Real-world evidence in achondroplasia: considerations for a standardized data set.

BACKGROUND: Collection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability, accessibility, interoperability, and reuse of digital assets, and that captures long-term, high-quality data, would improve understanding of the natural history of achondroplasia, quality of life, and related outcomes. METHODS: The Europe, Middle East, and Africa (EMEA) Achondroplasia Steering Committee comprises a multidisciplinary team of 17 clinical experts and 3 advocacy organization representatives. The committee undertook an exercise to identify essential data elements for a standardized prospective registry to study the natural history of achondroplasia and related outcomes. RESULTS: A range of RWE on achondroplasia is being collected at EMEA centres. Whereas commonalities exist, the data elements, methods used to collect and store them, and frequency of collection vary. The topics considered most important for collection were auxological measures, sleep studies, quality of life, and neurological manifestations. Data considered essential for a prospective registry were grouped into six categories: demographics; diagnosis and patient measurements; medical issues; investigations and surgical events; medications; and outcomes possibly associated with achondroplasia treatments. CONCLUSIONS: Long-term, high-quality data are needed for this rare, multifaceted condition. Establishing registries that collect predefined data elements across age spans will provide contemporaneous prospective and longitudinal information and will be useful to improve clinical decision-making and management. It should be feasible to collect a minimum dataset with the flexibility to include country-specific criteria and pool data across countries to examine clinical outcomes associated with achondroplasia and different therapeutic approaches.

Anaesthesia-Relevant Disease Manifestations and Perianaesthetic Complications in Patients with Mucolipidosis-A Retrospective Analysis of 44 Anaesthetic Cases in 12 Patients.

Mucolipidosis (ML) type II, intermediate, and III are lysosomal storage disorders with progressive multiorgan manifestations predisposing patients to a high risk of perioperative morbidity. The aims of the study were to systematically assess disease manifestations relevant to anaesthesia as well as anaesthesia-related complications. This retrospective study includes ML patients who underwent anaesthesia in two centres between 2008 and 2022. We reviewed patients' demographics, medical history, disease manifestations, as well as procedure- and outcome-related data. A total of 12 patients (7 MLII, 2 ML intermediate, 3 MLIII) underwent 44 anaesthesia procedures (per patient: median 3, range 1-11). The median age was 3.3 years (range 0.1-19.1). At least one complication occurred in 27.3% of the anaesthesia procedures. The vast majority of complications (94%) occurred in children with MLII and ML intermediate. A predicted difficult airway was found in 100% and 80% of the MLII and ML intermediate patients, respectively. Accordingly, most complications (59%) occurred during the induction of anaesthesia. Altogether, respiratory complications were the most frequent (18%), followed by difficult airway management (14%). The risk for anaesthesia-related complications is alarmingly high in patients with ML, particularly in those with MLII and ML intermediate. Multidisciplinary risk-benefit analysis and thoughtful anaesthesia planning are crucial in these patients.

Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III.

PURPOSE: Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. METHODS: We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgko and Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. RESULTS: The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. CONCLUSION: The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.

Disease Manifestations in Mucopolysaccharidoses and Their Impact on Anaesthesia-Related Complications-A Retrospective Analysis of 99 Patients.

Patients with mucopolysaccharidoses (MPS) frequently require anaesthesia for diagnostic or surgical interventions and thereby experience high morbidity. This study aimed to develop a multivariable prediction model for anaesthesia-related complications in MPS. This two-centred study was performed by retrospective chart review of children and adults with MPS undergoing anaesthesia from 2002 until 2018. We retrieved the patients' demographics, medical history, clinical manifestations, and indication by each anaesthesia. Multivariable mixed-effects logistic regression was calculated for a clinical model based on preoperative predictors preselected by lasso regression and another model based on disease subtypes only. Of the 484 anaesthesia cases in 99 patients, 22.7% experienced at least one adverse event. The clinical model resulted in a better forecast performance than the subtype-model (AICc 460.4 vs. 467.7). The most relevant predictors were hepatosplenomegaly (OR 3.10, CI 1.54-6.26), immobility (OR 3.80, CI 0.98-14.73), and planned major surgery (OR 6.64, CI 2.25-19.55), while disease-specific therapies, i.e., haematopoietic stem cell transplantation (OR 0.45, CI 0.20-1.03), produced a protective effect. Anaesthetic complications can best be predicted by surrogates for advanced disease stages and protective therapeutic factors. Further model validation in different cohorts is needed.

