, susceptibility to bac-terial infections, autoimmunity diagnosed as sJIA in early childhood, myositis, and, most notably, NXG resulting in facial asymmetry and vision loss. Although family mem-bers with the disease were deceased before we were able to perform genetic testing, we can presume based on history, that he is the fourth generation with autoimmunity related to IKAROS GOF, with increasingly severe disease in each generation.To our knowledge, at age 9 our patient is the youngest to present with NXG and the first to be diagnosed with NXG in relation to an underlying inborn error of immunity (IEI) [7]. Juvenile xanthogranuloma, a related non-Langerhans cell his-tiocytosis, has been associated with germline NF1, NF2, and WASP variants and somatic BRAF, MAP2K1, MET, KRAS, ALK, PI3CKD, and CSF1R variants, some of which are genes also associated with IEIs [8, 9]. IKAROS GOF leads to broad immune dysregulation, including early terminal differentia-tion of T lymphocytes and decreased memory B cells. There appears to be a tendency towards lymphoproliferation in IKAROS GOF patients, with lymphadenopathy and multiple myeloma previously described. Our patient had progressive orbital NXG without evidence of malignancy, suggesting it occurred secondary to his underlying immune dysregula-tion. This further exemplifies the hematologic abnormalities observed in IKAROS GOF. His lesion was IgG4 enriched Fig. 1  Evaluation of orbital mass and family history of a patient with IKAROS GOF. A Image of the patient’s right eye, used with permis-sion from the patient and parent. B T2 FLAIR MRI of mass with extensive inflammatory infiltration into the posterior orbital space and proptosis. C Partial family pedigree. The arrow represents the proband. Disease with confirmed IKAROS GOF genetic testing is represented in a circle with a black fill while disease not confirmed by genetics is represented in a circle with a striped fill. D T2 FLAIR MRI-PET of mass with extension of the inflammatory mass follow-ing a COVID infection. E MRI-PET with PET-avid lymph nodes in the right pre-auricular area, right upper soft palate, and right ante-rior cervical chain. F “Foamy” histiocytes (thick arrows) and multi-ple Touton giant cells (thin arrows) (H&E stain, original magnifica-tion 400 ×). G Classic Touton giant cell (thin arrow) with palisading macrophages (thick arrows) and cholesterol clefts (star) (H&E stain, original magnification 400 ×). H Palisading histiocytes (thick arrows) around a necrobiotic area (star), (H&E stain, original magnification 200 ×). I CD163 immunostain highlighting abundant histiocytes, including Touton giant cells (original magnification 400 ×). J CD138 immunostain highlighting plasma cell–rich areas (original magnifica-tion 400 ×). K IgG4 immunostain highlighting up to 100 plasma cells per high-power field, comprising about 25% of the total plasma cell population, indicating increased expression (original magnification 400 ×)◂Page 3 of 4 19Journal of Clinical Immunology (2024) 44:19 1 3and histiocyte-predominant. A previously described IKAROS GOF patient had histologic features of the histiocyte disorder, Rosai-Dorfman Disease [4]. Together, these findings suggest a role of IKAROS in histiocyte homeostasis. In conclusion, this case demonstrates a phenotypic expansion of IKAROS GOF to include systemic life-threatening hyperinflammation along with subsequent development of NXG at a very young age and highlights the treatment-resistant nature of this disease.Supplementary Information The online version contains supplemen-tary material available at https:// doi. org/ 10. 1007/ s10875- 023- 01622-4.Acknowledgements We would like to thank our patient and his family for allowing us to learn from and share their story.Author Contribution Conceptualizations: RG, TMB; analysis: RG, GH, JJB, LMH, TMB; resources: RG, GH, TMB; visualization: RG, GH, TMB; writing—original draft preparation: RG, GH, JJB, LMH, TMB; writing—revision: RG, TMB.Funding This work received support from The Center for Pediatric Immunology and The Jeffrey Model Diagnostic and Research Center for Primary Immunodeficiencies at St. Louis Children’s Hospital and Washington University.Data Availability The authors confirm that the data supporting the findings of this study are available within the article and/or its sup-plementary materials.Declarations Ethics Approval No human subject research was performed for this report therefore ethical approval was not required.Consent to Participate Signed informed consent to publish this report and images were obtained from the family.Consent for Publication Signed informed consent to publish this report and images were obtained from the family.Conflict of Interest The authors declare no competing interests.Open Access This article is licensed under a Creative Commons Attri-bution 4.0 International License, which permits use, sharing, adapta-tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Pediatric necrobiotic xanthogranuloma as a novel phenotype of IKAROS gain of function

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Pediatric necrobiotic xanthogranuloma as a novel phenotype of IKAROS gain of function

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