Pubofemoral distances correlate to acetabular morphology and sonological instability in screening for hip dysplasia.

Aims: The present study seeks to investigate the correlation of pubofemoral distances (PFD) to α angles, and hip displaceability status, defined as femoral head coverage (FHC) or FHC during manual provocation of the newborn hip < 50%. Methods: We retrospectively included all newborns referred for ultrasound screening at our institution based on primary risk factor, clinical, and PFD screening. α angles, PFD, FHC, and FHC at follow-up ultrasound for referred newborns were measured and compared using scatter plots, linear regression, paired t-test, and box-plots. Results: We included 2,735 newborns, of whom 754 received a follow-up hip ultrasound within six weeks of age. After exclusion, 1,500 hips were included for analysis. Sex distribution was 372 male and 380 female, and the mean age at examination was 36.6 days (4 to 87). We found a negative linear correlation of PFD to α angles (p < 0.001), FHC (p < 0.001), and FHC during provocation (p < 0.001) with a 1 mm increase in PFD corresponding to a -2.1° (95% confidence interval (CI) -2.3 to -1.9) change in α angle and a -3.4% (95% CI -3.7 to -3.0) change in FHC and a -6.0% (-6.6 to -5.5) change in FHC during provocation. The PFD was significantly higher with increasing Graf types and in displaceable hips (p < 0.001). Conclusion: PFD is strongly correlated to both α angles and hip displaceability, as measured by FHC and FHC during provocation, in ultrasound of newborn hips. The PFD increases as the hips become more dysplastic and/or displaceable.

B3GAT3-related linkeropathy and an in-frame homozygous deletion in an adult patient.

BACKGROUND: Proteoglycans (PGs) are complex macromolecules consisting of a core protein and glycosaminoglycan (GAG) side chains. PGs are important for the constitution and functioning of the connective tissue. The normal composition of the GAG side chains defines the nature of the PGs and a wide range of biological events. Deficiencies of specific enzymes involved in the linkage of GAGs to the core protein to form functional PGs, lead to a heterogeneous disease group called Linkeropathies. This is a group of multisystem conditions characterized by different phenotypes that include skeletal dysplasia and various extra-skeletal features: developmental delay/intellectual disability, ophthalmological abnormalities including blue sclerae, facial characteristics, cardiac defects, abdominal wall defects (hernias), cutis laxa, hypermobility and hypotonia. The conditions show variable severity and often overlapping phenotypes. The enzyme ß-1,3-glucuronyltransferase 3, encoded by B3GAT3, is involved in the linkage process to form functional PGs. Biallelic pathogenic variants in B3GAT3 hence lead to Linkeropathy due to loss of function or decreased activity of this enzyme. PATIENT PRESENTATION: We describe a 22-year-old female patient, born of consanguineous parents. The disease history includes congenital severe joint malalignment of elbows, hips, knees and feet, hypermobility, severe kyphoscoliosis, osteoporosis with multiple fractures in childhood, congenital diaphragmatic hernia, minor dental anomalies, digital malformations, and characteristic facial features. Whole exome sequencing was performed, and homozygosity for a novel in-frame deletion in B3GAT3, (c.61_63delCTC (p.(Leu21del))) was detected. Both unaffected parents (double second cousins) were shown to be heterozygous carriers. CONCLUSION: This is the first report to describe homozygosity for this specific in-frame deletion in B3GAT3 (p.(Leu21del)). We present a young adult phenotype and a summary of previous reported patients with other biallelic B3GAT3-variants for comparison. Previously described patients of B3GAT3-deficiency were, however, all children with phenotypes ranging from prenatal manifestation and early lethality to less severe. We suggest that this novel homozygous in-frame deletion in B3GAT3 may be the cause of a recessive form of Linkeropathy.

Diagnostic accuracy of ultrasound-guided core biopsy of peripheral nerve sheath tumors.

PURPOSE: To retrospectively evaluate the diagnostic accuracy of and complications from ultrasound-guided core needle biopsy (UGCNB) of suspected peripheral nerve sheath tumors (PNSTs). METHODS: Patients undergoing UGCNB from January 2004 to December 2016, based on the suspicion of PNST, were included in the study. Age, gender, anatomical location, dates of relevant events, and histopathological reports of the UGCNB cores and the resected tumors were retrieved from the patients' medical records. RESULTS: A total of 154 UGCNBs were identified. One hundred and forty (90.9%) of these resulted in a conclusive histopathological report, while 14 were unsuited for histopathological analysis due to insufficient amount of tissue and/or nonrepresentative tissue. The overall diagnostic accuracy of UGCNB with respect to discriminate malignant from benign tumors was 99.3%, while correct specific UGCNB diagnoses were confirmed in 95.1% of the cases. Sensitivity and specificity were 90.9% (95% CI: 58.7-99.8%) and 100% (95% CI: 97.2-100%), respectively. The positive predictive value was 100%, and the negative predictive value was 99.2%. Except for one patient, who reported mild dysesthesia, which resolved 2 days after the UGCNB, no complications were reported. CONCLUSION: This study suggests that UGCNB is accurate and safe in patients suspected for PNST.

TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes.

BACKGROUND: TLR9 agonists are being developed as immunotherapy against malignancies and infections. TLR9 is primarily expressed in B cells and plasmacytoid dendritic cells (pDCs). TLR9 signalling may be critically important for B cell activity in lymph nodes but little is known about the in vivo impact of TLR9 agonism on human lymph node B cells. As a pre-defined sub-study within our clinical trial investigating TLR9 agonist MGN1703 (lefitolimod) treatment in the context of developing HIV cure strategies (NCT02443935), we assessed TLR9 agonist-mediated effects in lymph nodes. METHODS: Participants received MGN1703 for 24 weeks concurrent with antiretroviral therapy. Seven participants completed the sub-study including lymph node resection at baseline and after 24 weeks of treatment. A variety of tissue-based immunologic and virologic parameters were assessed. FINDINGS: MGN1703 dosing increased B cell differentiation; activated pDCs, NK cells, and T cells; and induced a robust interferon response in lymph nodes. Expression of Activation-Induced cytidine Deaminase, an essential regulator of B cell diversification and somatic hypermutation, was highly elevated. During MGN1703 treatment IgG production increased and antibody glycosylation patterns were changed. INTERPRETATION: Our data present novel evidence that the TLR9 agonist MGN1703 modulates human lymph node B cells in vivo. These findings warrant further considerations in the development of TLR9 agonists as immunotherapy against cancers and infectious diseases. FUND: This work was supported by Aarhus University Research Foundation, the Danish Council for Independent Research and the NovoNordisk Foundation. Mologen AG provided study drug free of charge.

Suggestion for new 4.4 mm pubo-femoral distance cut-off value for hip instability in lateral position during DDH screening.

Background and purpose - Current selective screening algorithms for developmental dysplasia of the hip (DDH) are insufficient. Universal screening programs have been proposed but so far have been deemed too expensive and time consuming. The pubo-femoral distance may solve this problem as a quick, low-cost, highly sensitive, and specific sonographic measurement for DDH, but this has only been validated in the supine position. Therefore we validated pubo-femoral distance (PFD) in the lateral position as an indicator for instability of the hip. Methods - All participants had undergone ultrasonographic diagnostics using the modified Graf technique. In addition, PFD measurements in lateral position were performed. Results were compared between 25 infants who had been treated for DDH because of dysplastic appearance on ultrasound combined with clinical instability and a control group consisting of 100 untreated infants screened for DDH. Sensitivity, specificity, and cut-off points were determined using Receiver operating characteristics (ROC) analysis. Results - We found a mean PFD of 6.8 mm (6.2-7.4) in the treated group with a control group PFD of 3.4 mm (3.3-3.6) (p < 0.005). A PFD value above a threshold of 4.4 mm yielded a sensitivity of 100% and a specificity of 93% for detecting unstable DDH. Interpretation - PFD measured in lateral position was statistically significantly increased in hips of children treated for DDH with Denis Browne hip brace compared with healthy children with unaffected stable hips. Furthermore, the PFD measurement had a high level of sensitivity and specificity at a cut-off value of 4.4 mm. A cut-off value of 6.00 mm has previously been reported as the gold standard in supine position. We suggest that 4.4 mm is used in lateral position.

Low rate of clinically important avascular necrosis of the femoral head after Ludloff's procedure.

INTRODUCTION: Ludloff's procedure for open reduction of congenital dislocation of the hip (CDH) is recommended for its minimal tissue damage, but is criticised for the risk of late avascular necrosis (AVN) of the femoral head. The aim of present study was primarily to assess the risk of late AVN of the femoral head and secondly the range of motion (ROM) of the hip and the quality of life in children following Ludloff's procedure. METHODS AND MATERIALS: 13 hips in 11 children after Ludloff's procedure due to CDH were included retrospectively from 1997 to 2005 at Aarhus University Hospital. Radiographs were evaluated for the presence of AVN of the femoral head and classified according to the Bucholz and Ogden classification, with type 2-4 having clinical relevance. A clinical examination included range of motion (ROM) and leg length discrepancy (LLD) measurements. The HAGOS hip questionnaire evaluated activity, participation and quality of life. RESULTS: No severe type 3-4 AVN was observed. 2 type 2 and 5 type 1 were observed. AVN was observed in 7 of the 13 operated hips (54%). An 8.6° difference in flexion for unilaterally treated hips was observed (p<0.02). 8 of 11 patients had minor LLD (range 0.5-2 cm). CONCLUSIONS: Only minor AVN of clinical importance was seen after Ludloff's procedure.