Pathogenic Gene Variants Identified in Patients Presenting With Perthes or Perthes-like Hip Disorder.

AIMS: Legg-Calve-Perthes disease (LCPD) is a diagnosis of exclusion. Various conditions, such as skeletal dysplasias, can closely mimic LCPD and these must be ruled out to provide appropriate treatment, prognosis, and counseling. Traditionally, genetic testing has not been readily available in pediatric orthopaedic practice. Furthermore, the clinical value of genetic testing patients with LCPD is unclear. With the advance of next-generation sequencing (NGS) technology, genetic testing has become clinically available as a lab test. The purposes of this study were to assess the clinical utility of genetic testing in select patients with LCPD and to determine the patient characteristics of those who tested positive for skeletal dysplasia. METHODS: This is an IRB-approved, retrospective study of 63 consecutive patients who presented with Perthes-like symptoms and/or x-ray findings and who had genetic testing. The reason(s) for genetic testing included bilateral hip disease, family history of LCPD, short stature, suspected skeletal dysplasia, atypical radiographic findings, and/or combinations of these reasons. RESULTS: Of the 63 patients, 19 patients (30%) were found to have a pathogenic gene variant. In 8 of the 19, a variety of skeletal dysplasia was diagnosed. The remaining 11 patients were found to be carriers of autosomal recessive disorders. All 19 patients were referred for genetic counseling. Of the 8 patients found to have skeletal dysplasia, 3 had bilateral disease, 3 were <10 percentile in height, 1 had a family history of "LCPD," and 3 had atypical x-ray findings. In addition to the pathogenic variants, numerous genetic variants of unknown significance were found with 2 gene variants showing exactly the same variant found in 2 unrelated patients. CONCLUSIONS: With 30% of the patients showing pathogenic results, genetic testing of select patients with Perthes-like disease is valuable in detecting an underlying genetic disorder or a carrier status of a genetic disorder.

Does Screening Ultrasound Timing in Developmental Dysplasia of the Hip Need to be Adjusted for Moderate Preterm and Near-term Infants: A Prospective Study.

INTRODUCTION: An initial screening ultrasound is essential for patients at higher risk of developmental dysplasia of the hip (DDH) due to breech presentation or a family history of DDH. The American Academy of Pediatrics recommends screening ultrasounds to be performed after 6 weeks of age to reduce the rate of false positives. However, there is limited evidence regarding whether these screening ultrasounds need to be adjusted for gestational age in prematurity. The purpose of this study was to evaluate the influence of moderate preterm and near-term births on screening hip ultrasounds for high-risk DDH populations. METHODS: We identified all prospectively enrolled patients in a single-center database referred for screening hip ultrasound for DDH. We included those hips referred for risk factors of DDH, including breech presentation, family history of DDH, or hip click, and excluded those with known dysplasia or referral for hip instability. Each ultrasound was measured by a pediatric radiologist to determine the alpha angle and femoral head coverage. Patients were classified as "premature" if born at <37 weeks gestation or "full term" if born at ≥37 weeks gestation. All patients underwent screening hip ultrasound between 5 and 8 weeks of age. Sonographic markers of dysplasia and the incidences of abnormal ultrasound and Pavlik harness treatment were compared between cohorts. Significance was set at P <0.05. RESULTS: A total of 244 hips in 122 patients were included, 58 hips in the premature cohort and 186 hips in the full-term cohort. The premature cohort had a significantly decreased gestational age compared with the full-term cohort (35.4 ± 1.1 vs 38.5 ± 1.1 wk, respectively, P < 0.001). However, there was no difference between premature and full-term cohorts in sex distribution (69% vs 75%, females, P = 0.39), unadjusted age at the time of ultrasound (6.6 ± 0.7 vs 6.8±0.7 wk, respectively, P = 0.07), or referral reason ( P = 0.14). On hip ultrasound, there was no difference between premature and full-term cohorts with respect to alpha angle (62.6 ± 3.3 vs 62.2 ± 5.3 degrees, P = 0.41), femoral head coverage (54.9 ± 6.3 vs 55.1 ± 10.6, P = 0.19), rate of abnormal ultrasound (18.3% vs 20.7%, respectively, P = 0.68), or the rate of Pavlik harness treatment (0% vs 5.3%, respectively, P = 0.12). DISCUSSION: There was no significant difference in alpha angle or femoral head coverage between premature and full-term patients at 5 to 8 weeks of unadjusted age. This preliminary data suggests that screening ultrasounds can be performed without adjusting for prematurity. LEVEL OF EVIDENCE: Level II, prognostic study.

