Developmental Dysplasia of the Hip: Linkage Mapping and Whole Exome Sequencing Identify a Shared Variant in CX3CR1 in All Affected Members of a Large Multigeneration Family

Developmental dysplasia of the hip (DDH) is a debilitating condition characterized by incomplete formation of the acetabulum leading to dislocation of the femur, suboptimal joint function, and accelerated wear of the articular cartilage resulting in arthritis. DDH affects 1 in 1000 newborns in the United States; there are well‐defined “pockets” of high prevalence in Japan, and in Italy and other Mediterranean countries. Although reasonably accurate for detecting gross forms of hip dysplasia, existing techniques fail to find milder forms of dysplasia. Undetected hip dysplasia is the leading cause of osteoarthritis of the hip in young individuals, causing over 40% of cases in this age group. A sensitive and specific test for DDH has remained a desirable yet elusive goal in orthopedics for a long time. A 72‐member, four‐generation affected family has been recruited, and DNA from its members retrieved. Genomewide linkage analysis revealed a 2.61‐Mb candidate region (38.7–41.31 Mb from the p term of chromosome 3) co‐inherited by all affected members with a maximum logarithm (base 10) of odds (LOD) score of 3.31. Whole exome sequencing and analysis of this candidate region in four severely affected family members revealed one shared variant, rs3732378, that causes a threonine (polar) to methionine (non‐polar) alteration at position 280 in the transmembrane domain of CX3CR1. This mutation is predicted to have a deleterious effect on its encoded protein, which functions as a receptor for the ligand fractalkine. By Sanger sequencing this variant was found to be present in the DNA of all affected individuals and obligate heterozygotes. CX3CR1 mediates cellular adhesive and migratory functions and is known to be expressed in mesenchymal stem cells destined to become chondrocytes. A genetic risk factor that might be among the etiologic factors for the family in this study has been identified, along with other possible aggravating mutations shared by four severely affected family members. These findings might illuminate the molecular pathways affecting chondrocyte maturation and bone formation. © 2013 American Society for Bone and Mineral Research.     

Associations between fibroblast growth factor 23 and cardiac characteristics in pediatric heart failure

Background

In adults with heart failure, elevated levels of fibroblast growth factor 23 (FGF23) are associated with mortality. Data on FGF23 levels in pediatric heart failure are lacking.

Patients and methods

We conducted a cross-sectional study of 17 healthy children (mean age 13 years) and 20 pediatric patients with heart failure (mean age 12 years) who underwent echocardiography and for whom the following measurements were taken: plasma FGF23 and parathyroid hormone (PTH) and serum phosphate, creatinine and N-terminal prohormone brain natriuretic peptide (NT-proBNP). Symptom severity was assessed with the New York Heart Association and the Ross classification systems.

Results

Of the 20 patients, 11 had dilated cardiomyopathy, four had congenital heart disease, three had hypertrophic cardiomyopathy, one had a failing heart transplant and one had pulmonary hypertension. Mean phosphate levels in these patients were within the reported reference range for healthy children. Median PTH levels were in the normal range in patients and controls. The median FGF23 level was higher in patients versus controls (110.9 vs. 66.4 RU/ml; P?=?0.03) and higher in patients on diuretics versus other patients (222.4 vs. 82.1 RU/ml; P?=?0.01). Levels of FGF23 and NT-proBNP were directly correlated (r?=?0.47, P?=?0.04), and patients with greater physical functional impairment had higher FGF23 levels (142.5 in those with moderate-severe limitation vs. 92.8 RU/ml in those with no limitation; P?=?0.05). Among patients with dilated cardiomyopathy, higher FGF23 levels were associated with a greater left ventricular end-diastolic diameter (r?=?0.63, P?=?0.04).

Conclusion

FGF23 levels are elevated in children with heart failure and are associated with diuretic use, severity of heart failure and left ventricular dilation.     

