Are Generative Pretrained Transformer 4 Responses to Developmental Dysplasia of the Hip Clinical Scenarios Universal? An International Review.

OBJECTIVE: There is increasing interest in applying artificial intelligence chatbots like generative pretrained transformer 4 (GPT-4) in the medical field. This study aimed to explore the universality of GPT-4 responses to simulated clinical scenarios of developmental dysplasia of the hip (DDH) across diverse global settings. METHODS: Seventeen international experts with more than 15 years of experience in pediatric orthopaedics were selected for the evaluation panel. Eight simulated DDH clinical scenarios were created, covering 4 key areas: (1) initial evaluation and diagnosis, (2) initial examination and treatment, (3) nursing care and follow-up, and (4) prognosis and rehabilitation planning. Each scenario was completed independently in a new GPT-4 session. Interrater reliability was assessed using Fleiss kappa, and the quality, relevance, and applicability of GPT-4 responses were analyzed using median scores and interquartile ranges. Following scoring, experts met in ZOOM sessions to generate Regional Consensus Assessment Scores, which were intended to represent a consistent regional assessment of the use of the GPT-4 in pediatric orthopaedic care. RESULTS: GPT-4's responses to the 8 clinical DDH scenarios received performance scores ranging from 44.3% to 98.9% of the 88-point maximum. The Fleiss kappa statistic of 0.113 ( P = 0.001) indicated low agreement among experts in their ratings. When assessing the responses' quality, relevance, and applicability, the median scores were 3, with interquartile ranges of 3 to 4, 3 to 4, and 2 to 3, respectively. Significant differences were noted in the prognosis and rehabilitation domain scores ( P < 0.05 for all). Regional consensus scores were 75 for Africa, 74 for Asia, 73 for India, 80 for Europe, and 65 for North America, with the Kruskal-Wallis test highlighting significant disparities between these regions ( P = 0.034). CONCLUSIONS: This study demonstrates the promise of GPT-4 in pediatric orthopaedic care, particularly in supporting preliminary DDH assessments and guiding treatment strategies for specialist care. However, effective integration of GPT-4 into clinical practice will require adaptation to specific regional health care contexts, highlighting the importance of a nuanced approach to health technology adaptation. LEVEL OF EVIDENCE: Level IV.

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.

Meclozine ameliorates skeletal muscle pathology and increases muscle forces in mdx mice.

We screened pre-approved drugs for the survival of the Hu5/KD3 human myogenic progenitors. We found that meclozine, an anti-histamine drug that has long been used for motion sickness, promoted the proliferation and survival of Hu5/KD3 cells. Meclozine increased expression of MyoD, but reduced expression of myosin heavy chain and suppressed myotube formation. Withdrawal of meclozine, however, resumed the ability of Hu5/KD3 cells to differentiate into myotubes. We examined the effects of meclozine on mdx mouse carrying a nonsense mutation in the dystrophin gene and modeling for Duchenne muscular dystrophy. Intragastric administration of meclozine in mdx mouse increased the body weight, the muscle mass in the lower limbs, the cross-sectional area of the paravertebral muscle, and improved exercise performances. Previous reports show that inhibition of phosphorylation of ERK1/2 improves muscle functions in mouse models for Emery-Dreifuss muscular dystrophy and cancer cachexia, as well as in mdx mice. We and others previously showed that meclozine blocks the phosphorylation of ERK1/2 in cultured cells. We currently showed that meclozine decreased phosphorylation of ERK1/2 in muscles in mdx mice but not in wild-type mice. This was likely to be one of the underlying mechanisms of the effects of meclozine on mdx mice.

Gain-of-Function of FGFR3 Accelerates Bone Repair Following Ischemic Osteonecrosis in Juvenile Mice.

