Inborn errors of immunity presenting with lymphoproliferation: lessons from a case series

Abstract

Lymphoproliferation can represent the first or leading disease sign in different inborn errors of immunity (IEI), which include autoimmune lymphoproliferative syndrome (ALPS), common variable immunodeficiency (CVID), combined immunodeficiencies, activated phosphoinositide 3-kinase δ syndrome (APDS), Epstein-Barr (EBV)-related disorders, and others. The genetic and molecular background and the clinical implications of IEI presenting with lymphoproliferation are partly unexplored. Therefore, the diagnosis and clinical management of this category of patients is particularly challenging. As treatments targeting the specific genetic defect are available for some of the IEIs associated with lymphoproliferation, identifying the molecular diagnosis is of great clinical relevance and could significantly improve the patient's long-term outcome. To this purpose, a first-level immunological assessment is strongly recommended in patients with persistent or recurrent unexplained lymphoproliferation, and specific second-level analysis can orient towards the correct clinical suspicion. The mechanisms responsible for polyclonal, benign lymphoproliferation in IEI also cause an increased susceptibility to clonal, malignant lymphoproliferation. Therefore, a careful follow-up is recommended in all the patients with IEI and polyclonal lymphoproliferation, to promptly identify the development of clonality. Moreover, as malignant lymphoproliferation can be the first disease sign of some IEI, there is increasing interest in the possibility of recognizing IEIs in patients presenting with lymphoid malignancies. This work, by describing some relevant case studies, reviews the role of lymphoproliferative features in three of the most paradigmatic conditions, particularly ALPS, CVID, and APDS, and provides an updated discussion on the diagnosis, treatment, and follow-up of patients with IEI and lymphoproliferative features.

Keywords: Activated phosphoinositide 3-kinase δ syndrome; Autoimmune lymphoproliferative syndrome; Common variable immunodeficiency; Hodgkin lymphoma; Lymphadenopathy; Pediatrics; Splenomegaly.

Fig. 1

Splenomegaly in an 18-month-old patient with ALPS

Fig. 2

Expansion of TCR αβ + double-negative T-cells in a 30-year-old patient with ALPS

Fig. 3

PET scan findings in a patient with common variable immunodeficiency developing nodular lymphocyte-predominant Hodgkin’s lymphoma (maximum standardized uptake value [SUV] of 15 in the axillary lymphadenopathies)

Fig. 4

An overview of IEI presenting clinical overlaps between the ALPD and CVID spectrum

Fig. 5

Warning signs for the diagnosis of an underlying IEI in patients presenting with lymphoma and red flags for the early identification of lymphoproliferative diseases in patients with IEI