The IMPACT survey: a mixed methods study to understand the experience of children, adolescents and adults with osteogenesis imperfecta and their caregivers.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare, heritable connective tissue disorder associated with a variety of symptoms, that affect individuals' quality of life (QoL) and can be associated with increased healthcare resource use. While some aspects of OI are well studied, others remain poorly understood. Therefore, the IMPACT survey aimed to elucidate the humanistic, clinical and economic burden of OI on individuals with OI, their families, caregivers and wider society. METHODS: We developed an international mixed methods online survey in eight languages (fielded July-September 2021), aimed at adults (aged ≥ 18 years) or adolescents (aged ≥ 12-17 years) with OI, caregivers (with or without OI) of individuals with OI and other close relatives. All respondents provided data on themselves; caregivers additionally provided data on individuals in their care by proxy. Data were cleaned, coded, and analysed using the pandas Python software package and Excel. RESULTS: IMPACT collected 2208 eligible questionnaires (covering 2988 individuals of whom 2312 had OI) including 1290 non-caregiver adults with OI, 92 adolescents with OI, 150 caregiver adults with OI, 560 caregivers for individuals with OI, 116 close relatives and 780 proxy care-recipients with OI. Most individuals with OI (direct or proxy) described their OI as moderate (41-52% across populations) and reported OI type 1 (33-38%). Pain (72-82%) was the most reported clinical condition experienced in the past 12 months and was also most frequently rated as severely or moderately impactful. Further, among adults, 67% reported fatigue, 47% scoliosis, and 46% sleep disturbance; in adolescents, fatigue affected 65%, scoliosis and other bone problems 60%, and mental health problems 46%; in children, fractures were common in 67%, fatigue in 47%, and dental problems in 46%. CONCLUSION: IMPACT has generated an extensive dataset on the experience of individuals with OI, their caregivers and relatives. We found that, irrespective of age, individuals with OI experience numerous and evolving symptoms that affect their QoL; however, pain and fatigue are consistently present. Upcoming analyses will provide further insights into the economic impact, healthcare journey and caregiver wellbeing, aiming to contribute to improved treatment and care for the OI community.

Burosumab for the treatment of cutaneous-skeletal hypophosphatemia syndrome.

Cutaneous-skeletal hypophosphatemia syndrome (CSHS) is a rare bone disorder featuring fibroblast growth factor-23 (FGF23)-mediated hypophosphatemic rickets. We report a 2-year, 10-month-old girl with CSHS treated with burosumab, a novel human monoclonal antibody targeting FGF23. This approach was associated with rickets healing, improvement in growth and lower limb deformity, and clinically significant benefit to her functional mobility and motor development. This case report provides evidence for the effective use of FGF23-neutralizing antibody therapy beyond the classic FGF23-mediated disorders of X-linked hypophosphatemia and tumor-induced osteomalacia.

Arthrogryposis multiplex congenita: dental and maxillofacial phenotype - A scoping review.

INTRODUCTION: Arthrogryposis multiplex congenita (AMC) is a heterogeneous group of disorders associated with decreased fetal movement, with a prevalence between 1/3000 and 1/5200 live births. Typical features of AMC include multiple joint contractures present at birth, and can affect all joints of the body, from the jaw, and involving the upper limbs, lower limbs and spine. The jaws may be affected in 25 % of individuals with AMC, with limited jaw movement and mouth opening. Other oral and maxillofacial deformities may be present in AMC, including cleft palate, micrognathia, periodontitis and delayed teething. To our knowledge, oral and maxillofacial abnormalities have not been systematically assessed in individuals with AMC. Therefore, this scoping review was conducted to identify, collect, and describe a comprehensive map of the existing knowledge on dental and maxillofacial involvement in individuals with AMC. METHODOLOGY: A scoping review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. The PRISMA guidelines for scoping reviews were followed and databases were searched for empirical articles in English and French published until October 2022. We searched MEDLINE, Embase, Web of Science and ERIC databases. Two authors independently reviewed the articles and extracted the data. RESULTS: Of a total of 997 studies that were identified, 96 met the inclusion criteria and were subsequently included in this scoping review. These 96 studies collectively provided insights into 167 patients who exhibited some form of oral and/or maxillofacial involvement. Notably, 25 % of these patients were within the age range of 0-6 months. It is worth highlighting that only 22 out of the 96 studies (22.9 %), had the primary objective of evaluating dental and/or maxillofacial deformities. Among the patients studied, a prevalent pattern emerged, revealing that severe anomalies such as micrognathia (56 %), high-arched palate (29 %), cleft palate (40 %), limited mouth opening (31 %), and dental anomalies (28 %) were frequently observed. Importantly, many of these patients were found to have more than one of these anomalies. Even though these maxillofacial impairments are known to be associated with dental problems (e.g., cleft palate is associated with oligodontia, hypodontia, and malocclusion), their secondary effects on the dental phenotype were not reported in the studies. CONCLUSION: Our findings have uncovered a notable deficiency in existing literature concerning dental and maxillofacial manifestations in AMC. This underscores the need for interdisciplinary collaboration and the undertaking of extensive prospective cohort studies focused on AMC. These studies should assess the oral and maxillofacial abnormalities that can impact daily functioning and overall quality of life.

