シュワルツ・ヤンペル症候群

RUNX2 (Runt-related transcription factor 2) is a master regulator of osteogenesis, and its genetic mutations are associated with ~65% cases of cleidocranial dysplasia (CCD), an autosomal dominant abnormal bone development disorder in humans with defective intramembranous bone formation. However, how these mutations affect bone formation remains to be investigated. Here, we report that RUNX2 interacts with the F-box protein JFK and is destabilized by the SKP1-CUL1-JFK E3 ubiquitin ligase complex (SCFJFK). We find that several CCD-associated mutations of RUNX2 acquire an increased affinity toward SCFJFK thus an accelerated proteasomal degradation. We demonstrate that SCFJFK-mediated RUNX2 degradation suppresses osteoblast differentiation. Consistently, Jfk-null mice exhibit increased trabecular bone volume and bone mineral density and are resistant to Runx2 haploinsufficiency-induced CCD-like syndrome. Interestingly, RUNX2 binds to the JFK promoter and represses its transcription, establishing a feedback loop to promote osteoblast differentiation, and remarkably, the CCD-associated RUNX2 mutants also display an impaired transcription repression of JFK. Our study demonstrates SCFJFK as an E3 ligase for RUNX2 and uncovers a feedback regulatory loop between SCFJFK and RUNX2 that is implemented in bone development and implicated in CCD, supporting the pursuit of JFK as a potential target to ameliorate CCD-like syndrome.

Stüve-Wiedemann syndrome (SWS) is an ultra-rare autosomal recessive skeletal dysplasia caused by loss-of-function variants in the leukemia inhibitory factor receptor (LIFR) gene. While characterized by bone deformities and dysautonomia, severe persistent pulmonary hypertension of the newborn (PPHN) significantly contributes to high early mortality. We report a neonate with genetically confirmed SWS who presented with severe, suprasystemic PPHN refractory to standard pulmonary vasodilators, including inhaled nitric oxide. This case provides a detailed longitudinal hemodynamic characterization of severe suprasystemic PPHN in genetically confirmed SWS, including serial assessment of pulmonary pressures, shunt direction, and right ventricular function during treatment. Rather than identifying PPHN as a novel manifestation of SWS, it extends the phenotypic and hemodynamic characterization of pulmonary vascular involvement in this rare disorder.

PURPOSE: Achondroplasia is a genetic syndrome characterized by short stature and rhizomelic shortening of the limbs. Many patients also exhibit craniocervical junction stenosis, which often progresses to spinal cord compression or hydrocephalus. Foramen magnum decompression (FMD) is performed to relieve stenosis at the craniovertebral junction. The purpose of this study was to analyze the clinical outcomes of FMD in achondroplasia patients and to discuss restenosis due to bone regrowth (bony restenosis), an important cause of postoperative worsening. METHODS: Medical records and brain imaging data of 89 pediatric achondroplasia patients who visited our institution between January 2012 and April 2022 were retrospectively analyzed. RESULTS: Among 89 achondroplasia patients, FMD was performed in 38 patients. During the median 60 months of follow-up after FMD, eleven patients developed warning changes at MRI. Warning changes consisted of four types: restenosis due to bone regrowth (bony restenosis), restenosis due to soft tissue thickening, de novo T2 HSI of the cervical spinal cord, and progression of ventriculomegaly. Patients with bony restenosis (3 of 38; 7.9%) required reoperation of FMD. The age of restenosis was 46, 48, and 98 months old, and the time interval after FMD was 38, 34, and 87 months, respectively. Removal of bony spur was performed and no recurrence of bony restenosis was found until the most recent follow-up. CONCLUSION: Bony restenosis was observed in 3 of 38 patients (7.9%) after FMD during the follow-up. Regular imaging studies and close observation until late childhood may be reasonable for early detection and management of bony restenosis.

CASE: A 44-year-old man with hereditary multiple exostoses (HME) presented with recurrent patellar dislocation of the left knee. Radiographs revealed valgus deformity and trochlear dysplasia. The patient underwent lateral opening-wedge distal femoral osteotomy with medial patellofemoral ligament reconstruction using FiberTape and knotless SwiveLock anchors. Postoperatively, patellar tracking normalized with no recurrence. CONCLUSIONS: This case highlights the need to address bony alignment and medial soft-tissue insufficiency concurrently in complex patellofemoral instability, particularly in HME, to achieve stable outcomes.

BackgroundAlthough in situ pinning (ISP) is the standard primary treatment for slipped capital femoral epiphysis (SCFE), some patients are left with residual deformity that may lead to long-term complications, including an increased risk of osteoarthritis. This study evaluates the radiographic and clinical outcomes of a secondary corrective procedure, the Pre-Operative computed Tomography-assisted intertrochanteric Flexion (POTOF) osteotomy, for treating these persistent deformities.MethodsWe retrospectively reviewed patients who underwent a POTOF osteotomy as a secondary procedure for SCFE between 2004 and 2020. Patients with less than two years of follow-up were excluded. We evaluated changes in the modified β angle, incidence of avascular necrosis (AVN), relative joint space (RJS), and the modified Harris Hip Score at the final follow-up. Statistical significance was set at p < 0.05.ResultsEleven patients (nine male, two female; 11 hips) were included, with a mean follow-up of 9.0 years. Seven patients had undergone prior ISP, and four were neglected cases. The mean modified β angle significantly improved from 120° to 91° (p < 0.01). No AVN was observed. The mean RJS was 92% (range, 42-128%). The mean modified Harris Hip Score, available for 7 of the 11 hips, was 92.4, indicating good hip function.ConclusionsThe POTOF osteotomy may serve as a viable secondary procedure for treating residual deformities after SCFE. In this small cohort it improved hip alignment and function, supporting its potential as a treatment option for patients with post-SCFE deformities or neglected cases, although further comparative studies are required to confirm its definitive efficacy.