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Background <p>CD40 ligand (CD40L) deficiency causes X-linked Hyper-Immunoglobulin M syndrome (XHIGM) with variable clinical severity. The splice variant c.156G &gt; A (p.Lys52Lys) in <i>CD40LG</i> gene has been previously reported in patients with severe opportunistic infections, including Pneumocystis jirovecii pneumonia and cryptococcal meningoencephalitis. Exploring the phenotypic variability in patients with identical genotype is critical for prognosis and genetic counseling.</p> Methods <p>We described comprehensive immunological characterization and long-term follow-up of a patient with the c.156G &gt; A variant in <i>CD40LG</i> gene. Quantitative real-time (qRT-PCR) and flow cytometry were used to evaluate the CD40L protein expression. We performed in-depth analysis of lymphocyte subsets and functional assays that include T-cell proliferation and intracellular cytokine staining for IFN-γ and TNF-α.</p> Results <p>A hemizygous c.156G &gt; A (p.Lys52Lys) variant at the last nucleotide of exon 1 of <i>CD40LG</i> gene was identified. In silico tools predicted splice donor site disruption. qRT-PCR and flow cytometry revealed marked reduction in CD40L expression. Over 23 years of follow-up with immunoglobulin replacement therapy, the patient experienced only mild recurrent sinusitis with no opportunistic infections or hospitalizations. This favorable outcome stands in contrast to a previously reported patient carrying the identical variant who developed P. jirovecii pneumonia at 3 months and cryptococcal meningoencephalitis at 26 years.</p> Conclusion <p>This case demonstrates significant phenotypic heterogeneity in CD40L deficiency, with markedly different clinical outcomes in patients harboring identical <i>CD40LG</i> splice variants. Favorable long-term outcomes are achievable with early diagnosis and optimal management, even with severe genetic defects. Prognosis in CD40L deficiency should be individualized and cannot rely on genotype alone. Further research to identify genetic, immunological, and environmental modifiers of disease severity will enable personalized risk stratification and targeted therapeutic approaches.</p>

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Phenotypic Heterogeneity in CD40 Ligand Deficiency: Long-term Follow-up of a Patient with the c.156G > A Splice Variant

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月21日

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  • Fayhan Alroqi,
  • Abdulrahman N. AlJaber,
  • Nouf Althubaiti,
  • Abeer Al Tuwaijri,
  • Shouq Alzaaqi,
  • Tlili Barhoumi,
  • Abduarahman Almutairi,
  • Bader Almuzzaini,
  • Leena Alsayegh,
  • Maysa Nogoud,
  • Modhi Aljedaie

摘要

Background

CD40 ligand (CD40L) deficiency causes X-linked Hyper-Immunoglobulin M syndrome (XHIGM) with variable clinical severity. The splice variant c.156G > A (p.Lys52Lys) in CD40LG gene has been previously reported in patients with severe opportunistic infections, including Pneumocystis jirovecii pneumonia and cryptococcal meningoencephalitis. Exploring the phenotypic variability in patients with identical genotype is critical for prognosis and genetic counseling.

Methods

We described comprehensive immunological characterization and long-term follow-up of a patient with the c.156G > A variant in CD40LG gene. Quantitative real-time (qRT-PCR) and flow cytometry were used to evaluate the CD40L protein expression. We performed in-depth analysis of lymphocyte subsets and functional assays that include T-cell proliferation and intracellular cytokine staining for IFN-γ and TNF-α.

Results

A hemizygous c.156G > A (p.Lys52Lys) variant at the last nucleotide of exon 1 of CD40LG gene was identified. In silico tools predicted splice donor site disruption. qRT-PCR and flow cytometry revealed marked reduction in CD40L expression. Over 23 years of follow-up with immunoglobulin replacement therapy, the patient experienced only mild recurrent sinusitis with no opportunistic infections or hospitalizations. This favorable outcome stands in contrast to a previously reported patient carrying the identical variant who developed P. jirovecii pneumonia at 3 months and cryptococcal meningoencephalitis at 26 years.

Conclusion

This case demonstrates significant phenotypic heterogeneity in CD40L deficiency, with markedly different clinical outcomes in patients harboring identical CD40LG splice variants. Favorable long-term outcomes are achievable with early diagnosis and optimal management, even with severe genetic defects. Prognosis in CD40L deficiency should be individualized and cannot rely on genotype alone. Further research to identify genetic, immunological, and environmental modifiers of disease severity will enable personalized risk stratification and targeted therapeutic approaches.