Publications by authors named "Tae-Joon Cho"

221 Publications

Gene therapy for Fibrodysplasia Ossificans Progressiva (FOP): feasibility and obstacles.

Hum Gene Ther 2022 May 2. Epub 2022 May 2.

Amsterdam UMC location VUMC, Human Genetics, Amsterdam, Netherlands;

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system's role in FOP activation and the as-yet unknown primary causative cell, are crucial issues which must be taken into account in the therapy design. While gene therapy offers a potential therapeutic solution, more knowledge about FOP is needed to enable its optimal and safe application.
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http://dx.doi.org/10.1089/hum.2022.023DOI Listing
May 2022

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

J Pediatr Orthop 2022 Mar;42(3):e295-e300

Division of Paediatric Orthopaedics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Jongno-gu, Seoul, Republic of Korea.

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.
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http://dx.doi.org/10.1097/BPO.0000000000002034DOI Listing
March 2022

Comparison of the kinematics, repeatability, and reproducibility of five different multi-segment foot models.

J Foot Ankle Res 2022 Jan 6;15(1). Epub 2022 Jan 6.

Department of Orthopedic Surgery, Seoul National University Hospital, 101 Daehak-no, Jongno-gu, Seoul, South Korea.

Background: Multi-segment foot models (MFMs) for assessing three-dimensional segmental foot motions are calculated via various analytical methods. Although validation studies have already been conducted, we cannot compare their results because the experimental environments in previous studies were different from each other. This study aims to compare the kinematics, repeatability, and reproducibility of five MFMs in the same experimental conditions.

Methods: Eleven healthy males with a mean age of 26.5 years participated in this study. We created a merged 29-marker set including five MFMs: Oxford (OFM), modified Rizzoli (mRFM), DuPont (DFM), Milwaukee (MiFM), and modified Shriners Hospital for Children Greenville (mSHCG). Two operators applied the merged model to participants twice, and then we analysed two relative angles of three segments: shank-hindfoot (HF) and hindfoot-forefoot (FF). Coefficients of multiple correlation (CMC) and mean standard errors were used to assess repeatability and reproducibility, and statistical parametric mapping (SPM) of the t-value was employed to compare kinematics.

Results: HF varus/valgus of the MiFM and mSHCG models, which rotated the segment according to radiographic or goniometric measurements during the reference frame construction, were significantly more repeatable and reproducible, compared to other models. They showed significantly more dorsiflexed HF and plantarflexed FF due to their static offset angles. DFM and mSHCG showed a greater range of motion (ROM), and some models had significantly different FF points of peak angle.

Conclusions: Under the same conditions, rotating the segment according to the appropriate offset angle obtained from radiographic or goniometric measurement increased reliability, but all MFMs had clinically acceptable reliability compared to previous studies. Moreover, in some models, especially HF varus/valgus, there were differences in ROM and points of peak angle even with no statistical difference in SPM curves. Therefore, based on the results of this study, clinicians and researchers involved in the evaluation of foot and ankle dysfunction need an understanding of the specific features of each MFM to make accurate decisions.
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http://dx.doi.org/10.1186/s13047-021-00508-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8734222PMC
January 2022

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

J Pediatr Orthop B 2022 Jan;31(1):e90-e94

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Republic of Korea.

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.
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http://dx.doi.org/10.1097/BPB.0000000000000889DOI Listing
January 2022

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

Orphanet J Rare Dis 2021 10 9;16(1):418. Epub 2021 Oct 9.

Division of Clinical Genetics, Department of Paediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, 101 Daehak-ro Jongno-gu, Seoul, 03080, Republic of Korea.

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.
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http://dx.doi.org/10.1186/s13023-021-02042-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501601PMC
October 2021

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

J Child Orthop 2021 Jun;15(3):255-260

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Korea.

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.
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http://dx.doi.org/10.1302/1863-2548.15.200187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223093PMC
June 2021

Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome.

Blood 2021 11;138(21):2117-2128

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.

