Samantha A. Spencer

Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome.

Congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. We hypothesized that CLOVES syndrome would be caused by a somatic mutation arising during early embryonic development. Therefore, we employed massively parallel sequencing to search for somatic mosaic mutations in fresh, frozen, or fixed archival tissue from six affected individuals. We identified mutations in PIK3CA in all six individuals, and mutant allele frequencies ranged from 3% to 30% in affected tissue from multiple embryonic lineages. Interestingly, these same mutations have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity. We conclude that CLOVES is caused by postzygotic activating mutations in PIK3CA. The application of similar sequencing strategies will probably identify additional genetic causes for sporadically occurring, nonheritable malformations.

Lymphatic and Other Vascular Malformative/Overgrowth Disorders Are Caused by Somatic Mutations in PIK3CA

OBJECTIVES To test the hypothesis that somatic phosphatidylinositol-4,5-bisphospate 3-kinase, catalytic subunit alpha (PIK3CA) mutations would be found in patients with more common disorders including isolated lymphatic malformation (LM) and Klippel-Trenaunay syndrome (KTS). STUDY DESIGN We used next generation sequencing, droplet digital polymerase chain reaction, and single molecule molecular inversion probes to search for somatic PIK3CA mutations in affected tissue from patients seen at Boston Childrens Hospital who had an isolated LM (n = 17), KTS (n = 21), fibro-adipose vascular anomaly (n = 8), or congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (n = 33), the disorder for which we first identified somatic PIK3CA mutations. We also screened 5 of the more common PIK3CA mutations in a second cohort of patients with LM (n = 31) from Seattle Childrens Hospital. RESULTS Most individuals from Boston Childrens Hospital who had isolated LM (16/17) or LM as part of a syndrome, such as KTS (19/21), fibro-adipose vascular anomaly (5/8), and congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (31/33) were somatic mosaic for PIK3CA mutations, with 5 specific PIK3CA mutations accounting for ∼ 80% of cases. Seventy-four percent of patients with LM from Seattle Childrens Hospital also were somatic mosaic for 1 of 5 specific PIK3CA mutations. Many affected tissue specimens from both cohorts contained fewer than 10% mutant cells. CONCLUSIONS Somatic PIK3CA mutations are the most common cause of isolated LMs and disorders in which LM is a component feature. Five PIK3CA mutations account for most cases. The search for causal mutations requires sampling of affected tissues and techniques that are capable of detecting low-level somatic mosaicism because the abundance of mutant cells in a malformed tissue can be low.

Early Results of Treatment of Hip Impingement Syndrome in Slipped Capital Femoral Epiphysis and Pistol Grip Deformity of the Femoral Head-neck Junction Using the Surgical Dislocation Technique

Abstract: Pistol grip deformity of the femoral head-neck junction and slipped capital femoral epiphysis can cause anterior impingement leading to pain, cartilage damage and eventual osteoarthritis.1-3 Osteoplasty of this metaphyseal prominence, with or without concomitant intertrochanteric osteotomy, using a surgical dislocation approach, can effectively treat this problem.4,5 Clinical and radiographic outcomes were assessed in 19 patients who underwent osteoplasty or osteoplasty/intertrochanteric osteotomy via Ganz-type surgical dislocation with average 12-month follow-up. Preoperative and postoperative Western Ontario and McMaster Osteoarthritis Index (WOMAC) questionnaires and radiographs were obtained and evaluated.6 In the osteoplasty group, 7 patients improved, 4 were unchanged, and 2 worsened. In the osteoplasty/osteotomy group, 5 of 6 patients improved. Patients with chondral flaps had less improvement. No avascular necrosis was noted postoperatively, and all trochanteric osteotomies healed. The surgical dislocation approach, combined with osteoplasty and/or bony realignment, is a safe efficacious treatment option for symptomatic pistol grip deformity. Outcomes are worse if there is preexisting cartilage damage.

Complications after modified Dunn osteotomy for the treatment of adolescent slipped capital femoral epiphysis.

