Lymphoproliferation in Inborn Errors of Immunity: The Eye Does Not See What the Mind Does Not Know

Abstract

Inborn errors of immunity (IEIs) are a group of heterogeneous disorders characterized by a broad clinical spectrum of recurrent infections and immune dysregulation including autoimmunity and lymphoproliferation (LP). LP in the context of IEI may be the presenting feature of underlying immune disorder or may develop during the disease course. However, the correct diagnosis of LP in IEI as benign or malignant often poses a diagnostic dilemma due to the non-specific clinical features and overlapping morphological and immunophenotypic features which make it difficult to treat. There are morphological clues to LP associated with certain IEIs. A combination of ancillary techniques including EBV-associated markers, flow cytometry, and molecular assays may prove useful in establishing a correct diagnosis in an appropriate clinical setting. The present review attempts to provide comprehensive insight into benign and malignant LP, especially the pathogenesis, histological clues, diagnostic strategies, and treatment options in patients with IEIs.

The Etiologic Landscape of Lymphoproliferation in Childhood: Proposal for a Diagnostic Approach Exploring from Infections to Inborn Errors of Immunity and Metabolic Diseases

“…Also, lymphoproliferative features are frequently observed in diseases caused by an altered control of specific infections, as evidenced in EBV-related disorders. 2,3,43 CVID is associated with lymphoproliferation in more than 10% of the patients. The incidence is specifically higher in patients carrying definite genetic mutations, including NFKB1 and TACI.…”

“…Apart from the infectious and malignant etiologies, the role of lymphoproliferative features as presenting signs of inborn errors of immunity (IEI) and inborn errors of metabolism (IEM) is being increasingly investigated. [2][3][4] Moreover, systemic autoimmune diseases, autoinflammatory disorders, and rare conditions such as sarcoidosis and Castleman diseases can also present with isolated lymphoproliferation.…”

“…This is particularly notable in the case of patients suffering from IEI who have an increased susceptibility to Epstein-Barr virus (EBV) infection and a consequent high risk of development of clonal, malignant lymphoproliferation. 2,3 Therefore, the clinical approach to patients presenting with lymphoproliferative features is of great complexity, and the diagnosis of some conditions is often delayed in clinical practice.…”

“…This is particularly notable in the case of patients suffering from IEI who have an increased susceptibility to Epstein-Barr virus (EBV) infection and a consequent high risk of development of clonal, malignant lymphoproliferation. 2 , 3 …”

CTP synthase: the hissing of the cellular serpent

“…Deficiency of CTPS1 causes severe immunodeficiency, and this could lead to death if infected with Epstein Barr virus (EBV) and varicella zoster virus (VZV), and viral EBV infections would especially result in lymphoproliferation (LP) and non-Hodgkin B-cell lymphoma (Sharma et al 2022 ). Hematopoietic stem cell transplantation (HSCT) could be the curative method to restore CTPS1-deficient immunodeficiency (Nademi et al 2019 ).…”