Shwachman-Diamond syndrome (SDS; OMIM #260400) is caused by variants in SBDS (Shwachman-Bodian-Diamond syndrome gene), which encodes a protein that plays an important role in ribosome assembly. Recent reports suggest that recessive variants in EFL1 are also responsible for SDS. However, the precise genetic mechanism that leads to EFL1-induced SDS remains incompletely understood. Here we present 3 unrelated Korean SDS patients who carry biallelic pathogenic variants in EFL1 with biased allele frequencies, resulting from a bone marrow-specific somatic uniparental disomy in chromosome 15. The recombination events generated cells that were homozygous for the relatively milder variant, allowing for the evasion of catastrophic physiologic consequences. However, the milder EFL1 variant was still solely able to impair 80S ribosome assembly and induce SDS features in cell line and animal models. The loss of EFL1 resulted in a pronounced inhibition of terminal oligopyrimidine element-containing ribosomal protein transcript 80S assembly. Therefore, we propose a more accurate pathogenesis mechanism of EFL1 dysfunction that eventually leads to aberrant translational control and ribosomopathy.
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http://dx.doi.org/10.1182/blood.2021010913DOI Listing
November 2021

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

J Pediatr Orthop B 2022 Mar;31(2):e114-e121

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital.

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.
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http://dx.doi.org/10.1097/BPB.0000000000000887DOI Listing
March 2022

Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome.

Hum Genome Var 2021 May 7;8(1):17. Epub 2021 May 7.

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital and Seoul National University College of Medicine, Seoul, Republic of Korea.

An 11-year-old Korean boy presented with short stature, hip dysplasia, radial head dislocation, carpal coalition, genu valgum, and fixed patellar dislocation and was clinically diagnosed with Steel syndrome. Scrutinizing the trio whole-exome sequencing data revealed novel compound heterozygous mutations of COL27A1 (c.[4229_4233dup]; [3718_5436del], p.[Gly1412Argfs*157];[Gly1240_Lys1812del]) in the proband, which were inherited from heterozygous parents. The maternal mutation was a large deletion encompassing exons 38-60, which was challenging to detect.
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http://dx.doi.org/10.1038/s41439-021-00149-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105406PMC
May 2021

MRI risk factors for development of avascular necrosis after closed reduction of developmental dysplasia of the hip: Predictive value of contrast-enhanced MRI.

PLoS One 2021 18;16(3):e0248701. Epub 2021 Mar 18.

Department of Orthopedic Surgery, Seoul National University College of Medicine, Seoul, Korea.

Purpose: The purpose of this study was to identify imaging risk factors on contrast-enhanced hip MRI after closed reduction of developmental dysplasia of the hip (DDH) that could predict future development of avascular necrosis (AVN) of the femoral head.

Materials And Methods: Fifty-eight infants (F: M = 53: 5, aged 3-18 months) who underwent immediate postoperative contrast-enhanced hip MRI after closed reduction of DDH were included in this study. Quality of reduction (concentric vs eccentric reduction with or without obstacles), abduction angle of the hip, presence of ossific nucleus, and pattern of contrast enhancement of the femoral head were retrospectively evaluated on MRI. Interobserver agreement of contrast enhancement pattern on MRI were evaluated by two radiologists. Development of AVN was determined through radiographic findings at 1 year after reduction.

Results: AVN of the femoral head developed in 13 (22%) of 58 patients. Excessive abduction of the hip joint (OR 4.65, [95% CI 1.20, 18.06] and global decreased enhancement of the femoral head (OR 71.66, [95% CI 10.54, 487.31]) exhibited statistically significant differences between the AVN and non-AVN groups (P < 0.05). Eccentric reduction (P = 0.320) did not show statistically significant difference between two groups and invisible ossific nucleus (P = 0.05) showed borderline significance. Multi-variable logistic regression indicated that global decreased enhancement of the femoral head was a significant risk factor of AVN (OR 27.92, 95% CI [4.17, 350.18]) (P = 0.0031). Interobserver agreement of contrast enhancement pattern analysis and diagnosis of AVN were good (0.66, 95% CI [0.52, 0.80]).

Conclusion: Contrast-enhanced hip MRI provides accurate anatomical assessment of the hip after closed reduction of DDH. Global decreased enhancement of the femoral head could be used as a good predictor for future development of AVN after closed reduction of DDH.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248701PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971487PMC
October 2021

Calcifying characteristics of peripheral vascular smooth muscle cells of chronic kidney disease patients with critical limb ischemia.