Hip pathologies in mucopolysaccharidosis type III.

BACKGROUND: Mucopolysaccharidosis type III (MPS III) comprises a group of rare lysosomal storage diseases. Although musculoskeletal symptoms are less pronounced than in other MPS subtypes, pathologies of hip and spine have been reported in MPS III patients. The purpose of this study was to describe hip pathologies and influencing parameters in MPS III patients. METHODS: A retrospective chart review was performed for 101 MPS III patients. Thirty-two patients met the inclusion criteria of enzymatically or genetically confirmed diagnosis and anteroposterior radiograph of the hips. Modified Ficat classification, Wiberg's center-edge angle, and Reimer's migration percentage were measured. RESULTS: The mean age at data assessment was 11.0 years (SD 5.7). Osteonecrosis of the femoral head was observed in 17/32 patients. No statistically significant association was found between these changes and age, sex, or MPS III subtype. Patients with a severe phenotype showed significantly higher rates of osteonecrosis (14/17) than patients with an intermediate phenotype. Hip dysplasia was present in 9/32 patients and was significantly associated with osteonecrosis of the femoral head (p = 0.04). CONCLUSIONS: The present study demonstrates a high rate of hip pathologies in MPS III patients. Hip dysplasia and severe phenotype were significantly correlated with osteonecrosis of the femoral head. Therefore, radiographs of the hips are highly recommended in baseline and follow-up assessments of MPS III patients. TRIAL REGISTRATION: Retrospectively registered.

Is hematopoietic stem cell transplantation a therapeutic option for mucolipidosis type II?

BACKGROUND: Mucolipidosis type II (MLII) is an ultra-rare lysosomal storage disorder caused by defective lysosomal enzyme trafficking. Clinical hallmarks are craniofacial dysmorphia, cardiorespiratory dysfunction, hepatosplenomegaly, skeletal deformities and neurocognitive retardation. Death usually occurs in the first decade of life and no cure exists. Hematopoietic stem cell transplantation (HSCT) has been performed in few MLII patients, but comprehensive follow-up data are extremely scarce. METHODS: MLII diagnosis was confirmed in a female three-month-old patient with the mutations c.2213C > A and c.2220_2221dup in the GNPTAB gene. At nine months of age, the patient received HSCT from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor. RESULTS: HSCT resulted in a sustained reduction of lysosomal storage und bone metabolism markers. At six years of age, the patient showed normal cardiac function, partial respiratory insufficiency and moderate hepatomegaly, whereas skeletal manifestations had progressed. However, the patient could walk and maintained an overall good quality of life. Neurocognitive testing revealed a developmental quotient of 36%. The patient died at 6.6 years of age following a human metapneumovirus (hMPV) pneumonia. CONCLUSIONS: The exact benefit remains unclear as current literature vastly lacks comparable data on MLII natural history patients. In order to evaluate experimental therapies, in-depth prospective studies and registries of untreated MLII patients are indispensable.

Does eight-plate epiphysiodesis of the proximal tibia in treating angular deformity create intra-articular deformity?

