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

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.

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Publication Details

Journal
European Journal of Human Genetics
Published
2025-07-19
DOI
https://doi.org/10.1038/s41431-025-01910-0
Citations
1
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
0.81
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article

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

Martijn S. Luijsterburg, Walter Chazin, Helene Kvistgaard, Areetha D’Souza et al.
1 citations
European Journal of Human Genetics
DNA Repair Mechanisms
0.81
article

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

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

Abstract

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.

European Journal of Human GeneticsVol. 33(10)
Griffith University (AU), Cincinnati Children's Hospital Medical Center (US), Royal Children's Hospital (AU), Children's Mercy Hospital (US), The University of Melbourne (AU), University of Calgary (CA), Vanderbilt University (US), Aarhus University (DK), Royal Brisbane and Women's Hospital (AU), Leiden University Medical Center (NL), Alberta Children's Hospital (CA), Aarhus University Hospital (DK), Victorian Clinical Genetics Services (AU), Levine Children's Hospital (US), Murdoch Children's Research Institute (AU), University of Cincinnati (US), University of Missouri–Kansas City (US), University of Cincinnati Medical Center (US)
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Openalex Percentile: Top 26%
DNA Repair Mechanisms
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