Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy

Facioscapulohumeral muscular dystrophy 1 (FSHD1) is caused by a contraction in the number of D4Z4 repeats on chromosome 4, resulting in relaxation of D4Z4 chromatin causing inappropriate expression of DUX4 in skeletal muscle. Clinical severity is inversely related to the number of repeats. In contrast, FSHD2 patients also have inappropriate expression of DUX4 in skeletal muscle, but due to constitutional mutations in SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1), which cause global hypomethylation and hence general relaxation of chromatin. Thirty patients originally referred for FSHD testing were screened for SMCHD1 mutations. Twenty-nine had >11 D4Z4 repeats. SMCHD1 c.1040+1G>A, a pathogenic splice-site variant, was identified in a FSHD1 family with a borderline number of D4Z4 repeats (10) and a variable phenotype (in which a LMNA1 sequence variant was previously described), and SMCHD1 c.2606 G>T, a putative missense variant (p.Gly869Val) with strong in vitro indications of pathogenicity, was identified in a family with an unusual muscular dystrophy with some FSHD-like features. The two families described here emphasise the genetic complexity of muscular dystrophies. As SMCHD1 has a wider role in global genomic methylation, the possibility exists that it could be involved in other complex undiagnosed muscle disorders. Thus far, only 15 constitutional mutations have been identified in SMCHD1, and these two sequence variants add to the molecular and phenotypic spectrum associated with FSHD.     

Nonreconstruction Options for Treating Medial Ulnar Collateral Ligament Injuries of the Elbow in Overhead Athletes

Purpose of Review

This review aims to describe the nonreconstructive options for treating ulnar collateral ligament (UCL) injuries ranging from nonoperative measures, including physical therapy and biologic injections, to ligament repair with and without augmentation.

Recent Findings

Nonoperative options for UCL injuries include guided physical therapy and biologic augmentation with platelet-rich plasma (PRP). In some patients, repair of the UCL has shown promising return to sport rates by using modern suture and suture anchor techniques. Proximal avulsion injuries have shown the best results after repair. Currently, there is growing interest in augmentation of UCL repair with an internal brace.

Summary

The treatment of UCL injuries involves complex decision making. UCL reconstruction remains the gold standard for attritional injuries and complete tears, which occur commonly in professional athletes. However, nonreconstructive options have shown promising results for simple avulsion or partial thickness UCL injuries. Future research comparing reconstructive versus nonreconstructive options is necessary.

     

Effectiveness of Implementing Evidence‐based Interventions to Reduce C‐spine Image Ordering in the Emergency Department: A Systematic Review

Objectives

Appropriate use of imaging for adult patients with cervical spine (C‐spine) injuries in the emergency department (ED) is a longstanding issue. Guidance for C‐spine ordering exists; however, the effectiveness of the decision support implementation in the ED is not well studied. This systematic review examines the implementation and effectiveness of evidence‐based interventions aimed at reducing C‐spine imaging in adults presenting to the ED with neck trauma.

Methods

Six electronic databases and the gray literature were searched. Comparative intervention studies were eligible for inclusion. Two independent reviewers screened for study eligibility, study quality, and extracted data. The change in imaging was reported using individual odds ratios (ORs) with 95% confidence intervals (CIs) using random effects.

Results

A total of 990 unique citations were screened for relevance of which six before–after studies and one randomized controlled trial were included. None of the studies were assessed as high quality. Interventions consisted primarily of locally developed guidelines or established clinical decision rules such as the NEXUS or the Canadian C‐spine rule. Overall, implementation of interventions aimed at reducing C‐spine image ordering resulted in a statistically significant reduction in imaging (OR = 0.69, 95% CI = 0.51–0.93); however, heterogeneity was high (I² = 82%). Subgroup analysis revealed no differences between studies that specified enrolling alert and stable patients compared to unspecified trauma (p = 0.81) or between studies employing multifaceted versus nonmultifaceted interventions (p = 0.66). While studies generally provided details on implementation strategies (e.g., teaching sessions, pocket cards, posters, computerized decision support) the effectiveness of these implementation strategies were frequently not reported.

Conclusion

There is moderate evidence regarding the effectiveness of interventions to reduce C‐spine image ordering in adult patients seen in the ED with neck trauma. Given the national and international focus on improving appropriateness and reducing unnecessary C‐spine imaging through campaigns such as Choosing Wisely, additional interventional research in this field is warranted.

     

Preimplantation genetic diagnosis for severe albright hereditary osteodystrophy

CONTEXT: Preimplantation genetic diagnosis (PGD) enables the selection of embryos without mutations for implantation and has not been described to our knowledge for mutations in GNAS. Phocomelia in a patient with Albright hereditary osteodystrophy (AHO) has also not been previously described. OBJECTIVE: The aim of this study was to identify a GNAS mutation in a patient with a severe form of AHO and pseudohypoparathyroidism type 1a with phocomelia and to perform PGD on embryos derived by in vitro fertilization to deliver an unaffected infant. DESIGN: A proband and his family are described clinically, the GNAS gene was sequenced to identify a novel mutation in the proband, and PGD was performed on embryos. SETTING: The setting was in a tertiary-care hospital. PATIENTS: The patients were from a single family in which the proband has a severe form of AHO. INTERVENTIONS: Interventions were PGD and in vitro fertilization. MAIN OUTCOME MEASURES: The main outcome measures were the clinical phenotypes and GNAS gene sequences of the proband, embryos, and family members. RESULTS: After PGD, three genotypically normal embryos were transferred back to the mother. Pregnancy ensued, and a healthy male infant was delivered at 36.5 wk gestation. The GNAS genes in the baby were confirmed as wild-type, and the infant is free of any signs of AHO. CONCLUSIONS: We describe herein a proband with AHO and severe skeletal deformities (including phocomelia) related to a novel GNAS mutation and the delivery of a male infant with homozygous normal GNAS genotype after PGD.     

SUMO-1 conjugation to topoisomerase I: A possible repair response to topoisomerase-mediated DNA damage

Ubiquitin/26S proteasome-dependent degradation of topoisomerase I (TOP1) has been suggested to be a unique repair response to TOP1-mediated DNA damage. In the current study, we show that treatment of mammalian cells or yeast cells expressing human DNA TOP1 with camptothecin (CPT) induces covalent modification of the TOP1 by SUMO-1/Smt3p, a ubiquitin-like protein. This conclusion is based on the following observations: (i) Mammalian DNA TOP1 conjugates induced by CPT were cross-reactive with SUMO-1/Smt3p-specific antibodies both in yeast expressing human DNA TOP1 as well as mammalian cells. (ii) The formation of TOP1 conjugates was shown to be dependent on UBC9, the E2 enzyme for SUMO-1/Smt3p. (iii) TOP1 physically interacts with UBC9. (iv) Ubc9 mutant yeast cells expressing human DNA TOP1 was hypersensitive to CPT, suggesting that UBC9/SUMO-1 may be involved in the repair of TOP1-mediated DNA damage.     

Intrapericardial benign teratoma with unusual presentation

Benign teratoma, also referred as dermoid cyst, do occur in the mediastinum. However, their intrapericardial location has been reported very occasionally. This case of intrapericardial benign solid teratoma is being presented because of its rarity and its unusual presentation as a case of empyema, with features of cardiac compression and pericardial effusion.