Bone collapse, bone deformity, and a long treatment period are major clinical problems associated with juvenile ischemic osteonecrosis (JIO). Accelerating the process of bone repair in JIO is expected to shorten the treatment duration and better maintain morphology. We previously indicated that both bone formation and resorption were accelerated following distraction osteogenesis-mediated limb lengthening in genetically engineered mutant mice with a gain-of-function mutation in fibroblast growth factor receptor 3 (FGFR3) gene (i.e., Fgfr3 mice). The purpose of this study was to investigate the role of FGFR3 in the bone repair process following surgically induced ischemic osteonecrosis in the mutant mice. Epiphyseal deformity was less in the Fgfr3 mice compared to the wild-type mice at 6 weeks following ischemic osteonecrosis in skeletally immature age. Assessment of the morphology by micro-computed tomography (CT) revealed that the trabecular bone volume was increased in the Fgfr3 mice. Dynamic bone histomorphometry revealed increased rates of bone formation and mineral apposition in the Fgfr3 mice at 4 weeks post-surgery. The number of tartrate-resistant acid phosphatase (TRAP)-positive cells rapidly increased, and the numbers of TdT-mediated dUTP nick-end labeling (TUNEL)-positive cells rapidly decreased in the Fgfr3 mice. Vascular endothelial growth factor (VEGF) expression was increased at the earlier phase post-surgery in the Fgfr3 mice. The activation of FGFR3 signaling shortens the time needed for bone repair after ischemic osteonecrosis by accelerating revascularization, bone resorption, and new bone formation. Our findings are clinically relevant as a new potential strategy for the treatment of JIO.

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.

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.

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.

Impact of fracture characteristics and disease-specific complications on health-related quality of life in osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a connective tissue disease with bone fragility. Several studies have indicated that physical function in adult OI was correlated to the disease severity, but there have been no reports delineating the impact of the fracture characteristics and disease-specific complications on health-related quality of life (HRQoL). The purpose of this study is to clarify the factors impacted on HRQoL in adult OI patients. We conducted a cross-sectional study between July 2016 and March 2018 and sent a questionnaire regarding HRQoL using Short Form-36 (SF-36) to the OI patients at the age of 20 years or older who had a medical history of the investigators' institutions. The 40 patients completely answered the SF-36. Mental component summary and role/social component summary were unremarkable. Physical component summary (PCS) was significantly associated with z-score for height, teeth abnormality, and cardiopulmonary insufficiency (partial regression coefficient, 3.04, - 9.70, and - 11.35; p, < 0.001, 0.047, and 0.025, respectively). PCS was also significantly lower in the patients who had an initial fracture before the age of 2 years than those without occurrence of fractures until 2 years old (25.80 ± 17.15 versus 44.20 ± 16.54; p = 0.002), or those who had lower extremity fractures more than five times as compared with normal populations. Physical function was decreased in OI patients who had fractures before 2 years old, especially in lower extremity. Appropriate medical managements for cardiopulmonary insufficiency are required not only to maintain physical function but also to decrease mortality.

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.

Physical, Mental, and Social Problems of Adolescent and Adult Patients with Achondroplasia.

Patients with achondroplasia (ACH) require various medical interventions throughout the lifetime. Survey of health-related quality of life (HRQoL) in adult ACH patients is essential for the evaluation of treatment outcomes performed during childhood such as growth hormone administration and limb lengthening surgeries, but no study focused on the treatment strategy by analyzing HRQoL of ACH patients. The purpose of this study was to assess whether final height impacted on HRQoL and to evaluate what kinds of medical interventions were positively or negatively associated with HRQoL. We included 184 ACH patients (10-67 years old) who were registered in the patients' associations or who had a medical history of the investigators' institutions, and analyzed HRQoL by using Short Form-36 and patient demographics. Physical component summary (PCS) was significantly lower than the standard values in each age, especially in elderly populations, while mental component summary (MCS) was similar to the standard values. Role/social component summary was deteriorated only in elderly populations. The PCS was improved in the patients who had a height of 140 cm or taller (p < 0.001). The PCS and MCS were strongly associated with the past medical history of spine surgeries (p < 0.001 and p = 0.028, respectively). A treatment strategy would be planned to gain a final height of 140 cm or taller during childhood in combination with growth hormone administration and limb lengthening surgeries. Appropriate medical management for neurological complications of adult ACH patients is required to maintain physical and mental function.

