Ekrem Ünal

Osteopetrorickets and calcium homeostasis in children with osteopetrosis: an endocrinological single-center study

Background Osteopetrosis is a rare inherited disorder caused by impaired osteoclast number or function, leading to increased bone density, fractures, neurologic complications, and disturbances in calcium-phosphate homeostasis. This study aimed to describe the endocrine manifestations of childhood osteopetrosis, particularly osteopetrorickets, and to evaluate treatment responses and post-transplant calcium disorders. Methods We retrospectively reviewed 17 children diagnosed with osteopetrosis at a single tertiary center between 2015 and 2025. Clinical, biochemical, radiologic, genetic, and treatment data were analyzed. Results The median age at diagnosis was 14 months (range, 15 days–130 months), and short stature was observed in 13 of 17 patients (76.4%). Ophthalmologic abnormalities were present in 10 patients (58.8%), hearing loss in 7 patients (41.1%), and hepatosplenomegaly in 7 patients (41.1%). TCIRG1 was the most frequent mutation, followed by CLCN7, TNFSF11, TNFRSF11A, and CA2. Osteopetrorickets was identified in 13 of 17 patients (76.4%); among these patients, hypocalcemia occurred in 11 of 13, hypophosphatemia in 8 of 13, and vitamin D deficiency in 4 of 13. Generalized osteosclerosis was observed in all patients, whereas classic osteopetrosis-associated radiographic findings, including bone-in-bone appearance, sandwich vertebrae, and Erlenmeyer flask deformity, were identified only in a subset of patients. Hematopoietic stem cell transplantation was performed in 11 of 13 patients with osteopetrorickets. Four of these 11 patients died during the early post-transplant period. Among patients with osteopetrorickets who underwent hematopoietic stem cell transplantation (HSCT) (n=11), seven surviving patients achieved complete resolution of rickets (7/11, 63.6%), allowing discontinuation of replacement therapy within 15 days to 8 months. Post-transplant hypercalcemia developed in 4 of 13 transplant recipients (30.8%). Conclusions Osteopetrorickets is a frequent and clinically significant complication of pediatric osteopetrosis. Early recognition of mineral disturbances, genotype-based treatment planning, and close surveillance for rebound hypercalcemia after transplantation are essential to improve outcomes.

A novel FLNA p.Pro2469Ser variant is associated with impaired T and NK cell function and immune dysregulation

Eltrombopag-associated remodeling of the MAIT, MR1+ and γδ T cells in pediatric immune thrombocytopenia.

Pediatric immune thrombocytopenia (ITP) is an autoimmune cytopenia characterized by immune-mediated platelet destruction and impaired thrombopoiesis. Mucosa-associated invariant T (MAIT) cells are innate-like T cells activated by MR1-presented microbial metabolites and inflammatory cytokines, but their role in pediatric ITP and their relationship to eltrombopag therapy remain unclear. We analyzed peripheral blood mononuclear cells from healthy controls (n = 20), untreated pediatric ITP patients (n = 60), and eltrombopag-treated patients (n = 16). MAIT cells were quantified using MR1-5-OP-RU tetramers and surrogate gating (CD3+Vα7.2+CD161+). MAIT subsets, memory phenotype, chemokine receptor expression (CXCR3, CXCR5, CCR6), HLA-DR, intracellular cytokines (IFN-γ, TNF-α, IL-17 A, IL-22), and MR1+CD3- cells were analyzed by flow cytometry. Tetramer-defined MAIT cells were reduced in absolute number in pediatric ITP, including eltrombopag-treated patients, most prominently within the CD8+ subset, whereas their frequency among CD3+ T cells did not differ between untreated and eltrombopag-treated groups. In contrast, CD3+Vα7.2+CD161+ cells increased in untreated ITP and were lower in eltrombopag-treated patients. Untreated ITP patients exhibited reduced frequencies of IFN-γ- and TNF-α-producing MAIT cells, accompanied by increased IL-17-producing cells and TNF-α signal intensity. Conventional αβ T cells were reduced, whereas γδ T cells were increased; eltrombopag-treated patients exhibited γδ T-cell frequencies and cytokine-positive fractions closer to those of healthy controls. MR1+CD3- cells were expanded and displayed reduced HLA-DR expression in untreated ITP, whereas eltrombopag-treated patients showed lower MR1+CD3- frequencies and HLA-DR levels closer to healthy controls. These findings demonstrate coordinated alterations of the MAIT/MR1 axis and unconventional T-cell compartments in pediatric ITP and identify immunophenotypic differences associated with eltrombopag treatment.