AIMS: Eight-plates are used to correct varus-valgus deformity (VVD) or limb-length discrepancy (LLD) in children and adolescents. It was reported that these implants might create a bony deformity within the knee joint by change of the roof angle (RA) after epiphysiodesis of the proximal tibia following a radiological assessment limited to anteroposterior (AP) radiographs. The aim of this study was to analyze the RA, complemented with lateral knee radiographs, with focus on the tibial slope (TS) and the degree of deformity correction. METHODS: A retrospective, single-centre study was conducted. The treatment group (n = 64 knees in 44 patients) was subclassified according to the implant location in two groups: 1) medial hemiepiphysiodesis; and 2) lateral hemiepiphysiodesis. A third control group consisted of 25 untreated knees. The limb axes and RA were measured on long standing AP leg radiographs. Lateral radiographs of 40 knees were available for TS analysis. The mean age of the patients was 10.6 years (4 to 15) in the treatment group and 8.4 years (4 to 14) in the control group. Implants were removed after a mean 1.2 years (0.5 to 3). RESULTS: No significant differences in RA (p = 0.174) and TS (p = 0.787) were observed. The limb axes were significantly corrected in patients with VVD (p < 0.001). The change in tibial slope (∆TS) did not correlate (r = -0.026; p = 0.885) to the plate's position on the physis when assessed by lateral radiographs. CONCLUSION: We were not able to confirm the reported change in the bony morphology of the proximal tibia on AP radiographs in our patient population. In addition, no significant change in TS was detected on the lateral radiographs. A significant correction of the VVD in the lower limb axes was evident. Position of the implant did not correlate with TS change. Therefore, eight-plate epiphysiodesis is a safe and effective procedure for correcting VVD in children without disturbing the knee joint morphology. Cite this article: Bone Joint J 2020;102-B(10):1412-1418.

Hip Morphology in Mucolipidosis Type II.

Mucolipidosis type II (MLII) is a rare lysosomal storage disorder caused by defective trafficking of lysosomal enzymes. Severe skeletal manifestations are a hallmark of the disease including hip dysplasia. This study aims to describe hip morphology and the natural course of hip pathologies in MLII by systematic evaluation of plain radiographs, ultrasounds and magnetic resonance imaging (MRI). An international two-centered study was performed by retrospective chart review. All MLII patients with at least one pelvic radiograph were included. A total of 16 patients were followed over a mean of 3.5 years (range 0.2-10.7 years). Typical age-dependent radiographic signs identified were femoral cloaking (7/16), rickets/hyperparathyroidism-like changes (6/16) and constrictions of the supra-acetabular part of the os ilium (16/16) and the femoral neck (7/16). The course of acetabular and migration indexes (AI, MI) significantly increased in female patients. However, in the overall group, there was no relevant progression of acetabular dysplasia with a mean AI of 23.0 (range 5°-41°) and 23.7° (range 5°-40°) at the first and last assessments, respectively. Better knowledge on hip morphology in MLII could lead to earlier diagnosis, improved clinical management and enables assessment of effects of upcoming therapies on the skeletal system.

Airway management and perioperative adverse events in children with mucopolysaccharidoses and mucolipidoses: A retrospective cohort study.

BACKGROUND: Children suffering from mucopolysaccharidoses (subtypes I, II, III, IV, VI, and VII) or mucolipidoses often require anesthesia, but are at high risk for perioperative adverse events. However, the impact of the disease subtype and the standard of care for airway management are still unclear. AIMS: This study aimed to assess independent risk factors for perioperative adverse events in individuals with mucopolysaccharidoses/mucolipidoses and to analyze the interaction with the primary airway technique implemented. METHODS: This retrospective study included individuals with mucopolysaccharidoses/mucolipidoses who underwent anesthesia at two high-volume centers from 2002 to 2016. The data were analyzed in a multivariate hierarchical model, accounting for repeated anesthesia procedures within the same patient and for multiple events within a single anesthesia. RESULTS: Of 141 identified inpatients, 67 (63 mucopolysaccharidoses and 4 mucolipidoses) underwent 269 anesthesia procedures (study cases) for 353 surgical or diagnostic interventions. At least one perioperative adverse event occurred in 25.6% of the cases. The risk for perioperative adverse events was higher in mucopolysaccharidoses type I (OR 8.0 [1.5-42.7]; P = .014) or type II (OR 8.8 [1.3-58.6]; P = .025) than in type III. Fiberoptic intubation through a supraglottic airway was associated with the lowest risk for perioperative adverse events and lowest conversion rate. Direct laryngoscopy was associated with a significantly higher risk for airway management problems than indirect techniques (estimated event rates 47.8% vs 10.1%, OR 24.05 [5.20-111.24]; P < .001). The risk for respiratory adverse events was significantly higher for supraglottic airway (22.6%; OR 31.53 [2.79-355.88]; P = .001) and direct laryngoscopy (14.8%; OR 14.70 [1.32-163.44]; P = .029) than for fiberoptic intubation through a supraglottic airway (2.1%). CONCLUSIONS: The disease subtype and primary airway technique were the most important independent risk factors for perioperative adverse events. Our findings indicate that in MPS/ML children with predicted difficult airway indirect techniques should be favored for the first tracheal intubation attempt.