Early radiographic risk factors for rigid relapse in idiopathic clubfoot treated with the Ponseti method.

BACKGROUND: This study aimed at identifying early risk factors for rigid relapse in idiopathic clubfoot using foot radiographs. METHODS: Thirty-four patients with 43 idiopathic clubfeet treated with the Ponseti method were retrospectively reviewed. RESULTS: There were seven rigid relapse recalcitrant to manipulation and requiring extensive soft-tissue release. Three radiograabphic measurements on the maximum dorsiflexion lateral (MD-Lat) radiograph, talocalcaneal (TaloCalc-Lat), tibiocalcaneal (TibCalc-Lat), and calcaneus-first metatarsal (CalcMT1-Lat) angles, showed significant differences between patients with and without rigid relapse. The TaloCalc-Lat and CalcMT1-Lat angles showed significant hazard ratio for rigid relapse by multivariate survival analysis. Clubfeet demonstrating TibCalc-Lat>90° and CalcMT1-Lat<5° have a 24.9-fold odds ratio to develop rigid relapse compared to those demonstrating TibCalc-Lat≤90° or CalcMT1-Lat≥5°. CONCLUSIONS: The TaloCalc-Lat, TibCalc-Lat, and CalcMT1-Lat angles on the MD-Lat radiograph immediately before the tenotomy, probably representing intrinsic tightness of the midfoot and/or hindfoot, are significant risk factors for rigid relapse in patients treated with the Ponseti method.

Is the timing of surgery associated with avascular necrosis after unstable slipped capital femoral epiphysis? A multicenter study.

BACKGROUND: An unstable slipped capital femoral epiphysis (SCFE) is associated with a high rate of avascular necrosis (AVN). The etiology of AVN seems to be multifactorial, although it is not thoroughly known. The aims of our study were to determine the rate of AVN after an unstable SCFE and to investigate the risk factors for AVN, specifically evaluating the notion of an "unsafe window", during which medical interventions would increase the risk for AVN. METHODS: This retrospective multicenter study included 60 patients with an unstable SCFE diagnosed between 1985 and 2014. Timing of surgery was evaluated for three time periods, from acute onset of symptoms to surgery: period I, <24 h; period II, between 24 h and 7 days; and period III, >7 days. Multivariate logistic regression analysis was used to identify risk factors for AVN. RESULTS: Closed reduction and pinning was performed in 43 patients and in situ pinning in 17. Among these cases, 16 patients (27%) developed AVN. The rate of AVN was significantly higher in patients treated by closed reduction and pinning (15/43, 35%) than in those treated by in situ pinning (1/17, 5.9%) (p = 0.022). In patients treated by closed reduction and pinning, the incidence of AVN was 2/11 (18%) in period I, 10/13 (77%) in period II and 3/15 (20%) in period III, showing the significantly higher rate in period II (p = 0.002). The surgery provided in period II was identified as an independent risk factor for the development of AVN. CONCLUSIONS: Our rate of AVN was 27% using two classical treatment methods. Time-to-surgery, between 24 h and 7 days, was independently associated with AVN, supporting the possible existence of an "unsafe window" in patients with unstable SCFE treated by closed reduction and pinning.

Tranilast stimulates endochondral ossification by upregulating SOX9 and RUNX2 promoters.

