Reanalysis of RNA sequencing data ends diagnostic odyssey and expands the phenotypic spectrum of congenital titinopathy.

Although next-generation sequencing has enabled diagnoses for many patients with Mendelian disorders, the majority remain undiagnosed. Here, we present a sibling pair who were clinically diagnosed with Escobar syndrome, however targeted gene testing was negative. Exome sequencing (ES), and later genome sequencing (GS), revealed compound heterozygous TTN variants in both siblings, a maternally inherited frameshift variant [(NM_133378.4):c.36812del; p.(Asp12271Valfs*10)], and a paternally inherited missense variant [(NM_133378.4):c.12322G > A; p.(Asp4108Asn)]. This result was considered nondiagnostic due to poor clinical fit and limited pathogenicity evidence for the missense variant of uncertain significance (VUS). Following initial nondiagnostic RNA sequencing (RNAseq) on muscle and further pursuit of other variants detected on the ES/GS, a reanalysis of noncanonical splice sites in the muscle transcriptome identified an out-of-frame exon retraction in TTN, near the known VUS. Interim literature included reports of patients with similar TTN variants who had phenotypic concordance with the siblings, and a diagnosis of a congenital titinopathy was given 4 years after the TTN variants had been initially reported. This report highlights the value of reanalysis of RNAseq with a different approach, expands the phenotypic spectrum of congenital titinopathy and also illustrates how a perceived phenotypic mismatch, and failure to consider known variants, can result in a prolongation of the diagnostic journey.

Impact of growth friendly interventions on spine and pulmonary outcomes of patients with spinal muscular atrophy.

PURPOSE: Patients with spinal muscular atrophy (SMA) are often treated with growth friendly devices such as vertical expandable prosthetic titanium rib(VEPTR) and magnetically controlled growing rods(MCGR) to correct spinal deformity and improve pulmonary function. There is limited data on this topic, and the purpose of this study was to assess the effect of these constructs and the addition of chest wall support (CWS) on spinal deformity, thorax morphology and pulmonary outcomes. METHODS: This is a retrospective analysis of prospectively collected data. We included patients with chest wall deformity and scoliosis secondary to SMA who were treated with growth friendly interventions and had two-year follow-up. Descriptive statistics and univariate analyses were performed. RESULTS: This study included 66 patients (25% MCGR, 73% VEPTR, 2% unknown). Approximately 23% of constructs included CWS. The average Cobb angle improved from 67° (SD: 27°) to 50° (SD: 26°) at 2 years in patients with CWS (p = 0.02), and from 59° (SD: 20°) to 46° (SD: 15°) at 2 years in patients without CWS (p < 0.01). Hemithorax height improved in patients treated with and without CWS (p = 0.01), but hemithorax width only improved in patients with CWS (p = 0.01). One patient with CWS and two patients without CWS required additional respiratory support at 2 years. The rates of postoperative complications were not significantly different in patients treated with and without CWS (p = 0.31). CONCLUSIONS: Growth friendly constructs improve spinal deformity and may be effective in altering the progression toward respiratory failure in patients with SMA. Patients treated with CWS have significant improvements in thorax morphology compared to patients without CWS.

Gradual Deformity Correction in Blount Disease.

BACKGROUND: Blount disease is a disorder of the posteromedial proximal tibial physis which causes a progressive varus, procurvatum, and internal rotation deformity of the tibia. Untreated, it can cause significant limb malalignment. The goal of this study is to evaluate the results of correction of Blount disease using types of external fixation. METHODS: We conducted a retrospective review of 41 patients (51 limbs) who underwent correction of Blount disease with an Ilizarov external fixator or a Taylor spatial frame (TSF) by a single surgeon. The medial proximal tibial angle (MPTA), mean axis deviation (MAD), posterior proximal tibial angle, and joint line congruence angle (JLCA) were measured on radiographs preoperatively, at frame removal and at final follow-up. RESULTS: The average age at treatment was 9.6 years old, with a mean follow-up time of 34 months. Mean preoperative MPTA, MAD, and JLCA were significantly improved at the time of frame removal as well as at final follow-up with no significant changes in correction between the time of frame removal and final follow-up. There was no difference in MPTA and MAD in patients treated with an Ilizarov frame versus a TSF. MPTA, MAD, and JLCA all significantly improved regardless of the underlying diagnosis (infantile vs. adolescent Blount disease) or history of prior surgical intervention. The most common complication was superficial pin-site infection. CONCLUSIONS: Both Iliazarov and TSF are viable treatment options for infantile and adolescent Blount disease, with the ability to significantly improve both the limb mechanical axis and the mechanical axis of the affected tibia. Correction can be attained regardless of whether patients have previously failed surgical intervention. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.