Outcome of the modified Dunn procedure in severe chronic or acute on chronic slipped capital femoral epiphysis.

BACKGROUND: In recent years, the modified Dunn osteotomy has gained popularity to treat slipped capital femoral epiphysis (SCFE) with various complication rates. Most studies included patients with different severities. This study aimed to determine (1) the radiological and clinical outcome, (2) the health-related quality of life, and (3) the incidence of avascular necrosis of the femoral head (AVN) in patients with severe chronic or acute on chronic SCFE treated by the modified Dunn procedure. METHODS: Out of 150 patients with SCFE treated at our institution between 2001 and 2014, 15 patients (mean age 12.9 years (range 11.8-15)) were treated by the modified Dunn procedure. Eight SCFE were chronic and 7 acute on chronic. All slips were severe with a mean Southwick slip angle (SSA) of 67° (range 60-80). Radiographic and clinical outcomes were measured. Mean time of follow-up was 3.8 years (range 1-10). RESULTS: Anatomical reduction was achieved in all cases. Good radiological results according to the Stulberg Classification (grade 1 + 2) and the Sphericity Deviation Score (< 30) were found in 9 out of 13 patients at the last follow-up. Clinical and functional outcome analysis revealed good results in 8 out of 10 patients (Harris Hip Score > 80). The quality of life measured by the Nottingham Health Profile (NHP) was described good in 10 out of 10 patients. Four out of 15 patients developed an AVN. CONCLUSIONS: The modified Dunn procedure has a great potential to restore proximal femur geometry in severe chronic or acute on chronic SCFE. It should be considered only if there is no other possibility to restore proximal femur geometry, as is the case in severe slips, due to the risk of AVN.

Growth charts for patients with Sanfilippo syndrome (Mucopolysaccharidosis type III).

BACKGROUND: Mucopolysaccharidosis (MPS) type III (Sanfilippo syndrome) comprises a group of rare, lysosomal storage diseases caused by the deficiency of one of four enzymes involved in the degradation of heparan sulfate. The clinical hallmark of the disease is severe neurological deterioration leading to dementia and death in the second decade of life. Adult MPS patients are generally of short stature. To date there is no clear description of the physical development of MPS III patients. The aim of this study was to document growth reference data for MPS III patients. We collected growth data of 182 German MPS III patients and were able to develop growth charts for this cohort. Growth curves for height, weight, head circumference, and body mass index were calculated and compared to German reference charts. RESULTS: Birth height, weight and head circumference were within the physiological ranges. Both genders were significantly taller than healthy children at 2 years of age, while only male patients were taller at the age of four. Growth velocity decelerated after the ages of 4.5 and 5 years for female and male patients, respectively. Both genders were significantly shorter than the reference group at the age of 17.5 years. Head circumference was larger compared to healthy matched controls within the first 2 years of life and remained enlarged until physical maturity. CONCLUSION: MPS III is a not yet treatable severe neuro-degenerative disease, developing new therapeutic strategies might change the course of the disease significantly. The present charts contribute to the understanding of the natural history of MPS III. Specific growth charts represent an important tool for families and physicians as the expected height at physical maturity can be estimated and therapeutic effects can be monitored.

Nerve transfer from the median to musculocutaneous nerve to induce active elbow flexion in selected cases of arthrogryposis multiplex congenita.

