Characteristics of terminal hemimelia: What is the difference between terminal hemimelia and classic fibular hemimelia?

Purpose: Fibular hemimelia has denoted a spectrum of postaxial longitudinal deficiency with fibular aplasia/hypoplasia; the term "terminal hemimelia" is reserved for patients with postaxial longitudinal deficiency having a normal fibula. We aimed to delineate the characteristics of terminal hemimelia. Methods: In total, 30 patients with postaxial longitudinal deficiency who had a normal or hypoplastic fibula and visited our institution between 1992 and 2022 were reviewed. Patients were divided into terminal hemimelia and classic fibular hemimelia groups, and their demographic characteristics and clinical and radiographic findings were compared. Results: Femoral shortening, knee valgus, and tibial spine hypoplasia were less common in terminal hemimelia (n = 13) than in classic fibular hemimelia (n = 17) (p = 0.03, p < 0.001, and p = 0.003, respectively). None of the patients in the terminal hemimelia group exhibited knee instability, whereas 12% of patients with classic fibular hemimelia did. Ball-and-socket ankle and absence of lateral rays were commonly observed in both groups. However, tarsal coalition was observed less frequently in terminal hemimelia (p = 0.004). All terminal hemimelia patients exhibited a painless plantigrade foot without ankle instability. Despite limb-length discrepancy at maturity averaging 40.4 mm for terminal hemimelia and 67.0 mm for classic fibular hemimelia (p < 0.001), patients with terminal hemimelia, except for one, exhibited > 20 mm of limb-length discrepancy. However, 46% of them underwent limb-length equalization procedures, mostly single-stage tibial lengthening, at a mean age of 11.2 years. Conclusion: Terminal hemimelia may present with a milder phenotype than classic fibular hemimelia. It mainly overlaps with the symptoms of fibular hemimelia below the ankle joint and manifests as limb-length discrepancy. However, a considerable number of patients with terminal hemimelia required limb-length equalization procedures, for example single-stage tibial lengthening. Level of evidence: level IV.

Incidence and Clinical Characteristics of Slipped Capital Femoral Epiphysis in Patients with Endocrinopathy: A Population-Based Cohort Study.

BACKGROUND: Endocrinopathy is a risk factor for slipped capital femoral epiphysis (SCFE). We aimed to determine (1) the incidence of endocrinopathy-associated SCFE compared with that of non-endocrinopathy-associated SCFE, (2) whether the incidence of SCFE increases with the number of deficient hormones, and (3) the clinical characteristics of endocrinopathy-associated SCFE. METHODS: We conducted a population-based cohort study using a nationwide database in South Korea. All new diagnoses of endocrinopathy or SCFE between 2002 and 2019 in children born between 2002 and 2005 were identified. The incidence of SCFE was calculated for each type of endocrinopathy. The trend of the incidence of SCFE relative to the number of deficient hormones was analyzed. The male:female ratio was compared between endocrinopathy-associated SCFE and non-endocrinopathy-associated SCFE. For endocrinopathy-associated SCFE, the time between the diagnoses of SCFE and endocrinopathy was evaluated. RESULTS: The incidence of SCFE was higher in children with endocrinopathy than in those without endocrinopathy (37.1/100,000 versus 9.0/100,000 children) (relative risk, 4.1 [95% confidence interval, 2.8-6.1]). Among various endocrinopathies, growth hormone deficiency showed the highest incidence of SCFE (583.8/100,000 children). The Cochran-Armitage test showed a linear trend, with an increased number of deficient hormones being associated with a higher incidence of SCFE (p < 0.001). Male sex was dominant in the non-endocrinopathy-associated SCFE group (73%; 117 of 161), whereas female sex was dominant in the endocrinopathy-associated SCFE group (53%; 16 of 30) (p = 0.009). Twenty-two of the 30 cases of endocrinopathy-associated SCFE were diagnosed after the diagnosis of endocrinopathy, with a median time of 3.6 years between the diagnoses. Six (27%) of these 22 children developed SCFE >5 years after the diagnosis of endocrinopathy. CONCLUSIONS: The incidence of SCFE was approximately 4 times higher in children with endocrinopathy than in those without endocrinopathy. The risk of SCFE increased with an increased number of deficient hormones. Long-term monitoring of SCFE occurrence in children with endocrinopathies is strongly recommended. LEVEL OF EVIDENCE: Diagnostic Level III . See Instructions for Authors for a complete description of levels of evidence.

The role of 99mTc-DPD bone SPECT/CT in the management of growth disturbance of the long bones in pediatric patients: a retrospective observational study.