Analysis of the impact of race on blood transfusion in pediatric scoliosis surgery.

INTRODUCTION: Surgical correction of pediatric scoliosis is associated with significant blood loss. Minimizing estimated blood loss and blood transfusion is beneficial as transfusions have been associated with increased morbidity, including risk of surgical site infections, longer hospitalizations, and increased cost. Although there is evidence that African-American or Black adults are more likely to require intraoperative blood transfusion compared with Caucasian or White adults, the reasons for this difference are unclear. METHODS: The electronic records for all patients <18 y/o undergoing primary corrective scoliosis surgery by a single pediatric orthopedic surgeon at a single academic medical center between 2013 and 2015 were collected and reviewed. Multivariate models were performed to assess the association between Black race and blood loss/transfusion in primary pediatric scoliosis surgery. RESULTS: In a multivariate model, Black race was independently associated with 1.61 times higher estimated blood loss than White race (P < .01; 95% CI = 1.16-2.23). Additionally, compared to a White patient, the odds a Black patient received blood transfusion was 6.25 times higher (P = .03; 95% CI = 1.56-25.06) and among the patients who received blood transfusion, Black race was independently associated with 2.61 times greater volume of blood transfusion than White race (P < .01; 95% CI = 1.54-4.41). CONCLUSION: Black race was independently associated with increased estimated blood loss, increased rate of blood transfusion, and increased amount of blood transfused during surgical correction of pediatric scoliosis. Further investigation is needed to better understand the etiology of the disparity and assess opportunities for improving outcomes.

Current Concepts in the Treatment of Early Onset Scoliosis.

Despite many surgical advances in the treatment of early onset scoliosis (EOS) over the past two decades, this condition remains a challenge to address. While otherwise healthy children can have EOS, many of these patients have complicated comorbidities making proper treatment algorithms extraordinarily difficult. Non-operative measures can be successful when initiated early, but are many times utilized as a delay tactic until growth-friendly operative procedures can be safely performed. This article will summarize the current concepts in the treatment of EOS with a focus on the surgical advances that have recently been made.

Vascularized fibular grafts for avascular necrosis after slipped capital femoral epiphysis: is hip preservation possible?

BACKGROUND: Avascular necrosis (AVN) of the femoral head is a potential complication in patients with slipped capital femoral epiphysis (SCFE), radiographically occurring in 3-60%. This may lead to early hip fusion or hip arthroplasty. Free vascularized fibular grafting (FVFG) may provide a reasonable means to preserve the femoral head. QUESTIONS/PURPOSES: We asked: (1) What percentage of patients with AVN after SCFE treated with FVFG underwent subsequent THA or hip fusion and what was the lifespan of the FVFG? (2) Did the graft survival rate of FVFG for AVN after SCFE coincide with historically reported rates of FVFG for idiopathic AVN? And (3) did hip function improve after FVFG? METHODS: We retrospectively reviewed 52 patients who underwent FVFG for SCFE. We calculated the longevity of the graft and factors associated with graft survival. Harris hip scores (HHS) were recorded pre- and postoperatively. Minimum followup was 1 month (median, 19 months; range, 1-136 months). RESULTS: Five of the 52 patients (10%) underwent conversion to THA (four) or hip fusion (one). Mean age was greater in these patients than in those not requiring further procedures: 16 versus 13 years. Median graft survival time before arthroplasty/fusion was 12 years (range, 2-16 years) while it is currently 8 years (range, 2-16 years) in patients not undergoing subsequent procedures. HHSs improved 35 points on average (38 points preoperatively to 73 points postoperatively). CONCLUSIONS: In patients undergoing FVFG for AVN secondary to SCFE, 90% have maintained their native hips for 8 years with improved hip function, similar to other published reports of FVFG. Further followup is needed of patients currently retaining their FVFGs as to eventual conversion to THA or fusion. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