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is a rare disease which affects mainly upper and lower extremities. Affected patients are not able to eat unassisted due to elbow contracture and nonexistent active elbow flexion. In traumatic brachial plexus palsies, a nerve transfer from either median or ulnar nerve to the musculocutaneous nerve has proved to induce active elbow flexion, and we report our results of such a procedure in a nontraumatic condition, that is, arthrogryposis. METHODS: We selected four patients with AMC type 1 (6 extremities, 2 males, 2 females) diagnosed with AMC presenting to our institution shortly after birth from 2014 to 2016 to perform a nerve transfer from the median nerve to the musculocutaneous nerve in order to induce active elbow flexion. The indication of application of this surgical procedure was based on active finger and wrist flexion, limited contracture of elbow joints and evidence of flexing muscle fibers detected by sonography. RESULTS: Five nerve transfers were conducted with a follow up of 2-5 years. Two extremities reached active elbow flexion motorgrade M4, two M3, and one M1 at latest follow up. One patient developed a postoperative suture granuloma. One nerve transfer was abandoned due to neuroanatomic variation. One extremity was treated with botulinum toxin in triceps muscle in addition to the nerve transfer. CONCLUSIONS: In this series of selected cases of AMC Type 1 we were able to induce active elbow flexion using a nerve transfer technique developed for traumatic and obstetric brachial plexus palsies. In four extremities the procedure achieved independent hand-to-mouth active elbow flexion. Level of evidence four.

Treatment of thoracolumbar kyphosis in patients with mucopolysaccharidosis type I: results of an international consensus procedure.

BACKGROUND: In all patients with mucopolysaccharidosis type I (MPS I), skeletal disease (dysostosis multiplex) is a prominent, debilitating, condition related complication that may impact strongly on activities of daily living. Unfortunately, it is not alleviated by treatment with hematopoietic cell transplantation (HCT) or enzyme replacement therapy (ERT). Although early kyphosis is one of the key features of dysostosis multiplex, there is no international consensus on the optimal management. Therefore, an international consensus procedure was organized with the aim to develop the first clinical practice guideline for the management of thoracolumbar kyphosis in MPS I patients. METHODS: A literature review was conducted to identify all available information about kyphosis and related surgery in MPS I patients. Subsequently, a modified Delphi procedure was used to develop consensus statements. The expert panel included 10 spinal orthopedic surgeons, 6 pediatricians and 3 physiotherapists, all experienced in MPS I. The procedure consisted of 2 written rounds, a face-to-face meeting and a final written round. The first 2 rounds contained case histories, general questions and draft statements. During the face-to-face meeting consensus statements were developed. In the final round, the panel had the opportunity to anonymously express their opinion about the proposed statements. RESULTS: Eighteen case series and case reports were retrieved from literature reporting on different surgical approaches and timing of thoracolumbar kyphosis surgery in MPS I. During the face-to-face meeting 16 statements were discussed and revised. Consensus was reached on all statements. CONCLUSION: This international consensus procedure resulted in the first clinical practice guideline for the management of thoracolumbar kyphosis in MPS I patients, focusing on the goals and timing of surgery, as well as the optimal surgical approach, the utility of bracing and required additional assessments (e.g. radiographs). Most importantly, it was concluded that the decision for surgery depends not only on the kyphotic angle, but also on additional factors such as the progression of the deformity and its flexibility, the presence of symptoms, growth potential and comorbidities. The eventual goal of treatment is the maintenance or improvement of quality of life. Further international collaborative research related to long-term outcome of kyphosis surgery in MPS I is essential as prognostic information is lacking.

The Lysosomal Protein Arylsulfatase B Is a Key Enzyme Involved in Skeletal Turnover.

