Peer-reviewed article
A new multisystem ERCC1-hepatorenal syndrome: insights from a clinical cohort, molecular pathogenesis, and management guidelines.
Susan M White, Annelotte P Wondergem, Isa Breet, Maren Dittmaier, Katrina Bell et al. ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This is a medical research paper describing a rare genetic disorder (ERCC1-hepatorenal syndrome) affecting DNA repair in children. It reports findings from seven individuals with biallelic ERCC1 gene variants who experienced growth restriction, kidney and liver dysfunction, and high cancer risk. The paper presents molecular analysis of the genetic defect and proposes clinical management guidelines for affected children.
Key points
- Seven individuals from five families with biallelic ERCC1 variants presented with growth restriction, photosensitivity, and kidney/liver dysfunction
- Three children required liver transplants; four children developed hepatocellular carcinoma with two deaths
- Older individuals exhibited additional complications including ataxia, skin cancers, pancreatic insufficiency, and lung disease
- Functional assays showed defective DNA nucleotide excision repair and interstrand crosslink repair
- Management guidelines emphasize cancer surveillance and caution with chemotherapy
Limitations
This is a case series describing a rare genetic condition affecting only seven individuals; it does not evaluate an intervention or programme to improve child well-being outcomes and cannot provide evidence about the effectiveness of any specific treatment or policy.
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.