We report on the largest single dataset of patients with PMM2-CDG enrolled in an ongoing international, multicenter natural history study collecting genetic, clinical, and biological information to evaluate similarities with previous studies, report on novel findings, and, additionally, examine potential genotype/phenotype correlations. A total of 137 participants had complete genotype information, representing 60 unique variants, of which the most common were found to be p.Arg141His in 58.4% (n = 80) of participants, followed by p.Pro113Leu (21.2%, n = 29), and p.Phe119Leu (12.4%, n = 17), consistent with previous studies. Interestingly, six new variants were reported, comprised of five missense variants (p.Pro20Leu, p.Tyr64Ser, p.Phe68Cys, p.Tyr76His, and p.Arg238His) and one frameshift (c.696del p.Ala233Argfs∗100). Patient phenotypes were characterized via the Nijmegen Progression CDG Rating Scale (NPCRS), together with biochemical parameters, the most consistently dysregulated of which were coagulation factors, specifically antithrombin (below normal in 79.5%, 93 of 117), in addition to Factor XI and protein C activity. Patient genotypes were classified based upon the predicted pathogenetic mechanism of disease-associated mutations, of which most were found in the catalysis/activation, folding, or dimerization regions of the PMM2 enzyme. Two different approaches were used to uncover genotype/phenotype relationships. The first characterized genotype only by the predicted pathogenic mechanisms and uncovered associated changes in biochemical parameters, not apparent using only NPCRS, involving catalysis/activation, dimerization, folding, and no protein variants. The second approach characterized genotype by the predicted pathogenic mechanism and/or individual variants when paired with a subset of severe nonfunctioning variants and uncovered correlations with both NPCRS and biochemical parameters, demonstrating that p.Cys241Ser was associated with milder disease, while p.Val231Met, dimerization, and folding variants with more severe disease. Although determining comprehensive genotype/phenotype relationships has previously proven challenging for PMM2-CDG, the larger sample size, plus inclusion of biochemical parameters in the current study, has provided new insights into the interplay of genetics with disease. Trial Registration: NCT03173300.

Congenital disorders of glycosylation (CDG) are a growing group of rare genetic disorders. The most common CDG is phosphomannomutase 2 (PMM2)-CDG which often has a severe clinical presentation and life-limiting consequences. There are no approved therapies for this condition. Also, there are no validated disease-specific quality of life (QoL) scales to assess the heterogeneous clinical burden of PMM2-CDG which presents a challenge for the assessment of the disease severity and the impact of a certain treatment on the course of the disease. This study aimed to identify the most impactful clinical signs and symptoms of PMM2-CDG, and specific patient and observer reported outcome measures (PROMs and ObsROMs, respectively) that can adequately measure such impact on patients’ QoL. The most burdensome signs and symptoms were identified through input from the CDG community using a survey targeting PMM2-CDG families and experts, followed by family interviews to understand the real burden of these symptoms in daily life. The list of signs and symptoms was then verified and refined by patient representatives and medical experts in the field. Finally, a literature search for PROMs and ObsROMs used in other rare or common diseases with similar signs and symptoms to those of PMM2-CDG was performed. Twenty-four signs/symptoms were identified as the most impactful throughout PMM2-CDG patients’ lifetime. We found 239 articles that included tools to measure those community-selected PMM2-CDG symptoms. Among them, we identified 80 QoL scales that address those signs and symptoms and, subsequently, their psychometric quality was analysed. These scales could be applied directly to the PMM2-CDG population or adapted to create the first PMM2-CDG-specific QoL questionnaire. Identifying the impactful clinical manifestations of PMM2-CDG, along with the collection of PROMs/ObsROMs assessing QoL using a creative and community-centric methodology are the first step towards the development of a new, tailored, and specific PMM2-CDG QoL questionnaire. These findings can be used to fill a gap in PMM2-CDG clinical development. Importantly, this methodology is transferable to other CDG and rare diseases with multiple signs and symptoms.

PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 μg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG.

In 2003, we briefly reported the remarkable osteopathy of a 12-year-old boy who at age two months began fracturing his limbs with subsequent hyperplastic callus formation and expansion and fusion of appendicular bones. By age ten years he had coalesced his lumbosacral spine, pelvis, femurs, and leg and foot bones as a single structure. Computed tomography of expanded bone revealed a thin cortical shell, diminished irregular trabeculae, and cystic areas. Histopathology featured foci of woven bone, densely packed osteocytes, cartilage, fibrovascular tissue, and massive fat deposition in the marrow space lacking hematogenous precursor cells. Bone turnover markers indicated accelerated remodeling and the few radiographically assessable appendicular bones improved during brief adherence to alendronate therapy. Following puberty, serum multiplex biomarker profiling confirmed accelerated bone turnover. At age 23 years, macrospecimens from leg amputation revealed ossification along capsular tissue together with hyaline cartilage degeneration. Concurrently, the life-long course of this same disorder was delineated in an unrelated woman until her death at age 51 years. Both patients demonstrated the radiographic hallmarks and harbored the heterozygous point mutation (c.-14C>T) in the 5'-UTR of IFITM5 associated with osteogenesis imperfecta type V (OI-V). Herein, we detail the clinical, radiological, histopathological, biochemical, and molecular findings and discuss the etiology and pathogenesis of this extraordinary osteopathy that we call coalescing expansile skeletal disease.

Hypophosphatasia (HPP) is a rare monogenetic and multisystemic disease with involvement of different organs, including bone, muscle, kidney, lung, gastrointestinal tract and the nervous system. The exact metabolic mechanisms of the effects of TNAP deficiency in different tissues are not understood in detail. There is no approved specific treatment for HPP; therefore symptomatic treatment in order to improve the clinical features is of major interest. Enzyme replacement therapy (ERT) is a relatively new type of treatment based on the principle of administering a medical treatment replacing a defective or absent enzyme. Recently ERT with a bone targeted recombinant human TNAP molecule has been reported to be efficient in ten severely affected patients and improved survival of life threatening forms. These results are very promising especially with regard to the skeletal phenotype but it is unclear whether ERT also has beneficial effects for craniosynostosis and in other affected tissues in HPP such as brain and kidney. Long-term data are not yet available and further systematic clinical trials are needed. It is also necessary to establish therapeutic approaches to help patients who are affected by less severe forms of HPP but also suffer from a significant reduction in quality of life. Further basic research on TNAP function and role in different tissues and on its physiological substrates is critical to gain a better insight in the pathogenesis in HPP. This and further experiences in new therapeutic strategies may improve the prognosis and quality of life of patients with all forms of HPP.

One of the most striking features of moderate to severe osteogenesis imperfecta (OI) is impaired linear growth. In fact, even in mild OI, there are often signs of growth retardation. The heights of patients in all OI types are compromised compared to the heights of unaffected family members, thereby suggesting that the collagen defect per se plays a role in the impaired growth. In addition, the severity of the growth impairment correlates with the severity of the OI in general. The etiology of growth retardation in patients with OI is not completely understood. In general the poor growth in OI appears to be more notable in patients with qualitative collagen defects than in those patients with quantitative defects, thereby making the examination of growth in children with OI an important area for translational studies for genotype–phenotype correlations. Investigations of the genotype–phenotype correlations over the past several years have provided an important avenue through which an understanding of linear growth in OI may even be determined at the molecular and cellular level. The use of recombinant growth hormone (rGH) in the treatment of impaired linear growth in OI has been preliminarily investigated, both alone and in combination with bisphosphonates. Longer, properly controlled treatment trials involving more patients are warranted in order to draw generalized conclusions regarding the effects of rGH use in patients with OI. The data, however, do present a possible case for the importance of selection of patients for rGH treatment based on molecular and biochemical studies, and thus reinforce the need for a translational approach to the future of rGH treatment in OI. Further investigations on the effects on final height as well as the long-term benefits and safety of growth hormone in OI will be important in determining the use of this treatment for the growth retardation that is such a salient feature of this condition.