The Significance of Isolated Hip Click as a Sign of DDH: Implications on Referral Guidelines.

BACKGROUND: The clinical significance of an isolated hip click remains unclear. The rates of developmental dysplasia of the hip (DDH) in those referred for hip click vary from 0% to 28%. The purpose of this study was to evaluate the rate of DDH in patients prospectively referred for isolated hip click. METHODS: We prospectively enrolled patients referred to a single pediatric orthopaedic center with concern for DDH secondary to isolated hip click felt by the pediatrician on examination. Patients with known sonographic abnormalities or risk factors for DDH (breech presentation or positive family history) were excluded. Ultrasounds were obtained upon initial presentation and defined as abnormal if alpha angle <60 degrees and/or femoral head coverage (FHC) <50%. Mild dysplasia, analogous to Graf IIa physiological immaturity, was defined as alpha angle 50<α<60 and/or <50% FHC in a patient <3 months age. Severe dysplasia was defined as ≤33% FHC, which has been proposed to be sonographically consistent with a hip dislocation. RESULTS: Two hundred fifty-five children were referred for isolated hip click. One hundred eighty-nine patients (74%) had normal ultrasound whereas 66 patients (26%) had sonographic abnormalities (mean age 6.5±6.2 wk at initial ultrasound). Fifty patients (19.6%) demonstrated physiological immaturity, 3 patients (1.2%) demonstrated moderate sonographic dysplasia, and 13 patients (5.1%) had sonographic findings consistent with severe dysplasia or dislocated hip. Hips with severe dysplasia were younger than the remaining population (2.8±2.4 wk vs. 6.6±6.2 wk, P <0.001) with no difference in sex distribution ( P =0.07) or first-born birth order ( P =0.36). For those with sonographic abnormality, 18 (27%) patients were treated with Pavlik harness, 1 (2%) was treated with abduction orthosis, and the remainder (71%) were observed for resolution of physiological immaturity. CONCLUSIONS: Infants with isolated hip click identified by their pediatrician may have higher rates of dysplasia than previously reported. We recommend screening ultrasound and/or orthopaedic referral for all infants with isolated hip click. LEVEL OF EVIDENCE: Level II-prospective prognostic study.

Functional Outcomes Following Operative Treatment of Tibial Tubercle Fractures.

BACKGROUND: Quantitative evaluation of the functional results of surgically managed tibial tubercle fractures in adolescents is unreported in the orthopaedic literature. METHODS: All patients treated surgically for unilateral tibial tubercle fractures at a single institution from 2007 to 2011 were invited to return for functional evaluation. Fractures were classified using the Ogden classification system. Clinical examination at follow-up included passive knee range of motion and thigh circumference. Side-to-side knee extension strength deficits were evaluated using a Biodex dynamometer. Patient-reported outcomes were assessed using the Pediatric-International Knee Documentation Committee Subjective Knee Form (Pedi-IKDC), Tegner-Lysholm Knee Scoring Scale, and Visual Analog Pain Scale. Chart review was performed to determine postoperative protocols including the use of physical therapy and protected weight bearing. Functional parameters were compared between the involved and uninvolved extremities using the Wilcoxon Signed Ranks Test and the Spearman correlations were performed to identify any relationships between perioperative factors, functional parameters, and subjective outcomes. RESULTS: In total, 19 of 42 patients completed clinical and functional testing and 18 of 19 completed all outcome surveys. Average age at injury was 13.9 years and average follow-up was 3.0 years. There was no statistical difference in knee range of motion between sides, however, thigh circumference was slightly smaller in the injured extremity (median difference, 1.7 cm at 15 cm above the patella and 4.0 cm at 50% of the length of the thigh). In total 5/19 subjects (26%) had a significant quadriceps extension strength deficit on the involved leg compared with the contralateral side. The median Visual Analog Pain Scale for affected limbs was 8/100 and for unaffected limbs was 6/100 (P=0.017). The Tegner-Lysholm Scale revealed 9 excellent results, 5 good, 4 fair, and 1 poor (median, 90/100). Results of the Pedi-IKDC were 11 excellent, 3 good, 2 fair, and 3 poor results (median, 91/100). Outcome scores did not correlate to diminished strength or thigh circumference. No difference in outcome based upon body mass index, postoperative weight-bearing status, Ogden classification, or postoperative physical therapy was noted using regression analysis. CONCLUSIONS: Despite promising objective results, clinical outcomes measured by subjective validated surveys are not all excellent. LEVEL OF EVIDENCE: Level III.

