VPS 45-associated primary infantile myelofibrosis--successful treatment with hematopoietic stem cell transplantation

Area of Science:

• Genetics and Molecular Biology
• Hematology
• Immunology

Background:

• Primary Autosomal Recessive Microcephaly (PMF) of infancy is a rare genetic disorder characterized by severe bone marrow failure.
• The condition results from mutations in the VPS45 gene, leading to neutrophil apoptosis and platelet dysfunction.
• Understanding the clinical spectrum and treatment efficacy is crucial for managing this primary immune deficiency.

Purpose of the Study:

• To update clinical data and hematological features of patients with VPS45-associated PMF of infancy.
• To evaluate the effectiveness of Hematopoietic Stem Cell Transplantation (HSCT) as a treatment modality.
• To highlight diagnostic considerations and long-term follow-up needs for VPS45 deficiency.

Main Methods:

• Retrospective analysis of clinical data, hematological parameters, and molecular findings in four children with VPS45-associated PMF.
• Detailed assessment of treatment protocols and outcomes for patients undergoing HSCT.
• Molecular studies confirmed homozygous Thr224Asn mutation in the VPS45 gene in all affected individuals.

Main Results:

• All four patients presented with clinical and hematological findings consistent with microcephaly.
• HSCT was performed in three patients, achieving successful engraftment and clinical improvement in two.
• The Thr224Asn mutation in the VPS45 gene was identified as the causative genetic defect.

Conclusions:

• VPS45-associated PMF is a treatable primary immune deficiency that can be corrected by HSCT.
• Early intervention with HSCT and appropriate conditioning is critical for successful outcomes.
• Diagnosis should be considered in infants with severe congenital neutropenia progressing to pancytopenia; long-term monitoring for extra-hematological manifestations is essential.