Quality of life in adult patients with developmental dysplasia of the hip who were treated for hip dislocation during childhood.

Developmental dysplasia of the hip (DDH) can lead to premature loss of hip function if not properly treated; however, few studies have focused on the long-term outcomes of DDH. We conducted a survey of health-related quality of life in adult patients with DDH who were treated for hip dislocation during childhood. We sent a questionnaire to 287 adult patients with DDH who were treated for hip dislocation during childhood in our institutions. We examined patient demographics, disease-specific medical history, and health-related quality of life using the short form-36. Physical component summary (PCS), mental component summary (MCS) and role/social component summary (RCS) were compared between the patients and Japanese standard values. Sixty-eight patients were evaluated after exclusion. The overall mean PCS, MCS and RCS scores of the patients were comparable to the standard values. The PCS was maintained until the age of 50, but it was significantly decreased in 10 patients over 50 years old. In addition, PCS was significantly lower in patients who underwent open reduction than in those who were conservatively reduced. The MCS and RCS of the patients did not differ from the standard values in each age and treatment group. Additionally, the PCS, MCS and RCS did not differ according to bilaterality, age at diagnosis, or requirement for additional surgeries. Physical quality of life was maintained until the age of 50 but rapidly declined thereafter in patients with DDH, especially in those who required open reduction during childhood.

Long-term oral meclozine administration improves survival rate and spinal canal stenosis during postnatal growth in a mouse model of achondroplasia in both sexes.

Achondroplasia (ACH) is a skeletal dysplasia characterized by short-limbed short stature caused by the gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Activated FGFR3, which is a negative regulator of bone elongation, impairs the growth of long bones and the spinal arch by inhibiting chondrocyte proliferation and differentiation. Most patients with ACH have spinal canal stenosis in addition to short stature. Meclozine has been found to inhibit FGFR3 via drug repurposing. A 10-d treatment with meclozine promoted long-bone growth in a mouse model of ACH (Fgfr3ach mice). This study aimed to evaluate the effects of long-term meclozine administration on promoting bone growth and the spinal canal in Fgfr3ach mice. Meclozine (2 mg/kg/d) was orally administered to Fgfr3ach mice for 5 d per wk from the age of 7 d to 56 d. Meclozine (2 mg/kg/d) significantly reduced the rate of death or paralysis and improved the length of the body, cranium, and long bones in male and female Fgfr3ach mice. Micro-computed tomography analysis revealed that meclozine ameliorated kyphotic deformities and trabecular parameters, including BMD, bone volume/tissue volume, trabecular thickness, and trabecular number at distal femur of Fgfr3ach mice in both sexes. Histological analyses revealed that the hypertrophic zone in the growth plate was restored in Fgfr3ach mice following meclozine treatment, suggesting upregulation of endochondral ossification. Skeletal preparations demonstrated that meclozine restored the spinal canal diameter in Fgfr3ach mice in addition to improving the length of each bone. The 2 mg/kg/d dose of meclozine reduced the rate of spinal paralysis caused by spinal canal stenosis, maintained the growth plate structure, and recovered the bone quality and growth of axial and appendicular skeletons of Fgfr3ach mice in both sexes. Long-term meclozine administration has the potential to ameliorate spinal paralysis and bone growth in patients with ACH.

Phase 1b study on the repurposing of meclizine hydrochloride for children with achondroplasia.

Achondroplasia (ACH) is a common skeletal dysplasia characterized by a disproportionately short stature. We found that meclizine, which is an over-the-counter drug for motion sickness, inhibited the fibroblast growth factor receptor 3 (FGFR3) gene using a drug repositioning strategy, and meclizine 1 and 2 mg/kg/day promoted bone growth in a mouse model of ACH. A previous phase 1a clinical trial for children with ACH demonstrated that a single dose of meclizine 25 and 50 mg was safe and that the simulated plasma concentration achieved steady state approximately 10 days after the first dose. The current study aimed to evaluate the safety and pharmacokinetics (PK) of meclizine in children with ACH after a 14-day-repeated dose of meclizine. Twelve patients with ACH aged 5-10 years were enrolled. Meclizine 12.5 (cohort 1) and 25 mg/day (cohort 2) were administered after meals for 14 days, and adverse events (AEs) and PK were evaluated. No patient experienced serious AEs in either group. The average (95% confidential interval [CI]) maximum drug concentration (Cmax), peak drug concentration (Tmax), area under the curve (AUC) from 0 to 24 h, and terminal elimination half-life (t1/2) after a 14-day-repeated administration of meclizine (12.5 mg) were 167 (83-250) ng/mL, 3.7 (3.1-4.2) h, 1170 (765-1570) ng·h/mL, and 7.4 (6.7-8.0) h, respectively. The AUC0-6h after the final administration was 1.5 times that after the initial dose. Cmax and AUC were higher in cohort 2 than in cohort 1 in a dose-dependent manner. Regarding the regimen of meclizine 12.5 and 25 mg in patients < 20 kg and ≥ 20 kg, respectively, the average (95% CI) AUC0-24h was 1270 (1100-1440) ng·h/mL. Compartment models demonstrated that the plasma concentration of meclizine achieved at a steady state after the 14th administration. Long-term administration of meclizine 12.5 or 25 mg/day is recommended for phase 2 clinical trials in children with ACH.

