Riddle syndrome with RNF168 mutation in first Asian family cluster exhibiting pulmonary fibrosis and achalasia

Abstract Riddle syndrome is a rare autosomal recessive disorder caused by RNF168 mutations, characterized by radiosensitivity, immunodeficiency, and dysmorphic features. We reported the first Asian family cluster involving a homozygous RNF168 c.91T>C (p.Cys31Arg) mutation in three siblings. The proband, a 37-year-old female, presented with severe restrictive lung disease, achalasia, and progressive respiratory failure requiring mechanical ventilation. Two sisters exhibited milder phenotypes with dysmorphic features and elevated alpha-fetoprotein. Whole-genome sequencing confirmed the mutation in all affected individuals. The cluster highlighted phenotypic heterogeneities, including neuromuscular and gastrointestinal involvement not previously reported in Riddle syndrome. These findings underscored genetic evaluation for RNF168 mutations in patients with unexplained recurrent infections, elevated alpha-fetoprotein and esophageal motility disorders. Early recognition remained crucial for genetic counseling and clinical managements.