Vasc Med 2021 04 16;26(2):139-146. Epub 2021 Feb 16.

Department of Orthopedic Surgery, Seoul National University Hospital, Jongno-gu, Seoul, Korea.

The role of vascular smooth muscle cells (VSMCs) in vascular calcification, which is related to chronic kidney disease (CKD), has been studied in greater detail in the major arteries relative to the peripheral arteries. We compared the calcifying characteristics of peripheral VSMCs relative to non-pathologic major VSMCs in patients with severe peripheral artery disease (PAD). We isolated peripheral VSMCs from the posterior tibial artery of 10 patients with CKD who underwent below-knee amputation for critical limb ischemia (CLI). Using normal human aortic VSMCs as a control group, we cultured the cells in normal and high phosphate media for 10 days, and subsequently tested by immunofluorescence staining. We compared the calcification levels between the two groups using various assays, tests for cell viability, and scanning electron microscopy. As a result, calcification of pathologic peripheral VSMCs increased significantly with time ( = 0.028) and was significantly higher than that in human aortic VSMCs in calcium assays ( = 0.043). Dead cells in the pathologic VSMC group were more distinct in high phosphate media than in human aortic VSMCs. In conclusion, VSMCs from the peripheral artery of patients with severe CKD and CLI who underwent amputation surgery showed marked calcifying characteristics compared to normal human aortic VSMCs.
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http://dx.doi.org/10.1177/1358863X20984525DOI Listing
April 2021

Predictors of cervical myelopathy and hydrocephalus in young children with achondroplasia.

Orphanet J Rare Dis 2021 02 12;16(1):81. Epub 2021 Feb 12.

Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, 03080, Seoul, Republic of Korea.

Background: Cervical myelopathy and hydrocephalus occasionally occur in young children with achondroplasia. However, these conditions are not evaluated in a timely manner in many cases. The current study presents significant predictors for cervical myelopathy and hydrocephalus in young children with achondroplasia.

Methods: A retrospective analysis of 65 patients with achondroplasia who visited Seoul National University Children's Hospital since 2012 was performed. The patients were divided into groups according to the presence of cervical myelopathy and hydrocephalus, and differences in foramen magnum parameters and ventricular parameters by magnetic resonance imaging between groups were analyzed. Predictors for cervical myelopathy and hydrocephalus were analyzed, and the cut-off points for significant ones were calculated.

Results: The group with cervical myelopathy showed foramen magnum parameters that indicated significantly lower cord thickness than in the group without cervical myelopathy, and the group with hydrocephalus showed significantly higher ventricular parameters and 'Posterior indentation' grade than the group without hydrocephalus. 'Cord constriction ratio' (OR 5199.90, p = 0.001) for cervical myelopathy and 'Frontal horn width' (OR 1.14, p = 0.001) and 'Posterior indentation' grade (grade 1: OR 9.25, p = 0.06; grade 2: OR 18.50, p = 0.01) for hydrocephalus were significant predictors. The cut-off points for cervical myelopathy were 'Cord constriction ratio' of 0.25 and 'FM AP' of 8 mm (AUC 0.821 and 0.862, respectively) and 'Frontal horn width' of 50 mm and 'Posterior indentation' grade of 0 (AUC 0.788 and 0.758, respectively) for hydrocephalus.

Conclusion: 'Cord constriction ratio' for cervical myelopathy and 'Frontal horn width' and 'Posterior indentation' grade for hydrocephalus were significant predictors and may be used as useful parameters for management. 'Posterior indentation' grade may also be used to determine the treatment method for hydrocephalus.
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http://dx.doi.org/10.1186/s13023-021-01725-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881633PMC
February 2021

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

Ann Lab Med 2021 Jul;41(4):401-408

Division of Clinical Genetics, Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.

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, on chromosome 7q32.2, and 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.
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http://dx.doi.org/10.3343/alm.2021.41.4.401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884196PMC
July 2021

Pseudo-Protrusio Acetabular Deformity in Osteogenesis Imperfecta Patients.