BACKGROUNDS: Determining the precise localization of diseased physes is crucial for guiding the treatment of growth disturbances. Conventional radiography, computed tomography (CT), and magnetic resonance imaging only provide information on physeal anatomy. Planar bone scintigraphy and bone single-photon emission computed tomography (SPECT) resolutions are suboptimal for clinically managing growth disturbances. Bone SPECT/CT, which provides high-resolution functional information, can be a useful tool for evaluating growth disturbances. The purposes of this study were to identify the conditions in which bone SPECT/CT outperforms planar scintigraphy or SPECT for evaluating the location and activity of diseased physes and to assess surgical outcomes using bone SPECT/CT findings in pediatric patients experiencing long bone growth disturbances. METHODS: Fifty-nine patients who underwent bone SPECT/CT between January 2018 and January 2021 to evaluate physeal activity using technetium-99 m-labeled 2,3-dicarboxypropane-1,1-diphosphonate (99mTc-DPD) were included. The proportions of patients for whom certain modalities provided sufficient data for selecting treatment plans for growth disturbances were compared based on the site of the diseased physis, growth disturbance cause, and shape of deformity (i.e., SPECT/CT vs. planar scintigraphy and SPECT/CT vs. SPECT). For assessing surgical outcomes, progression of post-surgical deformity was investigated by measuring the angles reflecting the degree of deformity, iliac crest height difference, or ulnar variance on radiographs. RESULTS: Bone SPECT/CT was sufficient for selecting a treatment plan, but planar scintigraphy or SPECT alone was insufficient in every 10 patients with diseased physes inside the femoral head (p = 0.002) and in every six with physes that were severely deformed or whose locations were unclear on conventional radiography (p = 0.03). In the proximal or distal tibia, where the tibial and fibular physes often overlapped on planar scintigraphy due to leg rotation, bone SPECT/CT was sufficient in 33/34 patients (97%), but planar scintigraphy and SPECT were sufficient in 10/34 (29%) (p < 0.001) and 24/34 (71%) patients, respectively (p = 0.004). No progression or deformity recurrence occurred. CONCLUSIONS: Bone SPECT/CT may be indicated in proximal femoral growth disturbance, when the physis is unclear on conventional radiography or severely deformed, the leg exhibits rotational deformity, or the patient is noncompliant.

Uncovering the phenotypic consequences of multi-locus imprinting disturbances using genome-wide methylation analysis in genomic imprinting disorders.

Imprinted genes are regulated by DNA methylation of imprinted differentially methylated regions (iDMRs). An increasing number of patients with congenital imprinting disorders (IDs) exhibit aberrant methylation at multiple imprinted loci, multi-locus imprinting disturbance (MLID). We examined MLID and its possible impact on clinical features in patients with IDs. Genome-wide DNA methylation analysis (GWMA) using blood leukocyte DNA was performed on 13 patients with Beckwith-Wiedemann syndrome (BWS), two patients with Silver-Russell syndrome (SRS), and four controls. HumanMethylation850 BeadChip analysis for 77 iDMRs (809 CpG sites) identified three patients with BWS and one patient with SRS showing additional hypomethylation, other than the disease-related iDMRs, suggestive of MLID. Two regions were aberrantly methylated in at least two patients with BWS showing MLID: PPIEL locus (chromosome 1: 39559298 to 39559744), and FAM50B locus (chromosome 6: 3849096 to 3849469). All patients with BWS- and SRS-MLID did not show any other clinical characteristics associated with additional involved iDMRs. Exome analysis in three patients with BWS who exhibited multiple hypomethylation did not identify any causative variant related to MLID. This study indicates that a genome-wide approach can unravel MLID in patients with an apparently isolated ID. Patients with MLID showed only clinical features related to the original IDs. Long-term follow-up studies in larger cohorts are warranted to evaluate any possible phenotypic consequences of other disturbed imprinted loci.

When to Combine Acetabular Osteotomy in Patients With Proximal Femoral Deformity Causing Residual Hip Dysplasia/Subluxation After Reduction of Developmental Dysplasia of the Hip.

BACKGROUND: After the successful reduction of developmental dysplasia of the hip, residual hip dysplasia may persist and lead to early osteoarthritis. Femoral and/or acetabular osteotomy has been used to address this problem. The purpose of this study is to determine the indication of femoral versus combined femoral-acetabular osteotomy in the management of residual hip dysplasia. METHODS: Fifty-five patients with unilateral dislocated-type dysplasia of the hip, who had residual hip dysplasia after reduction, underwent femoral osteotomy with or without acetabular osteotomy before 8 years of age, and were followed for more than 2 years and over 8 years of age, were the subjects of this retrospective study. Twenty-eight patients underwent femoral osteotomy only at a median age of 34 months (group F), and 27 underwent combined femoral-Dega osteotomy at a median age of 49 months (group C). Seventeen patients in group F and 4 in group C had an additional osteotomy due to persistent hip dysplasia. Acetabular index (AI), lateral center-edge angle, and center-head distance difference were measured on serial radiographs. The z-value of AI (Z AI ) was calculated. At the latest follow-up, patients in group F with Severin I/II who did not have an additional osteotomy were considered satisfactory, and patients with Severin III/IV or those who had an additional osteotomy were considered unsatisfactory. Preoperative variables were tested for the difference between satisfactory and unsatisfactory cases. Receiver operating characteristic analysis was performed to delineate a cutoff value of a significant parameter dividing the outcome. RESULTS: AI and Z AI before index osteotomy were significant parameters predicting a satisfactory outcome in group F. Receiver operating characteristic analysis returned a cutoff value of Z AI 2.6 (Area Under the Curve=0.86, P =0.001). Eight of 12 cases (66.7%) with Z AI <2.6 in group F achieved a satisfactory outcome, whereas only 2 of 14 cases with Z AI ≥2.6 in group F did ( P =0.02). CONCLUSION: Z AI 2.6 may serve as a threshold to combine acetabular osteotomy with femoral osteotomy in the management of residual hip dysplasia before 8 years of age. LEVEL OF EVIDENCE: Therapeutic III.