Molecular characterization of articular cartilage from young adults with femoroacetabular impingement.

BACKGROUND: Femoroacetabular impingement is a frequent cause of hip pain and may lead to secondary osteoarthritis, yet little is known about the molecular events linking mechanical hip impingement and articular cartilage degeneration. The first goal of this study was to quantify the expression of inflammatory cytokine and chemokine, matrix-degrading, and extracellular matrix genes in articular cartilage harvested from control hips and hips with femoroacetabular impingement and end-stage osteoarthritis. The second goal was to analyze the relative expression of these genes in articular cartilage harvested at various stages of osteoarthritis. METHODS: Cartilage samples were obtained from thirty-two hips undergoing hip preservation surgery for femoroacetabular impingement or hip arthroplasty. Three control cartilage samples were also analyzed. Specimens were graded intraoperatively with regard to the severity of cartilage damage, the radiographic osteoarthritis grade was recorded, and quantitative RT-PCR (real-time polymerase chain reaction) was performed to determine relative gene expression. RESULTS: Except for interleukin-1ß (IL-1ß) and CXCL2, the mRNA (messenger RNA) expression of all other chemokine (IL-8, CXCL1, CXCL3, CXCL6, CCL3, and CCL3L1), matrix-degrading (matrix metalloproteinase [MMP]-13 and ADAMTS-4), and structural matrix (COL2A1 [collagen, type II, alpha] and ACAN [aggregan]) genes was higher overall in cartilage from hips with femoroacetabular impingement compared with hips with osteoarthritis and normal controls. The differences reached significance (p ≤ 0.05) for seven of these ten quantified genes, with CXCL3, CXCL6, and COL2A1 being elevated in the femoroacetabular impingement group compared with only the control group and IL-8, CCL3L1, ADAMTS-4, and ACAN being elevated compared with both the osteoarthritis and control groups. When samples were grouped according to the stage of the degenerative cascade, mRNA expression was relatively higher in one of the two middle stages of femoroacetabular impingement (chondromalacia or cleavage/thinning), with the difference reaching significance for IL-8, CXCL2, CXCL3, CCL3L1, and ACAN. ACAN expression was diminished in hips with osteoarthritis compared with femoroacetabular impingement but elevated compared with the control articular cartilage. CONCLUSIONS: Articular cartilage from the impingement zone of hips with femoroacetabular impingement (and particularly those hips in the cleavage/thinning stage) expressed higher levels of certain inflammatory, anabolic, and catabolic genes, representing a heightened metabolic state. CLINICAL RELEVANCE: The articular cartilage from the impingement zone of hips with femoroacetabular impingement was metabolically hyperactive, supporting the concept that such impingement is a structural precursor to hip osteoarthritis.

Outcome of revision anterior cruciate ligament reconstruction: a systematic review.