J Pediatr Orthop 2021 Mar;41(3):e285-e290

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul.

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.
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http://dx.doi.org/10.1097/BPO.0000000000001739DOI Listing
March 2021

Best practice guidelines in managing the craniofacial aspects of skeletal dysplasia.

Orphanet J Rare Dis 2021 01 14;16(1):31. Epub 2021 Jan 14.

Department of Orthopedics and Sports Medicine, Seattle Children's Hospital, Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA, USA.

Background: Recognition and appropriate management of the craniofacial manifestations of patients with skeletal dysplasia are challenging, due to the rarity of these conditions, and dearth of literature to support evidence-based clinical decision making.

Methods: Using the Delphi method, an international, multi-disciplinary group of individuals, with significant experience in the care of patients with skeletal dysplasia, convened to develop multi-disciplinary, best practice guidelines in the management of craniofacial aspects of these patients.

Results: After a comprehensive literature review, 23 initial statements were generated and critically discussed, with subsequent development of a list of 22 best practice guidelines after a second round voting.

Conclusions: The guidelines are presented and discussed to provide context and assistance for clinicians in their decision making in this important and challenging component of care for patients with skeletal dysplasia, in order standardize care and improve outcomes.
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http://dx.doi.org/10.1186/s13023-021-01678-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809733PMC
January 2021

Management of Osteogenesis Imperfecta: A Multidisciplinary Comprehensive Approach.

Clin Orthop Surg 2020 Dec 18;12(4):417-429. Epub 2020 Nov 18.

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.

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.
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http://dx.doi.org/10.4055/cios20060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683189PMC
December 2020

Parallel Multiparameter Study of PEI-Functionalized Gold Nanoparticle Synthesis for Biomedical Applications: Part 2. Elucidating the Role of Surface Chemistry and Polymer Structure in Performance.

Langmuir 2020 11 10;36(46):14058-14069. Epub 2020 Nov 10.

Materials Measurement Science Division, National Institute of Standards and Technology, Gaithersburg, Maryland 20899, United States.

Elucidating the polyethyleneimine (PEI) chemistry to predictively and reproducibly synthesize gold nanoparticle (AuNP)-PEI conjugates with desired properties has been elusive despite evaluation in numerous studies and reported enhanced properties. The lack of reproducible methods to control the core size and stability has led to contradictory results for performance and safety; thus, advancement of the conjugate platform for commercial use has likely been hindered. Recently, we reported a robust, reproducible method for synthesizing PEI-functionalized AuNPs (Au-PEIs), providing an opportunity to investigate structure-function relationships and to further investigate synthesis parameters affecting performance, where only materials stable in biological media are candidates for use. The properties of Au-PEIs prepared by the optimized reduction of HAuCl using four different structural variants of PEI changed significantly with the PEI molar mass and backbone form (branched or linear). In the present study using our previously reported synthesis procedure, comprehensive analysis of properties such as size distribution, surface plasmon resonance (SPR), morphological state, surface functionality, and the shelf life has been systematically evaluated to elucidate the role of surface chemistry and reactive groups involved in conjugation, as a function of conjugate size and morphology. Being important for commercial adoption, the chemistry was related to the observed colloidal stability of the product in relevant media, including exposure to physiological variables such as salt, pH, proteins, and thermal changes. Overall, this work advances progress toward smart design of engineered nanoscale drug delivery systems and devices by providing unreported details of contributions affecting formation, stability, and fate.
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http://dx.doi.org/10.1021/acs.langmuir.0c02630DOI Listing
November 2020

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

J Bone Joint Surg Am 2020 Oct;102(20):1792-1798

Divisions of Pediatric Orthopaedics (C.H.S., T.-J.C., I.H.C., and W.J.Y.), and Pediatrics (E.H.C.), Seoul National University Children's Hospital, Seoul, Republic of Korea.

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.
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http://dx.doi.org/10.2106/JBJS.20.00219DOI Listing
October 2020

Clinical and Genetic Characteristics of 23 Korean Patients with Haploinsufficiency of the Short-stature Homeobox-containing Gene.