Clinical and radiological outcomes of surgically treated osteochondral lesions of the talus in children and adolescents.

Background: Osteochondral lesions of the talus are uncommon in children and adolescents. Surgical procedures differ from those used for adults to avoid iatrogenic physeal injuries. This study aimed to evaluate the clinical and radiological outcomes of surgical treatment in pediatric patients with osteochondral lesions, specifically investigating the patient age and the status of distal tibial physis as factors associated with surgical success. Methods: We retrospectively reviewed 28 patients who had symptomatic osteochondral lesions of the talus that were treated surgically between 2003 and 2016. If the lesion was stable and articular cartilage was intact, retrograde drilling was performed under fluoroscopic guidance. Lesions with detached overlying cartilages were treated by debridement of the cartilage combined with microfracture and drilling. Radiographic outcomes, American Orthopaedic Foot & Ankle Society ankle-hindfoot score, and skeletal maturity were evaluated. Results: Radiological improvement was observed in 24 (24/28, 86%) patients and complete and incomplete healing in 8 and 16 patients, respectively. Changes in pain grades, American Orthopaedic Foot & Ankle Society scores, and radiological healing after surgery were significant (pain grade, p < 0.001; American Orthopaedic Foot & Ankle Society, p = 0.018; radiological healing, p < 0.001). In addition, patients in the younger age group (≤13 years) showed greater improvements in pain grades than older patients (p = 0.02). Improvement in pain grade after surgery was better in the skeletally immature group than in the skeletally mature group (p = 0.048). Conclusion: Clinical and radiological improvements were observed after surgical treatment. The younger age group and open physis group showed more pain improvement. Level of evidence: Therapeutic level IV.

Development and evaluation of deep-learning measurement of leg length discrepancy: bilateral iliac crest height difference measurement.

BACKGROUND: Leg length discrepancy (LLD) is a common problem that can cause long-term musculoskeletal problems. However, measuring LLD on radiography is time-consuming and labor intensive, despite being a simple task. OBJECTIVE: To develop and evaluate a deep-learning algorithm for measurement of LLD on radiographs. MATERIALS AND METHODS: In this Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study, radiographs were obtained to develop a deep-learning algorithm. The algorithm developed with two U-Net models measures LLD using the difference between the bilateral iliac crest heights. For performance evaluation of the algorithm, 300 different radiographs were collected and LLD was measured by two radiologists, the algorithm alone and the model-assisting method. Statistical analysis was performed to compare the measurement differences with the measurement results of an experienced radiologist considered as the ground truth. The time spent on each measurement was then compared. RESULTS: Of the 300 cases, the deep-learning model successfully delineated both iliac crests in 284. All human measurements, the deep-learning model and the model-assisting method, showed a significant correlation with ground truth measurements, while Pearson correlation coefficients and interclass correlations (ICCs) decreased in the order listed. (Pearson correlation coefficients ranged from 0.880 to 0.996 and ICCs ranged from 0.914 to 0.997.) The mean absolute errors of the human measurement, deep-learning-assisting model and deep-learning-alone model were 0.7 ± 0.6 mm, 1.1 ± 1.1 mm and 2.3 ± 5.2 mm, respectively. The reading time was 7 h and 12 min on average for human reading, while the deep-learning measurement took 7 min and 26 s. The radiologist took 74 min to complete measurements in the deep-learning mode. CONCLUSION: A deep-learning U-Net model measuring the iliac crest height difference was possible on teleroentgenograms in children. LLD measurements assisted by the deep-learning algorithm saved time and labor while producing comparable results with human measurements.

Deciphering Epigenetic Backgrounds in a Korean Cohort with Beckwith-Wiedemann Syndrome.

