From syndromic clues to diagnosis: understanding CARD11-driven disorders

TL;DR

This paper reviews disorders caused by CARD11 gene mutations, explaining how they lead to immune system issues and how early diagnosis can improve treatment.

Contribution

The paper provides a comprehensive overview of CARD11-driven immunodeficiencies and their management, highlighting the need for early diagnosis.

Findings

Gain-of-function CARD11 mutations cause BENTA syndrome with uncontrolled NF-κB activity.

Loss-of-function variants are linked to Hyper-IgE-like syndromes with immunodeficiency and autoimmunity.

CARD11-related diseases may be underdiagnosed due to overlap with other immune and hematological disorders.

Abstract

CARD11 is primarily expressed in hematopoietic tissues and lymphocytes and plays a crucial role in the proper activation of B and T cells in response to antigen recognition. Pathogenic variants in the CARD11 gene result in a broad spectrum of syndromic immunodeficiencies with variable severity and clinical outcomes. Gain-of-function mutations lead to uncontrolled NF-κB activity in lymphocytes and are associated with BENTA syndrome (B-cell Expansion with NF-κB and T-cell Anergy), an autosomal dominant disorder characterized by resistance to conventional therapies used for lymphoproliferative conditions. In contrast, loss-of-function variants are linked to Hyper-IgE-like syndromes, presenting with varying degrees of immunodeficiency—ranging from combined immunodeficiency to specific humoral defects—accompanied by atopic manifestations and autoimmunity. CARD11-associated diseases may be more prevalent than previously recognized due to their clinical overlap with atopic and hematological syndromic disorders. Consequently, a high index of suspicion for these conditions facilitates early diagnosis and enables personalized treatment. In this review, we summarize the broad spectrum of CARD11-related diseases, their underlying pathophysiological mechanisms, multidisciplinary management strategies, and current therapeutic options, along with potential future approaches.

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