Risk Factors Associated with Incident Vertebral Fractures in Steroid-treated Males with Duchenne Muscular Dystrophy.

PURPOSE: Prevention of fractures is an unmet need in glucocorticoid (GC)-treated Duchenne muscular dystrophy. This study explored factors associated with incident vertebral fractures (VFs) to inform future fracture prevention efforts. METHODS: VFs were evaluated prospectively at study baseline and 12 months on lateral spine radiographs in participants aged 4 to 25 years with Duchenne muscular dystrophy. Clinical factors were analyzed for their association with the change in Spinal Deformity Index (sum of the Genant-defined VF grades from T4 to L4) between baseline and 12 months. RESULTS: Thirty-eight males were evaluated (mean ± SD age at baseline 11.0 ± 3.6 years; mean ± SD GC duration at baseline 4.1 ± 3.1 years; 74% ambulatory). Nine of 38 participants (24%) had 17 incident VFs, of which 3/17 VFs (18%) were moderate/severe. Participants with 12-month incident VF had lower mean ± SD baseline lumbar spine areal bone mineral density Z-scores (-2.9 ± 1.0 vs -1.9 ± 1.1; P = .049) and lower total body less head areal bone mineral density Z-scores (-3.1 ± 1.2 vs -1.6 ± 1.7; P = .036). Multivariable linear regression showed that at least 1 VF at baseline (P < .001), a higher number of antecedent non-VF (P < .001), and greater bone age delay at baseline (P = .027) were significant predictors of an increase in the Spinal Deformity Index from baseline to 12 months. CONCLUSION: The observation that ≥ 1 prevalent VF and/or non-VF were the strongest predictors of incident VFs at 12 months supports the need for prevention of first fractures in this high-risk setting. Bone age delay, a marker of GC exposure, may assist in the prioritization of patients in efforts to prevent first fractures.

Cranio-cervical abnormalities in moderate-to-severe osteogenesis imperfecta - Genotypic and phenotypic determinants.

INTRODUCTION: Cranio-cervical anomalies are significant complications of osteogenesis imperfecta (OI), a rare bone fragility disorder that is usually caused by mutations in collagen type I encoding genes. OBJECTIVE: To assess cranio-cervical anomalies and associated clinical findings in patients with moderate-to-severe OI using 3D cone beam computed tomography (CBCT) scans. METHODS: Cross-sectional analysis of CBCT scans in 52 individuals with OI (age 10-37 years; 32 females) and 40 healthy controls (age 10-32 years; 26 females). Individuals with a diagnosis of OI type III (severe, n = 11), type IV (moderate, n = 33) and non-collagen OI (n = 8) were recruited through the Brittle Bone Disorders Consortium. Controls were recruited through the orthodontic clinic of the University of Missouri-Kansas City (UMKC). RESULTS: OI and control groups were similar in mean age (OI: 18.4 [SD: 7.2] years, controls: 18.1 [SD: 6.3] years). The cranial base angle was increased in the OI group (OI: mean 148.6° [SD: 19.3], controls: mean 130.4° [SD: 5.7], P = .001), indicating a flatter cranial base. Protrusion of the odontoid process into the foramen magnum (n = 7, 14%) and abnormally located odontoid process (n = 19, 37%) were observed in the OI group but not in controls. Low stature, expressed as height z-score (P = .01), presence of DI (P = .04) and being male (P = .04) were strong predictors of platybasia, whereas height z-score (P = .049) alone was found as positive predictor for basilar impression as per the Chamberlain measurement. CONCLUSION: The severity of the phenotype in OI, as expressed by the height z-score, correlates with the severity of cranial base anomalies such as platybasia and basilar impression in moderate-to-severe OI. Screening for cranial base anomalies is advisable in individuals with moderate-to-severe OI, with special regards to the individuals with a shorter stature and DI.

