Biallelic mutations in VPS45 disrupt endosomal protein trafficking, leading to a rare immunodeficiency syndrome characterized by neutrophil dysfunction, with fewer than 40 cases reported. Key features of the condition include neutropenia, recurrent infections, hepatosplenomegaly, nephromegaly, and myelofibrosis. Neurodevelopmental abnormalities, such as global developmental delay, hypotonia, nystagmus, and cortical blindness, have been associated with a specific variant c.712G>A; p.Glu238Lys. Here we present a case with presumed familial hemophagocytic lymphohistiocytosis (HLH) in infancy and progressive neurological symptoms.
The patient is a 15-year-old female, who initially presented at 4 weeks of age with severe mastoiditis. She was found to have poor NK cell function, perforin deficiency, and neutropenia. Bone marrow biopsy showed toxic granulation and cytoplasmic vacuolation in some neutrophils. Few histiocytes and no hemophagocytes were seen. She underwent bone marrow transplant (BMT) at 4 months old due to presumed HLH and a history of a brother with HLH who died from an infection post-BMT. She has a history of global developmental delay, dysgraphia, ADHD, primary ovarian insufficiency, multiple fractures, atypical bony development in the feet, and hypercholesterolemia. On examination, she has short stature, facial dysmorphism, atypical dentition, nystagmus, choreiform movements, and gait ataxia. Brain imaging at 10 years of age showed basal ganglia and subcortical white matter calcifications in the frontal lobes.
Extensive genetic testing, including genome sequencing and mitochondrial DNA sequencing, was negative. Research-based reanalysis revealed novel biallelic VPS45 missense variants (c.652C>T; p.Arg218Cys and c.1157G>A; p.Arg386His), confirmed by Sanger sequencing. Parental testing demonstrated the variants were inherited in trans from unaffected carriers and were also found in the deceased brother’s exome data.
While a specific variant (p.Glu238Lys) has been linked to neurological symptoms in VPS45 deficiency, it was absent in our case. The patient’s progressive neurological phenotype, including chorea, basal ganglia, and subcortical white matter calcifications, suggests further phenotype expansion. The overlap with HLH and post-BMT complications underscores the diagnostic and therapeutic complexities, emphasizing the need for further research into VPS45-related pathophysiology and its clinical implications.
This case expands the understanding of VPS45 deficiency by highlighting pronounced neurological involvement, which appears more striking in our proband.