Exp Clin Endocrinol Diabetes 2021 Aug 15;129(8):611-620. Epub 2020 Sep 15.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul.

Background: The short-stature homeobox-containing gene () is one of the major growth genes in humans. The clinical spectrum of haploinsufficiency ranges from Léri-Weill dyschondrosteosis to idiopathic short stature. Herein, we describe the clinical and genetic characteristics of 23 Korean patients with deficiency disorders.

Methods: Medical records of 23 patients (19 females and 4 males) from 15 unrelated families who were genetically confirmed to have deficiency were retrospectively reviewed. gene deletions or mutations were determined by sequence analyses using multiplex ligation-dependent probe amplification, chromosomal microarray, and/or Sanger sequencing methods.

Results: In the 15 families, 9 probands were cases. All 23 patients showed mesomelia. Madelung deformity and tibia vara were observed in 13 (56.5%) and 3 (13.1%) patients, respectively. Genetically, 11 (73.3%) of the 15 families showed deletions of various sizes, and the other 4 families harboured sequence variants. Four patients had undergone orthopaedic surgeries (3 for tibia vara and 1 for Madelung deformity). Among 7 patients who had received growth hormone treatment for ≥1 year, 5 showed good responses, with a median first-year change-in-height standard deviation score of +0.6. There were no significant differences in the clinical characteristics of the deletion and point mutation groups.

Conclusions: A high index of suspicion and the genetic confirmation of deficiency are helpful for the timely management of the condition and are needed to provide genetic counselling to the family members of the patients.
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http://dx.doi.org/10.1055/a-1247-4863DOI Listing
August 2021

Novel RPL13 Variants and Variable Clinical Expressivity in a Human Ribosomopathy With Spondyloepimetaphyseal Dysplasia.

J Bone Miner Res 2021 02 13;36(2):283-297. Epub 2020 Oct 13.

Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Spondyloepimetaphyseal dysplasias (SEMDs) are a heterogeneous group of disorders with variable growth failure and skeletal impairments affecting the spine and long bone epiphyses and metaphyses. Here we report on four unrelated families with SEMD in which we identified two monoallelic missense variants and one monoallelic splice site variant in RPL13, encoding the ribosomal protein eL13. In two out of four families, we observed autosomal dominant inheritance with incomplete penetrance and variable clinical expressivity; the phenotypes of the mutation-positive subjects ranged from normal height with or without hip dysplasia to severe SEMD with severe short stature and marked skeletal dysplasia. In vitro studies on patient-derived dermal fibroblasts harboring RPL13 missense mutations demonstrated normal eL13 expression, with proper subcellular localization but reduced colocalization with eL28 (p < 0.001). Cellular functional defects in fibroblasts from mutation-positive subjects indicated a significant increase in the ratio of 60S subunits to 80S ribosomes (p = 0.007) and attenuated global translation (p = 0.017). In line with the human phenotype, our rpl13 mutant zebrafish model, generated by CRISPR-Cas9 editing, showed cartilage deformities at embryonic and juvenile stages. These findings extend the genetic spectrum of RPL13 mutations causing this novel human ribosomopathy with variable skeletal features. Our study underscores for the first time incomplete penetrance and broad phenotypic variability in SEMD-RPL13 type and confirms impaired ribosomal function. Furthermore, the newly generated rpl13 mutant zebrafish model corroborates the role of eL13 in skeletogenesis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..
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http://dx.doi.org/10.1002/jbmr.4177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988564PMC
February 2021

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

Orphanet J Rare Dis 2020 08 10;15(1):205. Epub 2020 Aug 10.

Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Jongnogu Daehakro 101, Seoul, 03080, Republic of Korea.

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.
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http://dx.doi.org/10.1186/s13023-020-01480-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418424PMC
August 2020

Best practice guidelines for management of spinal disorders in skeletal dysplasia.

Orphanet J Rare Dis 2020 06 24;15(1):161. Epub 2020 Jun 24.

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, University of Melbourne, Parkville, Victoria, Australia.

Background: Disorders of the spine present a common and difficult management concern in patients with skeletal dysplasia. Due to the rarity of these conditions however, the literature, largely consisting of small, single institution case series, is sparse in regard to well-designed studies to support clinical decision making in these situations.