Vertebral Body Reshaping after Fractures: An Important Index of Recovery in Glucocorticoid-Treated Children.

PURPOSE: In this 6-year study we identified factors associated with spontaneous vertebral body reshaping in glucocorticoid (GC)-treated children with leukemia, rheumatic disorders, and nephrotic syndrome. METHODS: Subjects were 79 children (mean age 7.4 years) who had vertebral fracture (VF) evaluation on lateral spine radiographs at least 1 year after VF detection. VF were graded using the modified Genant semiquantitative method and fracture burden for individuals was quantified using the spinal deformity index (SDI; sum of grades from T4 to L4). RESULTS: Sixty-five children (82.3%) underwent complete vertebral body reshaping (median time from VF detection to complete reshaping 1.3 years by Cox proportional hazard modeling). Of 237 VF, the majority (83.1%) ultimately reshaped, with 87.2% reshaping in the thoracic region vs 70.7% in the lumbar region (P = .004). Cox models showed that (1) every g/m2 increase in GC exposure in the first year after VF detection was associated with a 19% decline in the probability of reshaping; (2) each unit increase in the SDI at the time of VF detection was associated with a 19% decline in the probability of reshaping [hazard ratio (HR) = 0.81; 95% confidence interval (CI) = 0.71, 0.92; P = .001]; (3) each additional VF present at the time of VF detection reduced reshaping by 25% (HR = 0.75; 95% CI = 0.62, 0.90; P = .002); and (4) each higher grade of VF severity decreased reshaping by 65% (HR = 0.35; 95% CI = 0.21, 0.57; P < .001). CONCLUSION: After experiencing a VF, children with higher GC exposure, higher SDI, more severe fractures, or lumbar VF were at increased risk for persistent vertebral deformity.

Combination of osteogenesis imperfecta and hypophosphatasia in three children with multiple fractures, low bone mass and severe osteomalacia, a challenge for therapeutic management.

Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and tissue-non-specific isoenzyme of alkaline phosphatase (ALPL), respectively. Both conditions result in skeletal deformities and bone fragility although bone tissue abnormalities differ considerably. Children with OI have low bone mass and hypermineralized matrix, whereas HPP children develop rickets and osteomalacia. We report a family, father and three children, affected with growth retardation, low bone mass and recurrent fractures. None of them had rickets, blue sclera or dentinogenesis imperfecta. ALP serum levels were low and genetics revealed in the four probands heterozygous pathogenic mutations in COL1A2 c.838G > A (p.Gly280Ser) and in ALPL c.1333T > C (p.Ser445Pro). After multidisciplinary meeting, a diagnostic transiliac bone biopsy was indicated for each sibling for therapeutic decision. Bone histology and histomorphometry, as compared to reference values of children with OI type I as well as, to a control pediatric patient harboring the same COL1A2 mutation, revealed similarly decreased trabecular bone volume, increased osteocyte lacunae, but additionally severe osteomalacia. Quantitative backscattered electron imaging demonstrated that bone matrix mineralization was not as decreased as expected for osteomalacia. In summary, we observed within each biopsy samples classical features of OI and classical features of HPP. The apparent nearly normal bone mineralization density distribution results presumably from divergent effects of OI and HPP on matrix mineralization. A combination therapy was initiated with ALP enzyme-replacement and one month later with bisphosphonates. The ongoing treatment led to improved skeletal growth, increased BMD and markedly reduced fracture incidence.