Bovine xenograft failures in pediatric foot reconstructive surgery.

BACKGROUND: Structural bone grafting serves an important and necessary role during pediatric foot reconstruction. Different bone grafts have been used for such reconstructions including corticocancellous autografts, allografts, and synthetic grafts. Bovine xenografts represent a novel option with multiple potential advantages; however, there are limited clinical data on the efficacy and success of such grafts. This retrospective case series was performed to review the anecdotally recognized high failure rate of bovine xenograft transplantation in pediatric foot reconstruction at a tertiary institution. MATERIALS AND METHODS: Ten pediatric patients with 13 feet underwent reconstructive procedures involving implantation of bovine xenografts for various foot deformities. The mean age at time of surgery was 14.1 years with an average clinical follow-up of 21.6 months. All patients received lateral column lengthening with additional various other reconstructive procedures performed by 3 separate orthopaedic surgeons in a similar step-wise manner. Clinical outcomes were obtained through a retrospective chart review of standard preoperative and postoperative clinical and radiographic data. RESULTS: Seven of 13 (53.8%) bovine xenografts implanted resulted in clinical symptoms of failure with corresponding radiographic failed graft incorporation. The most common presenting symptom was foot pain with activity and each failure was easily identified on plain radiographs by lucency surrounding the graft sites. All 7 failures required a subsequent revision surgery to remove the bovine graft followed by placement of human iliac crest allograft. After revision surgery, each patient reported subjective improvement in pain and return to daily activity with radiographic evidence of complete incorporation of the graft. CONCLUSIONS: Bovine xenografts used as structural grafts in pediatric foot reconstruction resulted in unacceptably high rates of failure and the need for further revision surgery. For this reason, surgeons should be cautioned against the use of bovine xenograft material in the surgical management of pediatric foot deformity. LEVEL OF EVIDENCE: Level IV case series.

Radiographic outcomes of ring external fixation for malunion and nonunion.

Ring external fixators such as the Ilizarov external fixator (IEF) and Taylor Spatial Frame (TSF) have revolutionized management of limb deformity. This study examines radiographic outcomes for treatment of malunions and nonunions with secondary emphasis on comparing radiographic union rates of TSF and IEF. A retrospective chart and radiograph review was performed. Fifty-four patients were included. Most injuries were in the tibia (96%). Fifty patients (93%) achieved radiographic union, two patients required further fixation, and two patients elected to undergo amputation. The preoperative coronal deformity improved from a mean of 12° (range, 0°-41°) to within 3° anatomic. Sagittal deformity improved from a mean of 11° (range, 0°-49°) to within 5° anatomic with some patients intentionally left in recurvatum to accommodate plantarflexion contractures. Limb length discrepancies were corrected to within 1 cm. Twenty-five patients experienced complications (mostly superficial pin tract infections). No statistically significant differences in the radiographic outcomes of TSF compared to IEF were identified.

Prevalence of painful peroneal tubercles in the pediatric population.