Skeletal pathologies are frequently observed in lysosomal storage disorders, yet the relevance of specific lysosomal enzymes in bone remodeling cell types is poorly defined. Two lysosomal enzymes, ie, cathepsin K (Ctsk) and Acp5 (also known as tartrate-resistant acid phosphatase), have long been known as molecular marker proteins of differentiated osteoclasts. However, whereas the cysteine protease Ctsk is directly involved in the degradation of bone matrix proteins, the molecular function of Acp5 in osteoclasts is still unknown. Here we show that Acp5, in concert with Acp2 (lysosomal acid phosphatase), is required for dephosphorylation of the lysosomal mannose 6-phosphate targeting signal to promote the activity of specific lysosomal enzymes. Using an unbiased approach we identified the glycosaminoglycan-degrading enzyme arylsulfatase B (Arsb), mutated in mucopolysaccharidosis type VI (MPS-VI), as an osteoclast marker, whose activity depends on dephosphorylation by Acp2 and Acp5. Similar to Acp2/Acp5-/- mice, Arsb-deficient mice display lysosomal storage accumulation in osteoclasts, impaired osteoclast activity, and high trabecular bone mass. Of note, the most prominent lysosomal storage accumulation was observed in osteocytes from Arsb-deficient mice, yet this pathology did not impair production of sclerostin (Sost) and Fgf23. Because the influence of enzyme replacement therapy (ERT) on bone remodeling in MPS-VI is still unknown, we additionally treated Arsb-deficient mice by weekly injection of recombinant human ARSB from 12 to 24 weeks of age. We found that the high bone mass phenotype of Arsb-deficient mice and the underlying bone cell deficits were fully corrected by ERT in the trabecular compartment. Taken together, our results do not only show that the function of Acp5 in osteoclasts is linked to dephosphorylation and activation of lysosomal enzymes, they also provide an important proof-of-principle for the feasibility of ERT to correct bone cell pathologies in lysosomal storage disorders. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Treatment of pediatric spinal deformity with use of recombinant human bone morphogenetic protein-2.

In pediatric spine surgery nonunion is a challenging issue. Instability may cause neurological impairment and lead to numerous surgeries in order to achieve fusion. The use of rhBMP-2 for pediatric spinal fusion has not been widely reported. In this study, a series of 13 children (14 procedures) that underwent spinal rhBMP-2 application were analyzed in order to measure clinical and radiographic outcome. Therefore, patient data, diagnosis, construct of instrumentation, type of bone graft, quantity of BMP used, and fusion outcome were reviewed. The study cohort included four female and nine male patients with a mean age of 11.2 years (range 2.6-19.2 years) at the time of rhBMP-2 application. Rh-BMP-2 was used in both primary (n = 6) and revision surgery (n = 8) in patients with a high risk for the development of nonunion. The mean follow-up was 51 months (range 12-108 months). Fusion occurred in 11 patients. Complications that may be due to application of rhBMP-2 were seen after four operations. Three patients had an increased body temperature and in one case prolonged wound secretion was evident, treated by local wound care or observation. In one of these patients an extensive postoperative hematoma occurred, necessitating surgical treatment. In conclusion, we could detect high fusion rates following the use of rhBMP-2 in pediatric spine surgery without an increased complication rate attributable to its application. Therefore we consider recombinant human BMP-2 to be an option in selected pediatric spinal procedures, especially in cases with compromised bone healing due to congenital, systemic, or local conditions.

Anterior distal femoral hemiepiphysiodesis can reduce fixed flexion deformity of the knee: a retrospective study of 83 knees.

Background and purpose - Fixed knee flexion deformity in children is a common problem in various diseases including myelomeningocele and cerebral palsy. Until now, only a few studies focusing on the surgical procedure of anterior distal femoral hemiepiphysiodesis have been published. We analyzed outcome and correction rate in the largest case series to date of patients treated by staples or 8-plates. Patients and methods - We reviewed the medical records of all patients with fixed knee flexion deformity who were treated with anterior distal femoral hemiepiphysiodesis using either staples or 8-plates between the years 2002 and 2017 (73 patients; 130 knees). 49 patients (83 knees) had completed treatment with implant removal at the time of full correction of the deformity or at skeletal maturity and were included. The average age at operation was 12 years (6-20). Patients were assigned to 3 different groups based on their diagnosis: cerebral palsy, myelomeningocele, and the "other" group.d Results - Mean fixed knee flexion deformity improved from 21° (10-60°) to 8° (0-50°) (p < 0.001) with an average correction rate of 0.44° per month (range -2.14° to 1.74°). The correction rate per month was lowest for patients with cerebral palsy (0.20°), followed by the myelomeningocele group (0.50°), and the "other" group (0.58°). Implant loosening occurred in 10% of the treated knees with consecutive re-implantation in 5% of the cases. Interpretation - Anterior distal femoral hemiepiphysiodesis is an effective and safe method for the treatment of fixed knee flexion deformity in children. The optimal timing depends on the remaining individual growth potential, the underlying disease, and the extent of the deformity.

