Expanding the Clinical Spectrum of NR4A2-Related Disorder: A Systematic Literature Review and Case Series

NR4A2 encodes a nuclear transcription factor in the steroid-thyroid hormone-retinoid receptor family. Pathogenic variants in NR4A2 are rare and until now have been associated exclusively with neurodevelopmental phenotypes. A systematic literature review of NR4A2-related disorder was conducted using the PubMed and ClinVar databases. We also report two novel cases. Twenty-eight PubMed records and 55 ClinVar reports were screened, and 16 studies were included in the final report. Thirty-two patients with 31 unique pathogenic variants in NR4A2 have been reported. This cohort is 53% female with a median age of 12 years (IQR 8-25). The neurodevelopmental phenotypic spectrum included intellectual disability and/or developmental delay in 93%, language impairment in 63%, recurrent seizures or epilepsy in 41%, and movement disorders in 31%. Extra-neurologic phenotypes were present in 47% and included craniofacial dysmorphism in 25%, musculoskeletal anomalies in 28%, gastrointestinal anomalies in 19%, and renal anomalies in 6%. Endocrine anomalies and dysregulated glucose and lipid metabolism were present exclusively in our two novel cases. The clinical spectrum of NR4A2-related disorder is likely much broader and more heterogeneous than originally suspected. This heterogeneity has likely contributed to under-detection of NR4A2 pathogenic variants.