Prognostic value of bone resorption pattern in the anterior portion of the femoral head in Legg-Calvé-Perthes disease.

Purpose: To examine whether differences in bone resorption patterns in the anterior portion of the femoral head correlate with the prognosis of Legg-Calvé-Perthes disease. Methods: Seventy-eight patients with unilateral Legg-Calvé-Perthes disease, who were diagnosed after 6.0 years of age, underwent the Salter innominate osteotomy from 1987 to 2013, and were followed up to skeletal maturity. The anterior bone resorption pattern of the femoral head was evaluated from a frog-leg lateral hip radiograph made in the middle of the fragmentation period, and classified into two types, an epiphysis-preserved type (P) and a physis-disrupted type (D). The correlation between the type of bone resorption and the Stulberg outcome was analyzed. Results: The Stulberg outcomes were grade I for 9 patients, grade II for 31, grade III for 35, and grade IV for 3, with a mean follow-up period of 8.3 ± 2.7 years. Fifty-one patients demonstrated the type P hips and 27 did the type D hip. In a subset analysis of patients with the modified lateral pillar group-B hips in the younger group (6.0-8.9 years of age at diagnosis), the percentages of the favorable and unfavorable outcomes significantly differed between the two types (p = 0.013). Anteroposterior enlargement of the affected femoral head was significantly greater in the type D hips than the type P hips (p = 0.014). Conclusion: Unfavorable hip morphology at skeletal maturity can be predicted in patients with the lateral pillar group-B hips by focusing on bone resorption patterns of the anterior portion of the femoral head. Level of evidence: Level III, prognostic study.

Activated FGFR3 suppresses bone regeneration and bone mineralization in an ovariectomized mouse model.

BACKGROUND: Postmenopausal osteoporosis is a widespread health concern due to its prevalence among older adults and an associated high risk of fracture. The downregulation of bone regeneration delays fracture healing. Activated fibroblast growth factor receptor 3 (FGFR3) accelerates bone regeneration at juvenile age and downregulates bone mineralization at all ages. However, the impact of FGFR3 signaling on bone regeneration and bone mineralization post-menopause is still unknown. This study aimed to evaluate the impact of FGFR3 signaling on bone regeneration and bone mineralization during menopause by developing a distraction osteogenesis (DO) mouse model after ovariectomy (OVX) using transgenic mice with activated FGFR3 driven by Col2a1 promoter (Fgfr3 mice). METHODS: The OVX or sham operations were performed in 8-week-old female Fgfr3 and wild-type mice. After 8 weeks of OVX surgery, DO surgery in the lower limb was performed. The 5-day-latency period followed by performing distraction for 9 days. Bone mineral density (BMD) and bone regeneration was assessed by micro-computed tomography (micro-CT) scan and soft X-ray. Bone volume in the distraction area was also evaluated by histological analysis after 7 days at the end of distraction. Osteogenic differentiation and mineralization of bone marrow-derived mesenchymal stem cells (BMSCs) derived from each mouse after 8 weeks of the OVX or sham operations were also evaluated with and without an inhibitor for FGFR3 signaling (meclozine). RESULTS: BMD decreased after OVX in both groups, and it further deteriorated in Fgfr3 mice. Poor callus formation after DO was also observed in both groups with OVX, and the amount of regenerated bone was further decreased in Fgfr3 mice. Similarly, histological analysis revealed that Fgfr3 OVX mice showed lower bone volume. Osteogenic differentiation and mineralization of BMSCs were also deteriorated in Fgfr3 OVX mice. An inhibitor for FGFR3 signaling dramatically reversed the inhibitory effect of OVX and FGFR3 signaling on BMSC mineralization. CONCLUSION: Upregulated FGFR3 decreased newly regenerated bone after DO and BMD in OVX mice. FGFR3 signaling can be a potential therapeutic target in patients with postmenopausal osteoporosis.