Hip Morphology in MPS-1H Patients: An MRI-based Study.

BACKGROUND: Hip dysplasia is common in mucopolysaccharidosis type-1H (MPS-1H) patients, but its morphology is not completely understood. No magnetic resonance imaging (MRI)-based studies have been reported in the literature. The purpose of this study was to improve knowledge of hip dysplasia pathology by describing the hip morphology of these patients in MRI scans, plain radiographs, and arthrograms. METHODS: We performed a retrospective chart review of 18 MPS-1H patients. Supine anteroposterior pelvic radiographs of 36 hips and MRI scans of 18 hips were analyzed. Six arthrographs were also available. RESULTS: Plain radiographs were available for 18 patients. The mean age was 6.0 (SD=3.8) years. The mean acetabular index (AI) was 36.2 degrees (SD=5.8), and the mean migration percentage was 59.0% (SD=17.2). MRI data were available for 9 patients. The MRI findings were compared with the radiographs of the same patient. The mean AI (39.3 degrees, SD=5.8) was confirmed by the MRI findings (39.1 degrees, SD=5.5). The migration percentage was lower in the MRI scans than in the radiographs. Radiologically, the center-edge angle was negative in all patients, with a mean of -16.8 degrees (SD=7.9), and the MRI images produced a more negative value (-19.6 degrees, SD=7.6). The soft tissue coverage of the femoral head was described with the inclusion of the cartilaginous roof and labrum. The cartilaginous AI was 22.4 degrees (SD=7.5), and the labral AI was 13.5 degrees (SD=6.7). All 6 arthrograms revealed stability during dynamic testing. CONCLUSIONS: This study provides the first description of hip morphology in MPS-1H patients through MRI-based data. The cartilaginous coverage of the hip was increased compared with that of healthy children. The use of radiography alone may lead to a misunderstanding of hip morphology. MRI and arthrogram is highly recommended if surgery is considered.

Hip Dysplasia in Mucopolysaccharidosis Type IVA (Morquio A Syndrome) Treated by Proximal Femoral Valgization Osteotomy: A Case Report.

INTRODUCTION: Morquio A syndrome or mucopolysaccharidosis type IVA (MPS IVA) is a progressive lysosomal storage disorder caused by an N-acetylgalactosamine-6-sulfatase deficiency. The abnormal metabolism of glycosaminoglycans among other medical problems leads to various skeletal disorders caused by a dysfunction of endochondral ossification of epiphyseal cartilage. Severe hip dysplasia is common and can lead to pain and impaired mobility. CASE REPORT: We report on a 15-year-old girl suffering from MPS IVA. At the age of 5 years, hip pain and a reduced walking distance were described for the 1sttime. At the age of 9 years, acetabulofemoral dysplasia associated with genuavalga was diagnosed. After pre-operative assessment of the hips including plain radiographs, magnetic resonance imaging, and arthrography with dynamic testing a valgization osteotomy of the proximal femur in combination with a shelf acetabuloplasty was performed. The patient was followed for 6 years with a stable hip joint and without any sign of redislocation. CONCLUSION: Some treatment strategies of hip dysplasia in patients with MPS IVA are described in the literature. The techniques used for congenital hip dysplasia, varisation of the femur in combination with Pemberton, Salter, or shelf acetabuloplasty, are widely reported. Nevertheless, resubluxations were described in some cases. The well-known surgical procedure with valgization of the proximal femur is not reported in literature for MPS IVA patients. In our opinion, dynamic testing with arthrography should strongly be considered for this particular problem before surgical intervention. Pathology-related decisions should be made under consideration of the different surgical techniques.