Methods: Using the Delphi method, an international, multi-disciplinary group of individuals, with significant experience in the care of patients with skeletal dysplasia, convened to develop multi-disciplinary, "best practice" guidelines in the care of spinal disorders in patients with skeletal dysplasia.

Results: Starting with 33 statements, the group a developed a list of 31 "best practice" guidelines.

Conclusions: The guidelines are presented and discussed to provide context for clinicians in their decision making in this often-challenging realm of care.
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http://dx.doi.org/10.1186/s13023-020-01415-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313125PMC
June 2020

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.

Clin Orthop Relat Res 2020 09;478(9):2120-2131

C. H. Shin, E. Yang, C. Lim, W. J. Yoo, I. H. Choi, T-J. Cho, Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Republic of Korea.

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.
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http://dx.doi.org/10.1097/CORR.0000000000001289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431232PMC
September 2020

Functional Outcomes of Hip Arthroscopy for Pediatric and Adolescent Hip Disorders.

Clin Orthop Surg 2020 Mar 13;12(1):94-99. Epub 2020 Feb 13.

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Korea.

Background: There is a paucity of literature on the use of hip arthroscopy for pathologic conditions in skeletally immature patients. Thus, the indications and safety of the procedure are still unclear. The purpose of this study was to investigate the safety and functional outcomes of hip arthroscopy for pediatric and adolescent hip disorders. We further attempted to characterize arthroscopic findings in each disease.

Methods: We retrospectively reviewed 32 children and adolescents with hip disorders who underwent 34 hip arthroscopic procedures at a tertiary care children's hospital from January 2010 to December 2016. We evaluated functional limitations and improvement after operation by using the modified Harris hip score (HHS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), subjective pain assessment with a visual analog scale (VAS), and range of hip motion as well as the complications of hip arthroscopy. Arthroscopic findings in each disease were recorded.

Results: Hip arthroscopy was performed for Legg-Calvé-Perthes disease (n = 6), developmental dysplasia of the hip (n = 6), slipped capital femoral epiphysis (n = 5), idiopathic femoroacetabular impingement (n = 6), sequelae of septic arthritis of the hip (n = 3), hereditary multiple exostosis (n = 2), synovial giant cell tumor (n = 3), idiopathic chondrolysis (n = 2), and posttraumatic osteonecrosis of the femoral head (n = 1). Overall, there was a significant improvement in the modified HHS, WOMAC, VAS, and range of hip motion. Symptom improvement was not observed for more than 18 months in four patients who had dysplastic acetabulum with a labral tear (n = 2) or a recurrent femoral head bump (n = 2). There were no complications except transient perineal numbness in five patients.

Conclusions: Our short-term follow-up evaluation shows that hip arthroscopy for pediatric and adolescent hip disorder is a less invasive and safe procedure. It appears to be effective in improving functional impairment caused by femoroacetabular impingement between the deformed femoral head and acetabulum or intra-articular focal problems in pediatric and adolescent hip disorders.
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http://dx.doi.org/10.4055/cios.2020.12.1.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031430PMC
March 2020

Diagnosis and Management of Hip Dislocation in Patients with Kabuki Syndrome.

Clin Orthop Surg 2019 Dec 12;11(4):474-481. Epub 2019 Nov 12.

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Korea.

Background: Kabuki syndrome is a rare genetic disorder characterized by distinct dysmorphic facial features, growth deficiency, intellectual disabilities, unusual dermatoglyphic patterns, and skeletal abnormalities. The incidence of hip dislocation in Kabuki syndrome ranges from 18% to 62%. We reviewed the outcomes of management of hip dislocations in patients with Kabuki syndrome with special attention to the diagnostic processes for hip dislocation and Kabuki syndrome.

Methods: Among 30 patients with mutation-confirmed Kabuki syndrome, we selected six patients who had hip dislocations and reviewed their medical records and plain radiographs. The modes of presentation and diagnostic processes for both hip dislocations and Kabuki syndrome were investigated. The management and treatment outcomes of hip dislocations in patients with Kabuki syndrome were evaluated.