Pain isolated to the lateral aspect of the heel can be difficult to diagnose, particularly in the growing child. Peroneal tendinopathy or frank tears of the peroneal tendons secondary to an enlarged peroneal tubercle has been implicated as a potential source of pain in adults. Neither the prevalence of enlarged peroneal tubercles in the pediatric population nor the number of symptomatic tubercles in children has been elucidated. We conducted a review of children who presented to our institution with foot and/or ankle pain and who underwent 3-dimensional computed tomography. Initially, a radiographic review was undertaken of all computed tomography scans to determine the prevalence of peroneal tubercles in children. The peroneal tubercles were measured and then classified according to height. The children with tubercles 3 mm or greater in height (adult mean height) underwent a more detailed chart review to evaluate for the incidence of painful tubercles. During the study period, 2,689 children were seen for foot and ankle pain, and 367 underwent a computed tomography scan during their treatment course. Of these 367 patients, 57% had a measurable peroneal tubercle, and 162 (44%) met the criteria for chart review. Only 3 adolescents (1.9%) were found to have clinical symptoms and ultimately underwent surgical excision with successful relief of symptoms. Peroneal tubercle hypertrophy appears to exist in the pediatric population; however, in contrast to adults with associated peroneal tendinopathy and tears, the children in our series had isolated painful tubercles without significant tendinopathy. The clinical examination is important in the diagnosis, and treatment by excision appears to be successful. Although a relatively rare etiology of pain, it is important that treating physicians keep this pathologic process in the differential diagnosis, because conservative management might not reduce the pain in these children.

Implant Distribution Versus Implant Density in Lenke Type 1 Adolescent Idiopathic Scoliosis: Does the Position of the Screw Matter?

STUDY DESIGN: Retrospective study. OBJECTIVE: Previous studies have demonstrated that increased implant density (ID) results in improved coronal deformity correction. However, low-density constructs with strategically placed fixation points may achieve similar coronal correction. The purpose of this study was to identify key zones along the spinal fusion where high ID statistically correlated to improved coronal deformity correction. Our hypothesis was that high ID within the periapical zone would not be associated with increased percent Cobb correction. METHODS: We identified patients with Lenke type 1 curves with a minimum 2-year follow up. The instrumented vertebral levels were divided into 4 zones: (1) cephalad zone, (2) caudal zone, (3) apical zone, and (4) periapical zone. High and low percent Cobb correction groups were compared, high percent Cobb group was defined as percent correction >67%. Total ID, total concave ID, total convex ID, and ID within each zone of the curve were compared between the groups. A multivariable analysis was performed to identify independent predictors for coronal correction. Subsequently increased and decreased thoracic kyphosis (TK) groups were compared, increased TK was defined as post-operative TK being larger than preoperative TK and decreased TK was defined as post-operative TK being less than preoperative TK. RESULTS: The cohort included 68 patients. The high percent Cobb group compared with the low percent Cobb group had significantly greater ID for the entire construct, the total concave side, the total convex side, the apical convex zone, the periapical zone, and the cephalad concave zone. The high percent Cobb group had greater pedicle screw density for the total construct, total convex side, and total concave side. In the multivariate model ID and pedicle screw density remained significant for percent Cobb correction. Ability to achieve coronal balance was not statistically correlated to ID (P = .78). CONCLUSIONS: Increased ID for the entire construct, the entire convex side, the entire concave side, and within each spinal zone was associated with improved percent Cobb correction. The ability to achieve coronal balance was not statistically influence by ID. The results of this study support that increasing ID along the entire length of the construct improves percent Cobb correction.

Growth Modulation by Stimulating the Growth Plate: A Pilot Study.

This study investigates the ability of low-intensity pulsed ultrasound (LIPUS) or direct injection of recombinant growth hormone (rGH) to stimulate local growth of long bones. In a randomized controlled animal trial, healthy immature rabbits were allocated to 1 of the following 4 conditions: epiphyseal rGH periosteal injection, transdermal LIPUS, saline periosteal injection, or no treatment. New bone deposition was labeled with calcein at days 1 and 18, and microscopic measurements of growth were conducted by blinded observers. Statistically significant differences in growth were observed between the LIPUS and rGH stimulated legs compared with contralateral control legs (35% p = 0.04 and 41% p = 0.04, respectively); whereas no difference was observed between the 4 control groups (p = 0.37). There was no evidence of physeal bar formation, suggesting that direct injection of rGH and application of LIPUS around the distal femoral physis in rabbits may have a positive effect on microscopic growth without short-term adverse sequelae.