Background: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder caused by genetic or epigenetic alterations at two imprinting centers (ICs) in the 11p15.5 region. Delineation of the molecular defects is important for prognosis and predicting familial recurrence. We evaluated epigenetic alterations and potential epigenotype-phenotype correlations in Korean children with BWS. Methods: Forty children with BWS with proven genetic or epigenetic defects in the 11p15.5 region were included. The phenotype was scored using the BWS consensus scoring system. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), bisulfite pyrosequencing, a single-nucleotide polymorphism microarray, and CDKN1C sequencing were used for confirmative diagnosis. Results: Patients met the criteria for genetic testing, with a mean clinical score of 5.4±2.0. Methylation alterations were consistent between MS-MLPA and bisulfite pyrosequencing in all patients. Twenty-six patients (65.0%) had IC2 loss of methylation (IC2-LoM), 11 (27.5%) had paternal uniparental disomy (patUPD), and one (2.5%) had IC1 gain of methylation. Macroglossia and external ear anomalies were more common in IC2-LoM than in patUPD, and lateralized overgrowth was more common in patUPD than in IC2-LoM (all P<0.05). Methylation levels at IC2 were inversely correlated with birth weight standard deviation score (r=-0.476, P=0.014) and clinical score (r=-0.520, P=0.006) in the IC2-LoM group. Conclusions: Comprehensive molecular analysis of the 11p15.5 region revealed epigenotype-phenotype correlations in our BWS cohort. Bisulfite pyrosequencing can help clarify epigenotypes. Methylation levels were correlated with fetal growth and clinical severity in patients with BWS.

Effect of Leg Length Discrepancy on Lateral Center-edge Angle Measurement.

BACKGROUND: In patients with leg length discrepancy (LLD) and consequent pelvic obliquity, either the longitudinal axis of the pelvis or a line perpendicular to the ground may be used as the longitudinal reference line for measuring the lateral center-edge angle (LCEA). We aimed to (1) systematically inspect which longitudinal reference line has been used for measuring the LCEA in previous studies; (2) evaluate the frequency of change in the radiographical classification of acetabular overcoverage or undercoverage per the longitudinal reference line; and (3) validate the trigonometric method, predicting the change in the LCEA according to the LLD. METHODS: Studies investigating the LCEA published between January 1976 and July 2019 in the MEDLINE database were categorized according to the longitudinal reference line used. Further, in a retrospective analysis of 238 patients surgically treated for LLD, the LCEA was first measured on standing pelvic radiographs using the longitudinal axis of the pelvis (pLCEA) and measured again using a line perpendicular to the ground (gLCEA). Femoral head coverage was categorized as undercoverage, normal, or overcoverage based on the pLCEA and gLCEA. The theoretically calculated difference between the pLCEA and gLCEA (dLCEA) as determined using a trigonometric method was compared with the dLCEA measured on radiographs. RESULTS: Of 229 previous studies, 188 did not specify the longitudinal reference line. The number of patients who were diagnosed with acetabular overcoverage using the pLCEA and gLCEA was one and fourteen, respectively (P<0.001). The number of patients who were diagnosed with acetabular undercoverage using the pLCEA and gLCEA was one and zero, respectively (P=1.000). There was no difference (P=0.433) between the theoretically calculated (9±5 degrees) and measured (9±5 degrees) dLCEAs. CONCLUSIONS: The definition of the longitudinal reference line should be clarified when measuring the LCEA. The trigonometric method can accurately predict the change in the LCEA according to LLD in concentric hips without proximal femoral and pelvic deformities. LEVEL OF EVIDENCE: Level IV-diagnostic study.

Patterns of femoral neck fracture and its treatment methods in patients with osteogenesis imperfecta.

Femoral neck fracture (FNF) is not common in osteogenesis imperfecta patients but may result in serious complications if not properly treated in due time. We present three types of FNF in osteogenesis imperfecta and their characteristics, treatment methods and outcomes. Cases of FNF followed for more than 2 years were selected from the osteogenesis imperfecta database. Medical records and radiographs were reviewed to obtain demographic information and to determine ambulatory status, mode of injury, location of the fracture line, presence of preexisting implants, treatment methods and complications. Outcomes were evaluated according to the radiographic results and ambulatory function. The study investigated 15 FNFs in 10 patients including 1 Sillence type I, 1 type III and 8 type IV. They were either community or household ambulators. The mean age at fracture was 11.7 years. The fractures were followed for an average of 6.3 years. Six fractures were attributed to accidental injuries and nine without noticeable trauma. The fracture pattern was categorized into undisplaced (n = 3), angulated-stable (n = 7) or displaced-unstable (n = 5) types. Five fractures were fixed in-situ using screws or Kirschner wires. Other five fractures were treated by closed reduction and screw fixation and the remaining five fractures were managed by femoral valgus osteotomy. Bony union was achieved, and prefracture ambulatory status was restored in all cases. A high index of suspicion is required in the diagnosis of undisplaced or angulated-stable fractures. Treatment is usually challenging, but a judicious approach considering the fracture pattern and patient characteristics result in successful outcomes. The angulated-stable pattern of fracture is unique in osteogenesis imperfecta patients and requires special attention.

Intra-articular acetabular osteochondroma in patients with multiple hereditary exostoses.