Results: The average age of patients at the time of diagnosis of hip dislocation was 7.7 months (range, 1 week to 22 months). None of the patients were diagnosed as having Kabuki syndrome at that time. Two patients were treated with a Pavlik harness; one, with closed reduction; two, with open reduction and later pelvic and/or femoral osteotomies; and one, with open reduction combined with pelvic osteotomy. The patients were followed up for 5.8 years on average (range, 2.0 to 10.5 years). The radiologic outcome was graded as Severin IA or IB for three patients who were older than 6 years at the latest follow-up (mean age, 9.9 years; range, 7.8 to 12.4 years). In the remaining three patients younger than 6 years (mean age, 3.8 years; range, 2.7 to 5.3 years), the lateral center edge angle was more than 15°. The clinical diagnosis of Kabuki syndrome was made during follow-up after hip dislocation treatment and confirmed by mutational analysis at a mean age of 4.7 years. The mean interval between the diagnosis of hip dislocation and Kabuki syndrome was 4.0 years.

Conclusions: The management of hip dislocation by conservative or surgical method showed successful results. Awareness of Kabuki syndrome could lead to an early diagnosis of this rare disease in patients with hip dislocation and allow for early detection of other underlying conditions and multidisciplinary management.
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http://dx.doi.org/10.4055/cios.2019.11.4.474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867925PMC
December 2019

Overgrowth of the lower limb after treatment of developmental dysplasia of the hip: incidence and risk factors in 101 children with a mean follow-up of 15 years.

Acta Orthop 2020 04 12;91(2):197-202. Epub 2019 Nov 12.

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul.

Background and purpose - There are few studies on overgrowth of the affected limb after treatment of developmental dysplasia of the hip (DDH). We investigated the incidence of overgrowth and its risk factors in DDH patients.Patients and methods - 101 patients were included in this study. Overgrowth was defined by 2 criteria: when the height of the femoral head of the affected side was higher than that of the contralateral side by more than 10 mm, or by more than 15 mm. The potential risk factors of distinct overgrowth were retrospectively examined using multivariable analysis.Results - When overgrowth was defined as femoral head height difference (FHHD) > 10 mm, its incidence was 44%, and only femoral osteotomy was identified as a significant risk factor with a relative risk (RR) of 1.6 (95% confidence interval [CI] 1.0-2.5). When overgrowth was defined as FHHD > 15 mm, its incidence was 23%, and femoral osteotomy was identified as the only significant risk factor with an RR of 2.3 (CI 1.2-4.5). Overgrowth developed more frequently in patients who underwent femoral osteotomy at the age of 2 to 4 years (87%) than in the others (46%) (p = 0.04).Interpretation - Overgrowth of the affected limb is common in DDH patients. Patients who underwent femoral osteotomy, especially at the age of 2 to 4 years, may require careful follow-up because of the substantial risk for overgrowth.
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http://dx.doi.org/10.1080/17453674.2019.1688485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144334PMC
April 2020

Clinical and Molecular Characteristics of GNAS Inactivation Disorders Observed in 18 Korean Patients.

Exp Clin Endocrinol Diabetes 2021 Feb 23;129(2):118-125. Epub 2019 Sep 23.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea.

Background: The gene on chromosome 20q13.3 is a complex, imprinted locus regulated in a tissue-specific manner. inactivation disorders are a heterogeneous group of rare disorders caused by mutations and methylation defects. These are divided into pseudohypoparathyroidism (PHP) types 1A and 1B, pseudo-pseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH), depending on the presence or absence of hormone resistance, Albright's hereditary osteodystrophy (AHO), and ectopic ossification.

Methods: This study analyzed the clinical characteristics and molecular genetic backgrounds of 18 Korean patients from 16 families with a genetically confirmed defect. Auxological parameters, AHO phenotypes, types of hormonal resistance, family history, and molecular genetic disturbances were reviewed retrospectively.