Hepatic ischemia reperfusion injury is associated with acute kidney injury following donation after brain death liver transplantation

Donation after cardiac death liver transplant recipients have an increased frequency of acute kidney injury (AKI). This suggests that hepatic ischemia‐reperfusion injury may play a critical role in the pathogenesis of AKI after liver transplantation. The aim of this single‐center study was to determine if hepatic ischemia‐reperfusion injury, estimated by peak peri‐operative serum amino‐transferase (AST), is associated with AKI following donation after brain death (DBD) liver transplantation. A total of 296 patients received 298 DBD liver transplants from January 2007 to June 2011. The incidence of AKI was 35.9%. AKI was a risk factor for chronic kidney disease (P = 0.037) and mortality (P = 0.002). On univariate analysis, peak AST correlated with peak creatinine (P < 0.001) and peak change in creatinine from baseline (P < 0.001). Peak AST was higher in AKI patients (P < 0.001). The incidence of AKI in patients with a peak AST of <1500, 1500–2999 and ≥3000 U/l was 26.1%, 39.8% and 71.2%, respectively (P < 0.001). On multiple logistic regression analysis, peak AST was independently associated with the development of AKI (P < 0.001). In conclusion, hepatic ischemia‐reperfusion injury demonstrates a strong relationship with peri‐operative AKI in DBD liver transplant recipients.     

A case of severe osteomalacia secondary to phosphate diabetes in a renal transplant recipient

Transient hypophosphatemia is frequently observed during the first months after renal transplantation and is usually asymptomatic. Phosphate diabetes is defined as inadequate tubular phosphorus reabsorption leading to persistent renal phosphorus wasting, which is an important but overlooked cause of osteodystrophy in the post-renal transplantation population. We report the case of a 58-year-old male who presented with severe multiple osteoarticular pains within 3 months after successful first kidney transplantation. Bone disease was attributed initially to mild hyperparathyroidism secondary to vitamin D deficiency. Despite the correction of the hyperparathyroidism, the withdrawal of corticosteroids, and the reduction of immunosuppressive treatment to tacrolimus-based monotherapy, the osteoarticular pains persisted. Skeletal investigations at month 9 post-transplantation demonstrated a significant bone mineral density loss associated with osteomalacia and osteoporosis on the bone biopsy. Laboratory data showed persistent hypophosphatemia, and phosphate diabetes was then diagnosed explaining the post-transplant bone disease. A tacrolimus-induced renal tubular disorder was suspected to contribute to the excessive renal phosphorus wasting. The replacement of tacrolimus by sirolimus, in addition to oral phosphorus and vitamin D supplementations, led to the disappearance of pains, the normalization of urinary and plasma phosphate level, and a significant improvement of bone mineralization.     

Utility of Choline Positron Emission Tomography/Computed Tomography for Lymph Node Involvement Identification in Intermediate- to High-risk Prostate Cancer: A Systematic Literature Review and Meta-analysis

Context

Determination of tumour involvement of regional lymph nodes in patients with prostate cancer (PCa) is of key importance for the proper planning of treatment.

Objectives

To provide a critical overview of published reports and to perform a meta-analysis about the diagnostic performance of 18F-choline and 11C-choline positron emission tomography (PET) or PET/computed tomography (CT) in the lymph node staging of PCa.

Evidence acquisition

A Medline, Web of Knowledge, and Google Scholar search was carried out to select English-language articles published before January 2012 that discussed the diagnostic performance of choline PET to individualise lymph node disease at initial staging in PCa patients. Articles were included only if absolute numbers of true-positive, true-negative, false-positive, and false-negative test results were available or derivable from the text and focused on lymph node metastases. Reviews, clinical reports, and editorial articles were excluded. All complete studies were reviewed; thus qualitative and quantitative analyses were performed.