Delivering a Home-Based Exercise Program to Youth With Osteogenesis Imperfecta: Protocol for a Comparative-Approach Study.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare bone fragility disorder associated with muscle weakness. Individuals with OI may therefore benefit from exercise interventions aiming to improve muscle and bone strength. Given the rarity of OI, many patients do not have access to exercise specialists who are familiar with the disorder. As such, telemedicine, the provision of health care through technology to provide care at a distance, may be well suited for this population. OBJECTIVE: The main objectives are (1) to investigate the feasibility and cost-effectiveness of 2 telemedicine approaches for the delivery of an exercise intervention for youth with OI and (2) to assess the impact of the exercise intervention on muscle function and cardiopulmonary fitness in youth with OI. METHODS: Patients with OI type I (the mildest form of OI; n=12, aged 12-16 years) from a pediatric orthopedic tertiary hospital will be randomized to receive a 12-week remote exercise intervention in either (1) a supervised group (n=6), monitored every session, or (2) a follow-up group (n=6), receiving monthly progress update appointments. Participants will undergo the following pre- and postintervention evaluations: sit-to-stand test, push-up test, sit-up test, single-legged balance test, and a heel-rise test. Both groups will be given the same 12-week exercise regimen, which includes cardiovascular, resistance, and flexibility training. For each exercise training session involving the supervised group, a kinesiologist will provide instructions to participants through live video sessions using a teleconferencing application. On the other hand, the follow-up group will discuss their progress with the kinesiologist every 4 weeks over a teleconferencing video call. Feasibility will be assessed by recruitment, adherence, and completion rates. A cost-effectiveness analysis of both approaches will be computed. Changes in muscle function and cardiopulmonary fitness will be examined between the 2 groups, pre- and postintervention. RESULTS: It is anticipated that the supervised group will have higher adherence and completion rates compared to the follow-up group, which may be associated with greater physiological benefits; however, it may not be as cost-effective compared to the follow-up approach. CONCLUSIONS: By determining the most feasible telemedicine approach, this study may serve as a basis for providing increased access to specialized adjunct therapies for individuals with rare disorders. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/40262.

X-linked hypophosphatemia caused by a deep intronic variant in PHEX identified by PCR-based RNA analysis of urine-derived cells.

X-linked hypophosphatemia (XLH) is caused by dominant inactivating mutations in the phosphate regulating endopeptidase homology, X-linked (PHEX), resulting in elevated fibroblast growth factor 23 (FGF23), hypophosphatemia, rickets and osteomalacia. PHEX variants are identified in approximately 85 % of individuals with XLH, which leaves a substantial proportion of patients with negative DNA-based genetic testing. Here we describe a 16-year-old male who had typical features of XLH on clinical and radiological examination. Genomic DNA sequencing of a hypophosphatemia gene panel did not reveal a pathogenic variant. We therefore obtained a urine sample, established cell cultures and obtained PHEX cDNA from urine-derived cells. Sequencing of exon-spanning PCR products demonstrated the presence of an 84 bp pseudoexon in PHEX intron 21 due to a deep intronic variant (c.2147+1197A>G), which created a new splice donor site in intron 21. The corresponding PHEX protein would lack 33 amino acids on the C-terminus and instead include an unrelated sequence of 17 amino acids. The patient and his affected mother both had this variant. This report highlights that individuals with the typical clinical characteristics of XLH and negative genomic DNA sequence analysis can have deep intronic PHEX variants that are detectable by PCR-based RNA diagnostics.

RNA Sequencing of Urine-Derived Cells for the Characterization and Diagnosis of Osteogenesis Imperfecta.

DNA sequencing is a reliable tool for identifying genetic variants in osteogenesis imperfecta (OI) but cannot always establish pathogenicity, particularly in variants altering splicing. RNA sequencing can provide functional evidence of the effect of a variant on the transcript but requires cells expressing the relevant genes. Here, we used urine-derived cells (UDC) to characterize genetic variants in patients with suspected or confirmed OI and provide evidence on the pathogenicity of variants of uncertain significance (VUS). Urine samples were obtained from 45 children and adolescents; UDC culture was successful in 40 of these participants (age range 4-20 years, 21 females), including 18 participants with OI or suspected OI who had a candidate variant or VUS on DNA sequencing. RNA was extracted from UDC and sequenced on an Illumina NextSeq550 device. Principal component analysis showed that the gene expression profiles of UDC and fibroblasts (based on Genotype Tissue Expression [GTEx] Consortium data) clustered close together and had less variability than those of whole blood cells. Transcript abundance was sufficient for analysis by RNA sequencing (defined as a median gene expression level of ≥10 transcripts per million) for 25 of the 32 bone fragility genes (78%) that were included in our diagnostic DNA sequencing panel. These results were similar to GTEx data for fibroblasts. Abnormal splicing was identified in 7 of the 8 participants with pathogenic or likely pathogenic variants in the splice region or deeper within the intron. Abnormal splicing was also observed in 2 VUS (COL1A1 c.2829+5G>A and COL1A2 c.693+6T>G), but no splice abnormality was observed in 3 other VUS. Abnormal deletions and duplications could also be observed in UDC transcripts. In conclusion, UDC are suitable for RNA transcript analysis in patients with suspected OI and can provide functional evidence for pathogenicity, in particular of variants affecting splicing. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Transition from Pediatric to Adult Health Care in Osteogenesis Imperfecta.

