Novel invariant features of Good syndrome

Abstract

Good syndrome (GS), originally described in 1954 by Dr Robert Good in a series of three patients, classically comprises hypogammaglobulinemia (HG) and thymoma [1]. We encountered a challenging 85-year-old patient with 5 months duration of normocytic, normochromic, reticulocytopenic anemia, a thymoma, and HG, compatible with a provisional diagnosis of pure red cell aplasia (PRCA). A blood smear revealed reactive large granular lymphocytic (LGL) leukemia with an absolute LGL count of 2020/μL. A bone marrow aspiration/biopsy showed a paucity of erythroid precursors, increased myeloid/erythroid ratio, no dysplastic changes, nor cytogenetic abnormalities suggestive for a concomitant myelodysplastic syndrome and CD8 lymphocytic infiltrates negative for somatic STAT3/STAT5B mutations. Flow cytometry demonstrated increased CD56CD16CD8 cells with a positive TCR-gamma rearrangement. This presentation resembled GS, with the additional presence of PRCA and LGL. We subsequently identified two additional cases, both presenting with the combination of GS, PRCA, and LGL, TCR-gamma rearrangement but no bone marrow dysplasia, cytogenetic abnormalities, STAT3/STAT5B, or other myeloid mutations. Of note, all these three patients were male and two of them presented with lichen planus, a chronic autoinflammatory disorder that most often affects middle-aged adults, involving both the skin and mucous membranes. While the association between LGL and PRCA has been previously studied [2, 3], to the best of our knowledge, only one patient with coexisting GS and LGL has been reported [4]. This suggests that our series did not represent a random combination of rare clinical features, pointing instead to common pathogenetic links. They may include regulatory circuits involving precursor Band T-cell maturation and thymic epithelium function explaining coexistence of HG, T-cell autoimmunity, and propensity for clonal expansion [5]. This report investigates whether GS associations constitute a novel continuum of clinical features with unifying pathogenesis. We analyzed three separate cohorts of patients with thymoma (N= 327), PRCA (N= 74), and LGL (N= 257) referred to The Cleveland Clinic Foundation between the years of 2000 and 2019 (Fig. 1A, B). Thymoma was classified according to the Suster–Moran classification based on morphologic features of differentiation (thymoma, atypical thymoma, and thymic carcinoma) and on whether the cellular nuclei had a spindle/oval shape (type A), an epithelioid appearance (type B), or mixed (AB) [6]. GS was defined as “classic” in case of concomitant presence of thymoma and HG or “probable” with any unclassified immunodeficiency [7]. T-LGL was diagnosed if more than three of the following criteria were present: (i) LGL count >500/μL, (ii) marrow LGL aggregates, (iii) phenotypically aberrant cytotoxic T-lymphocytes expressing CD2, CD56, and CD57 and lacking CD28, (iv) preferential usage of a TCR Vb-family by flow cytometry, and (v) positive These authors contributed equally: Carmelo Gurnari, Jibran Durrani