SH2D1A Deficiency

Abstract: To the Editor: X-linked lymphoproliferative disease (XLP) is a rare primary immune deficiency (PID) characterized by fulminant infectious mononucleosis from Epstein–Barr virus (EBV), hemophagocytic lymphohistiocytosis (HLH), hypo/dysgammaglobulinemia, and lymphoproliferative disease, including lymphomas.1,2 XLP is caused by inactivating mutations in SH2D1A, which encodes signaling lymphocytic activation molecule (SLAM)-associated protein (SAP).3 SAP is critical for function of cytotoxic CD8+ T cells, natural killer (NK) cells, and NKT cells, which are important in cancer surveillance.3–5 Below describes a case of ganglioneuroblastoma incidentally discovered during pre-hematopoietic stem cell transplant (HSCT) workup in a child with XLP. The case highlights that development of solid tumorsmay be possible in individuals with XLP. This could occur due to dysfunction of those innate immune cells that require SAP for normal cytolytic effector function (e.g., NK andNKT cells).6 This would further be supported by the fact that NK and NKT-directed therapies are currently being studied in neuroblastoma.7–11 A 2-year-old male presented with 3-day history of fevers and cervical lymphadenopathy. He was discharged with amoxicillinclavulanate and dexamethasone for possible lymphadenitis, and family was encouraged to utilize anti-pyretics and hydration. Four days later, he returned after having a febrile seizure. Physical exam demonstrated persistent bilateral anterior cervical lymphadenopathy and splenomegaly. He was noted to have anemia, thrombocytopenia, leukocytosis, and transaminitis. He was diagnosed EBV positive based on elevated IgM and IgG antibodies to EBV viral capsid antigen. Family history revealed a maternal uncle who died as a teenager from a metastatic abdominal tumor and neck masses of uncertain histology. There was no clearly documented family history of EBV infection or autoimmunity. He was treated, prior to immune deficiency diagnosis, with intravenous immunoglobulin for suspected atypical Kawasaki and later transferred to another hospital. There, he was evaluated for HLH, including HLH genetic panel, which demonstrated a hemizygous SH2D1A mutation (NM_002351.4(SH2D1A):c.385T>G) classified as likely pathogenic, as well as NK-cell activity, which was noted to be decreased (NK percent cytotoxicity at 50:1 was 8%). He was then referred for curative allogeneic HSCT for diagnosis of XLP. During subsequent pre-HSCT evaluation (6 months after initial presentation), his immunoglobulins demonstrated a low IgM (19.6 mg/dl), normal IgG (838 mg/dl), and normal IgA (113 mg/dl). Additionally, cross-sectional imaging of his chest, abdomen, and pelvis revealed an incidental left adrenal mass (Figure 1). The mass was fully resected by laparoscopy and final pathology revealed ganglioneuroblastoma with no myc-n amplification. Metastatic workup including bilateral bone marrow aspirates and biopsies along with meta-iodo-benzylguanidine (MIBG) scan was negative. His malignancy was classified as low risk, and as he required no additional treatment, he proceeded to allogeneic HSCT as planned as curative therapy for underlying XLP. His conditioning regimen included fludarabine, thiotepa, melphalan, and rabbit antithymocyte globulin. He received his HSCT from a 10/10 matched unrelated donor. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and mycophenolate. His transplant course was generally uncomplicated, with the exception of transient adenoviremia requiring cidofovir and transient reactivations of human herpes virus 6 treated with ganciclovir. He continues with post-HSCT monitoring with no signs of GVHD, and surveillance screening for neuroblastoma, for which he remains relapse-free. This is the first case reported of a non-lymphoma malignancy in an individual diagnosedwith XLP, a rare primary immune deficiency (PID).