Pathogenic heterozygous TRPM7 variants and hypomagnesemia with developmental delay.

Background: Heterozygous variants in Transient receptor potential melastatin type 7 (TRPM7), encoding an essential and ubiquitously expressed cation channel, may cause hypomagnesemia, but current evidence is insufficient to draw definite conclusions and it is unclear whether any other phenotypes can occur. Methods: Individuals with unexplained hypomagnesemia underwent whole-exome sequencing which identified TRPM7 variants. Pathogenicity of the identified variants was assessed by combining phenotypic, functional and in silico analyses. Results: We report three new heterozygous missense variants in TRPM7 (p.Met1000Thr, p.Gly1046Arg, p.Leu1081Arg) in individuals with hypomagnesemia. Strikingly, autism spectrum disorder and developmental delay, mainly affecting speech and motor skills, was observed in all three individuals, while two out of three also presented with seizures. The three variants are predicted to be severely damaging by in silico prediction tools and structural modeling. Furthermore, these variants result in a clear loss-of-function of TRPM7-mediated magnesium uptake in vitro, while not affecting TRPM7 expression or insertion into the plasma membrane. Conclusions: This study provides additional evidence for the association between heterozygous TRPM7 variants and hypomagnesemia and adds developmental delay to the phenotypic spectrum of TRPM7-related disorders. Considering that the TRPM7 gene is relatively tolerant to loss-of-function variants, future research should aim to unravel by what mechanisms specific heterozygous TRPM7 variants can cause disease.

Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous CNNM2 variants.

Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable. This study aims to understand the genotype-phenotype relationship in affected individuals with CNNM2 variants by phenotypic, functional and structural analysis of new as well as previously reported variants. This results in the identification of seven variants that significantly affect CNNM2-mediated Mg2+ transport. Pathogenicity of these variants is further supported by structural modelling, which predicts CNNM2 structure to be affected by all of them. Strikingly, seizures and intellectual disability are absent in 4 out of 7 cases, indicating these phenotypes are caused either by specific CNNM2 variant only or by additional risk factors. Moreover, in line with sporadic observations from previous reports, CNNM2 variants might be associated with disturbances in parathyroid hormone and Ca2+ homeostasis.

IntAct: A nondisruptive internal tagging strategy to study the organization and function of actin isoforms.

Mammals have 6 highly conserved actin isoforms with nonredundant biological functions. The molecular basis of isoform specificity, however, remains elusive due to a lack of tools. Here, we describe the development of IntAct, an internal tagging strategy to study actin isoforms in fixed and living cells. We identified a residue pair in ß-actin that permits tag integration and used knock-in cell lines to demonstrate that IntAct ß-actin expression and filament incorporation is indistinguishable from wild type. Furthermore, IntAct ß-actin remains associated with common actin-binding proteins (ABPs) and can be targeted in living cells. We demonstrate the usability of IntAct for actin isoform investigations by showing that actin isoform-specific distribution is maintained in human cells. Lastly, we observed a variant-dependent incorporation of tagged actin variants into yeast actin patches, cables, and cytokinetic rings demonstrating cross species applicability. Together, our data indicate that IntAct is a versatile tool to study actin isoform localization, dynamics, and molecular interactions.

Genetic and drug-induced hypomagnesemia: different cause, same mechanism.

Magnesium (Mg2+) plays an essential role in many biological processes. Mg2+ deficiency is therefore associated with a wide range of clinical effects including muscle cramps, fatigue, seizures and arrhythmias. To maintain sufficient Mg2+ levels, (re)absorption of Mg2+ in the intestine and kidney is tightly regulated. Genetic defects that disturb Mg2+ uptake pathways, as well as drugs interfering with Mg2+ (re)absorption cause hypomagnesemia. The aim of this review is to provide an overview of the molecular mechanisms underlying genetic and drug-induced Mg2+ deficiencies. This leads to the identification of four main mechanisms that are affected by hypomagnesemia-causing mutations or drugs: luminal transient receptor potential melastatin type 6/7-mediated Mg2+ uptake, paracellular Mg2+ reabsorption in the thick ascending limb of Henle's loop, structural integrity of the distal convoluted tubule and Na+-dependent Mg2+ extrusion driven by the Na+/K+-ATPase. Our analysis demonstrates that genetic and drug-induced causes of hypomagnesemia share common molecular mechanisms. Targeting these shared pathways can lead to novel treatment options for patients with hypomagnesemia.