Background: Modified Dunn osteotomy has gained popularity over the past decade in the treatment of moderate to severe adolescent slipped capital femoral epiphysis. The purpose of this study was to retrospectively evaluate a consecutive series of adolescent slipped capital femoral epiphysis patients treated with the modified Dunn procedure at a single institution. We analyze the indications for the procedure as well as the complications after surgical treatment. Methods: Forty-three adolescent patients (18 boys and 25 girls) were treated with the modified Dunn procedure at our institution between September 2001 and August 2012. The average follow-up for this cohort was 2.6 years (range, 1 to 8 y). Complications were graded according to the modified Dindo-Clavien classification. Results: Twenty-six patients (60%) had an unstable injury with an inability to ambulate with our without crutches. Seventeen patients (40%) had an acute injury with duration of symptoms <3 weeks. Thirty-seven patients (86%) had a severe slip based on a Southwick slip angle of >50 degrees. Twenty-two complications occurred in 16 patients (37%) in this cohort. Fifteen revision procedures were performed for femoral head avascular necrosis, fixation failure with deformity progression, or postoperative hip dislocation. Two patients developed end-stage degenerative joint disease and severe femoral head avascular necrosis and were referred for a total hip arthroplasty. Conclusions: The complication rate in this series is higher than most previous reports. This may be in part because of the fact that as a tertiary referral center our patient population was more complex. However, we identified a clear inverse relationship between surgeon-volume and patient-outcomes. On the basis of our results we have modified our practice. A high-volume surgeon must be present during each modified Dunn procedure, and only patients that have sustained an acute severe (>50 degrees) epiphyseal displacement with mild chronic remodeling of the metaphysis that can be addressed within 24 hours of the slip may be treated with the modified Dunn technique. Level of Evidence: Level IV—therapeutic study.

Fibro-adipose vascular anomaly: clinical-radiologic-pathologic features of a newly delineated disorder of the extremity.

Background: The diagnosis and management of vascular anomalies of the extremities can be challenging as these disorders are uncommon and may clinically overlap. The aim of this paper is to describe the clinical, radiologic, and histopathologic features of fibro-adipose vascular anomaly (FAVA), a previously unrecognized disorder of the limb. Methods: The clinical, imaging, operative, and histopathologic data from patients with a unique intramuscular lesion of the extremities comprising dense fibrofatty tissue and slow-flow vascular malformations were retrospectively reviewed. Results: Sixteen patients diagnosed with FAVA of the extremity (3 male and 13 female individuals) met the clinical, radiologic, and histopathologic inclusion criteria. The age at presentation ranged from the time of birth to 28 years. The locations of the lesions were: calf (n=10), forearm/wrist (n=3), and thigh (n=3). Fourteen patients presented with severe pain. Seven of the patients with calf lesions had limited ankle dorsiflexion. On imaging, the complex intramuscular lesions replaced muscle fibers with fibrofatty overgrowth and phlebectasia (dilation of the veins). The extrafascial component comprised fatty overgrowth, phlebectasia, and an occasional lymphatic malformation. The histopathologic features comprised dense fibrous tissue, fat, and lymphoplasmacytic aggregates within atrophied skeletal muscle. Adipose tissue also infiltrated skeletal muscle at the periphery of the lesion. There were large, irregular, and sometimes excessively muscularized venous channels and smaller, clustered channels. Other findings include organizing thrombi, a lymphatic component, and dense fibrous tissue–encircled nerves. Conclusions: The constellation of clinical, radiologic, and histopathologic features constitutes a distinct entity comprising fibrofatty infiltration of muscle, unusual phlebectasia with pain, and contracture of the affected extremity. The clinical and radiologic findings permit the diagnosis of FAVA with major therapeutic implications. Level of Evidence: Level III.