Acute osteomyelitis of the patella due to Pseudomonas aeruginosa in an immunocompetent child: A case report.

RATIONALE: Plentiful vascularity and lack of the physis are thought to render the patella less vulnerable to osteomyelitis. Pseudomonas aeruginosa (PA) is an opportunistic pathogen predominantly affecting immunocompromised hosts. Despite the ubiquitous nature of PA, osteomyelitis of the patella caused by PA has been rarely reported in children. PATIENT CONCERNS: A 5-year-old boy who had presented with a prolonged history of the left anterior knee pain following minor trauma was diagnosed with prepatellar bacterial cellulitis and bursitis. Afterward, a focal osteolytic lesion emerged at the ventral surface of the patella despite oral and intravenous antibiotic therapy lasting for weeks. We described clinical presentation as well as medical and surgical management of pediatric patellar osteomyelitis secondary to prepatellar septic bursitis. DIAGNOSES: Pseudomonas aeruginosa-associated osteomyelitis of the patella. Magnetic resonance imaging of the left knee showed a focal destructive change of the ventral half of the cartilaginous patella and a suprapatellar joint effusion. Bacterial culture from the bursa revealed Pseudomonas aeruginosa. INTERVENTIONS: Systemic inflammation, patellar osteochondral destruction, and purulent synovial fluid of the knee were prolonged for 6 weeks despite antibiotics use deemed appropriate and reparative surgical debridement, whereas they were eventually resolved with a 6-week course of intravenous ceftazidime and cessation of continuous intracapsular irrigation. OUTCOMES: He was clinically asymptomatic at the latest follow-up but exhibited a minor leg length discrepancy <2 cm associated with overgrowth of the affected femur. LESSONS: This is a rare case of Pseudomonas osteomyelitis of the patella in a healthy pediatric patient. Uncommon osteochondral sequelae occurred probably because of a protracted arthritis of the affected knee. We would like to emphasize the ineffectiveness of continuous irrigation without antibiotics for Pseudomonas aeruginosa-associated osteomyelitis.

Guided growth for coronal lower limb deformities in skeletal dysplasia.

Coronal angular deformities of the lower limbs are common in young children with skeletal dysplasia . The guided growth technique has been applied to correct deformities in children, but there are few comprehensive reports on the effectiveness of the procedure in skeletal dysplasia. We reviewed 44 limbs of 22 patients with various types of skeletal dysplasias who underwent guided growth surgery. Fifteen varus and 29 valgus limbs were treated with 102 epiphysiodesis. The average age at surgery, at implant removal, and at the latest examination was 10.4 ± 3.6 years, 11.8 ± 3.7 years and 14.1 ± 4.4 years, respectively. The mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (mMPTA), lateral distal tibial angle (mLDTA) and mechanical axis deviation (MAD) were measured from standing anteroposterior radiographs of both lower limbs. The mLDTA, mMPTA and MAD were successfully improved after surgery. Moderate or severe deformities were observed in 100% of the varus and 83% of the valgus limbs preoperatively, whereas only 14% of the varus and 20% of the valgus limbs had residual deformities at the latest examination. Correction of deformities was limited in some older children. Fifteen limbs (34%) required repeated implantations due to recurrence or inverted deformity. The guided growth surgery is effective in correcting coronal angular deformities in children with skeletal dysplasia with a limited risk of complications. The timing of surgery and implant removal is critical in obtaining satisfactory correction and preventing recurrence or inverted deformities.

Meclozine ameliorates bone mineralization and growth plate structure in a mouse model of X­linked hypophosphatemia.

