P0883 - Discovery of a Novel Mutation in the Excision Repair Cross-Complementing 1 Gene in a Teenage Patient with Cerebro-Oculo-Facio-Skeletal Syndrome

Introduction
Mutations in excision repair cross-complementing (ERCC) genes have been associated with the congenital disorder cerebro-oculo-facio-skeletal (COFS) syndrome, although mutations leading to other conditions such as Cockayne syndrome and Xeroderm Pigmentosum are more common. Symptoms associated with COFS syndrome include arthrogryposis, microcephaly, micropthalmia, short stature, developmental delay, photosensitivity, sensorineural hearing loss, visual impairment, and infantile death, among others. COFS syndrome can result from multiple genetic defects, including mutations in ERCC genes. However, mutations in the ERCC1 gene have only been associated with COFS syndrome once in the literature.
Case description
A teenage female patient presented with a complex medical history and clinical features suggestive of an ERCC mutation or another nucleotide excision repair defect. The patient’s symptoms included microcephaly, intellectual disability, extreme photosensitivity, joint contractures, hypoplastic digits, sensorineural hearing loss, visual impairment, short stature, and persistent anemia among others. The patient did not have a history of similarly affected family members. The patient was diagnosed with cerebro-oculo-facio-skeletal (COFS) syndrome based on clinical presentation and subsequently underwent genetic testing using next generation sequencing (NGS). A novel autosomal homozygous recessive variant in the ERCC1 gene, p.K37X, was found. Additionally, a mutation in the hepatocyte nuclear factor homebox 1 B (HNF1B) gene was found. The patient was referred to multiple medical specialists for continued care and is now being followed primarily by non-pediatric medical specialists.
Discussion
The specific variant discovered in this patient in the ERCC1 gene has never been reported in the literature. The patient previously reported in the literature with an ERCC1 mutation leading to COFS syndrome experienced similar symptoms. However, the previously reported patient was much more severely affected and did not survive past infancy. The patient presented here has survived into adulthood.
Conclusion
The clinical features and outcome of this patient suggest that the severity of ERCC1 mutations leading to COFS syndrome may depend partially upon the specific variant involved. Additionally, this patient demonstrates that survival beyond childhood is possible for patients affected by ERCC1 mutations leading to COFS syndrome. As NGS is increasingly utilized for diagnostic purposes, it is possible that more patients previously diagnosed clinically with COFS syndrome will be found to be affected by ERCC1 mutations. The life-expectancy and prognosis for such patients may be better than previously believed.