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<p>DNA repair disorders are a group of conditions characterized by progressive, multisystem phenotypes. Defining new clinical presentations of these disorders is essential for optimizing patient care. ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. We sought to define a novel multisystem phenotype associated with biallelic <i>ERCC1</i> variants and impaired DNA repair. Through international collaboration, we identified seven individuals from five families carrying biallelic <i>ERCC1</i> variants, including p.Arg156Trp and p.Ala266Pro, who exhibited a distinct clinical phenotype. All individuals presented with growth restriction, photosensitivity, and kidney and liver dysfunction. Notably, three children required liver transplants. Hepatocellular carcinoma developed in four children, resulting in two deaths, including one following treatment with doxorubicin and cisplatin. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Functional assays using patient-derived fibroblasts demonstrated significant destabilization of the ERCC1-XPF complex and defects in NER and ICL repair. However, residual NER and ICL repair activity was observed, suggesting a hypomorphic effect of the missense variants, which were present either in the homozygous state or in trans with a predicted loss-of-function allele. We define <i>ERCC1</i>-hepatorenal syndrome as a severe, multisystem DNA repair disorder associated with high morbidity and mortality, including a significant risk of pediatric hepatocellular carcinoma. We propose management guidelines emphasizing cancer surveillance and caution with chemotherapy to minimize treatment-related toxicity.</p>

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A new multisystem ERCC1-hepatorenal syndrome: insights from a clinical cohort, molecular pathogenesis, and management guidelines

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月19日

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  • Susan M. White,
  • Annelotte P. Wondergem,
  • Isa Breet,
  • Maren Dittmaier,
  • Katrina Bell,
  • Christopher M. Richmond,
  • Winita Hardikar,
  • Kanika Bhatia,
  • Catherine Quinlan,
  • David Orchard,
  • Areetha D’Souza,
  • Walter J. Chazin,
  • Christopher Smith,
  • Rebecca Sparkes,
  • Simon Lam,
  • Alexandra Carter,
  • Robert J. Hopkin,
  • Leticia Khendek,
  • Bonnie R. Sullivan,
  • Naja Becher,
  • Anne Katrine W. Simonsen,
  • Helene Kvistgaard,
  • Katherine Dempsey,
  • Alexander G. Miethke,
  • Pernille Axél Gregersen,
  • Eliza Phillips,
  • Martijn S. Luijsterburg

摘要

DNA repair disorders are a group of conditions characterized by progressive, multisystem phenotypes. Defining new clinical presentations of these disorders is essential for optimizing patient care. ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. We sought to define a novel multisystem phenotype associated with biallelic ERCC1 variants and impaired DNA repair. Through international collaboration, we identified seven individuals from five families carrying biallelic ERCC1 variants, including p.Arg156Trp and p.Ala266Pro, who exhibited a distinct clinical phenotype. All individuals presented with growth restriction, photosensitivity, and kidney and liver dysfunction. Notably, three children required liver transplants. Hepatocellular carcinoma developed in four children, resulting in two deaths, including one following treatment with doxorubicin and cisplatin. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Functional assays using patient-derived fibroblasts demonstrated significant destabilization of the ERCC1-XPF complex and defects in NER and ICL repair. However, residual NER and ICL repair activity was observed, suggesting a hypomorphic effect of the missense variants, which were present either in the homozygous state or in trans with a predicted loss-of-function allele. We define ERCC1-hepatorenal syndrome as a severe, multisystem DNA repair disorder associated with high morbidity and mortality, including a significant risk of pediatric hepatocellular carcinoma. We propose management guidelines emphasizing cancer surveillance and caution with chemotherapy to minimize treatment-related toxicity.