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Background <p>Severe combined immunodeficiency (SCID) is a congenital immunodeficiency characterized by significant numerical or functional defects in T lymphocytes and is often accompanied by B lymphocyte dysfunction. It presents early in life with severe, recurrent opportunistic infections. Early diagnosis and hematopoietic stem cell transplantation (HSCT) are vital for patient survival. Cernunnos/XLF deficiency is an autosomal recessive form of SCID caused by mutations in the <i>NHEJ1</i> gene, which plays a critical role in repairing DNA double-strand breaks. First described in 2006, this condition remains exceedingly rare, with only about 55 cases reported to date. This study aimed to describe a novel infant with Cernunnos/XLF deficiency and to review previously reported patients carrying the same variant, thereby expanding the clinical spectrum of this rare disease.</p> Methods <p>With written informed consent, we retrospectively evaluated a pediatric patient with Cernunnos/XLF deficiency followed at our clinic. Demographic, clinical, laboratory, and radiological findings were reviewed. The diagnosis was based on clinical and immunological features and confirmed via clinical exome sequencing. A literature review was conducted to compare the genotype–phenotype correlations of previously reported patients carrying the same <i>NHEJ1</i> variant.</p> Results <p>We report an infant who was hospitalized at 6.5&#xa0;months of age with a preliminary diagnosis of meningitis and was subsequently diagnosed with Cernunnos/XLF deficiency. The patient exhibited microcephaly, growth retardation, recurrent infections, prolonged SARS-CoV-2 PCR positivity, and localized BCGitis following live Bacillus Calmette–Guérin (BCG) vaccination. Immunological evaluation revealed T- and B-cell lymphopenia and hypogammaglobulinemia. Genetic testing confirmed a homozygous nonsense mutation in <i>NHEJ1</i>. HSCT from a matched sibling donor was performed.</p> Conclusion <p>This study describes a rare case of Cernunnos/XLF deficiency diagnosed in early infancy, underscoring the value of early recognition and the critical role of genetic testing and HSCT. It also expands the clinical spectrum of the disease and provides a comparative perspective with previously reported patients carrying the same mutation. In infants presenting with unexplained infections or complications related to live vaccines, inborn errors of immunity should be considered. Our findings emphasize the importance of timely diagnosis and comprehensive, multidisciplinary follow-up, particularly in patients with additional complications.</p>

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Expanding the clinical spectrum of Cernunnos/XLF deficiency: a literature review of a rare cause of severe combined immunodeficiency including a novel case

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  • 发表日期：

    2025年11月12日

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  • Gizem Kabadayı,
  • Özge Atay,
  • Damla Baysal Bakır,
  • Halime Yağmur,
  • Esma Tuğba Kaşıkçı Mermer,
  • Sultan Okur Acar,
  • Şerife Öztürk Yılmaz,
  • Filiz Hazan,
  • Salih Gözmen,
  • Nevin Uzuner

摘要

Background

Severe combined immunodeficiency (SCID) is a congenital immunodeficiency characterized by significant numerical or functional defects in T lymphocytes and is often accompanied by B lymphocyte dysfunction. It presents early in life with severe, recurrent opportunistic infections. Early diagnosis and hematopoietic stem cell transplantation (HSCT) are vital for patient survival. Cernunnos/XLF deficiency is an autosomal recessive form of SCID caused by mutations in the NHEJ1 gene, which plays a critical role in repairing DNA double-strand breaks. First described in 2006, this condition remains exceedingly rare, with only about 55 cases reported to date. This study aimed to describe a novel infant with Cernunnos/XLF deficiency and to review previously reported patients carrying the same variant, thereby expanding the clinical spectrum of this rare disease.

Methods

With written informed consent, we retrospectively evaluated a pediatric patient with Cernunnos/XLF deficiency followed at our clinic. Demographic, clinical, laboratory, and radiological findings were reviewed. The diagnosis was based on clinical and immunological features and confirmed via clinical exome sequencing. A literature review was conducted to compare the genotype–phenotype correlations of previously reported patients carrying the same NHEJ1 variant.

Results

We report an infant who was hospitalized at 6.5 months of age with a preliminary diagnosis of meningitis and was subsequently diagnosed with Cernunnos/XLF deficiency. The patient exhibited microcephaly, growth retardation, recurrent infections, prolonged SARS-CoV-2 PCR positivity, and localized BCGitis following live Bacillus Calmette–Guérin (BCG) vaccination. Immunological evaluation revealed T- and B-cell lymphopenia and hypogammaglobulinemia. Genetic testing confirmed a homozygous nonsense mutation in NHEJ1. HSCT from a matched sibling donor was performed.

Conclusion

This study describes a rare case of Cernunnos/XLF deficiency diagnosed in early infancy, underscoring the value of early recognition and the critical role of genetic testing and HSCT. It also expands the clinical spectrum of the disease and provides a comparative perspective with previously reported patients carrying the same mutation. In infants presenting with unexplained infections or complications related to live vaccines, inborn errors of immunity should be considered. Our findings emphasize the importance of timely diagnosis and comprehensive, multidisciplinary follow-up, particularly in patients with additional complications.