Lymphadenopathy at the crossroad between immunodeficiency and autoinflammation: An intriguing challenge

Clin Exp Immunol. 2021 Sep;205(3):288-305. doi: 10.1111/cei.13620. Epub 2021 Jun 20.


Lymphadenopathies can be part of the clinical spectrum of several primary immunodeficiencies, including diseases with immune dysregulation and autoinflammatory disorders, as the clinical expression of benign polyclonal lymphoproliferation, granulomatous disease or lymphoid malignancy. Lymphadenopathy poses a significant diagnostic dilemma when it represents the first sign of a disorder of the immune system, leading to a consequently delayed diagnosis. Additionally, the finding of lymphadenopathy in a patient with diagnosed immunodeficiency raises the question of the differential diagnosis between benign lymphoproliferation and malignancies. Lymphadenopathies are evidenced in 15-20% of the patients with common variable immunodeficiency, while in other antibody deficiencies the prevalence is lower. They are also evidenced in different combined immunodeficiency disorders, including Omenn syndrome, which presents in the first months of life. Interestingly, in the activated phosphoinositide 3-kinase delta syndrome, autoimmune lymphoproliferative syndrome, Epstein-Barr virus (EBV)-related lymphoproliferative disorders and regulatory T cell disorders, lymphadenopathy is one of the leading signs of the entire clinical picture. Among autoinflammatory diseases, the highest prevalence of lymphadenopathies is observed in patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and hyper-immunoglobulin (Ig)D syndrome. The mechanisms underlying lymphoproliferation in the different disorders of the immune system are multiple and not completely elucidated. The advances in genetic techniques provide the opportunity of identifying new monogenic disorders, allowing genotype-phenotype correlations to be made and to provide adequate follow-up and treatment in the single diseases. In this work, we provide an overview of the most relevant immune disorders associated with lymphadenopathy, focusing on their diagnostic and prognostic implications.

Keywords: CTLA-4; LRBA; activated phosphoinositide 3-kinase δ syndrome; autoimmune lymphoproliferative syndrome; common variable immunodeficiency.

Publication types

  • Review

MeSH terms

  • Common Variable Immunodeficiency / diagnosis
  • Common Variable Immunodeficiency / genetics
  • Common Variable Immunodeficiency / immunology*
  • Common Variable Immunodeficiency / pathology
  • Epstein-Barr Virus Infections / immunology
  • Genetic Predisposition to Disease / genetics
  • Herpesvirus 4, Human / immunology
  • Humans
  • Immunologic Deficiency Syndromes / diagnosis
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / immunology*
  • Immunologic Deficiency Syndromes / pathology
  • Infant
  • Infant, Newborn
  • Lymphadenopathy / diagnosis
  • Lymphadenopathy / immunology*
  • Lymphadenopathy / pathology
  • Lymphoproliferative Disorders / diagnosis
  • Lymphoproliferative Disorders / genetics
  • Lymphoproliferative Disorders / immunology*
  • Lymphoproliferative Disorders / pathology