BACKGROUND: Revision anterior cruciate ligament (ACL) reconstruction is believed to have an inferior outcome compared with primary ACL reconstruction. The available literature on the outcome of revision ACL reconstruction is sparse compared with that for primary reconstruction. The purpose of this systematic review was to test the hypothesis that the outcome of revision ACL reconstruction compares unfavorably with the historical outcome of primary ACL reconstruction. METHODS: A systematic review of studies evaluating the outcome of revision ACL reconstructions with a minimum of two years of follow-up was performed. Pooled data were collected when appropriate and a mixed-effect-model meta-analysis was performed for important outcome measures that were reported in several studies (objective graft failure, Lysholm score, International Knee Documentation Committee [IKDC] subjective score, and IKDC objective score). Objective failure was defined as repeat revision, a side-to-side difference of >5 mm measured with use of a KT1000 arthrometer, or a pivot-shift grade of 2+ or 3+. RESULTS: Twenty-one studies were included, and 863 of the 1004 patients in these studies had a minimum of two years of follow-up and were analyzed. The pooled mean age of the patients at the time of the revision procedure was 30.6 years, and 66% were male. Objective failure occurred in 13.7% ± 2.7% of the patients (95% confidence interval, 8.0% to 19.4%). The mean Lysholm score in 491 patients was 82.1 ± 3.3 (95% confidence interval, 74.6 to 89.5) according to a mixed-model meta-analysis. The mean IKDC subjective score in 202 patients was 74.8 ± 4.4 (95% confidence interval, 62.5 to 87.0). CONCLUSIONS: Revision ACL reconstruction resulted in a worse outcome compared with primary ACL reconstruction. Patient-reported outcome scores were inferior to previously published results of primary ACL reconstruction, but these differences may not be clinically important. A dramatically elevated failure rate was noted after revision ACL reconstruction; this rate was nearly three to four times the failure rate in prospective series of primary ACL reconstructions.

Incidence of symptomatic venous thromboembolism in oncologic patients undergoing lower-extremity endoprosthetic arthroplasty.

BACKGROUND: As both cancer and major orthopaedic surgery are risk factors for venous thromboembolism, patients undergoing lower-extremity oncologic endoprosthetic arthroplasty for neoplastic processes are at substantial risk of the development of symptomatic venous thromboembolism. Therefore, the primary purpose of this study was to determine the incidence of symptomatic venous thromboembolism in patients undergoing lower-extremity oncologic endoprosthetic arthroplasty. Secondary purposes were to assess whether chemoprophylaxis influenced the incidence of venous thromboembolism, surgical complications, or the incidence of local sarcoma recurrence. We also sought to determine whether any known risk factors for venous thromboembolism could be identified in this patient population. METHODS: We performed a retrospective comparative review of 423 patients who had undergone mega-endoprosthetic reconstruction following cancer resection. Univariate analysis was used to assess the association between chemoprophylaxis and the incidence of venous thromboembolism, to postulate the surgical complications associated with chemoprophylaxis, and to assess the rate of recurrence of local sarcoma as well the association between risk factors and venous thromboembolism. RESULTS: Seventeen patients (4.0%) (95% confidence interval: 2.5% to 6.3%) had a venous thromboembolic event, ten with deep venous thrombosis and seven with nonfatal pulmonary embolism. Risk factors and chemoprophylactic regimens were not statistically associated with the occurrence of venous thromboembolism. CONCLUSIONS: The incidence of symptomatic venous thromboembolism in our group of cancer patients who underwent lower-extremity endoprosthetic arthroplasty was lower than anticipated. A significant difference was not identified between the use of any or no chemoprophylactic agent and the incidence of venous thromboembolism or complication rates. No risk factors were associated with the incidence of symptomatic venous thromboembolism.

Effect of shoulder stabilization on career length in national football league athletes.

