シュワルツ・ヤンペル症候群

UNLABELLED: This study explored whether Romosozumab, an anti-sclerostin antibody, can improve bone quality in women with Osteogenesis imperfecta. After 12 months, spinal areal bone mineral density increased, showing a beneficial treatment effect, although changes in hip bone density and bone structure were less pronounced than in women with severe osteoporosis. PURPOSE: Osteogenesis imperfecta (OI) is the most common hereditary bone disorder, characterized by increased bone fragility and impaired bone quality, but pharmacological treatment is limited. Ongoing clinical trials investigate monoclonal anti-sclerostin antibodies for OI patients, offering new hope for reducing bone fragility by increasing bone mass. METHODS: Postmenopausal women with either OI (n = 5) or severe osteoporosis (OPO, n = 10) receiving Romosozumab monthly (210 mg s.c.) for 12 months were analyzed retrospectively. Clinical assessments were performed at baseline, after 6 months, and after 12 months. Bone mass and structure were evaluated at baseline and after 12 months of treatment. In addition, serum and urine markers of bone turnover were analyzed at each time point. RESULTS: The mean age of the participants was 53.6 ± 8.9 years for OI patients and 57.2 ± 5.8 years for OPO patients (p = 0.444). After 12 months of Romosozumab treatment, spinal aBMD and osteocalcin increased significantly in OI patients, indicating an anabolic response. HR-pQCT analysis revealed no statistically significant microstructural changes in patients with OI, although trends and moderate effect sizes suggested potential improvements. In patients with OPO, we observed a more pronounced response of bone turnover markers with greater aBMD gains at both the spine and femur, as well as significant improvements in bone microstructure, particularly at the tibia. CONCLUSIONS: Romosozumab treatment in postmenopausal women with OI resulted in a significant increase in spinal aBMD, though the effect on hip aBMD and peripheral bone microstructure was limited in contrast to postmenopausal osteoporosis.

Atypical femoral fractures (AFF) are rare fractures with characteristic radiographic features, most commonly associated with long-term bisphosphonate use. Their occurrence in patients with osteogenesis imperfecta (OI), a hereditary bone disease leading to bone fragility, is not well understood. In this study, 138 adults with genetically confirmed classical OI were screened for AFF. Five patients with AFF were identified and compared to an age- and treatment-matched adult OI cohort without AFF (n = 23). Demographical parameters, biochemical markers, bone mineral density (DXA), bone microarchitecture (HR-pQCT), and radiographs were analyzed. In addition, antiresorptive therapy and the duration of treatment were determined and compared. In the screened OI cohort, AFF prevalence was 3.6%. No significant differences were observed between groups regarding age, weight, height, BMI, fracture history, bone mineral density, or antiresorptive therapy exposure and duration. HR-pQCT showed no significant microarchitectural differences, although a trend toward higher cortical thickness was noted in AFF patients. AFF are a rare complication in adults with classical OI and appear to be multifactorial in origin. Our findings suggest that AFF are not exclusively related to antiresorptive therapy but may be influenced by disease-specific factors, particularly the underlying collagen defect, femoral deformities and altered biomechanics. Individualized management strategies are essential, and further studies are needed to clarify underlying mechanisms and best treatment options.

Osteogenesis imperfecta (OI) is a rare bone fragility disorder. Previously, in a severe OI mouse model (Col1a1Jrt/+), a sex- and age-dependent metabolic phenotype was observed, correlating with elevated levels of the bone-derived hormone osteocalcin (OCN). This hormone is known to play a crucial role in managing energy metabolism, including glucose regulation and fat mass. In fact, upon high-fat diet (HFD) exposure, OI mice developed a metabolic syndrome linked to sex and OCN. To assess OCN's role in OI, Col1a1Jrt/+ mice were crossed with OCN-deficient mice (Bglap). Under regular chow and HFD conditions, both OCN-dependent and OCN-independent metabolic alterations were identified. OCN-dependent processes were adipose tissue, liver, and insulin metabolism in a sex-, age-, and diet-dependent manner. OCN-independent traits included the pancreas in juvenile mice, HFD-induced pancreatic insulin levels and glucose intolerance, besides overall growth, fertility, and bone phenotype. Notably, increased juvenile energy expenditure was OCN-independent, while HFD-induced changes were OCN-driven. These findings demonstrate OCN's role in shaping the metabolic phenotype while revealing distinct OCN-independent effects, emphasizing the complex genetic regulation of metabolism in OI.

BACKGROUND: Fibrous dysplasia (FD) affecting the upper cervical spine is exceptionally rare and results in severe cervico-occipital pain and limited neck mobility due to altered biomechanics and irritation of the third occipital nerve (TON). Surgical management is challenging because of the proximity to critical neurovascular structures. In the absence of neurological deficits, targeted TON blocks have shown promise as part of conservative management. CASE REPORT: A 33-year-old woman presented with a 7-year history of neck and suboccipital pain. Imaging revealed expansile FD at C1-C2 with partial fusion and no neurovascular compromise. An ultrasound-guided right-sided TON therapeutic block was administered, which resulted in immediate and substantial pain relief (Numeric Rating Scale 8/10 reduced to 3/10) and sustained functional improvement for 3 months. CONCLUSIONS: Ultrasound-guided TON block provided meaningful long-term pain relief and avoided high-risk surgical intervention in this rare case of C1-C2 FD.

Spondylometaphyseal dysplasia, Kozlowski type (SMDK), is an autosomal dominant skeletal disorder characterized by abnormalities of the spine, metaphyses and epiphyses. It is associated with variants in TRPV4, although the underlying molecular mechanisms remain unclear. A de novo heterozygous TRPV4 variant (c.2479C>G, p.Pro827Ala) was detected in a patient with SMDK by whole-exome sequencing, and transcriptome sequencing was performed in available family members. Expression analyses showed reduced TRPV4 transcript and protein levels associated with the p.Pro827Ala variant. Cellular functional assays further showed decreased intracellular Ca2+ concentrations without detectable changes in plasma membrane localization. In addition, ATP2B1 and PRKCQ were downregulated. To further investigate the pathogenic mechanism, a heterozygous knock-in Trpv4P827A/+ mouse model was generated using CRISPR/Cas9. Trpv4P827A/P827A homozygous mice exhibited significant skeletal developmental delay, and transcriptome profiling revealed dysregulated expression of homeobox, zf_C2H2, and forkhead transcription factor families during early development. Collectively, these findings expand the spectrum of pathogenic TRPV4 variants and provide mechanistic insights into the pathogenic effect of TRPV4 p.Pro827Ala in SMDK, supporting improved clinical diagnosis and future functional studies.