Complications of Talus Fractures in Children

Background Pediatric talus fractures are rare with variable rates of posttraumatic complications reported in the literature. The purpose of this retrospective study was to evaluate posttraumatic complications in children after talus fracture and report injury characteristics. Methods This study included 29 children with talus fractures sustained between 1999 and 2008 at an average age of 13.5 years (range, 1.2-17.8). Patient records and radiographs were reviewed to determine the mechanism of injury, fracture type, associated injuries, and treatment. Posttraumatic complications assessed were avascular necrosis, arthrosis, nonunion or delayed union, neurapraxia, infection or wound-healing problems, and the need for further unanticipated surgery. Clinical follow-up averaged 24 months (range, 6 mo-5 y). Results Twenty-nine children sustained a major fracture of the talar body, neck, or head. Avascular necrosis occurred in 2 patients (7%), arthrosis in 5 (17%), delayed union in 1 (3%), neurapraxia in 2 (7%), infection in 0, and the need for further surgery in 3 (10%). Both high-energy mechanism and fracture displacement corresponded to a greater number of posttraumatic complications. The number and severity of talus fractures increased in older children. Conclusions In this case series, posttraumatic complications after pediatric talus fractures occurred more frequently after a high-energy mechanism of injury or a displaced fracture. Talus fractures occurred more commonly and with more severity in older children. Level of Evidence Level IV. Retrospective case series.

Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia during infancy

Achondroplasia is the most common inherited disorder of bone growth (skeletal dysplasia). Despite this fact, consistent and evidence‐based management approaches to recognized, life‐threatening complications, such as foramen magnum stenosis, are lacking. This study aims to outline best practice, based on evidence and expert consensus, regarding the diagnosis, assessment, and management of foramen magnum stenosis in achondroplasia during infancy. A panel of 11 multidisciplinary international experts on skeletal dysplasia was invited to participate in a Delphi process. They were: 1) presented with a list of 26 indications and a thorough literature review, 2) given the opportunity to anonymously rate the indications and discuss in face to face discussion; 3) edit the list and rate it in a second round. Those indications with more than 80% agreement were considered as consensual. After two rounds of rating and a face‐to‐face meeting, consensus was reached to support 22 recommendations for the evaluation and treatment of foramen magnum stenosis in infants with achondroplasia. These recommendations include indications for surgical decompression, ventriculomegaly, and hydrocephalus, sleep‐disordered breathing, physical exams and the use of polysomnography and imaging in this condition. We present a consensus‐based best practice guidelines consisting of 22 recommendations. It is hoped that these guidelines will lead to more uniform and structured evaluation, standardizing care pathways, and improving mortality and morbidity outcomes for this cohort.

Prenatally diagnosed clubfeet: comparing ultrasonographic severity with objective clinical outcomes.

Background Improvements in obstetric sonography (US) have led to an increased prenatal detection of clubfoot, but studies have not been able to correlate sonographic severity to clinical deformity at birth. The purpose of this study was to decrease the false positive (FP) rate for prenatally identified clubfeet, and to predict clinical severity using a new prenatal sonographic classification system. Methods We retrospectively identified all pregnant patients referred to the fetal care center at our institution for a diagnosis of clubfoot between 2002 and 2007. A total of 113 fetuses were identified. Follow-up information was available for 107 fetuses (95%). Out of 107 fetuses, 17 were terminated or died shortly after birth. Seven patients had normal studies or were not seen at our center. Out of 83 patients, 42 had an US available for rereview. A novel sonographic severity scale for clubfoot (mild/moderate/severe) was assigned by a radiologist specializing in prenatal US to each fetus based on specific anatomic features. The prenatal sonographic scores were then assessed with respect to final postnatal clinical diagnosis and to clinical severity. Results None of the pregnancies were terminated because of an isolated diagnosis of clubfoot. Of the remaining 83 fetuses with a prenatal diagnosis of at least 1 clubfoot, 67 had a clubfoot documented at birth (FP=19%). A foot classified as “mild” on prenatal US was significantly less likely to be a true clubfoot at birth than when a “moderate” or “severe” diagnosis was given (Odds Ratio=21, P<0.0001). If “mild” clubfoot patients were removed from the analysis, our FP rate decreased to 3/42. For a subgroup in which postnatal DiMeglio scoring was available, prenatal sonographic stratification of clubfoot did not relate to postnatal clinical severity. Conclusions Our initial experience with this novel sonographic scoring system showed improved detection of a true clubfoot prenatally and a decrease in the FP rate. An isolated “mild” clubfoot diagnosed on a prenatal sonogram is less likely to be a clubfoot at birth; this will have substantial impact on prenatal counseling. Level of Evidence Level III Diagnostic Study.