Complications After Pediatric Hip Fractures: Evaluation and Management.

Pediatric proximal femur fractures are high-energy injuries with predictable and morbid complications. Osteonecrosis of the femoral head is the most common complication with identified risk factors including fracture type, patient's age, degree of displacement, timing to reduction, and stability of fixation. Additional complications include nonunion, coxa vara, and premature physeal arrest. The mainstay of treatment for traumatic pediatric osteonecrosis is hip preservation with total hip arthroplasty being reserved as a salvage procedure. An anatomic fracture reduction and a biomechanically stable construct are critical to prevent both nonunion and osteonecrosis. This review will look at the individual surgical interventions for the management of the associated complications of pediatric proximal femur fractures.

Staying ahead of the curve: the use of spinopelvic parameters to predict curve progression and bracing success in adolescent idiopathic scoliosis.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To investigate radiographic sagittal and spinopelvic parameters of patients with adolescent idiopathic scoliosis (AIS) treated with bracing and assess differences among those treated successfully and unsuccessfully. AIS is a three-dimensional deformity of the spine, sharing an intricate relationship with pelvic morphology. However, the most relevant predictors of curve progression have historically been coronal parameters and skeletal maturity. Sagittal and spinopelvic parameters have not been thoroughly investigated as predictors of curve progression and brace treatment success. METHODS: Retrospective review of AIS patients who underwent brace treatment. Coronal Cobb angles (CC), pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), thoracic kyphosis (TK), lumbar lordosis (LL), and thoracic spinopelvic angles (T1SP, T9SP) were measured prior to initiation of bracing. The sagittal and spinopelvic parameters of patients requiring surgical treatment due to curve progression were compared to those treated successfully with bracing. RESULTS: No significant differences were found for age, race, gender, Risser category (0/1 vs 2/3), initial CC, TK, LL, T1SP, or T9SP between cohorts. The cohort requiring surgery had significantly lower PI (p < 0.001, 42.0 v. 54.6), SS (p < 0.001, 37.0 v. 44.5), and PT (p = 0.003, 5.0 v. 10.2) compared to those successfully treated with bracing. Multivariable models controlling for Risser stage and Initial CC revealed the odds for successful brace treatment increases with an increase in PI (OR = 1.47, CI 1.18-1.83, p < 0.001), SS (OR = 1.26, CI 1.07-1.48, p = 0.006), and PT (OR = 1.43, CI 1.09-1.86, p = 0.006) (Table 3). The odds of successful brace treatment is given per one-unit increase for each radiographic measure after adjusting for Initial CC and Risser sign which were forced into each multivariable model. CONCLUSIONS: Spinopelvic parameters may indicate potential spine adaptability and skeletal maturity. For these reasons, we proposed that spinopelvic parameters may be a potential predictor of curve progression and brace treatment success. Our results demonstrated a higher risk of curve progression with lower PI, PT, or SS which support this hypothesis, however, given the small sample size and high variability, the magnitude of this effect should be viewed with caution and should serve as an impetus to further, larger scale studies to investigate the value spinopelvic parameters in curve progression and bracing efficacy. LEVEL OF EVIDENCE: IV.

Periapical Wires Result in Less Curve Correction Than Pedicle Screw Constructs in Idiopathic Scoliosis.

