Abstract
BACKGROUND: Jordan syndrome is a rare neurodevelopmental disorder caused by mutations in the PPP2R5D gene. It is characterized by developmental delay, macrocephaly, hypotonia, epilepsy, and autism spectrum disorder. This study aims to enhance clinical recognition of the disease by presenting two genetically confirmed cases and a comprehensive literature review. CASE DESCRIPTION: This study retrospectively analyzed two unrelated male patients diagnosed with Jordan syndrome, both carrying the heterozygous PPP2R5D variant c.598G>A (p.Glu200Lys), confirmed as de novo. Both patients exhibited global developmental delay, macrocephaly, dysmorphic facial features, and abnormal cranial magnetic resonance imaging (MRI) findings. One patient also presented with epilepsy and experienced unexplained recurrent fever for 8 months during infancy. Electroencephalogram (EEG) abnormalities persisted over long-term follow-up despite antiepileptic treatment. Genetic testing confirmed the absence of this variant in their parents, and the variant was not found in the gnomAD database. In silico predictions using PolyPhen-2 and AlphaFold indicated a deleterious effect. According to American College of Medical Genetics and Genomics (ACMG) guidelines, this variant was classified as "pathogenic". CONCLUSIONS: The c.598G>A (p.Glu200Lys) mutation is one of the most frequently reported pathogenic variants of PPP2R5D. The two cases reported here not only align with the known clinical spectrum of Jordan syndrome but also highlight a potentially novel phenotype of persistent unexplained fever in early infancy. Our literature review summarizes 213 reported cases and emphasizes the genotype-phenotype correlations, especially among patients with the c.598G>A (p.Glu200Lys) variant. Early diagnosis through genetic testing and multidisciplinary management is essential to optimize outcomes.