Endochondral ossification is an essential process for reparative phase of fracture healing, which starts with the differentiation of mesenchymal cells into chondrocytes followed by substitution of bone tissue. It is strictly controlled by the expression of crucial transcriptional factors: SOX9 in the early phase and RUNX2 in the late phase. Screening of FDA-approved compounds revealed that an anti-allergic drug, tranilast, that has been used for more than 30 years in clinical practice, enhanced the SOX9 promoter in chondrogenic cells and the RUNX2 promoter in osteoblastic cells. We observed that tranilast increased mRNA expression of both Sox9 and Runx2 in differentiating ATDC5 chondrogenic progenitor cells. Tranilast upregulated mRNA expression of chondrogenic marker genes (Col2a1, Acan, Col10a1, and Mmp13) in differentiating ATDC5 cells. Moreover, tranilast upregulated mRNA expression of essential signaling molecules involved in endochondral ossification (Pthrp, Ihh, and Axin2). In the later phase of differentiation of ATDC5 cells, tranilast increased synthesis of matrix proteoglycans, induced the alkaline phosphatase activity, and tended to accelerate mineralization. Tranilast is a potential agent that accelerates fracture repair by promoting the regulatory steps of endochondral ossification.

Characterisation of novel RUNX2 mutation with alanine tract expansion from Japanese cleidocranial dysplasia patient.

Cleidocranial dysplasia (CCD; MIM 119600) is an autosomal dominant skeletal dysplasia characterised by hypopalstic and/or aplastic clavicles, midface hypoplasia, absent or delayed closure of cranial sutures, moderately short stature, delayed eruption of permanent dentition and supernumerary teeth. The molecular pathogenesis can be explained in about two-thirds of CCD patients by haploinsufficiency of the RUNX2 gene. In our current study, we identified a novel and rare variant of the RUNX2 gene (c.181_189dupGCGGCGGCT) in a Japanese patient with phenotypic features of CCD. The insertion led an alanine tripeptide expansion (+3Ala) in the polyalanine tract. To date, a RUNX2 variant with alanine decapeptide expansion (+10Ala) is the only example of a causative variant of RUNX2 with polyalanine tract expansion to be reported, whilst RUNX2 (+1Ala) has been isolated from the healthy population. Thus, precise analyses of the RUNX2 (+3Ala) variant were needed to clarify whether the tripeptide expanded RUNX2 is a second disease-causing mutant with alanine tract expansion. We therefore investigated the biochemical properties of the mutant RUNX2 (+3Ala), which contains 20 alanine residues in the polyalanine tract. When transfected in COS7 cells, RUNX2 (+3Ala) formed intracellular ubiquitinated aggregates after 24h, and exerted a dominant negative effect in vitro. At 24h after gene transfection, whereas slight reduction was observed in RUNX2 (+10Ala), all of these mutants significantly activated osteoblast-specific element-2, a cis-acting sequence in the promoter of the RUNX2 target gene osteocalcin. The aggregation growth of RUNX2 (+3Ala) was clearly lower and slower than that of RUNX2 (+10Ala). Furthermore, we investigated several other RUNX2 variants with various alanine tract lengths, and found that the threshold for aggregation may be RUNX2 (+3Ala). We conclude that RUNX2 (+3Ala) is the cause of CCD in our current case, and that the accumulation of intracellular aggregates in vitro is related to the length of the alanine tract.

Low bone mineral density in achondroplasia and hypochondroplasia.

BACKGROUND: Achondroplasia (ACH) and hypochondroplasia (HCH) are the most common form of short-limb skeletal dysplasias caused by activated fibroblast growth factor receptor 3 (FGFR3) signaling. Although decreased bone mass was reported in gain-of-function mutation in Fgfr3 mice, both disorders have never been described as osteoporotic. In the present study, we evaluated bone mineral density (BMD) in ACH and HCH patients. METHODS: We measured spinal BMD (L1-L4) in 18 ACH and four HCH patients with an average age of 19.8 ± 7.5 years (range, 10-33 years). BMD Z-score in each individual was calculated for normalizing age and gender. Correlation between body mass index (BMI) and BMD was analyzed. Moreover, BMD and Z-score were compared between ACH patients and HCH patients. RESULTS: The average BMD of ACH/HCH patients was 0.805 ± 0.141 g/cm(2) (range, 0.554-1.056 g/cm(2) ), resulting in an average Z-score of -1.1 ± 0.8 (range, -2.4 to 0.6) of the standard value. A slightly positive correlation was observed between BMI and BMD (r = 0.45; P = 0.13). There was no significant difference in BMD and Z-score between ACH and HCH patients. CONCLUSION: Spinal BMD was reduced in ACH/HCH patients, and was mildly correlated with individual BMI. We should carefully monitor BMD and examine osteoporosis-related symptoms in adolescent and adult ACH/HCH patients. © 2016 Japan Pediatric Society.