Retrograde intramedullary nailing for humeral midshaft fractures : a retrospective cohort study.

This study evaluates the patient-reported functional outcome, clinical functional outcome and frequency of complications of simple oblique and transverse humeral midshaft fractures treated with a retrograde expert humeral nail. A retrospective cohort study of humeral midshaft fractures (AO 12-A2, 12-A3) treated with retrograde nailing between January 2010 and February 2018 in a level II trauma center was performed. Patients' perception of functional outcome was measured using the Disabilities of the Arm, Shoulder and Hand (DASH) scores. Thirteen patients with a median age of 20-years were treated with a retrograde nail. The median DASH score, administered 29 months (IQR 74) after surgery, was 7.9 (IQR 15.9). There were no perioperative frac- tures and the frequency of complications was 8%, being one nonunion. Retrograde nailing for humeral midshaft fractures is a safe technique, with excellent patient reported and clinical functional outcome. No iatrogenic peri- operative fractures occurred and the frequency of complications was low. We recommend the retrograde technique, if surgical fixation of humeral midshaft fractures is needed, especially in younger patients for who rotator cuff associated injuries will have a major impact on quality of life.

Correction to: Intramedullary screw fixation for simple displaced olecranon fractures.

The original version of this article unfortunately contained some mistakes. The spelling of the Willem Maarten P. F. Bosmans' name was incorrect.

Intramedullary screw fixation for simple displaced olecranon fractures.

PURPOSE: Olecranon fractures are common and typically require surgical fixation due to displacement generated by the pull of the triceps muscle. The most common techniques for repairing olecranon fractures are tension-band wiring or plate fixation, but these methods are associated with high rates of implant-related soft-tissue irritation. Another treatment option is fixation with an intramedullary screw, but less is known about surgical results using this strategy. Thus, the purpose of this study was to report the clinical and functional outcomes of olecranon fractures treated with an intramedullary cannulated screw. METHODS: We identified 15 patients (average age at index procedure 44 years, range 16-83) with a Mayo type I or IIA olecranon fracture who were treated with an intramedullary cannulated screw at a single level 2 trauma center between 2012 and 2017. The medical record was reviewed to assess radiographic union, postoperative range of motion and complications (including hardware removal). Patient-reported outcome was evaluated using the Disabilities of the Arm, Shoulder and Hand (DASH) score. Average follow-up was 22 months (range 8-36 months). RESULTS: By the 6th month post-operative visit, 14 patients had complete union of their fracture and 1 patient had an asymptomatic non-union that did not require further intervention. Average flexion was 145° (range 135-160) and the average extension lag was 11° (range 0-30). Implants were removed in 5 patients due to soft-tissue irritation. Average DASH score (± standard deviation) by final follow-up was 16 ± 10. CONCLUSIONS: Fixation of simple olecranon fractures with an intramedullary screw is a safe and easy fixation method in young patients, leading to good functional and radiological results. Compared to available data, less hardware removal is necessary than with tension-band wiring or plate fixation.

Hoffa fracture accompanied by dissection of the popliteal artery.

After a high-energy trauma, a 37-year-old motorcyclist presented to the emergency ward with a Hoffa fracture of the lateral femoral condyle of the right knee. Following admission, the patient developed a pale, cold and pulseless right foot. CT angiography scan showed a 5 cm dissection of the popliteal artery. Emergency arterial reconstruction was performed and the Hoffa fracture was repaired in a second stage. To our knowledge, this is the first report of a patient with a Hoffa fracture accompanied by a popliteal artery dissection.

Nonunion of the Capitate due to Delayed Diagnosis of an Isolated Fracture: A Case Report.

CASE: A 14-year-old girl was diagnosed with nonunion of an isolated capitate fracture 5 months after she first presented to the emergency department. The fracture of the capitate was treated by cancellous proximal bone graft and screw fixation. This current case provides details of the surgical fixation method and long-term functional outcome after nonunion of an isolated capitate fracture after a follow-up of 18 months following fixation. CONCLUSIONS: Persisting localized tenderness over the capitate should be an indication to perform an additional computed tomography or magnetic resonance imaging scan. Nonunion of isolated capitate fractures can be treated by means of open reduction and internal fixation, with autologous bone grafting.