Musculoskeletal manifestations in mucopolysaccharidosis type I (Hurler syndrome) following hematopoietic stem cell transplantation.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for young Hurler patients. Despite halting of neurocognitive decline and improvement of life expectancy, the beneficial effect on the skeletal system is limited. As orthopedic complications are one of the most disabling factors following HSCT, this points to the need for new treatment strategies. The study summarizes musculoskeletal manifestations in 19 transplanted Hurler patients. METHODS: Data were obtained retrospectively. Patients' charts for physical examinations of the joint range of motion (JROM) of shoulders, elbows, hips and knees were reviewed. Radiographic evaluations of thorax, spine, pelvis and hands were performed. MRI scans of the craniocervical junction were analyzed to determine odontoid hypoplasia and the prevalence of craniocervical stenosis. RESULTS: Nineteen Hurler patients (10 females, 9 males) with an average age of 8.1 years (range 2.5-23.8) at the latest follow-up, who underwent allogenic HSCT between 1991 and 2012, were assessed after an average follow-up period of 6.4 years (range 0.7-22.5). Seventeen patients achieved long-term engraftment, two developed graft failures. The majority of patients showed a steady state or improvements in the mobility of knees (31 %/63 %), hips (47 %/40 %) and elbows (56 %/38 %). However, shoulder abduction was impaired in ¾ of patients and showed the highest rate of progression (31 %). In patients with graft failure, progressive restrictions in JROM were noted. Assessments of the craniocervical junction by MRI showed stable or improved diameters in 67 % of patients. Correction or stabilization of odontoid hypoplasia was found in 64 %. However thoracolumbar kyphosis, scoliosis, hip dysplasia and genua valga were progressive despite HSCT. At the last follow up, 47 % of patients were partially wheelchair dependent, 10 % wheelchair bound and 25 % regularly experienced pain in the spine, hips and lower extremities due to orthopedic problems. CONCLUSION: Joint mobility, odontoid hypoplasia and craniocervical stenosis might stabilize or even improve in Hurler patients following HSCT. However, despite the beneficial effects on some musculoskeletal manifestations, skeletal complications are frequently observed and the overall burden of orthopedic disease is significant. Frequent multi-disciplinary follow-up in a specialized center are essential. Novel therapeutic approaches (e.g. anti-inflammatory drugs) are needed to improve musculoskeletal outcomes.

Impaired bone remodeling and its correction by combination therapy in a mouse model of mucopolysaccharidosis-I.

Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disease (LSD) caused by inactivating mutations of IDUA, encoding the glycosaminoglycan-degrading enzyme α-l-iduronidase. Although MPS-I is associated with skeletal abnormalities, the impact of IDUA deficiency on bone remodeling is poorly defined. Here we report that Idua-deficient mice progressively develop a high bone mass phenotype with pathological lysosomal storage in cells of the osteoblast lineage. Histomorphometric quantification identified shortening of bone-forming units and reduced osteoclast numbers per bone surface. This phenotype was not transferable into wild-type mice by bone marrow transplantation (BMT). In contrast, the high bone mass phenotype of Idua-deficient mice was prevented by BMT from wild-type donors. At the cellular level, BMT did not only normalize defects of Idua-deficient osteoblasts and osteocytes but additionally caused increased osteoclastogenesis. Based on clinical observations in an individual with MPS-I, previously subjected to BMT and enzyme replacement therapy (ERT), we treated Idua-deficient mice accordingly and found that combining both treatments normalized all histomorphometric parameters of bone remodeling. Our results demonstrate that BMT and ERT profoundly affect skeletal remodeling of Idua-deficient mice, thereby suggesting that individuals with MPS-I should be monitored for their bone remodeling status, before and after treatment, to avoid long-term skeletal complications.