A novel in-frame deletion of the RUNX2 gene causes a classic form of cleidocranial dysplasia.

The runt-related transcription factor 2 (RUNX2) is a physiological regulatory gene implicated in the development of cleidocranial dysplasia (CCD). Molecular analysis of the RUNX2 gene in a 2-year-old boy with a diagnosis of CCD demonstrated a heterozygous in-frame 9-bp deletion (c.593_601delCCTTGACCA, corresponding to the amino-acid deletion p.ΔTLT198_200). Transcription activity of the ΔTLT198_200 mutant decreased in a similar degree to that of the L199F mutant, which was previously reported in the case with classic CCD. Atomic model assessment demonstrated that the ΔTLT198_200 mutation abolished the heterodimerization of the RUNX2 protein with the partner subunit, polyomavirus enhancer-binding protein 2ß (PEBP2ß). Destruction of RUNX2/PEBP2ß heterodimerization activity appears to impair the function of the RUNX2 protein and cause the disease.

Benign prenatal hypophosphatasia: a treatable disease not to be missed.

Prenatal bowing of the long bones is often associated with severe bone dysplasias. We report a child who presented marked bowing of the long bones at birth but showed a relatively benign postnatal course with spontaneous improvement of bowing. The fetal imaging showed normal skeletal mineralization and normal chest and abdominal circumferences despite the limb bowing and shortening. Decreased serum alkaline phosphatase activity and elevated urine phosphoethanolamine was biochemically evident, and compound heterozygous mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene were identified, which confirmed the diagnosis of a benign form of prenatal hypophosphatasia. Benign prenatal hypophosphatasia should be considered in the differential diagnosis of congenital bowing of the long bones.

A case of severe proximal focal femoral deficiency with overlapping phenotypes of Al-Awadi-Raas-Rothschild syndrome and Fuhrmann syndrome.

Proximal focal femoral deficiency (PFFD) is a heterogeneous disorder characterized by various degrees of femoral deficiencies and associated anomalies of the pelvis and lower limbs. The etiology of the disease has not been determined. We report on a 3-year-old boy with severe PFFD, who showed almost completely absent femora and fibulae, malformed pelvis and ectrodactyly of the left foot. These features were partially overlapped with those of Al-Awadi-Raas-Rothschild syndrome or Fuhrmann syndrome, both of which are caused by WNT7A mutations. Molecular analysis of our case, however, demonstrated no disease-causing mutations in the WNT7A gene.

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.

Neglected Sprengel's deformity in an 80-year-old female cadaver: a case report.

BACKGROUND: Sprengel's deformity is a congenital abnormality of the shoulder girdle. Because scapular retraction, such as the Green procedure, is usually performed during childhood to improve esthetics and shoulder function, Sprengel's deformity is rarely found in older patients. CASE PRESENTATION: We presented a unique case of a Japanese female cadaver with Sprengel's deformity at the age of 80 years. Anatomical dissection and radiological imaging revealed musculoskeletal anomalies associated with Sprengel's deformity, including Klippel-Feil syndrome, presence of an omovertebral bone, and absence of the trapezius muscle. In addition, bilateral cervical ribs were in contact with the brachial plexus. These anomalies may lead to numbness, pain, and limited range of motion of the neck and upper girdle with aging. CONCLUSIONS: Because most adult patients with Sprengel's deformity experience neck pain and limited movement of the shoulder, the presented case is a rare case of neglected Sprengel's deformity in an 80-year-old cadaver.