Background Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease.Methods In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2: 1 ratio to receive either daily risedronate (2.5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028.Findings Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16.3% in the risedronate group and 7.6% in the placebo group (difference 8.7%, 95% CI 5.7-11.7; p<0.0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0.0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events.Interpretation Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta.

Hypophosphatasia (HPP), a heritable metabolic bone disease, results from inactivating mutation(s) in the gene for the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP). The natural substrates that accumulate in HPP include inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5′ phosphate (PLP), the principal circulating form of vitamin B6. PPi excess blocks hydroxyapatite crystal formation causing rickets in growing children and osteomalacia in adults. There is no approved therapy. ENB-0040, a bone-targeted, recombinant, human TNSALP given subcutaneously has improved severely affected infants and children with HPP. Objective: Evaluate TNSALP substrate levels following 24 weeks of ENB-0040 treatment (Rx) and six-minute walk test (6MWT) function in adolescents and adults with HPP. The 6MWT is a performance-based measure of functional exercise capacity. Methods: 6 adolescents and 13 adults with HPP (mean age 42 yrs [14–68]) were randomized in an open-label, multicenter, multinational, dose-ranging, concurrent control study of the safety, efficacy, and pharmacokinetics of ENB-0040. Patients received 0, 2.1, or 3.5 mg/kg/wk of ENB-0040. Results: At baseline (BL), patients averaged 349 m during the 6MWT (6–620 m), but 10 required assistive devices. The differences walked for the Rx vs no Rx groups were +26 vs −14 m at week 24. Among those with functional impairment (n=12) whose BL 6MWT was 25%N75% of normal, 9 improved (8/9 Rx, and 1/3 no Rx). The mean improvements for the 2.1 and 3.5 mg/kg/wk groups were +35.4 m (n=5) and +43.5 m (n=4), respectively. Injection site reactions occurred in 7 patients, but did not cause discontinuation of treatment. Six serious adverse events (SAEs) were reported among 3 patients, two observation patients had 4 of the SAEs. No SAEs were from ENB-0040. Serum PLP levels decreased in both groups, from 324 and 602 ng/mL at BL to 69 ng/mL and 38 ng/L at week 24, respectively (p=0.009). Conclusion: ENB-0040 significantly decreases TNSALP substrates and improves the 6MWT in adolescents and adults with HPP. This article is part of a Special Issue entitled ECTS 2012. Disclosure of interest: M. Whyte grant/research support from Enobia, consulting fees from Enobia, C. Greenberg grant/research support from Enobia, Advisory Board Membership of Enobia, consulting fees from Enobia, P. Kishnani grant/research support from Enobia, Advisory Board Membership of Enobia, consulting fees from Enobia, K. Madson grant/research support from Enobia, A. Mhanni grant/research support from Enobia, T. Weber: none declared, K. Mack grant/research support from Enobia, A. Reeves grant/research support from Enobia, H. Plotkin employee of Enobia, N. Kreher employee of Enobia, H. Landy employee of Enobia. doi:10.1016/j.bone.2012.02.101 OC31 (recipient of a 2012 ECTS Travel Award) Detection of autoantibodies to osteoprotegerin in patients with severe idiopathic osteoporosis P. Riches⁎, T. Gilchrist, W.D. Fraser, S.H. Ralston Rheumatology Department, Institute of Genetics and Molecular Medicine, Edinburgh, UK Faculty of Medicine and Health Sciences, University of East Anglia,

Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) in the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). The disease has been classified according to patient age when the first signs and symptoms manifest; i.e., perinatal, infantile, childhood, adult HPP. Other types include odonto HPP and perinatal benign. Babies with the perinatal/infantile forms of HPP often die with severe rickets and respiratory insufficiency and sometimes hypercalcemia and vitamin B6-responsive seizures. The primary biochemical defect in HPP is a deficiency of TNAP activity that leads to elevated circulating levels of substrates, in particular inorganic pyrophosphate (PPi), a potent calcification inhibitor. To-date, the management of HPP has been essentially symptomatic or orthopedic. However, enzyme replacement therapy with mineral-targeting TNAP (sALP-FcD10, also known as ENB-0040 or asfotase alfa) has shown promising results in a mouse model of HPP (Alpl-/- mice). Administration of mineral-targeting TNAP from birth increased survival and prevented the seizures, rickets, as well as all the tooth abnormalities, including dentin, acellular cementum, and enamel defects in this model of severe HPP. Clinical trials using mineral-targeting TNAP in children 3 years of age or younger with life-threatening HPP was associated with healing of the skeletal manifestations of HPP as well as improved respiratory and motor function. Improvement is still being observed in the patients receiving continued asfotase alfa therapy, with more than 3 years of treatment in some children. Enzyme replacement therapy with asfotase alfa has to-date been successful in patients with life-threatening HPP.

Objective: Late-onset Pompe disease is a progressive, debilitating, and often fatal neuromuscular disorder resulting from the deficiency of a lysosomal enzyme, acid alpha-glucosidase. This extension study was conducted to determine the durability of the efficacy and safety of alglucosidase alfa observed over a period of 78 weeks in the Late-Onset Treatment Study (LOTS).Methods: Patients who completed the LOTS study were eligible for this open-label extension study and received alglucosidase alfa 20 mg/kg biweekly for an additional 26 weeks. The primary efficacy assessments were the distance walked during a 6-minute walk test and the percentage of predicted forced vital capacity in the upright position. Data are reported as change from patient's original LOTS baseline for each measure.Results: The benefit of alglucosidase alfa treatment observed in LOTS at Week 78 was, in general, maintained at Week 104. The mean increase in distance walked measured 28.2 +/- 66.5 m from LOTS baseline to Week 78 and 21.3 +/- 78.0 m from LOTS baseline to Week 104. The mean change from baseline in percentage of predicted forced vital capacity was 1.3%+/- 5.7% from LOTS baseline to Week 78 and 0.8%+/- 6.7% from LOTS baseline to Week 104. Treatment-related adverse events were mainly infusion-associated reactions observed in 35% of patients. No deaths or anaphylactic reactions were observed during the extension study.Conclusions: The LOTS Extension study showed that patients treated with alglucosidase alfa for up to 104 weeks maintained the improved walking distance and stabilization in pulmonary function observed in the first 78 weeks of alglucosidase alfa therapy. (C) 2012 Elsevier Inc. All rights reserved.

Children with limited or no ability to ambulate frequently sustain fragility fractures. Joint contractures, scoliosis, hip dysplasia, and metallic implants often prevent reliable measures of bone mineral density (BMD) in the proximal femur and lumbar spine, where BMD is commonly measured. Further, the relevance of lumbar spine BMD to fracture risk in this population is questionable. In an effort to obtain bone density measures that are both technically feasible and clinically relevant, a technique was developed involving dual‐energy X‐ray absorptiometry (DXA) measures of the distal femur projected in the lateral plane. The purpose of this study is to test the hypothesis that these new measures of BMD correlate with fractures in children with limited or no ability to ambulate. The relationship between distal femur BMD Z‐scores and fracture history was assessed in a cross‐sectional study of 619 children aged 6 to 18 years with muscular dystrophy or moderate to severe cerebral palsy compiled from eight centers. There was a strong correlation between fracture history and BMD Z‐scores in the distal femur; 35% to 42% of those with BMD Z‐scores less than −5 had fractured compared with 13% to 15% of those with BMD Z‐scores greater than −1. Risk ratios were 1.06 to 1.15 (95% confidence interval 1.04–1.22), meaning a 6% to 15% increased risk of fracture with each 1.0 decrease in BMD Z‐score. In clinical practice, DXA measure of BMD in the distal femur is the technique of choice for the assessment of children with impaired mobility. © 2010 American Society for Bone and Mineral Research