STUDY DESIGN: Retrospective study. PURPOSE: The objective of this study was to compare percent correction between apical and periapical pedicle screw (PS) and sublaminar wire constructs for Cobb correction and coronal balance correction. OVERVIEW OF LITERATURE: The current gold standard for deformity correction in adolescent idiopathic scoliosis (AIS) are PS constructs. Sublaminar wires provide an alternative means of fixation when PS fixation cannot be safely performed. Two previous studies have compared percent curve correction between sublaminar wires and PSs, with conflicting conclusions. METHODS: The study was a retrospective review of Lenke type 1 curves with minimum follow-up of at least 1 year. Cases were divided into two groups: constructs using apical/periapical sublaminar wires (SL group) versus PS only constructs (PS group). Percent Cobb correction and coronal balance were compared between the two groups at 1 year. A multivariable regression model was used to determine the impact of apical/periapical wires on percent Cobb correction and coronal balance at 1 year when accounting for additional variables. RESULTS: The cohort included 71 patients who were predominantly female (80.2%), with average age of 14.2 years. Only 21 (29.5%) of constructs utilized apical/periapical sublaminar wires. There was a significant difference in percent Cobb correction at 1 year for the PS and SL groups (70.26% vs. 60.09%, p=0.05). No difference was observed in overall coronal balance. A multivariable model revealed that apical/periapical wires were negatively associated with percent Cobb correction at 1 year (coefficient=-8.49, p=0.023), while total implant density of the construct was positively associated with correction (coefficient=24.2, p<0.001). CONCLUSIONS: Use of PSs in the apical and periapical zones resulted in improved percent Cobb correction at 1 year in patients with AIS Lenke type 1 curves. Sublaminar wires remain a useful surgical option and result in equivalent coronal balance compared to PSs.

Pediatric proximal femur fractures.

Pediatric proximal femur fractures are rare injuries resulting from high-energy trauma. The Delbet classification is used when describing these injuries, and associates fracture type to the development of avascular necrosis. Historically, casting was utilized in the treatment of these injuries, but high complication rates following this approach have changed the treatment modality to early and anatomic fixation. Complications associated with these injuries including avascular necrosis, non-union, coxa-vara, and premature physeal fusion. Achieving anatomic reduction and performing internal fixation within 24 h from time of injury has become the standard of care in the treatment of pediatric proximal femur fractures.

Pamidronate treatment and posttreatment bone density in children with spastic quadriplegic cerebral palsy.

Little is known about the long-term effects of a course of pamidronate treatment on bone mineral density (BMD) of children with spastic quadriplegic cerebral palsy (SQCP). Nine patients with SQCP who had low bone density and/or history of previous fracture(s) were studied during treatment and more than 1 yr after cyclic pamidronate treatment ended. Over the 12 mo of treatment, spine BMD increases raised average Z-score from -4.0 to -2.8. In the distal femoral metaphysis, BMD increase raised average Z-score from -3.6 to -1.7. Observations posttreatment ranged from 12 to 49 mo. Changes in BMD were variable among individuals. Group spine Z-score an average of 34 mo posttreatment approached pretreatment value. Six of eight patients had final distal femur posttreatment Z-scores the same or better than pretreatment baseline an average of 27.1 mo later. While most but not all gains in BMD were lost over the first 2 yr after treatment, no patient sustained fracture during or after treatment for a cumulative follow-up of more than 27 patient-yr.

Neuromuscular Scoliosis: Current Concepts.

Scoliosis is a common deformity in neuromuscular disorders. This spinal deformity usually presents at an early age, rapidly progresses during growth, and continues to progress even after skeletal maturity. Neuromuscular scoliosis classically involves the entire thoracolumbar spine, often extending to the pelvis and causing pelvic obliquity. Physical examination can be challenging, but it is important to assess the flexibility of the spinal curve and associated joint contractures. Upright anteroposterior and lateral radiographs are the preferred imaging. When formulating a treatment plan, it is important to take into account not only the degree of curvature, but also each patient's needs and quality of life, the potentially high perioperative complication rates, and the natural history of the underlying neuromuscular disorder. Different neuromuscular conditions behave differently and should therefore be treated differently. With the exception of steroids for Duchenne muscular dystrophy, bracing remains the only reliable nonoperative intervention available. Preoperative optimization of medical comorbidities is crucial given the relatively high complication rate. Posterior segmental instrumentation has revolutionized the surgical management of neuromuscular scoliosis and is the most commonly used technique today. Despite reported improvement in postoperative quality of life, there are several limitations with currently used outcome measures that prevent a well-informed discussion on the outcomes after surgery.