Evidence synthesis

From the year 2000 to January 2012, we found 18 complete articles that critically evaluated the role of choline PET and PCa at initial staging. The meta-analysis was carried out and consisted of 10 selected studies with a total of 441 patients. The meta-analysis provided the following results: pooled sensitivity 49.2% (95% confidence interval [CI], 39.9–58.4) and pooled specificity 95% (95% CI, 92–97.1). The area under the curve was 0.9446 (p < 0.05). The heterogeneity ranged between 22.7% and 78.4%. The diagnostic odds ratio was 18.999 (95% CI, 7.109–50.773).

Conclusions

Choline PET and PET/CT provide low sensitivity in the detection of lymph node metastases prior to surgery in PCa patients. A high specificity has been reported from the overall studies. Studies carried out on a larger scale with a homogeneous patient population together with the evaluation of cost effectiveness are warranted.     

Lateral ankle instability in high-demand athletes: reconstruction with fibular periosteal flap

Purpose

Fibular periosteal flaps have been used to address chronic lateral ankle instability, but there are no studies in the literature reporting functional outcomes after this particular procedure in high-demand athletes. We postulated that for chronic instability, nonanatomical reconstruction of the lateral ankle ligament with a fibular periosteal flap will return high-demand athletes to their previous levels of activity.

Methods

Forty patients who had grade III ankle sprain and experienced no success after a course of supervised conservative management lasting at least six months and who had a preinjury Tegner score of ≥6 underwent a lateral compartment reconstruction with a fibular periosteal flap. Each patient was given the Tegner and Karlsson questionnaire and was evaluated by the Zwipp method, Foot and Ankle Outcome Score (FAOS) and the American Orthopaedic Foot and Ankle Society (AOFAS) score at the six-month, one, two and three-year time points. Range of motion (ROM) of the affected ankle was assessed, and stress X-rays were performed. Mean patient age was 24.5 (range17–30) years, and no patient was lost to follow-up.

Results

Mean follow-up was 36 (minimum 18) months, mean Tegner scores at the one, two and three-year time points were 8.8, 8.9 and 8.9, respectively, and mean Karlsson scores were 93 ± 5.2, 95 ± 3.1 and 94.9, respectively. AOFAS and FAOS scores improved from a mean of 69.4 and 71.4, respectively, in the preoperative group to a mean of 97.2 and 94.4, respectively, at the last follow-up. The ROM was equal to the contralateral ankle in all but two patients at the two-year follow-up. No major complications were found.

Conclusion

Nonanatomical ligament reconstruction with a fibular periosteal flap for chronic lateral ankle instability was effective in returning high-demand athletes to their preinjury functional levels.     

Humeral shaft fractures treated with antegrade intramedullary nailing: What are the consequences for the rotator cuff?

Purpose

The purpose of this study was to investigate the clinical and sonographic impact on the rotator cuff (RC) of the use of the anterolateral approach for nailing.

Methods

A retrospective cohort of 48 patients treated for humeral diaphyseal fractures at the University Hospital of Parma between 2007 and 2011 was analysed. Inclusion criteria were (1) acute humeral shaft fractures treated with T2-proximal humeral nail (PHN) and (2) a minimum follow-up of one year. Exclusion criteria were (1) history of proximal and metaphyseal humeral fractures, (2) pathological fractures or open fractures of the humerus, and (3) RC lesions. Clinical assessment using the Constant score, simple shoulder test and through shoulder examination tests was carried out. The sonographic study investigated the integrity of the RC.

Results

Mean score on Constant’s scale was 78.21 points, with most patients achieving a good result (79 % obtained more than 65 points). One patient had a limited functional outcome (Constant’s score of 49 points). The sonographic findings described for supraspinatus tendon were a partial ruptures of less than 30 mm in three patients and a complete tendon rupture in one case.

Conclusions

The results of this study suggest that the use of the anterolateral approach for antegrade humeral nailing ensures a good functional result with no significant clinical-sonographic impact on the rotator cuff and a satisfactory long term clinical outcome.