Axenfeld-Rieger Syndrome with Negative Chromosomal Microarray and Whole-Exome Sequencing: A Case Report

Paulo de Camargo Moraes,1,* Victor Angelo Martins Montalli,1,* Marcelo Sperandio,1,* Ana Mondadori Dos Santos,2,* Ana Cláudia Garcia Rosa3,* 1Department of Oral Medicine and Pathology, Faculdade São Leopoldo Mandic Research Institute, Campinas, SP, Brazil; 2Department of Medical Genetics, Faculdade São Leopoldo Mandic Research Institute, Campinas, SP, Brazil; 3Department of General Pathology, Federal University of Tocantins, Palmas, TO, Brazil*These authors contributed equally to this workCorrespondence: Ana Cláudia Garcia Rosa, Department of General Pathology, Federal University of Tocantins, Palmas, TO, Brazil, Tel +55 63 3229 4658, Email [email protected]: Axenfeld-Rieger Syndrome (ARS) is a rare genetic disorder defined by ophthalmological abnormalities, frequently accompanied by craniofacial and dental anomalies. Although mutations in the PITX2 and FOXC1 genes are commonly identified, some patients do not receive molecular confirmation. This report describes a clinically compelling case of ARS with a typical phenotype but negative genetic testing. A 10-year-old male demonstrated physical abnormalities from early childhood and underwent multiple medical evaluations without a definitive diagnosis. He experienced difficulty and discomfort during mastication following the exfoliation of his deciduous teeth. Physical examination revealed short stature and ophthalmologic abnormalities, including strabismus and early-onset cataracts requiring bilateral phacoemulsification with intraocular lens implantation, as well as craniofacial and dental anomalies. Chromosomal microarray analysis identified inherited duplications in 4q26 and 7q31.2, but no pathogenic variants were detected. The diagnosis of ARS was established based on the characteristic phenotype. The patient remains under multidisciplinary care, receives orthodontic treatment, and continues regular ophthalmological monitoring. The recent onset of cataracts highlights the progressive nature of ocular involvement in ARS. Although molecular testing is essential for ARS, a subset of clinically diagnosed cases remains genetically unresolved. Advances in high-resolution and integrative genomic technologies are expected to improve diagnostic yield in these patients.Keywords: Axenfeld-Rieger syndrome, PITX2, FOXC1, craniofacial anomalies, dental anomalies