Clinical and Genetic Analysis of ERCC8-Related Cockayne Syndrome: Hepatic Dysfunction as a Biomarker, Anhidrosis as a Rare Feature, and Rehabilitation Outcomes for Ankle Contractures

Jing Chen¹Wei Su²Dan Gao¹Fangfang Liu¹Shuang Chen¹Wenhan Zhang³Min Peng⁴Tao Lei^1*Hongmin Zhu^1*

• ¹Department of Rehabilitation, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hebei Province, China
• ²Department of Gastroenterology,Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, wuhan, China
• ³Department of Radiology,Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, wuhan, China
• ⁴Chigene (Beijing) Translational Medical Research Center Co., Ltd., Beijing, P.R. China, Beijing, China

Objectives: Cockayne syndrome (CS), a rare hereditary neurodegenerative disorder caused by pathogenic variants in ERCC6 (CSB) and ERCC8 (CSA), often clinically overlaps with cerebral palsy (CP), leading to misdiagnosis. This study evaluates the role of genetic testing in differential diagnosis, examines hepatic dysfunction as a biomarker of disease severity, and delineates clinical characteristics of CSA-related CS. Methods: A retrospective case series of eight CSA-related CS patients was conducted. Clinical data, neuroimaging, genetic profiles, and hepatic function were analyzed. Disease severity was classified according to established CS subtypes (I–III).Results: All patients (6 males, 2 females) presented with early-onset motor delay and spasticity, initially misdiagnosed as CP. Genetic testing identified pathogenic ERCC8 variants, including exon deletions (Exon4; Exon6-12), a nonsense (c.856A>T), frameshift (c.394_398del), and splice-site (c.618-2A>G) variant, confirming autosomal recessive inheritance (compound heterozygous/homozygous). Subtype distribution included CS I (n=5), CS II (n=2), and CS III (n=1). CS II cases exhibited earlier diagnosis and classic CS features. Hepatic dysfunction correlated with disease severity, worsening with progression. Achilles tendon contractures developed in all patients; systematic rehabilitation (n=5) significantly reduced contracture severity compared to non-rehabilitated cases (n=3). Two patients displayed anhidrosis, a rarely reported dermatological manifestation. Conclusions: Genetic testing is essential to differentiate CSA-related CS from CP. Hepatic dysfunction serves as a biomarker for disease progression, warranting routine monitoring. Rehabilitation therapy mitigates Achilles tendon contractures, underscoring its clinical value. This study expands the phenotypic spectrum of CSA-related CS by identifying anhidrosis as a rarely reported feature, providing insights for diagnosis and management.