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<p>Phosphoinositide 3-kinases (PI3Ks), particularly the PI3Kδ pathway, play a crucial role in regulating immune functions. Alterations in this pathway, either as hyperactivation, such as in activated PI3Kδ syndrome (APDS), or rarely described hypoactivation, profoundly influence immune function and are linked to a spectrum of immunodeficiencies and autoimmune conditions. This report describes two cases of late-onset immunodeficiencies associated with PI3Kδ pathway dysregulation, each presenting with unique mutations and clinical manifestations. The first case involves a heterozygous mutation in PI3KR1 (c.5A &gt; T, p.Tyr2Phe) indicative of PI3Kδ hyperactivation, effectively managed with sirolimus. The second case is characterized by a homozygous mutation in PIK3CD (c.2608C &gt; T, p.Arg870Ter), suggesting PI3Kδ hypoactivation, with clinical features including psoriatic arthritis and ulcerative colitis. These cases underscore the heterogeneous clinical features and the challenges in managing such rare genetic variants. These cases underscore the importance of considering primary immunodeficiency in individuals exhibiting signs of both infectious and non-infectious autoimmune or immune dysregulation complications. Prompt genetic screening and strategic therapeutic approaches are crucial for effectively managing these conditions and mitigating the risks associated with immunosuppressive treatments. These insights emphasize the need for a deeper understanding of genetic factors in immunodeficiencies to devise personalized treatment strategies that substantially improve patients’ quality of life.</p>

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The double-edged sword of PI3Kδ pathway-related immune dysregulation: insights from two case reports

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月19日

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  • Marta Dafne Cabanero-Navalon,
  • Victor Garcia-Bustos,
  • Santos Ibanez-Barcelo,
  • Héctor Balastegui-Martin,
  • Javier Grimaldos-Lodares,
  • Pedro Moral-Moral

摘要

Phosphoinositide 3-kinases (PI3Ks), particularly the PI3Kδ pathway, play a crucial role in regulating immune functions. Alterations in this pathway, either as hyperactivation, such as in activated PI3Kδ syndrome (APDS), or rarely described hypoactivation, profoundly influence immune function and are linked to a spectrum of immunodeficiencies and autoimmune conditions. This report describes two cases of late-onset immunodeficiencies associated with PI3Kδ pathway dysregulation, each presenting with unique mutations and clinical manifestations. The first case involves a heterozygous mutation in PI3KR1 (c.5A > T, p.Tyr2Phe) indicative of PI3Kδ hyperactivation, effectively managed with sirolimus. The second case is characterized by a homozygous mutation in PIK3CD (c.2608C > T, p.Arg870Ter), suggesting PI3Kδ hypoactivation, with clinical features including psoriatic arthritis and ulcerative colitis. These cases underscore the heterogeneous clinical features and the challenges in managing such rare genetic variants. These cases underscore the importance of considering primary immunodeficiency in individuals exhibiting signs of both infectious and non-infectious autoimmune or immune dysregulation complications. Prompt genetic screening and strategic therapeutic approaches are crucial for effectively managing these conditions and mitigating the risks associated with immunosuppressive treatments. These insights emphasize the need for a deeper understanding of genetic factors in immunodeficiencies to devise personalized treatment strategies that substantially improve patients’ quality of life.