We report three additional cases of intra-articular acetabular osteochondroma in multiple hereditary exostoses patients in order to raise the awareness of this rare location, to prompt early diagnosis, and to present various treatment options according to the patient's condition. A 2.5-year-old boy presenting with an out-toeing gait had a large acetabular osteochondroma causing lateral displacement of the femoral head and acetabular dysplasia. Mass excision through hip subluxation via anterior approach and concomitant Dega osteotomy resulted in a congruent, well-developed, and well-covered hip joint at 11-year follow-up. A 10-year-old boy showing a pedunculated osteochondroma arising from the triradiate cartilage was successfully treated by arthroscopic excision. Normal development of the hip joint was observed at skeletal maturity. A 6-year-old boy presented with a painless limp. Acetabular osteochondroma could be confirmed by computed tomography scan, which was excised through hip subluxation by anterior approach. Persistent coxa valga and femoral head uncovering were addressed by femoral varization osteotomy at 9 years of age. A high index of suspicion is required to detect a lesion at this rare location. Various procedures may be considered according to the pathoanatomy. Acetabular dysplasia, coxa valga, and femoroacetabular impingement by femur neck mass, if associated, should be addressed in due time.

Prospective study of epigenetic alterations responsible for isolated hemihyperplasia/hemihypoplasia and their association with leg length discrepancy.

BACKGROUND: Hemihyperplasia and hemihypoplasia result in leg length discrepancy (LLD) by causing skeletal asymmetry. Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are opposite growth-affecting disorders caused by opposite epigenetic alterations at the same chromosomal locus, 11p15, to induce hemihyperplasia and hemihypoplasia, respectively. Because of their somatic mosaicism, BWS and SRS show a wide spectrum of clinical phenotypes. We evaluated the underlying epigenetic alterations and potential epigenotype-phenotype correlations, focusing on LLD, in a group of individuals with isolated hemihyperplasia/hemihypoplasia. RESULTS: We prospectively collected paired blood-tissue samples from 30 patients with isolated hemihyperplasia/hemihypoplasia who underwent surgery for LLD. Methylation-specific multiplex-ligation-dependent probe amplification assay (MS-MLPA) and bisulfite pyrosequencing for differentially methylated regions 1 and 2 (DMR1 and DMR2) on chromosome 11p15 were performed using the patient samples. Samples from patients showing no abnormalities in MS-MLPA or bisulfite pyrosequencing were analyzed by single nucleotide polymorphism (SNP) microarray and CDKN1C Sanger sequencing. We introduced a metric named as the methylation difference, defined as the difference in DNA methylation levels between DMR1 and DMR2. The correlation between the methylation difference and the predicted LLD at skeletal maturity, calculated using a multiplier method, was evaluated. Predicted LLD was standardized for stature. Ten patients (33%) showed epigenetic alterations in MS-MLPA and bisulfite pyrosequencing. Of these, six and four patients had epigenetic alterations related to BWS and SRS, respectively. The clinical diagnosis of hemihyperplasia/hemihypoplasia was not compatible with the epigenetic alterations in four of these ten patients. No patients showed abnormalities in SNP array or their CDKN1C sequences. The standardized predicted LLD was moderately correlated with the methylation difference using fat tissue (r = 0.53; p = 0.002) and skin tissue (r = 0.50; p = 0.005) in all patients. CONCLUSIONS: Isolated hemihyperplasia and hemihypoplasia can occur as a spectrum of BWS and SRS. Although the accurate differentiation between isolated hemihyperplasia and isolated hemihypoplasia is important in tumor surveillance planning, it is often difficult to clinically differentiate these two diseases without epigenetic tests. Epigenetic tests may play a role in the prediction of LLD, which would aid in treatment planning.

Acute correction of proximal tibial coronal plane deformity in small children using a small monolateral external fixator with or without cross-pinning.

PURPOSE: Surgical correction of proximal tibia deformity in small children can be challenging. We present the surgical technique and outcome of proximal tibia osteotomy fixed with small monolateral external fixator in this patient group. METHODS: A total of 17 cases in eight patients younger than nine years of age were study subjects. A proximal tibia osteotomy was fixed with a small monolateral external fixator with or without cross-pinning. Outcome was evaluated by changes of radiographic parameters such as medial proximal tibia angle (MPTA), metaphyseal diaphyseal angle (MDA) and clinical findings of complications, time interval until weight bearing and fixator removal time. RESULTS: MPTA improved from a preoperative mean of 73° (sd 4°; 66° to 78°) to an immediate postoperative mean of 90° (sd 3°; 85° to 96°) in varus tibiae, and from 104° (sd 1°; 103° to 105°) to 89° (sd 1°; 88° to 89°) in valgus tibiae. In all, 15 of the 17 cases (88.3 %) achieved postoperative MPTA within the normal range (85° to 90°). MDA improved from a preoperative mean of 19° (sd 5°; 11° to 24°) to an immediate postoperative mean of 0° (sd 4°; -6° to 7°) in varus tibiae, and from -25° (sd 2°; -22° to -24°) to 2° (SD 1°; 1° to 3°) in valgus tibiae. Full weight bearing was possible at mean 1.7 months (0.5 to 3.0). Mean follow-up period was 6.5 years (sd 5.4; 1.0 to 16.0). No complications developed during the follow-up. CONCLUSION: Proximal tibia osteotomy fixed with small monolateral external fixator provides accurate, safe and efficient correction in the management of coronal plane angular deformity in small children. LEVEL OF EVIDENCE: Level IV.

