Novel LMNA Gene Mutation in a Patient With Atypical Werner's Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) and Werner's syndrome are representative types of progeroid syndrome. LMNA (Lamin A/C) gene mutation with atypical Werner's syndrome have recently been reported. Atypical Werner's syndrome with the severe metabolic complications, the extent of the lipodystrophy is associated with A133L mutation in the LMNA gene and these patients present with phenotypically heterogeneous disorders. We experienced a 15-yr-old Korean female with progeroid features, generalized lipodystrophy, hypertriglyceridemia, fatty liver, steatohepatitis, and type 2 diabetes mellitus. Skin fibroblasts from the patient showed marked abnormal nuclear morphology, compared with that from normal persons. Gene analysis revealed that this patient had T506del of exon 2 in the LMNA gene. We report here the first case of atypical Werner's syndrome with frameshift mutation that was caused by T506del

Use of Allograft in Skeletally Immature Patients for Calcaneal Neck Lengthening Osteotomy

PURPOSE: To date, there have been no studies evaluating the usefulness of allograft as a substitute for autograft in calcaneal neck lengthening osteotomy. This retrospective study examined the results of calcaneal neck lengthening osteotomy using allograft for pathologic flatfoot deformity in children and adolescents with various neuromuscular diseases. MATERIALS AND METHODS: 118 feet in 79 children treated surgically between Mar 2000 and July 2005 were reviewed. The mean age at the time of the operation was 9+3 years (range, 3-17 years) and follow-up averaged 15.4 months (range, 13-21 months) postoperatively. Talo-1st metatarsal angle, talo-calcaneal angle, calcaneal pitch were measured before and after operation and bony union was estimated. RESULTS: Bony union was noted at the latest follow-up and there were no postoperative complications such as reduction loss, infection, nonunion, delayed union or graft loss during the follow-up period in all but one foot. All radiographic indices were improved postoperatively in all cases. CONCLUSION: Our results indicate that use of allograft in calcaneal neck lengthening osteotomy is a useful option for correction of the planovalgus deformity in skeletally immature patients whose enough autobone can not be obtained.ope

A New Classification for Idiopathic Genu Vara

PURPOSE: Past classification for the treatment of idiopathic genu vara depended simply on the measurement of distance between the knees, without attention to the rotational profile of the lower extremity. We retrospectively analyzed anatomical causes of idiopathic genu vara. PATIENTS AND METHODS: Twenty eight patients with idiopathic genu vara were included in this study. All patients were surgically treated. To evaluate the angular deformity, a standing orthoroentgenogram was taken and the lateral distal femoral angle and the medial proximal tibial angle were measured. In order to assess any accompanying torsional deformity, both femoral anteversion and tibial external rotation were measured using computerized tomographic scans. A derotational osteotomy was performed at the femur or tibia to correct rotational deformity, and a correctional osteotomy was performed at the tibia to correct angular deformity. RESULTS: Satisfactory functional results were obtained in all cases. Genu vara was divided into 3 groups according to the nature of the deformity; group 1 (6 patients) with increased femoral anteversion, group 2 (10 patients) with proximal tibial varus deformity alone, and group 3 (12 patients) with proximal tibial varus deformity accompanied by increased external tibial rotation. CONCLUSION: The success seen in our cases highlights the importance of an accurate preoperative analysis that accounts for both rotational and angular deformities that may underlie idiopathic genu vara.ope

Extraarticular Subtalar Arthrodesis for Pes Planovalgus: An Interim Result of 50 Feet in Patients with Spastic Diplegia

BACKGROUND: There are no reports of the pressure changes across the foot after extraarticular subtalar arthrodesis for a planovalgus foot deformity in cerebral palsy. This paper reviews our results of extraarticular subtalar arthrodesis using a cannulated screw and cancellous bone graft. METHODS: Fifty planovalgus feet in 30 patients with spastic diplegia were included. The mean age at the time of surgery was 9 years, and the mean follow-up period was 3 years. The radiographic, gait, and dynamic foot pressure changes after surgery were investigated. RESULTS: All patients showed union and no recurrence of the deformity. Correction of the abduction of the forefoot, subluxation of the talonavicular joint, and the hindfoot valgus was confirmed radiographically. However, the calcaneal pitch was not improved significantly after surgery. Peak dorsiflexion of the ankle during the stance phase was increased after surgery, and the peak plantarflexion at push off was decreased. The peak ankle plantar flexion moment and power were also decreased. Postoperative elevation of the medial longitudinal arch was expressed as a decreased relative vertical impulse of the medial midfoot and an increased relative vertical impulse (RVI) of the lateral midfoot. However, the lower than normal RVI of the 1st and 2nd metatarsal head after surgery suggested uncorrected forefoot supination. The anteroposterior and lateral paths of the center of pressure were improved postoperatively. CONCLUSIONS: Our experience suggests that the index operation reliably corrects the hindfoot valgus in patients with spastic diplegia. Although the operation corrects the plantar flexion of the talus, it does not necessarily correct the plantarflexed calcaneus and forefoot supination. However, these findings are short-term and longer term observations will be needed.ope

Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signaling to suppress tumorigenesis

The mechanistic target of rapamycin (mTOR) functions as a critical regulator of cellular growth and metabolism by forming multi-component, yet functionally distinct complexes mTORC1 and mTORC2. Although mTORC2 has been implicated in mTORC1 activation, little is known about how mTORC2 is regulated. Here we report that phosphorylation of Sin1 at T86 and T398 suppresses mTORC2 kinase activity by dissociating Sin1 from mTORC2. Importantly, Sin1 phosphorylation, triggered by S6K or Akt, in a cellular context-dependent manner, inhibits not only insulin/IGF-1-mediated, but also PDGF or EGF-induced Akt phosphorylation by mTORC2, demonstrating a negative regulation of mTORC2 independent of IRS-1 and Grb10. Lastly, a cancer patient-derived Sin1-R81T mutation impairs Sin1 phosphorylation, leading to hyper-mTORC2 activation via bypassing this negative regulation. Together, our work reveals a Sin1 phosphorylation-dependent mTORC2 regulation, providing a potential molecular mechanism by which mutations in the mTORC1/S6K/Sin1 signaling axis might cause aberrant hyper-activation of mTORC2/Akt that facilitates tumorigenesis