D2.387 - Hemophagocytic Lymphohistiocytosis and Progressive Neurological Involvement in Two Patients with Severe Congenital Neutropenia Due to VPS45 Deficiency

Background: VPS45 deficiency is a rare primary immunodeficiency caused by pathogenic variants in the VPS45 gene, characterized by refractory neutropenia, bone marrow fibrosis, and neurodevelopmental abnormalities. Impaired vesicular trafficking affects cytotoxic functions, predisposing patients to hemophagocytic lymphohistiocytosis (HLH). Here, we present the phenotypic spectrum and hematopoietic stem cell transplantation (HSCT) outcomes of two patients presenting with severe infections and HLH/HLH-like manifestations.Case presentations: Two female infants born to consanguineous parents were referred to our center in early infancy (at 2.5 and 1.5 months of age) due to pancytopenia and severe infections. Physical examination revealed hepatosplenomegaly and nystagmus, while laboratory evaluation demonstrated pancytopenia with markedly reduced CD8⁺ T lymphocyte counts (Table 1). Bone marrow examination showed myeloid maturation arrest, and cranial magnetic resonance imaging revealed hypoplasia of the corpus callosum. Ophthalmologic evaluation demonstrated optic disc pallor.Case 1 had a history of postnatal pneumonia and omphalitis and developed disseminated BCG infection, for which she received one year of antituberculous therapy and was treated with the HLH-2004 protocol for HLH. Case 2 exhibited an HLH-like course with persistent neutropenia and hyperferritinemia. Both cases were found to carry a homozygous pathogenic VPS45 variant (p.Glu238Lys). Following myeloablative conditioning, HSCT was performed from fully matched donors (unrelated donor and mother). In Case 1, myeloid and platelet engraftment occurred on days +13 and +14, respectively. At 1.5 years of age, Case 1 shows ongoing neuromotor development with an uneventful follow-up. In case 2, myeloid and platelet engraftment was achieved on day +14 and +17, respectively. She is under follow-up without any problems two months after HSCT.Conclusion: Biallelic VPS45 deficiency is characterized by refractory neutropenia accompanied by HLH/HLH-like manifestations and corpus callosum abnormalities. It should be considered in the differential diagnosis of infants presenting with early-onset pancytopenia neurological findings and CD8+ T cell lymphopenia. HSCT represents an effective curative treatment option for this complex multisystem disorder.