WWOX Gene Disease as Infantile Catastrophic Epileptic Encephalopathy (WOREE Syndrome Plus): A Comprehensive Case Study with Brief Literature Update

The WWOX gene, well-known as tumor suppressor, has also a crucial role as transcrip-tion factor in the developing brain. The bi-allelic loss of WWOX gene causes a condition characterized by drug-resistant epilepsy, developmental delay, and neurological impairments, often resulting in mortality within the first year of life, known as WOREE syndrome (MIM: 616211). Whole Exome Sequencing (WES) analysis was performed on a female patient who died within three months of birth and was diagnosed with mi-crocephaly, severe early-onset refractory seizures, and drug-resistant epileptic encephalopathy. WES revealed a 38 kb CNV deletion spanning WWOX exons 6-7, and a known frameshift variant in exon 8, impairing a highly clinically significant region of the encoded protein. Clinical and genetic features of reported WOREE patients with WWOX gene deletions similar to our patient were analyzed. Our case highlights the clinical heterogeneity of WWOX variants in WOREE syndrome and suggests that the novel compound heterozygous deletion may contribute to poor prognosis. A "WOREE syndrome plus" phenotype can be defined by severe neurological disorder, microcephaly, and a fatal outcome within the first year of life. Further researches need to elucidate WWOX pathophysiology and improve diagnostic and therapeutic strategies.