PURPOSE: Here, we review issues regarding the transition from pediatric to adult-focused health care for individuals with osteogenesis imperfecta (OI). RECENT FINDINGS: The clinical consequences of OI change during the lifespan. Fracture rates are lower in adults than in children with OI, whereas other manifestations are typically becoming more prominent in adults. The evidence base for the transition to adult health care in OI is thin, as the literature on the topic is limited to qualitative investigations on a small number of participants. A few tools to help with transition, such as a program to improve self-management skills, have been developed. The transition process varies markedly between health care systems, which makes generalizations difficult. However, a better definition of follow-up requirements and care of adults with OI might be helpful for the transition from pediatric to adult health care.

Reductions in Bone Mineral Density Are Apparent Early in Children With Prevalent Osteonecrosis Lesions Following Leukemia Therapy.

Osteonecrosis (ON) is a serious complication of childhood acute lymphoblastic leukemia. We determined the prevalence of osteonecrotic lesions in our patient population by a one-time multisite magnetic resonance imaging (MRI) more than 1 year following leukemia therapy. MRI findings were evaluated in relationship to clinical factors (including longitudinal changes in bone mineral density [BMD]). Eighty-six children enrolled in the Steroid Associated Osteoporosis in the Pediatric Population (STOPP) study were evaluated for ON at 3.1 ± 1.3 years following therapy. Thirty children had a total of 150 confirmed ON lesions (35%). Lumbar spine (LS) BMD Z-scores (mean ± SD) were low at diagnosis and similar between patients with and without ON (-1.09 ± 1.53 versus -1.27 ± 1.25, p = 0.549). LS BMD Z-scores declined from baseline to 12 months in children with ON (-0.31 ± 1.02) but not in those without (0.13 ± 0.82, p = 0.035); the hip BMD Z-scores from baseline to 24 months declined in both groups, but to a greater extent in those with ON (-1.77 ± 1.22) compared to those without (-1.03 ± 1.07, p = 0.045). At the time of the MRI, mean total hip and total body (TB) BMD Z-scores were lower in children with ON (hip -0.98 ± 0.95 versus -0.28 ± 1.06, p = 0.010; TB -1.36 ± 1.10 versus -0.48 ± 1.50, p = 0.018). Pain occurred in 11/30 (37%) with ON versus 20/56 (36%) without, p = 0.841. In multivariable models, older age at diagnosis (odds ratio [OR] 1.57; 95% confidence interval [CI], 1.15-2.13; p = 0.004), and hip BMD Z-score at MRI (OR 2.23; 95% CI, 1.02-4.87; p = 0.046) were independently associated with ON. Overall, one-third of children demonstrated ON after leukemia therapy. Those with ON had greater reductions in spine and hip BMD Z-scores in the first 1 and 2 years of therapy, respectively. Older age and lower hip BMD Z-scores at MRI were significantly associated with prevalent, off-therapy ON. These data assist in identifying children at risk of ON. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The Design, Development, and Usability Testing of an eHealth Program for Youths With Osteogenesis Imperfecta: Protocol for a 2-Phase User-Centered Mixed Methods Study.