X-linked hypophosphatemic rickets (XLH) is characterized by hypo-mineralization of the bone due to hypophosphatemia. XLH is caused by abnormally high levels of fibroblast growth factor 23, which trigger renal phosphate wasting. Activated fibroblast growth factor receptor 3 (FGFR3) signaling is considered to be involved in XLH pathology. Our previous study revealed that meclozine attenuated FGFR3 signaling and promoted longitudinal bone growth in an achondroplasia mouse model. The present study aimed to examine whether meclozine affected the bone phenotype in a mouse model of XLH [X-linked hypophosphatemic (Hyp) mice]. Meclozine was administered orally to 7-day-old Hyp mice for 10 days, after which the mice were subjected to blood sampling and histological analyses of the first coccygeal vertebra, femur and tibia. Villanueva Goldner staining was used to assess bone mineralization, hematoxylin and eosin staining was used to determine the growth plate structure and tartrate-resistant acid phosphatase staining was used to measure osteoclast activity. The osteoid volume/bone volume of cortical bone was lower in meclozine-treated Hyp mice compared with untreated Hyp mice. Meclozine treatment improved the abnormally thick hypertrophic zone of the growth plate and ameliorated the downregulation of osteoclast surface/bone surface in Hyp mice. However, meclozine had only a marginal effect on mineralization in the trabecular bone and on calcium and phosphate plasma levels. A 10-day-tratment with meclozine partially ameliorated bone mineralization in Hyp mice; hence, meclozine could alleviate XLH symptoms.

Predictive ability of inflammatory markers and laboratory parameters in Legg-Calvé-Perthes disease: A single-center retrospective comparative study.

ABSTRACT: Legg-Calvé-Perthes disease (LCPD) presents with chronic nature of inflammation, characterized by prolonged synovitis. So far, no single blood marker has been identified to guide clinicians in estimating the severity and prognosis. Blood neutrophil to lymphocyte ratio (NLR) or systemic immune inflammation index (SII) is a simple indicator of subclinical inflammation. This study aims to examine the predictive ability of NLR, SII, and common laboratory parameters for estimating the severity of LCPD. The pre-operative laboratory findings at the time of osteotomy and implant removal in patients with unilateral LCPD who had been treated with the Salter innominate osteotomy and followed up until skeletal maturity as well as those of age-matched control patients with idiopathic noninflammatory conditions were analyzed. The datasets of 26 or 38 LCPD patients at the time of osteotomy or implant removal, respectively, and those of 20 control patients were available for analysis. At the time of osteotomy, compared to the control group, a significantly higher mean NLR or SII and a significantly lower mean alkaline phosphatase value were observed in the LCPD group. The alkaline phosphatase levels of patients with the modified lateral pillar (LP) group-A hips were significantly lower than those with the non-LP-A hips, whereas no significant differences were observed in any of the parameters between patients with favorable LP-A or -B hips and those with unfavorable LP-B|C border or -C hips. In agreement with the conventional opinion, it may be difficult to predict a meaningful prognosis of LCPD with the use of inflammatory markers or common laboratory parameters obtained in the initial stage of the disease.

Bypass of Epiphyseal Fragmentation Following Early Salter Innominate Osteotomy and Its Clinical Relevance in Legg-Calvé-Perthes Disease.

BACKGROUND: It has been demonstrated that early femoral varus osteotomy (FVO) produces a greater probability of skipping or interruption of epiphyseal fragmentation, thereby shortening the length of fragmentation stage for hips in the active stage of Legg-Calvé-Perthes disease. This "bypassing phenomenon" is thought to effect less disease severity or outcome, whereas it remains to be elucidated whether this phenomenon is specific to early FVO. We sought to investigate the presence and characteristics of the "bypassing phenomenon" following pelvic osteotomy performed in the avascular necrosis or early fragmentation stage as well as its correlation with disease severity and radiographic outcomes. METHODS: A retrospective review of data was conducted for 79 patients with unilateral Legg-Calvé-Perthes disease who had been diagnosed from 1987 to 2015, undergone the Salter innominate osteotomy (SIO) during the stage of avascular necrosis or in the early part of the fragmentation stage between 6.0 and 12.0 years of age, and followed up until skeletal maturity. Epiphyseal fragmentation was classified into 4 patterns according to a previous study. We compared lateral pillar groups and Stulberg grades between patients with and without bypass of the fragmentation stage. RESULTS: The mean age at surgery and follow-up period was 8.1 and 7.9 years, respectively. Sixty hips were in the Waldenström stage I and 19 hips in stage IIa at the surgery. In hips receiving SIO during stage I, the mean duration of the fragmentation stage was 276 days. The fragmentation pattern was typical for 40 hips, abortive for 17 hips, and atypical with horizontal fissure for 3 hips. Patients whose fragmentation was aborted experienced significantly less severe lateral pillar involvement and more favorable Stulberg outcomes at skeletal maturity. CONCLUSIONS: Incomplete bypass of epiphyseal fragmentation was observed in 28% of patients following early SIO performed in the avascular necrosis stage. In contrast to FVO, no patient bypassed fragmentation completely. Patients with incomplete bypass had a significantly higher proportion of less severe hips and a significantly greater probability of being associated with favorable radiographic outcomes compared with those without bypass. LEVEL OF EVIDENCE: Level IV-therapeutic study.

