Recurrent Acute Liver Failure as the First Manifestation of ARCN1-Associated Disorder Caused by a Terminal Exon Frameshift Variant

Background: ARCN1-related syndrome (short stature-micrognathia syndrome, SSMG; OMIM #617164) is an autosomal dominant disorder caused by loss-of-function variants in the ARCN1 gene, which encodes the δ-COP (COPD) subunit of the COPI coatomer complex. The condition is classically characterized by intrauterine growth restriction (IUGR), short stature with rhizomelic shortening, microcephaly, micrognathia, facial dysmorphism, and global developmental delay. Methods: Clinical examination, blood tests and genetic analysis were performed. Whole-exome sequencing and Sanger analysis were conducted, followed by bioinformatics analysis and ACMG-based variant interpretation to identify and characterize the pathogenic variant. Results: We report a male proband with a previously undescribed variant in the ARCN1 gene, presenting with an atypical phenotype. Notably, the patient lacked the classical syndromic features, including short stature, microcephaly, IUGR, and developmental delay. The predominant clinical manifestation was transient hepatic dysfunction occurring during febrile episodes, which resolved between acute events. On physical examination, rhizomelic shortening and dysmorphic facial features, including mild micrognathia, were found. Overall, identified symptoms were mild in severity, which may be associated with the variant’s location within the gene. Conclusions: We describe a novel likely pathogenic variant in the ARCN1 gene associated with a mild phenotype of SSMG. This case expands the phenotypic spectrum of ARCN1-related syndrome and highlights the importance of considering this diagnosis in patients with unexplained recurrent liver injury, even in the absence of classical syndromic features.