Unveiling the Phenotypic Spectrum of Miller Syndrome: A Systematic Review

Miller syndrome is an extremely rare condition in the group of facial dysostosis syndromes. These syndromes have great phenotypic overlap and variability, even within families. To facilitate the differentiation of Miller syndrome from related facial dysostosis syndromes, such as Treacher Collins and Nager syndrome, this study aims to provide an overview of the phenotypic spectrum of the syndrome. A systematic literature search of Embase, MEDLINE/PubMed, Web of Science, and CINAHL was conducted until November 2024. Case reports and case series of patients with a clinical or genetic diagnosis of Miller syndrome in all languages were included. The quality of the included reports was assessed using the Joanna Briggs Institute critical appraisal tool and the Fichas de Lectura Critica 3.0 web application. In total, 44 cases of Miller syndrome were found, with only 18.2% having genetic confirmation. Craniofacial anomalies were prominent, including midface hypoplasia (72.7%) and micrognathia (75.0%), orofacial clefts (77.3%), eyelid anomalies (70.5%), and external ear anomalies (63.6%). Limb anomalies were present in all cases, primarily involving the hands (95.5%), forearms (52.3%), and feet (90.9%). Anomalies in other extracraniofacial tracts were also reported. Despite limitations, including limited genetic confirmation and reliance on literature, this study provides valuable insights into the phenotypic spectrum of Miller syndrome. Efforts for genetic confirmation, international collaboration, and comprehensive reporting are essential to advance research and care for rare conditions like Miller syndrome. Therefore, a detailed checklist for phenotypic evaluation in Miller syndrome cases is provided in this study.