Endocrine Abstracts

JOINT3337

Background: PURA syndrome (OMIM: 616158) is a neurodevelopmental disorder caused by heterozygous pathogenic variants in the PURA gene (5q31.3), which encodes a DNA/RNA-binding protein critical for neuronal myelination, synaptic plasticity, and cell cycle regulation. Characterized by neonatal hypotonia, feeding difficulties, hypersomnolence, and global developmental delay, this syndrome needs to be clinically differentiated from diseases such as Prader-Willi syndrome with hypotonia and developmental delay.

Clinical Case: An 8-month-old male presented with profound axial hypotonia (inability to lift head or roll over), hypersomnolence (18 hour/day), and delayed motor milestones. Neonatal history included respiratory distress syndrome, intraventricular hemorrhage (Grade II), and periventricular leukomalacia. Neurological examination revealed normocephalic head, intact visual tracking, absent auditory orientation, and preserved tendon reflexes. Serial evaluations excluded metabolic disorders (normal tandem mass spectrometry), cardiac defects (unremarkable echocardiography), and negative 15q11 methylation analysis. Trio whole-exome sequencing identified a de novo heterozygous PURA frameshift variant (NM_005859.5:c.523del, p.Asn175Thrfs50) in exon 1, classified as pathogenic (PVS1, PS2, PM2). At 3-year follow-up, the patient exhibited severe motor delay (non-ambulatory, absent sitting balance), growth restriction (<3rd percentile), and language impairment (no meaningful words). Neuroimaging showed persistent white matter hyperintensities. Management included enteral nutrition support, vitamin D supplementation, and intensive neurorehabilitation. This report delineates the natural history and molecular confirmation of a novel PURA frameshift variant.

Conclusion: This case reinforces the core phenotype of PURA syndrome: neonatal-onset hypotonia, hypersomnolence, and irreversible neurodevelopmental deficits. The identified exon 1 truncating variant likely disrupts PUR-alpha’s N-terminal domain, impairing its role in mRNA transport and translation. Given the lack of disease-modifying therapies, we advocate standardized surveillance protocols encompassing EEG (for seizure risk), spine imaging (scoliosis progression), and swallow studies. This study delineates the clinical and molecular characteristics of a novel PURA-associated syndrome. The variant (NM_005859.5:c.523del, p.Asn175Thrfs50) expands the mutational spectrum, correlating with extreme hypersomnolence severity.