Pseudo-Protrusio Acetabular Deformity in Osteogenesis Imperfecta Patients.

BACKGROUND: Osteogenesis imperfecta (OI) can develop a protrusio acetabuli deformity. However, the authors observed a pseudo-protrusio-type acetabular deformity (PPAD) on 3-dimensional computed tomography (3D-CT). Hence, we systematically reviewed 3D-CT and pelvis radiographs of OI patients and report the incidence and patterns of acetabular deformity in OI patients and the associated radiographic signs. METHODS: The study included 590 hips of 295 OI patients, who were older than 5 years, and did not have a pelvic fracture. The incidence of a deformed acetabulum (center-edge angle >40 degrees) and its correlation with disease severity were investigated. In 40 hips for which 3D-CT was available, 3-dimensional morphology of the acetabular deformity was analyzed to delineate PPAD. On plain radiographs, PPAD-related signs were determined, focusing on the contour of ilioischial line, iliopectineal line, acetabular line, and their relationship. These radiographic signs were also evaluated in the remaining hips with deformed acetabula that did not have 3D-CT. RESULTS: One hundred twenty-three hips of 590 hips (21%) showed deformed acetabula. The incidence of deformed acetabula was significantly associated with disease severity (P<0.001). Three-dimensional analysis showed that 10 hips had protrusio acetabuli, whereas 17 had PPAD, which showed that the hemipelvis was crumpled, the acetabular roof was rotated upwardly and medially, and the hip center migrated superiorly, uncovering the anterior femoral head. Among the PPAD-related signs, superomedial bulging of the iliopectineal line was the most predictive radiographic sign (73% sensitivity and 100% specificity). This sign was also observed in almost one third of deformed acetabula of those investigated only with plain radiographs. CONCLUSIONS: This study showed that acetabular deformity is common in OI patients and is associated with disease severity. A substantial number of hips showed PPAD, which may not cause femoroacetabular impingement but result in anterior uncovering of the hip joint. Superomedial bulging of the iliopectineal line suggests this pattern of acetabular deformity. LEVEL OF EVIDENCE: Lever IV-prognostic studies.

Clinical Application of Sequential Epigenetic Analysis for Diagnosis of Silver-Russell Syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) is a pre- or post-natal growth retardation disorder caused by (epi)genetic alterations. We evaluated the molecular basis and clinical value of sequential epigenetic analysis in pediatric patients with SRS. METHODS: Twenty-eight patients who met≥3 Netchine-Harbison clinical scoring system (NH-CSS) criteria for SRS were enrolled;26 (92.9%) were born small for gestational age, and 25 (89.3%) showed postnatal growth failure. Relative macrocephaly, body asymmetry, and feeding difficulty were noted in 18 (64.3%), 13 (46.4%), and 9 (32.1%) patients, respectively. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) on chromosome 11p15 was performed as the first diagnostic step. Subsequently, bisulfite pyrosequencing (BP) for imprinting center 1 and 2 (IC1 and IC2) at chromosome 11p15, MEST on chromosome 7q32.2, and MEG3 on chromosome 14q32.2 was performed. RESULTS: . Seventeen (60.7%) patients exhibited methylation defects, including loss of IC1 methylation (N=14; 11 detected by MS-MLPA and three detected by BP) and maternal uniparental disomy 7 (N=3). The diagnostic yield was comparable between patients who met three or four of the NH-CSS criteria (53.8% vs 50.0%). Patients with methylation defects responded better to growth hormone treatment. CONCLUSIONS: NH-CSS is a powerful tool for SRS screening. However, in practice, genetic analysis should be considered even in patients with a low NH-CSS score. BP analysis detected additional methylation defects that were missed by MS-MLPA and might be considered as a first-line diagnostic tool for SRS.

Management of Osteogenesis Imperfecta: A Multidisciplinary Comprehensive Approach.

Osteogenesis imperfecta (OI) is characterized by recurring fractures and limb and spine deformities. With the advent of medical therapeutics and the discovery of causative genes, as well as the introduction of a newly devised intramedullary rod, the general condition and ambulatory function of patients diagnosed with OI have been improved over the past decades. This review covers recent developments in research and management of OI.

Effective and Rapid Microbial Identification in Pediatric Osteoarticular Infections Using Blood Culture Bottles.