Proximal tibial osteotomy and taylor spatial frame application for correction of tibia vara in morbidly obese adolescents

Background: Four percent of children and adolescents in the United States are morbidly obese. Treatment for tibia vara includes proximal tibial osteotomy and correction with a Taylor Spatial Frame (TSF). There are no reports that specifically examine the success of this technique in morbidly obese adolescents. Methods: A retrospective review was conducted of patients between 12 and 18 years of age with a body mass index for age at or above the 99th percentile who had undergone gradual correction of tibia vara with proximal tibial osteotomy and application of a TSF at our institution between 2005 and 2009. Deformity analysis was performed on full-length standing anteroposterior radiographs of both lower extremities and lateral radiographs of the involved tibia obtained preoperatively and at latest follow-up. All complications were recorded. Results: Fourteen patients met the inclusion criteria. The mean age was 13 years. The average body mass index was 45 kg/m2. Preoperative deformity analysis demonstrated a mean mechanical axis deviation of 90 mm, mean mechanical medial proximal tibial angle of 66 degrees, and mean posterior proximal tibial angle of 80 degrees. Analysis at an average follow-up of 14 months demonstrated a mean mechanical axis deviation of 10 mm, mean mechanical medial proximal tibial angle of 88 degrees, and mean posterior proximal tibial angle of 81 degrees. Complications specifically related to the TSF occurred in 2 patients. Both experienced strut disengagement and loss of osteotomy position. This was treated with refastening of the strut and a new program of deformity correction. Complications related to the deformity correction occurred in 3 patients. One had premature fibular consolidation requiring repeat osteotomy, 1 developed a transient partial deep peroneal nerve palsy, and 1 experienced thigh soft tissue irritation from the proximal ring necessitating early TSF removal. One patient had a residual leg-length discrepancy that required tibial lengthening. Conclusions: Correction of tibia vara with proximal tibial osteotomy and application of a TSF is an effective treatment option in morbidly obese adolescents. Associated complications are minimal. Level of Evidence: Level IV—therapeutic study.

Primary lyme arthritis of the pediatric hip.

Background: Lyme arthritis most commonly affects the knee. It is not commonly considered in the differential diagnosis of monoarticular hip pain. There are only a few case reports describing Lyme disease presenting with isolated hip involvement. The purpose of this study is to review our experience with primary Lyme arthritis of the hip. Methods: Clinical records at a tertiary children’s referral center in a Lyme endemic region were scanned for key words “Lyme” and “hip.” Patients with isolated Lyme disease of the hip were included. Diagnosis was made based on Centers for Disease Control guidelines. Clinical presentation, laboratory evaluation, and treatment information were recorded for eligible patients. Results: Eight patients met eligibility criteria with an average age of 9.5 years (3 to 20y). All patients presented with hip pain (8), limp (3), or refusal to bear weight (5). One of 8 patients had a fever >38.5°C. Two of 8 patients had a peripheral white blood cell count >12,500/mm3 and 3 of 8 patients had an erythrocyte sedimentation rate>40 mm/h. Aspiration was performed on 5 patients, with a median synovial fluid white blood cell of 41,500/mm3 (21,500 to 73,500/mm3). Three of 8 patients were treated surgically; all patients were treated with antibiotics and were asymptomatic at last follow-up. With the exception of 1 case, there was a delay before appropriate antibiotics were started. Conclusions: Primary monoarticular Lyme arthritis of the hip is uncommon. Clinical presentation and laboratory findings are variable, and differentiating it from septic arthritis or toxic synovitis of the hip may be difficult. In areas where Lyme disease is endemic, it should be considered in the differential diagnosis of monoarticular hip pain associated with an effusion. Level of Evidence: Level IV, Case Series.