BACKGROUND: Shoulder instability and surgical stabilization are common in college football athletes. The effect of shoulder stabilization during college on the length of an athlete's career in the National Football League (NFL) has not been well examined. HYPOTHESIS: Athletes with a history of shoulder stabilization before the NFL combine have a shorter career than do matched controls. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A database containing the injury history and career NFL statistics of athletes from 1987 to 2000 was used to match athletes with a history of shoulder stabilization and no other surgery or significant injury to controls without a history of any previous surgery or significant injury. Athletes were matched by position, year drafted, round drafted, and additional minor injury history. RESULTS: Forty-two athletes with a history of shoulder stabilization were identified and matched with controls. A history of shoulder stabilization significantly reduced the length of career in terms of years (5.2 ± 3.9 vs 6.9 ± 3.6 years; P = .01) and games played (56 ± 53 vs 77 ± 50, P = .03) as compared with controls. By position, linemen and linebackers (20 athletes) with a history of shoulder stabilization had a significantly shorter career in years (4.7 ± 3.8 vs 6.7 ± 3.4 years; P = .049) and games played (51 ± 58 vs 81 ± 48; P = .046) than did controls. Among the other positions (22 athletes), the difference was not statistically significant in this small cohort. CONCLUSION: A history of shoulder stabilization shortens the expected career of a professional football player, particularly for linemen and linebackers. Further research is warranted to better understand how these injuries and surgeries affect an athlete's career and what can be done to improve the long-term outcome after treatment.

Chronic exertional compartment syndrome of the leg in athletes: evaluation and management.

Chronic exertional compartment syndrome (CECS) is a well-known cause of activity-related lower leg pain in both athletes and nonathletes. In contrast to acute compartment syndrome, CECS is generally not related to trauma, and is often suspected in the outpatient setting by primary care physicians, podiatrists, sports medicine clinicians, and orthopedic surgeons. The diagnosis of CECS is often overlooked because patients avoid or withdraw from exacerbating physical activities instead of seeking treatment for their symptoms from a health care professional. A thorough history and physical examination of an individual with activity-related lower leg pain is necessary for correct diagnosis to occur. Appropriate diagnostic testing with measurement of intracompartmental pressures reliably confirms the diagnosis of CECS. Nonoperative treatments of CECS rarely leads to complete resolution of symptoms or an individual's ability to return to previous levels of recreational or athletic activity. Fasciotomy of the involved compartments can reliably lead to resolution of pain and the ability to return to previous activities within 6 weeks.

Effect of anterior cruciate ligament reconstruction and meniscectomy on length of career in National Football League athletes: a case control study.

BACKGROUND: Meniscal and anterior cruciate ligament (ACL) injuries are common in college football athletes. The effect of meniscectomy and/or ACL surgery on the length of an athlete's career in the National Football League (NFL) has not been well examined. HYPOTHESIS: Athletes with a history of meniscectomy or ACL surgery before the NFL combine have a shorter career than matched controls. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A database containing the injury history and career NFL statistics of athletes from 1987-2000 was used to match athletes with a history of meniscectomy and/or ACL surgery, and no other surgery or major injury, to controls without previous surgeries. Athletes were matched by position, year drafted, round drafted, and additional injury history. RESULTS: Fifty-four athletes with a history of meniscectomy, 29 with a history of ACL reconstruction, and 11 with a history of both were identified and matched with controls. Isolated meniscectomy reduced the length of career in years (5.6 vs 7.0; P = .03) and games played (62 vs 85; P = .02). Isolated ACL surgery did not significantly reduce the length of career in years or games played. Comparing the athletes with meniscectomy or ACL reconstruction to athletes with combined ACL reconstruction and meniscectomy, a history of both surgeries, resulted in a shorter career in games started (7.9 vs 35.1; P <.01), games played (41 vs 63; P = .07), and years (4.0 vs 5.8; P = .08) than a history of either surgery alone. CONCLUSION: A history of meniscectomy, but not ACL reconstruction, shortens the expected career of a professional football player. A combination of ACL reconstruction and meniscectomy may be more detrimental to an athlete's durability than either surgery alone. Further research is warranted to better understand how these injuries and surgeries affect an athlete's career and what can be done to improve the long-term outcome after treatment.

Smoking delays chondrogenesis in a mouse model of closed tibial fracture healing.

