Biallelic mutations in FLNB cause a skeletal dysplasia with 46,XY gonadal dysgenesis by activating ß-catenin.

Filamin B (FLNB) functions as a switch that can affect chrondrocyte development and endochondral bone formation through a series of signaling molecules and transcription factors that also affect Sertoli cell development. Here, we report a subject with a novel skeletal dysplasia and co-existing 46,XY gonadal dysgenesis and biallelic mutations in FLNB. Whole exome sequencing was performed to identify mutations. Quantitative polymerase chain reaction (qPCR) and flow variant assays were performed to quantify RNA, proteins and phosphorylated proteins. The TOPFLASH reporter was performed to quantify ß-catenin activity. Mutations were identified in the FLNB gene (FLNB:p.F964L, FLNB:p.A1577V). These mutations increased binding of FLNB protein to the MAP3K1 and RAC1 signal transduction complex and activated ß-catenin and had different effects on phosphorylation of MAP kinase pathway intermediates and SOX9 expression. Direct activation of ß-catenin through the FLNB-MAP3K1-RAC1 complex by FLNB mutations is a novel mechanism for causing 46,XY gonadal dysgenesis. The mechanism of action varies from those reported previously for loss of function mutations in SOX9 and gain-of-function mutations in MAP3K1.

Diagnosing slipped capital femoral epiphysis amongst various medical specialists.

PURPOSE: To evaluate sensitivity, specificity and accuracy of a radiographic slipped capital femoral epiphysis (SCFE)-diagnosis among medical specialists. METHODS: Three paediatricians, three paediatric radiologists and three paediatric orthopaedic surgeons completed two rounds of a survey of anteroposterior and frog-leg lateral radiographs of patients with a diagnosis of SCFE (25), femoroacetabular impingement (four), Legg-Calvé-Perthes (11) or no hip pathology (ten). Intra- and interobserver agreement among specialties regarding the diagnosis of a SCFE were assessed using Cohen's kappa coefficient (κ). Diagnostic accuracy of SCFE relative to the benchmark, a combination of the radiographic diagnosis based on Klein's line, clinical symptoms and surgical treatment, was assessed computing sensitivity, specificity and accuracy. RESULTS: Intraobserver agreement between the surveys was moderate among paediatricians (κ-range, 0.44 to 0.52), moderate to almost perfect among orthopaedic surgeons (κ-range, 0.79 to 0.88) and almost perfect among paediatric radiologists (κ-range, 0.83 to 1.00). Interobserver agreement for survey 1 and 2 was slight among paediatricians (mean κ, 0.19), substantial among orthopaedic surgeons (mean κ, 0.77) and almost perfect among paediatric radiologists (mean κ, 0.86). Sensitivity of SCFE-diagnosis was high among radiologists and orthopaedic surgeons (88% to 100% for both specialties), but lower for paediatricians (24% to 76%). Specificity was high among radiologists and orthopaedic surgeons (72% to 84%), however, variable among paediatricians (56% to 80%). Accuracy of a SCFE-diagnosis was highest in radiologists (84% to 92%), followed by orthopaedic surgeons (80% to 88%) and paediatricians (48% to 78%). CONCLUSION: SCFE can be detected on radiographs by different medical specialties. Intra- and interobserver agreement, specificity, sensitivity and accuracy for radiographic SCFE-diagnosis amongst paediatric radiologists and orthopaedic surgeons are better than that of general paediatricians. LEVEL OF EVIDENCE: II.

Hypogastric artery coil embolization prior to endoluminal repair of aneurysms and fistulas: buttock claudication, a recognized but possibly preventable complication.

PURPOSE: Hypogastric artery embolization is considered to be necessary to prevent retrograde flow and potential endoleaks when a stent-graft crosses the origin of the hypogastric artery. The authors assess the incidence of buttock claudication, which is the primary complication encountered. The effect of coil location and the presence of antegrade flow at the completion of embolization are evaluated. MATERIALS AND METHODS: Hypogastric artery embolization and endoluminal repair of aneurysms and fistulas was performed in 34 patients (30 men; four women) aged 27-91 years (mean, 76 years). Ten patients were being treated for solitary abdominal aortic aneurysms, 13 were being treated for aortoiliac aneurysms, and six patients were being treated for isolated common iliac aneurysms, three for hypogastric artery aneurysms and two for iliac arteriovenous fistulas. Eleven patients had coils placed completely above the bifurcation of the hypogastric artery and 23 patients had coils placed at the bifurcation, or within the branches of the hypogastric artery. Preservation of antegrade flow after embolization was noted in 14 of 34 patients. RESULTS: Thirty-four patients underwent stent-graft repair after hypogastric artery embolization. There were two perioperative deaths, three proximal leaks, and one collateral leak. Of the 32 patients who survived the procedure, there was one retrograde leak, even though 13 of 32 (41%) patients had continued antegrade flow at completion of the hypogastric artery embolization. When coils were placed at or in the bifurcation of the hypogastric artery, 12 of 22 (55%) experienced claudication. When coils were placed in the proximal hypogastric artery, one of 10 (10%) claudicated. CONCLUSION: It is probably not necessary to completely occlude antegrade flow in the hypogastric artery to prevent a distal endoleak. Buttock claudication is rare when coils are placed in the proximal hypogastric artery rather than at its bifurcation or in its branches.