BACKGROUND: The detection and identification of pathogenic microorganisms are essential for the treatment of osteoarticular infection. However, obtaining a sufficient amount of specimen from pediatric patients is often difficult. Herein, we aimed to demonstrate the effectiveness of the blood culture bottle (BCB) system in pediatric osteoarticular infections. We hypothesized that our BCB culture method is superior to the conventional swab and tissue culture methods in terms of required specimen size, incubation time, and microbial identification rate. METHODS: We analyzed the prospectively collected data of pediatric patients who underwent surgical treatment for osteoarticular infections between August 2016 and October 2019. Four needles were dipped in the infected fluid or tissue during the surgical procedure as soon as the infected area was exposed and were used to inoculate 2 aerobic pediatric BCBs and 2 anaerobic general BCBs. We also collected 2 conventional swab samples and 2 tissue samples from the identical area. The microbial identification rate and the time required for identification were compared between BCB, swab, and tissue cultures. RESULTS: Forty patients constituted the study group; 13 patients had osteomyelitis, 17 patients had septic arthritis, and 10 patients had both. Of these 40 patients, the microbial identification rate was higher with BCB cultures (27 [68%]) than with swab cultures (18 [45%]; p = 0.004) or tissue cultures (15 [38%]; p < 0.001). Nine samples (9 patients [23%]) were only positive in the BCB culture. Positive microbial growth was not detected with conventional culture methods when microorganisms did not grow on the BCB culture. Compared with swab culture (4.3 ± 1.1 days; p < 0.001) or tissue culture (4.4 ± 1.1 days; p < 0.001), the BCB culture reduced the time required for microbial identification (3.5 ± 0.9 days). CONCLUSIONS: In pediatric osteoarticular infections, the BCB culture system improved the microbial identification rate, reduced the time to identification, and permitted a smaller-volume specimen, compared with traditional culture systems. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Detailed analysis of phenotypes and genotypes in megalencephaly-capillary malformation-polymicrogyria syndrome caused by somatic mosaicism of PIK3CA mutations.

BACKGROUND: Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) belongs to a group of conditions called the PIK3CA-related overgrowth spectrum (PROS). The varying phenotypes and low frequencies of each somatic mosaic variant make confirmative diagnosis difficult. We present 12 patients who were diagnosed clinically and genetically with MCAP. Genomic DNA was extracted mainly from the skin of affected lesions, also from peripheral blood leukocytes and buccal epithelial cells, and target panel sequencing using high-depth next-generation sequencing technology was performed. RESULTS: Macrocephaly was present in 11/12 patients (92%). All patients had normal body asymmetry. Cutaneous vascular malformation was found in 10/12 patients (83%). Megalencephaly or hemimegalencephaly was noted in all 11 patients who underwent brain magnetic resonance imaging. Arnold-Chiari type I malformation was also seen in 10 patients. Every patient was identified as having pathogenic or likely pathogenic variants of the PIK3CA gene. The variant allele frequency (VAF) ranged from 6.3 to 35.3%, however, there was no direct correlation between VAF and the severity of associated anomalies. c.2740G > A (p.Gly914Arg) was most commonly found, in four patients (33%). No malignancies developed during follow-up periods. CONCLUSIONS: This is the first and largest cohort of molecularly diagnosed patients with MCAP in Korea. Targeted therapy with a PI3K-specific inhibitor, alpelisib, has shown successful outcomes in patients with PROS in a pilot clinical study, so early diagnosis for genetic counseling and timely introduction of emerging treatments might be achieved in the future through optimal genetic testing.

Therapeutic Effects of Saline Groundwater Solution Baths on Atopic Dermatitis: A Pilot Study.

BACKGROUND: Saline groundwater, collected from the east coast of Korea, has been shown to have protective effects against 2,4-dinitrochlorobenzene- (DNCB-) induced atopic dermatitis-like skin lesions in the murine model. OBJECTIVES: To determine the effects of saline groundwater solution baths as a treatment of mild-to-moderate atopic dermatitis. METHODS: Twenty-four subjects with mild-to-moderate atopic dermatitis were instructed to take a bath in saline groundwater solution for 20 minutes per day for two weeks. Evaluations were performed at baseline and week 2, including SCORing Atopic Dermatitis (SCORAD) index, corneometry, transepidermal water loss, visual analogue scale for pruritus, and collection of adverse events. RESULTS: Subjects showed significant improvement with respect to the SCORAD index, skin hydration, transepidermal water loss, and pruritus at week 2 when compared with the baseline. CONCLUSION: Baths in saline groundwater solution may be an alternative therapeutic strategy for treating atopic dermatitis.

Which Acetabular Landmarks are the Most Useful for Measuring the Acetabular Index and Center-edge Angle in Developmental Dysplasia of the Hip? A Comparison of Two Methods.