Smoking delays the healing process and increases morbidity associated with many common musculoskeletal disorders, including long bone fracture. In the current study, a murine model of tibial fracture healing was used to test the hypothesis that smoking delays chondrogenesis after fracture. Mice were divided into two groups, a nonsmoking control group and a group exposed to cigarette smoke for 1 month prior to surgical tibial fracture. Mice were euthanized at 7, 14, and 28 days after surgery. The outcomes measured were immunohistochemical staining for type II collagen protein expression as a marker of cartilage matrix and proliferating cell nuclear antigen (PCNA) staining to measure proliferation at the site of injury. Toluidine blue staining and histomorphometry were used to quantify areas of cartilaginous and noncartilaginous fracture callus. Radiographs were analyzed for evidence of remodeling after injury. At day 7 after injury, mice exposed to cigarette smoke had a smaller fracture callus with less cartilage matrix compared to controls. Proliferation was present at high levels in both groups at this time point, but proliferating cells had a more immature morphology in the smoking group. At day 14, chondrogenesis was more active in smokers compared to controls, while a higher percentage of bone was present in the control animals. At day 28, X-ray analysis revealed a larger fracture callus remaining in the smoking animals. Together, these findings show that the chondrogenic phase of tibial fracture healing is delayed by smoking. This study represents, to our knowledge, the first analysis of molecular and cellular mechanisms of healing in a smoking mouse fracture model.

Effects of cigarette smoking on early medial collateral ligament healing in a mouse model.

Cigarette smoking delays the healing process and increases morbidity associated with many common musculoskeletal disorders such as medial collateral ligament (MCL) injury. In the current study, a murine model of MCL healing was used to test the hypothesis that smoking impairs extracellular matrix synthesis after injury. Mice were divided into two groups, a nonsmoking control group and a group exposed to smoke for 2 months prior to surgical MCL injury. Mice were euthanized at 3 and 7 days after surgery. Subsequently, propidium iodine staining was used to quantify cellular density of injured and sham ligaments. Immunohistochemical staining and in situ hybridization to mRNA were used to detect proliferation, apoptosis, and type I collagen gene expression at the site of injury. Cell density increased significantly from baseline to 7 days after injury in control mice. In mice exposed to cigarette smoke, there was a significantly lower cellular density compared to controls at this time point (p=0.01). There was no difference in proliferation between groups at the site of injury, and the low level of proliferation observed was not sufficient to account for the large increase in cell density by day 7. No evidence of apoptosis was observed in any of the groups at the site of injury. Type I collagen gene expression was higher in controls compared to smokers at day 7. Almost all of the cells in the substance of the injured MCL at day 7 were spindle-shaped and expressed type I collagen, suggesting that increased cell density from day 3 to day 7 represented an increase in ligament cells rather than an increased inflammatory response. We conclude that the decreased cellular density and type I collagen expression in the injured ligament of mice exposed to smoke begin to provide a cellular and molecular basis for delayed or deficient early healing in these animals.

Medial collateral ligament healing in macrophage metalloelastase (MMP-12)-deficient mice.

Medial collateral ligament (MCL) injuries heal by a wound repair scar response controlled by a complex cellular and cytokine environment. Many enzymes participate in wound repair, particularly the matrix metalloproteinases. We hypothesize macrophage metalloelastase (MME/MMP-12) deficiency results in impaired healing of MCL injury. One hundred fifty MME-deficient and 150 WT (MME+/+) mice underwent knee MCL transection with the opposite knee as a sham operated control. Mice were sacrificed at 3, 7, 28, 42, and 56 days. At each of the five time points, 15 mice were utilized for biological and 15 were utilized for biomechanical testing. Outcome measures were the presence of macrophages to represent the inflammatory phase of wound healing, collagen synthesis to assay for matrix repair, and biomechanical testing for repair strength. Immunohistochemistry demonstrated significantly fewer macrophages in cut MCLs from MME-deficient mice versus wild-type (WT) mice at 3, 7, 28, and 42 days (all p