BACKGROUND: Innovative approaches are needed to address the self-management needs of youths with osteogenesis imperfecta (OI) transitioning into adult-oriented health care systems. Using a sequentially phased research approach, the goal is to design, develop, and test the usability of an innovative eHealth program called "Teens Taking Charge: Managing OI Online," hereafter named "Teens OI." This program seeks to optimize self-management, facilitate a successful transition to adult care, and address a critical gap in the quality of care for youths with OI. OBJECTIVE: The study objectives are to (1) design and develop an English and French version of the Teens OI and (2) test the usability of the Teens OI in terms of efficiency, effectiveness, and satisfaction from the perspectives of youths with OI and their parents. METHODS: A user-centered design is presently in progress to design and develop Teens OI. A "Website Design and Development Council" (ie, Council) has been convened, with 20 youths and parent dyads recruited and global experts surveyed at an international meeting. With unanimous support from the Council, usability testing of the Teens OI will ensue in 4 iterative cycles with 32 youth-parent dyads. All sociodemographic and usability metrics will be descriptively analyzed. All recorded interview and focus group data are analyzed using content analysis techniques involving an iterative process of data reduction, data display, conclusion drawing, and verification. RESULTS: As of December 2022, an 8-person, interdisciplinary Teens OI council, comprising 4 health care professionals, 3 youths and young adults with OI, and 1 parent, has been convened to oversee the design and development of Teens OI. Two cycles of interviews have been conducted with 10 youths with OI with or without their parents (n=6) from December 2021 to September 2022. Data analysis has been in progress since April 2022. Aim 2 is ethically approved and will commence following the completion of content development, expected by late July 2023. Preliminary analysis indicates that the following topics need to be prioritized for the youths: mental health, pain, accessibility, medical care, education, community, and parental care. CONCLUSIONS: The proposed study will design and develop a self-management and transitional care program for youths with OI in partnership with patients, caregivers, and health care professionals. This study leverages youths' openness to adopt eHealth technologies to meet their needs and has the potential to actively engage them to autonomously manage their lifelong conditions, and facilitate a successful transition to adult health care. Finally, the proposed study will also address a critical gap in the quality of care and the growing concern that the OI population transitioning from pediatric to adult care is at risk of various adverse events associated with the transition. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47524.

Mitigating the Denosumab-Induced Rebound Phenomenon with Alternating Short- and Long-Acting Anti-resorptive Therapy in a Young Boy with Severe OI Type VI.

Osteogenesis imperfecta (OI) type VI, a recessively inherited form of OI caused by mutations in SERPINF1, is a severe form distinguished by osteomalacia on bone histomorphometry. We describe a boy with severe OI type VI who was initially treated with intravenous (IV) zoledronic acid (ZA) at 1.4 years of age; however, a year later he transitioned to denosumab 1 mg/kg sub-cutaneously every three months in an effort to decrease fracture rates. After two years on denosumab, he presented with symptomatic hypercalcemia due to the denosumab-induced, hyper-resorptive rebound phenomenon. Laboratory parameters at the time of the rebound were as follows: elevated serum ionized calcium (1.62 mmol/L, N 1.16-1.36), elevated serum creatinine due to hypercalcemia-induced muscle catabolism (83 µmol/L, N 9-55), and suppressed parathyroid hormone (PTH) (< 0.7 pmol/L, N 1.3-5.8). The hypercalcemia was responsive to low-dose IV pamidronate, with a rapid decline in serum ionized calcium, and otherwise normalization of the aforementioned parameters within 10 days. To benefit from the powerful, albeit short-term, anti-resorptive effect of denosumab without further rebound episodes, he was treated thereafter with denosumab 1 mg/kg alternating every three months with IV ZA 0.025 mg/kg. Five years later, he remained on dual alternating anti-resorptive therapy without further rebound episodes, and an overall improvement in his clinical status. This novel pharmacological approach of alternating short- and long-term anti-resorptive therapy every three months has not previously been described. Our report suggests this strategy may be an effective method for prevention of the rebound phenomenon in select children for whom denosumab may be beneficial.

From "ACAN" to "I CAN": Restoring wellness in a boy with severe osteochondritis dissecans through diagnostic precision combined with optimal medical, surgical and rehabilitation management.

Osteochondritis dissecans (OCD) is a disease of the joints characterized by idiopathic focal subchondral lesions. Aggrecan, a proteoglycan encoded by the ACAN gene, is important for cartilage structure and function. We describe the clinical evolution of a patient with short stature, multi-focal OCD, and subchondral osteopenia that appeared linked to a novel pathogenic ACAN variant. A multi-disciplinary approach including medical (bisphosphonate) therapy, surgical intervention and rehabilitation were successful in restoring wellness and physical function.