Disease-specific complications and multidisciplinary interventions in achondroplasia.

Achondroplasia (ACH) is the most common skeletal dysplasia and characterized by a disproportionate short stature, macrocephaly with frontal bossing, exaggerated lumbar lordosis, and trident hands. It is induced by activated mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. In addition to short stature, patients with ACH have a high prevalence of medical complications, including upper airway obstructive apnea, increased mortality, foramen magnum stenosis, hydrocephalus, developmental delay, recurrent ear infections, genu varum, obesity, and spinal canal stenosis, throughout their whole life. Several investigational drugs that modulate abnormal FGFR3 signaling have recently emerged, vosoritide being the most developed. This review presents the different disease-specific complications of ACH occurring in neonates, infants, childhood, adolescent, and adults and reports the current multidisciplinary interventions for these various complications. Moreover, we propose treatment strategies for children with ACH from the perspective of quality of life in adulthood.

A cross-sectional nationwide survey of osteosclerotic skeletal dysplasias in Japan.

BACKGROUND: The osteosclerotic skeletal dysplasias (OSSDs) are a heterogeneous group of disorders characterized by systemic bone sclerosis. Little is known about OSSDs because of their rarity. We conducted a cross-sectional nationwide survey of OSSDs and examined the incidence, epidemiology, and therapeutic interventions on these disorders. METHODS: This study consisted of a two-step survey. The number of patients with OSSDs who had visited medical institutions between April 2017 and March 2018 was reported from a total of 341 facilities (1364 departments from pediatrics, orthopaedic surgery, neurosurgery, and otolaryngology in each facility) by the first questionnaire. In the secondary survey, their clinical features were assessed by collecting demographic data, diagnostic details, current status, family histories, therapeutic interventions, histories of bone fracture and osteomyelitis, severity assessed by the modified Rankin Scale (mRS) and recent lifestyle conditions of the patient by the EQ-5D. RESULTS: In the first survey, 51 facilities (56 departments) reported one or more OSSDs patients, including 50 patients with osteopetrosis and 57 patients of other OSSDs. Among 87 patients eligible for inclusion in the analysis in the secondary survey, we investigated detailed information on the 42 patients with osteopetrosis. The number of initial visits of osteopetrosis patients during the surveillance period was five per year, indicating that the estimated incidence of osteopetrosis seemed to be 0.6 per 100,000 live births. Eighty-six bone fractures were reported in 22 patients (52%), and interventions of pseudarthrosis were conducted in five patients. Nine patients (23%) showed significant disabilities with the mRS of grade 3 or higher. Neurological complications and severe anemia were the factors that deteriorate patients' quality of life. CONCLUSIONS: This is the first study to examine the detailed epidemiology of OSSDs in Japan. We demonstrated that the incidence of OSSDs is extremely rare. Bone fragility and delayed fracture healing seem to be important orthopaedic problems for patients with osteopetrosis.

Health-related Quality of Life in Adult Patients with Multiple Epiphyseal Dysplasia and Spondyloepiphyseal Dysplasia.