BACKGROUND: The acetabular index and center-edge angle are widely used radiographic parameters. However, the exact landmarks for measuring these parameters are not clearly defined. Although their measurement is straightforward when the lateral osseous margin of the acetabular roof coincides with the lateral end of the acetabular sourcil, where these two landmarks disagree, recommendations have differed about which landmark should be used. Using a radiographic parameter with high reliability for predicting residual hip dysplasia helps avoid unnecessary treatment. QUESTIONS/PURPOSES: We aimed to (1) compare two landmarks (the lateral osseous margin of the acetabular roof and the lateral end of the acetabular sourcil) for measuring the acetabular index and center-edge angle with respect to intraobserver and interobserver reliability and the predictability of residual hip dysplasia in patients with developmental dysplasia of the hip (DDH) and (2) evaluate longitudinal change in the acetabular edge's shape after closed reduction with the patient under general anesthesia. METHODS: Between February 1985 and July 2006, we performed closed reduction with the patient under general anesthesia as well as cast immobilization in 116 patients with DDH. To be included in this study, a patient had to have dislocated-type DDH. We excluded patients with a hip dislocation associated with neuromuscular disease, arthrogryposis, or congenital anomalies of other organs or systems (n = 9); hips that underwent osteotomy within 1 year since closed reduction (n = 8); hips that underwent open reduction because of re-dislocation after closed reduction (n = 4); and hips with Type III or IV osteonecrosis according to Bucholz-Ogden's classification (n = 4). Ninety-one patients were eligible. We excluded 19% (17 of 91) of the patients, who were lost to follow-up before they were 8 years old, leaving 81% (74 of 91 patients) with full preoperative and most-recent data. Ninety-seven percent (72 patients) were girls and 3% (two patients) were boys. The mean ± standard deviation age was 14.0 months ± 6.4 months (range 3-40 months) at the time of closed reduction and 12.1 years ± 2.3 years (range 8.0-16.0 years) at the time of the latest follow-up examination, the duration of which averaged 11 years ± 2.2 years (range 6.5-15.4 years). To investigate whether longitudinal change in the acetabular edge's shape differed among hips with DDH, contralateral hips, and control hips, we identified control participants after searching our hospital's database for patients with a diagnosis of congenital idiopathic hemihypertrophy from October 2000 to November 2006 who had AP hip radiographs taken at 3 years old and then at older than 8 years. From 29 patients who met these criteria, we randomly excluded two male patients to match for sex because girls were predominant in the DDH group. We excluded another female patient from the control group because of a hip radiograph that revealed unacceptable rotation. Eventually, 26 patients were assigned to the control group. Control patients consisted of 24 girls (92%) and two boys (8%). The demographic characteristics of control patients was not different from those of 67 patients with unilateral DDH, except for laterality (left-side involvement: 64% [43 of 67] in the DDH group versus 38% [10 of 26] in the control group; odds ratio 1.7 [95% confidence interval, 1.0-2.8]; p = 0.035). The acetabular index and center-edge angle at 3 years old were measured using the lateral osseous margin of the acetabular roof (AIB and CEAB) and the lateral end of the acetabular sourcil (AIS and CEAS). The treatment outcome was classified as satisfactory (Severin Grade I or II) or unsatisfactory (Grade III or IV). The intraclass correlation coefficient (ICC) was used to compare the intraobserver and interobserver reliability of each method. We compared the predictability of residual hip dysplasia of each method at 3 years old as a proxy using the area under the receiver operating characteristic (AUC) curve. To evaluate longitudinal change in the acetabular edge's shape, we compared the proportion of hips showing coincidence of the two landmarks between 3 years old and the latest follow-up examination. To investigate whether the longitudinal change in the acetabular edge's shape differs among hips with DDH, contralateral hips, and control hips, we compared the proportion of coincidence among the three groups at both timepoints. RESULTS: Intraobserver and interobserver reliabilities were higher for the CEAB (ICC 0.96; 95% CI, 0.94-0.98 and ICC 0.88; 95% CI, 0.81-0.92, respectively) than for the CEAS (ICC 0.81; 95% CI, 0.70-0.88 and ICC 0.69; 95% CI, 0.55-0.79, respectively). The AIB (AUC 0.88; 95% CI, 0.80-0.96) and CEAB (AUC 0.841; 95% CI, 0.748-0.933) predicted residual hip dysplasia better than the AIS (AUC 0.776; 95% CI, 0.67-0.88) and CEAS (AUC 0.72; 95% CI, 0.59-0.84) (p = 0.03 and p = 0.01, respectively). The proportion of hips showing coincidence of the two landmarks increased from 3 years old to the latest follow-up examination in hips with DDH (37% [25 of 67] to 81% [54 of 67]; OR = 8.8 [95% CI, 3.1-33.9]; p < 0.001), contralateral hips (42% [28 of 67] to 85% [57 of 67]; OR = 16.5 [95% CI, 4.2-141.9]; p < 0.001), and control hips (38% [10 of 26] to 88% [23 of 26]; OR = 14 [95% CI, 2.1-592.0]; p = 0.001). The proportion of coincidence in hips with DDH was not different from that in the contralateral hips and control hips at both timepoints. CONCLUSIONS: Measuring the acetabular index and center-edge angle at 3 years old using the lateral osseous margin of the acetabular roof has higher reliability for predicting residual hip dysplasia than that using the lateral end of the acetabular sourcil in patients with DDH treated with closed reduction. Measuring the acetabular index and center-edge angle at an early age using the lateral end of the sourcil may lead to overdiagnosis of residual hip dysplasia and unnecessary treatment. LEVEL OF EVIDENCE: Level III, diagnostic study.