An Atypical Presentation of X-linked Lymphoproliferative Disease type 1 Presenting with Seronegative Coccidioidomycosis

Abstract

X-linked lymphoproliferative disease (XLP-1), an inborn error of immunity (IEI) caused by pathogenic variants in SH2D1A encoding signaling lymphocyte activation molecule-associated protein (SAP), is characterized by hemophagocytic lymphohistiocytosis (HLH), lymphoma, and hypogammaglobulinemia. We report the first known case of XLP-1 presenting with seronegative coccidioidomycosis. CaseA 13-year-old boy with persistent asthma, recurrent otitis media requiring four sets of tympanostomy tubes, chronic sinusitis, and Common Variable Immunodeficiency (CVID) presented with acute-on-chronic hypoxic respiratory failure. He had been off subcutaneous immunoglobulin (SCIg) replacement for 2 years. Sputum culture was positive for H. influenzae, treated with cefepime and azithromycin and supplemental oxygen for acute hypoxic respiratory failure. Fever persisted despite 48 hours of antibiotics. CT chest showed bronchiectasis with mediastinal, subcarinal and hilar adenopathy. Coccidioides immitis IgG and IgM were negative, but urine antigen was positive. There was no radiologic or cerebrospinal fluid evidence of disseminated coccidioidomycosis.Immunologic workup revealed undetectable IgG, IgA, IgM, and IgE (table 1). Lymphocyte subsets showed severe T and NK cell lymphopenia. Total B cell count was normal, but he had decreased CD19+27+ and transitional B cells, with absent switched memory B cells and no plasmablasts (table 1). Lymphocyte proliferation to mitogens/antigens was decreased. Serum ferritin was normal, and EBV PCR was negative. A targeted 429-gene panel identified a hemizygous variant of uncertain significance (VUS) in SH2D1A, c.82_102dup (p.Ser28_Ser34dup). SAP expression was absent in CD4+ T cells and NK cells with a bimodal expression in CD8+ T cells, suggesting possible mosaicism in this subset. He was diagnosed with X-linked lymphoproliferative disease 1 (XLP-1) and treated with fluconazole, trimethoprim-sulfamethoxazole prophylaxis, and IgG replacement (1 g/kg intravenous initially, then transitioned to weekly SCIg targeting an IgG >1000 mg/dL), with clinical improvement, resolution of fevers and acute hypoxia. He was referred for hematopoietic cell transplant evaluation.Coccidioidomycosis has not been described in a new diagnosis of XLP-1 and should be considered in this IEI. Coccidioidomycosis susceptibility has been reported in other IEIs including impaired interleukin-12/interferon-gamma axis signaling, STAT3 loss of function, chronic granulomatous disease, and recently cytidine triphosphate synthase 1 (CTPS1) deficiency.Table 1Patient’s immunologic variables compared to reference range. Absolute values are shownImmunologic VariablePatient ValuesReference RangeIgG<70 (L)<70 mg/dLIgA<15 (L)<15 mg/dLIgM<8 (L)<8 mg/dLIgE<1.5 (L)<1.5 IU/uLTotal CD4+ T Cells11 (L)570–2400 cells/uLTotal CD8+ T Cells63 (L)210–1200 cells/uLTotal CD19+ B cells173165–1154 cells/uLCD19+ CD24++ CD38++ (Transitional B Cells)0 (L)8–392 cells/uLCD19+CD24+CD38+ (Naïve B Cells)12159–1146 cells/uLCD19+CD27-(Naïve B cells)169140–2269 cells/uLCD19+ CD27+ CD38+ IgM- (Plasmablasts)0<30 cells/uLCD19+CD27+IgD-IgM- (Switched-memory B cells)0 (L)6–190 cells/uLCD16+ CD56+ (NK Cells)32 (L)78–470 cells/uLL – low