OBJECTIVES: Multiple epiphyseal dysplasia (MED) and spondyloepiphyseal dysplasia (SED) are skeletal dysplasias associated with premature osteoarthritis and short stature. Patients with SED often have spinal and ocular problems. Few reports have focused on the health-related quality of life (HRQoL) of patients with skeletal dysplasias associated with premature osteoarthritis. The purpose of this study was to evaluate the HRQoL of adult patients with MED and SED. METHODS: Questionnaires covering demographics, medical history (cataract, retinal detachment, and osteoarthritis), surgical history (osteotomy and arthroplasty), and the Short Form-36 (SF-36) health survey were sent to all patients with MED and SED with medical records at the investigators' institutions. Among the 27 patients who completed the questionnaire, patients aged 20 years or older were included in this cohort. RESULTS: The subjects were 18 affected individuals. The physical component summary score (PCS) was significantly lower in the MED and SED groups than in the normal population and tended to deteriorate with age. Conversely, there was a positive correlation between the mental component summary score and age. The role/social component summary score was not correlated with age. MED patients with osteoarthritis had a low PCS. PCS was particularly low in two SED patients with a medical history of cataract, whereas there was no association with a history of retinal detachment or osteoarthritis. CONCLUSIONS: The physical domain of HRQoL in MED and SED patients significantly deteriorated at a young age. Appropriate medical management of these skeletal dysplasias is required not only for orthopedic functions but also for ocular problems.

Asfotase alfa has a limited effect in improving the bowed limbs in perinatal benign hypophosphatasia: A case report.

Hypophosphatasia (HPP) is a rare skeletal dysplasia characterized by impaired bone mineralization, caused by loss-of-function mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Enzyme replacement therapy (ERT) by administration of asfotase alfa was reported to improve the survival rate, bone mineralization, and short stature in the severe form of HPP. However, the effect of asfotase alfa in improving the skeletal phenotypes for the mild form of HPP has not been elucidated. We report a case with perinatal benign HPP who had compound heterozygous mutations of p.F327L and p.R30X in the TNSALP gene. No hypomineralization was seen in the radiographs from the neonatal period, but bowing of the femurs and ulnares bilaterally was persistent. ERT was administered during the age of 7.8 to 10.8 yr, although there was an interruption in the treatment for one year. The bowed femurs and ulnares were not improved by the treatment with asfotase alfa at the age of 10.8 yr. Bone mineral density of the lumbar spine was between -0.5 and -1.0 of the z-score, and the patient's height was about -2.0 SD during the treatment. Asfotase alfa might have a limited effect in improving the bowed limbs in perinatal benign hypophosphatasia.

Legg-Calvé-Perthes disease in a patient with Bardet-Biedl syndrome: A case report of a novel MKKS/BBS6 mutation.

This article reports a girl with Bardet-Biedl syndrome (BBS) having a novel causative mutation who developed Legg-Calvé-Perthes disease (LCPD). There exists a possibility that the prognosis of LCPD had been adversely affected by the concomitant BBS.

A retrospective comparative study of corrective osteotomy for tibial deformities with the multiaxial correction fixator and the circular fixator.

PURPOSE: A multiaxial correction (MAC) fixator is a monolateral type of fixator that can correct multi-planer deformities. The purpose of this study is to compare the clinical outcome of correction for tibial deformities with the MAC fixator and the circular external fixators. METHODS: We retrospectively reviewed consecutive patients reconstructed with the MAC fixator (MAC group) or circular external fixators (Ring group) due to the congenital diseases or residual conditions after treatment of trauma, infection, tumor, or limb lengthening between 2003 and 2016. RESULTS: The 30 patients who had angular tibial deformity were included. In patients with tibia vara or lateral bowing, the average pre-operative mechanical medial proximal tibial angle (mMPTA) of the MAC group and the Ring group was significantly increased to 86.9 ± 3.5° in the MAC group and 88.0 ± 3.6° in the Ring group postoperatively. Medial bowing was also successfully corrected in both groups. Regarding the sagittal alignment, post-operative anatomical posterior proximal tibial angle (aPPTA) of the MAC group was deteriorated after coronal correction. The operative time was significantly shorter in the MAC group than the Ring group (p < 0.05). CONCLUSION: The MAC fixator successfully corrected coronal deformities of the tibia with shorter operative time, but it has a risk of occurrence of the procurvatum deformity compared with circular external fixators. Paying attention to the sagittal alignment, the MAC fixator can be one of the treatment options for correction of the coronal tibial deformities.

Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia.

Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We identified that meclizine hydrochloride inhibited FGFR3 signaling in various chondrocytic cells and promoted longitudinal bone growth in mouse model of ACH. Meclizine has safely been used for more than 50 years, but it lacks the safety data for repeated administration and pharmacokinetics (PK) when administered to children. We performed a phase Ia study to evaluate the PK and safety of meclizine administered orally to ACH children. Twelve ACH children aged from 5 to younger than 11 years were recruited, and the first 6 subjects received once a day of meclizine in the fasted condition, subsequent 6 subjects received twice a day of meclizine in the fed condition. Meclizine was well tolerated in ACH children with no serious adverse events. The mean Cmax, Tmax, AUC0-24h, t1/2 during 24 hours in the fasted condition were 130 ng/mL, 1.7 hours, 761 ng·h/mL, and 8.5 hours respectively. The simulation of repeated administration of meclizine for 14 days demonstrated that plasma concentration apparently reached steady state around 10 days after the first dose both at once a day and twice a day administration. The AUC0-10h of the fasting and fed condition were 504 ng·h/mL and 813 ng·h/mL, respectively, indicating exposure of meclizine increased with the diet. Although higher drug exposure was confirmed in ACH children compared to adults, a single administration of meclizine seemed to be well tolerated.

Correction: Association between Gait Deviation Index and Physical Function in Children with Bilateral Spastic Cerebral Palsy: A Cross-Sectional Study. J. Clin. Med. 2020, 9, 28.

The authors wish to make the following corrections to this paper [...].

Severe achondroplasia due to two de novo variants in the transmembrane domain of FGFR3 on the same allele: A case report.

BACKGROUND: Achondroplasia (ACH), the most common form of short-limbed skeletal dysplasia, is caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. More than 97% of patients result from a heterozygous p.G380R mutation in the FGFR3 gene. We present here a child who had two de novo variants in the FGFR3 on the same allele, a common p.G380R mutation and a novel p.S378N variant. METHODS: A 3-year-old Japanese girl born from non-consanguineous healthy parents showed more severe clinical and radiological phenotypes than classic ACH, including severe short-limbed short stature with marked ossification defects in the metaphysis and epiphysis, hydrocephalus and cervicomedullary compression due to foramen magnum stenosis, prolonged pulmonary hypoplasia, and significant delay in the gross motor development. Genomic DNA was extracted from the proband and whole-exome sequencing was performed. The variants were subsequently confirmed by Sanger sequencing. RESULTS: Mutation analysis demonstrated that the proband had p.S378N (c.1133G>A) and p.G380R (c.1138G>A) variants in the FGFR3 gene. Both variants were not detected in her parents and therefore considered de novo. An allele-specific PCR was developed in order to determine whether these mutations were on the same allele (cis) or on different alleles (trans). The c.1138G>A mutation was found in the PCR product generated with the primer for the mutant 1133A, but it was not detected in the product with the wild-type 1133G, confirming that p.S378N and p.G380R variants were located on the same allele (cis). CONCLUSION: This is the second case who had two FGFR3 variants in the transmembrane domain on the same allele. The p.S378N variant may provide an additive effect on the activating receptor with the p.G380R mutation and alter the protein function, which could be responsible for the severe phenotype of the present case.

Lower limb pain following allogeneic hematopoietic stem cell transplantation in Japanese children.

BACKGROUND: Patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) can experience musculoskeletal pains in their lower limbs in the early and late post-transplantation period. This study investigated demographics and clinical characteristics of the lower limb pain (LLP) among Japanese survivors of pediatric allo-HSCT. METHODS: A total of 143 consecutive Japanese patients who had undergone allo-HSCT less than 18 years of age in a single institute between 2005 and 2015 were reviewed. Patients referred for in-house orthopedic evaluation of their sustained LLPs that impaired ambulation were defined as LLP group. Illness/transplantation-related parameters were compared between LLP group and non-LLP group. RESULTS: Ninety children with a mean age of 8.5 years at transplantation were enrolled. Their median follow-up period following transplantation was 6.3 years (range, 2.1-12.5). There were four patients in LLP group, whose etiologies were AVN of the femoral head and insufficiency fracture (ISF) of the tibia or the medial cuneiform bone. Cumulative dose of steroids that administered from six months before transplantation to six months after discharge from hospitalization for transplantation was significantly higher in LLP group than non-LLP group. Additionally, the two groups differed significantly in terms of hospitalization period after transplantation. LLP caused by AVN of the femoral head manifested between six months and two years, whereas that caused by ISF within the first six months after transplantation. CONCLUSIONS: The incidence of sustained LLP that impairs ambulation following contemporary allo-HSCT is not common in Japanese pediatric survivors. The risk of developing musculoskeletal LLP may increase with a higher steroid dosage in the peri-transplant period. LLP caused by AVN of the femoral head is likely to manifest later than that caused by ISF.