大理石骨病

Pycnodysostosis (PYCD) is a rare genetic bone disease characterized by impaired osteoclastic bone resorption. The inability to resorb bone leads to sclerosis, with increased bone mineral density (BMD) but paradoxically increased bone fragility. We report a case of a young female with PYCD with multiple fragility fractures including bilateral atypical femur fractures (AFF). Areal and volumetric bone density were supranormal, measured by dual-energy x-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT), respectively. However, bone disorganization was prominent, observed on visual assessment of HR-pQCT images, with microfractures and sclerotic intramedullary lesions. ALIGNOGRAM1.0 is an artificial intelligence (AI) powered disorganization quantifier. It detected femoral lesions (including microfractures) on femoral radiographs up to two years prior to atypical femoral fractures at those sites. These microcracks were not visible on routine hip radiographs without the ALIGNOGRAM1.0 software. We postulate that disorganized bone, including microfractures, may be an underrecognized mechanism of bone fragility in patients with PYCD that could contribute to complications such as delayed fracture healing. Visual assessment via HR-pQCT may detect gross abnormalities but may miss subtle, subclinical changes - e.g., early sclerotic changes - that predate severe lesions and are not visible on routine HR-pQCT analysis. Quantitative tools such as ALIGNOGRAM1.0 may be particularly valuable in disorders characterized by paradoxical skeletal fragility despite normal or elevated bone density and apparently preserved microarchitecture. By quantifying bone disorganization on standard radiographs, these approaches may provide complementary information beyond conventional assessments of bone mass and structure. The paradox of severe fragility despite supranormal bone density has long remained unexplained. This diagnostic paradox is not unique to pycnodysostosis and is encountered across a range of genetic, metabolic, and treatment-related skeletal disorders in which fracture risk appears disproportionate to conventional measures of bone density or structure. Consequently, there is a need for complementary approaches capable of identifying abnormalities that are not captured by standard assessments. In genetic and metabolic bone disorders (e.g., pycnodysostosis or hypophosphatasia) that evade conventional assessments of bone health (e.g., DXA and HR-pQCT), we demonstrate how disorganization may act as a causative mechanism as an independent biomarker of fragility.

BACKGROUND: Infantile osteopetrosis is a rare inherited disorder caused by defective osteoclast-mediated bone resorption, resulting in increased bone density and marrow failure. The CLCN7 gene encodes a chloride channel essential for osteoclast acidification. CASE PRESENTATION: A 4-month-old male presented with failure to thrive, pallor, hepatosplenomegaly, and recurrent infections. Examination revealed frontal bossing and hypotonia. Laboratory evaluation showed anemia and persistent hypocalcemia (6.8 mg/dL; reference 8.5-10.5 mg/dL). Skeletal survey demonstrated diffuse osteosclerosis with a characteristic "bone-within-bone" appearance. Differential diagnoses, including storage disorders and leukemia, were excluded. Clinical exome sequencing identified a homozygous CLCN7 missense variant, c.613G>A (p.Gly205Arg), classified as a variant of uncertain significance (VUS) based on ACMG/AMP criteria (PM2, PP3). CONCLUSION: Diagnosis in this case was primarily clinico-radiological, with genetic findings providing supportive evidence. This report presents an educational case emphasizing the importance of integrated clinical, radiological, and laboratory evaluation, and highlights the challenges in interpreting variants of uncertain significance in clinical practice.

Current brain atlases are largely descriptive, cataloging correlative molecular snapshots such as gene expression signatures yet offering limited functional insight. Here, we develop a scalable, cell-type-resolved in vivo CRISPR interference (CRISPRi) platform enabling systematic gene function profiling in the mouse brain. Through genome-wide screens across four neuronal populations at three time points spanning youth to aging, we identify neuronal essential genes missed in vitro and define a consensus set of 269 neuronal core essential genes. The data reveal cell-type-specific genetic vulnerabilities, including divergent dependencies validated for exosome component 9 (Exosc9) and osteopetrosis-associated transmembrane protein 1 (Ostm1) between excitatory and inhibitory neurons. We uncover aging-specific dependencies enriched in mitochondrial and translational pathways, aligning with transcriptional changes in the aging human brain. Finally, we establish the CRISPRinvivo data portal as a community resource for in vivo screening. Altogether, this work provides a broadly applicable platform for in vivo functional genomics and a framework for building comprehensive gene-function brain atlases.

Osteopetrosis is an uncommon inherited skeletal condition arising from impaired osteoclast activity, with its autosomal recessive forms being linked to mutations in the TNFRSF11A gene. This study reports on a three-year-old Chinese girl presenting with recurrent fractures, short stature, and macrocephaly. Radiological examinations revealed diffusely elevated bone mineral density and constricted medullary spaces. Meanwhile, whole-exome sequencing detected compound heterozygous alterations in the TNFRSF11A gene: c.1567?+?2T>A inherited from the father and c.630C>G from the mother. The child underwent haploidentical hematopoietic stem cell transplantation (HSCT) from the father. Post-transplant follow-up showed improved growth (height/weight), resolved anemia, and alleviated optic foramen stenosis. The patient remained free of hepatosplenomegaly. This case report suggests that HSCT holds therapeutic potential for TNFRSF11A-related osteopetrosis and highlights the clinical value of early genetic diagnosis and timely transplantation for optimizing patient prognosis. Larger studies are required to confirm these findings and further guide the clinical management of similar rare disease cases.

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.