The clinical and genetic spectrum of infantile osteopetrosis: a single-center experience including a novel TCIRG1 mutation

Background: Osteopetrosis (OP) is a rare, severe inherited disorder of bone metabolism caused by impaired osteoclast function. The most severe form, malignant infantile osteopetrosis (MIOP), presents in early life with bone abnormalities, neurologic issues, and often hypocalcemia and carries a high mortality rate if left untreated. This study aimed to define the molecular spectrum and delineate genotype-phenotype correlations in a cohort of patients from a single pediatric hematology center. Methods: We retrospectively reviewed the medical, laboratory, radiological, and genetic data of 12 children with OP followed between 2012 and 2022. Whole-exome sequencing was used for genetic analysis. Results: The median age at diagnosis was three months. The most frequently mutated gene was TCIRG1 (n=7, 58.3%), followed by OSTM1 (n=3, 25%), and CLCN7 (n=2, 16.7%). A novel homozygous deletion in TCIRG1 was identified. A strong genotype-phenotype correlation was observed. Patients with TCIRG1 mutations predominantly presented with severe bone marrow failure and osteopetrorickets. In contrast, all patients with OSTM1 and CLCN7 mutations exhibited significant neurodegenerative changes. Two patients received hematopoietic stem cell transplantation (HSCT), with one survivor. Conclusion: This study highlights the distinct clinical and genetic heterogeneity of MIOP. Our findings reinforce that the specific genetic mutation is critical for predicting the disease course—hematological complications for TCIRG1 versus primary neurodegeneration for OSTM1 and CLCN7. This genetic diagnosis is essential for counseling families and determining eligibility for curative therapies like HSCT.