Progressive multifocal leukoencephalopathy in a 15-year-old boy with X-linked hyper-IgM syndrome: a case report

Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal infection caused by JC polyomavirus, primarily affecting individuals with impaired cellular immunity. We report a 15-year-old boy with genetically confirmed X-linked hyper-IgM syndrome due to a pathogenic CD40LG variant. Despite regular intravenous immunoglobulin replacement therapy and antimicrobial prophylaxis, he developed concurrent Pneumocystis jirovecii pneumonia and COVID-19. Approximately 2 months after recovery from the pulmonary infections, he developed progressive visual impairment, diplopia, impaired concentration, and mild generalized weakness. Brain magnetic resonance imaging revealed extensive bilateral temporo-parieto-occipital white-matter lesions. Cerebrospinal fluid polymerase chain reaction was positive for JC polyomavirus DNA, confirming the diagnosis of PML; HIV testing was negative. In the absence of an established antiviral therapy, a single intravenous dose of pembrolizumab (80 mg) was administered as an experimental immune-based intervention. Three weeks later, the patient developed rapidly progressive generalized muscle weakness and respiratory failure requiring intensive care and mechanical ventilation. Despite intensive supportive treatment, he subsequently died. The precise cause of this deterioration could not be conclusively established, and a multifactorial process involving progression of PML and treatment-related or critical-illness complications could not be excluded. PML should be considered in patients with X-linked hyper-IgM syndrome who develop new neurological manifestations. Pembrolizumab remains an experimental intervention in this setting, with uncertain efficacy and safety in primary immunodeficiency.