Proximal tibiofibular joint dislocation: a rare entity.

A 37-year-old woman was diagnosed with an isolated proximal tibiofibular joint dislocation (PTJD) after an accident during gymnastic exercise. The dislocation has a low incidence rate and is often missed in the emergency department as physical and radiology signs are subtle. Treatment consists of closed or open reduction and immobilisation. When it is not recognised it is associated with significant peroneal nerve injury.

Paediatric forearm fracture with a twist: a proximal radioulnar translocation combined with radial head fracture.

A 10-year-old girl presented to the emergency department with proximal radioulnar translocation and radial head fracture, after fall onto an outstretched hand. Open reduction was used to reduce and stabilise the elbow joint after which the radial head was fixated by Kirschner wires. Three months after surgery, full range of motion was regained and union of the radial head was achieved. Proximal radioulnar translocation is a rare injury which is often missed on initial radiographs. Persistent restriction of forearm rotation with seemingly normal elbow configuration must trigger to take a closer look at the relationship between the ulna, radius and distal humerus. We show that early diagnosis and treatment of a proximal radioulnar translocation associated with a radial head fracture results in an excellent functional outcome.

An avulsion fracture of the calcaneal tuberosity: delay of treatment causes the 'Achilles heel' of optimal recovery.

A 72-year-old woman was diagnosed with an avulsion fracture of the tuberosity of the calcaneus. The fracture was planned for elective fixation 12 days after the accident. The planned open reduction and internal fixation was not possible due to a decubital wound on the Achilles heel as a result of pressure on the skin of the fractured tuberosity. Closed reduction and internal fixation was performed, leading to an acceptable outcome. Avulsion fractures of the tuberosity of the calcaneus are rare injuries, and delay in treatment should be avoided as it may lead to preventable complications.

Gastric perforation due to foreign body ingestion mimicking acute cholecystitis.

An 82-year-old man presented with signs and symptoms that were suggestive of acute cholecystitis. He underwent a laparoscopic cholecystectomy. During the intervention, a wooden foreign body was removed from the infiltrated omentum, probably after it had perforated the gastric antrum. The gastric perforation had led to a secondary infection of the gallbladder. The presumed gastric perforation was treated conservatively, and the patient recovered well and was discharged after 7 days. Secondary inflamed gallbladders are rare; the current case is, to the best of our knowledge, the first case reporting a secondary infection of the gallbladder due to a gastric perforation. Clinicians should be aware of possible ingestion of foreign bodies in elderly patients wearing dental prosthetic devices.

Pathological fractures in a patient with chronic lymphatic leucaemia without disease progression.

We describe a case of a 59-year-old woman with a medical history of upper leg pain and chronic lymphatic leucaemia (CLL), with known diffuse bone marrow infiltration and without signs of lymphatic or extra-lymphatic disease activity on positron emission tomography CT (PET-CT). She presented with multiple fractures of the pelvis, sacrum and left proximal femur as a result of a low energy fall. During admission, she sustained a non-traumatic fracture of the right proximal femur. Pathological fractures in patients with CLL are usually based on Richter's transformation or multiple myeloma. However, in the current case, a PET-CT and a bone marrow biopsy showed no signs of this. We did see a normoparathyroid hypercalcaemia in our patient, most likely caused by a CLL-based release of local osteoclast stimulating factors. A combination of fludarabine/cyclofosfamide/rituximab was started as treatment in combination with allopurinol and sodium bicarbonate to prevent further osteolysis.

Cystic schwannoma of the recurrent laryngeal nerve: a rare finding posing diagnostic difficulties.

A 49-year-old woman with a painless mass in the neck was examined by the surgeon. Imaging and cytology prior to surgery suggested the mass to be either a thyroid cyst or a branchial cleft cyst. After surgery, the patient reported a hoarse voice and the pathologist confirmed the removed lesion to be a cystic schwannoma of the left recurrent laryngeal nerve. The inconclusive imaging results, combined with colloid-like material in the punctate should prompt the investigator to include cystic schwannoma in the differential diagnosis. With the probability of a neurogenic origin of the mass in mind, nerve-sparing surgery can be performed. As a future prospect, positron emission tomography scans are mentioned as a modality with possibilities to discriminate a cystic schwannoma from other common cystic lesions.