Purpose of review The treatment of osteogenesis imperfecta requires a multidisciplinary team to maximize function and comfort, and decrease fracture incidence. Medical treatment with bisphosphonates has allowed for safer, more effective surgical management of children with osteogenesis imperfecta. The purpose of this review is to outline treatment indications and choices of surgical techniques based on recent clinical studies, and in addition to identify persistent clinical problems addressed in recent literature. Recent findings Several new intramedullary rodding surgical techniques and modifications of older techniques have been developed to correct deformities of the long bones. These techniques decrease the trauma associated with surgical treatment. The newer techniques limit postoperative immobilization, enabling earlier rehabilitation, and allowing for treatment of multiple bones simultaneously. Summary Recent medical and surgical advances have allowed improved safety, function and comfort in treating children with osteogenesis imperfecta. The selection of surgical techniques is dependent on surgeon experience, severity of disease and patient function, and availability of specific instrumentation. Intramedullary fixation rather than plating is preferred, and allowing early protected weight bearing and rehabilitation of children with ambulatory potential is the ideal goal.

Osteoporosis in adults has been defined on the basis of densitometric criteria, but at present the term osteoporosis does not have a widely recognized definition in pediatrics. Consequently, the International Society for Clinical Densitometry (ISCD) 2007 Position Development Conference reviewed the literature describing the relationship between bone densitometric studies and fractures in apparently healthy children and adolescents, and prepared Official Positions regarding the definition of osteoporosis in children and adolescents. The ISCD Official Positions with respect to the above issues, as well as the rationale and evidence used to derive these positions, are presented here.

The International Society for Clinical Densitometry periodically holds Position Development Conferences (PDCs) for the purpose of establishing standards and guidelines for the assessment of skeletal health, including nomenclature, indications, acquisition, analysis, quality control, interpretation, and reporting of bone density tests. Topics are selected for consideration according to criteria that include clinical relevancy, uncertainty in the application of medical evidence to clinical practice, and the likelihood of the expert panel to reach a consensus agreement. The first Pediatric PDC was June 20 to 21, 2007 in Montreal, Quebec, Canada. Topics included fracture prediction and definition of osteoporosis in children; dual-energy x-ray absorptiometry (DXA) assessment in children with chronic disease that may affect the skeleton; DXA interpretation and reporting in children and adolescents; and the use of peripheral quantitative computed tomography in children and adolescents. This report describes the methodology and presents the results of this recent PDC.

The long-term effects of bisphosphonate treatment in children with osteogenesis imperfecta (OI) are unknown. The aim of this study was to evaluate whether treatment with bisphosphonates interferes with the healing of fractures in a group of children with OI. Seven subjects (6 boys), aged 11.4 +/- 5.95 years, were followed for 2.5 +/- 0.84 years after the start of treatment with intravenous pamidronate (9 mg/kg/y) and/or oral alendronate (5 or 10 mg/d). Orthopaedic surgery of 24 bones was performed after 2.33 +/- 4.14 months of treatment, with 1.6 +/- 0.84 osteotomies per bone. Ambulation was started after 26.1 +/- 32.28 days. Reoperation was required in 8% of the bones due to fracture below primary fixation. Pseudoarthrosis was seen in one fracture, an osteotomy of the proximal femur (14% of the patients, as expected in an OI population). These results suggest that treatment with bisphosphonates at the administered doses does not interfere with fracture healing. Larger and longer studies are warranted.

From the University of Nebraska Medical Center and Children's Hospital, Omaha, NE. Correspondence: Horacio Plotkin, MD, FAAP, Assistant Professor of Pediatrics and Orthopedic Surgery, 985456 Nebraska Medical Center, Omaha, NE 68198-5456 (e-mail: [email protected]).