Results: Nine (90%) patients with PHP1A showed resistance to parathyroid hormone (PTH) and all patients showed elevated thyroid-stimulating hormone (TSH) levels at diagnosis. Eight (80%) patients were managed with levothyroxine supplementation. Three of six patients with PHP1B had elevated TSH levels, but none of whom needed levothyroxine medication. AHO features were absent in PHP1B. Patients with PPHP and POH did not show any hormone resistance, and both of them were born as small for gestational age. Among the 11 families with PHP1A, PPHP, and POH, eight different (three novel) mutations in the gene were identified. Among the six patients with PHP1B, two were sporadic cases and four showed isolated loss of methylation at A/B:TSS-DMR.

Conclusions: Clinical and molecular characteristics of Korean patients with inactivation disorders were described in this study. Also, we reaffirmed heterogeneity of PHP, contributing to further accumulation and expansion of current knowledge of this complex disease.
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http://dx.doi.org/10.1055/a-1001-3575DOI Listing
February 2021

Physeal and Subphyseal Distraction Osteogenesis in Atrophic-type Congenital Pseudarthrosis of the Tibia: Efficacy and Safety.

J Pediatr Orthop 2019 Sep;39(8):422-428

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul.

Purpose: To examine the efficacy, safety, and clinical outcomes of distraction osteogenesis through the physis (PDO) or through subphyseal osteotomy (SPDO) in patients with atrophic-type congenital pseudarthrosis of tibia with proximal tibial dysplasia.

Methods: To validate the efficacy and safety of PDO and SPDO, radiographic and clinical parameters were compared between 5 patients who underwent proximal tibial metaphyseal or metadiaphyseal lengthening as a control (group 1) and 7 patients who underwent PDO or SPDO (group 2). Postoperative complication was also compared between the groups.

Results: A significant difference in terms of healing index (group 1, 83.3±24.7 d/cm; group 2, 35.0±11.1 d/cm; P=0.001) and percentage increase (11.0%±3.7% vs. 23.1%±10.5%, P=0.034) was observed between the 2 groups. According to the Paley classification, group 1 included 1 "problems" case and 3 "obstacles" cases, whereas group 2 included 2 "problems" cases and 1 "obstacles" case. According to the Lascombes classification, group 1 included 2 grade IIIb cases and 3 grade IV cases, whereas group 2 included 6 grade I cases and 1 grade IIa case. Severe complications were significantly higher in group 1 compared with the group 2 (P=0.007).

Conclusions: This study demonstrated that PDO or SPDO can be effectively and safely performed for tibial lengthening in atrophic-type congenital pseudarthrosis of tibia patients with proximal tibial dysplasia.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1097/BPO.0000000000000979DOI Listing
September 2019

In Vivo Response of Growth Plate to Biodegradable Mg-Ca-Zn Alloys Depending on the Surface Modification.

Int J Mol Sci 2019 Aug 1;20(15). Epub 2019 Aug 1.

Department of Orthopaedic Surgery, Chung-Ang University Medical Center, 102 Heukseok-ro, Dongjak-gu, Seoul 06973, Korea.

Because Mg-Ca-Zn alloys are biodegradable and obviate secondary implant removal, they are especially beneficial for pediatric patients. We examined the degradation performance of Mg-Ca-Zn alloys depending on the surface modification and investigated the in vivo effects on the growth plate in a skeletally immature rabbit model. Either plasma electrolyte oxidation (PEO)-coated ( = 18) or non-coated ( = 18) Mg-Ca-Zn alloy was inserted at the distal femoral physis. We measured the degradation performance and femoral segment lengths using micro-CT. In addition, we analyzed the histomorphometric and histopathologic characteristics of the growth plate. Although there were no acute, chronic inflammatory reactions in either group, they differed significantly in the tissue reactions to their degradation performance and physeal responses. Compared to non-coated alloys, PEO-coated alloys degraded significantly slowly with diminished hydrogen gas formation. Depending on the degradation rate, large bone bridge formation and premature physeal arrest occurred primarily in the non-coated group, whereas only a small-sized bone bridge formed in the PEO-coated group. This difference ultimately led to significant shortening of the femoral segment in the non-coated group. This study suggests that optimal degradation could be achieved with PEO-coated Mg-Ca-Zn alloys, making them promising and safe biodegradable materials with no growth plate damage.
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http://dx.doi.org/10.3390/ijms20153761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695941PMC
August 2019
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