Effect of sclerostin inactivation in a mouse model of severe dominant osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a rare bone disease that is associated with fractures and low bone mass. Sclerostin inhibition is being evaluated as a potential approach to increase bone mass in OI. We had previously found that in Col1a1Jrt/+ mice, a model of severe OI, treatment with an anti-sclerostin antibody had a minor effect on the skeletal phenotype. In the present study, we assessed the effect of genetic sclerostin inactivation in the Col1a1Jrt/+ mouse. We crossed Col1a1Jrt/+ mice with Sost knockout mice to generate Sost-deficient Col1a1Jrt/+ mice and assessed differences between Col1a1Jrt/+ mice with homozygous Sost deficiency and Col1a1Jrt/+ mice with heterozygous Sost deficiency. We found that Col1a1Jrt/+ mice with homozygous Sost deficiency had higher body mass, femur length, trabecular bone volume, cortical thickness and periosteal diameter as well as increased biomechanical parameters of bone strength. Differences between genotypes were larger at the age of 14 weeks than at 8 weeks of age. Transcriptome analysis of RNA extracted from the tibial diaphysis revealed only 5 differentially regulated genes. Thus, genetic inactivation of Sost increased bone mass and strength in the Col1a1Jrt/+ mouse. It appears from these observations that the degree of Sost suppression that is required for eliciting a beneficial response can vary with the genetic cause of OI.

Bi-allelic mutation in SEC16B alters collagen trafficking and increases ER stress.

Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous disorder characterized by bone fragility and reduced bone mass generally caused by defects in type I collagen structure or defects in proteins interacting with collagen processing. We identified a homozygous missense mutation in SEC16B in a child with vertebral fractures, leg bowing, short stature, muscular hypotonia, and bone densitometric and histomorphometric features in keeping with OI with distinct ultrastructural features. In line with the putative function of SEC16B as a regulator of trafficking between the ER and the Golgi complex, we showed that patient fibroblasts accumulated type I procollagen in the ER and exhibited a general trafficking defect at the level of the ER. Consequently, patient fibroblasts exhibited ER stress, enhanced autophagosome formation, and higher levels of apoptosis. Transfection of wild-type SEC16B into patient cells rescued the collagen trafficking. Mechanistically, we show that the defect is a consequence of reduced SEC16B expression, rather than due to alterations in protein function. These data suggest SEC16B as a recessive candidate gene for OI.

Standardized growth charts for children with osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is associated with short stature, which is mild, severe and moderate in OI types I, III and IV, respectively. Standardized OI type- and sex-specific growth charts across all pediatric ages do not exist. METHODS: We assessed 573 individuals with OI (type I, III or IV), each with at least one height measurement between ages 3 months and 20 years (total 6523 observations). Analogous to the Centers for Disease Control pediatric growth charts, we generated OI type- and sex-specific growth charts for infants (ages 3-36 months) as well as children and adolescents (ages 2-20 years). Growth curves were fitted to the data using the LMS method and percentiles were smoothed. RESULTS: Age was associated with a decline in height z-scores (p < 0.001 for all OI types), which was more pronounced in females. Height multiplier curves were produced to predict adult height in children with OI. Among individuals with OI type I, those with COL1A1 pathogenic variants leading to haploinsufficiency were taller than those with COL1A1 or COL1A2 pathogenic variants not leading to haploinsufficiency. CONCLUSION: Our standardized OI type- and sex-specific growth charts can be used to assess the growth of individuals with OI from infancy to adulthood. IMPACT: Standardized osteogenesis imperfecta (OI) type- and sex-specific growth charts across all pediatric ages do not exist. Our study is the first to generate OI type- and sex-specific growth charts across all pediatric ages. Our height multiplier curves can be utilized to predict adult height in children with OI.

Effect of Vitamin D Supplementation on Bone Mass in Infants With 25-Hydroxyvitamin D Concentrations Less Than 50 nmol/L: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

Importance: The dose of supplemental vitamin D needed in infants born with serum 25-hydroxyvitamin D (25[OH]D) concentrations less than 50 nmol/L (ie, 20 ng/mL) is unclear. Objective: To determine whether a higher dose (1000 IU vs 400 IU per day) is required in infants born with 25(OH)D concentrations less than 50 nmol/L for bone mineral accretion across infancy. Design, Setting, and Participants: In this prespecified secondary analysis of a double-blinded randomized clinical trial, conducted from March 2016 to March 2019 in a single center in Greater Montreal, Quebec, Canada, a consecutive sample of 139 healthy term singletons were recruited from 866 infants screened for vitamin D status at birth. Data were analyzed from June 2021 to November 2022. Interventions: Capillary blood was collected 24 to 36 hours after birth to measure serum total 25(OH)D concentrations. Infants with 25(OH)D concentrations less than 50 nmol/L were randomized to receive either 1000 IU or 400 IU per day of oral vitamin D3 supplementation from age 1 to 12 months. Infants with 25(OH)D concentrations of 50 nmol/L or greater formed a reference group. Main Outcomes and Measures: Measures at age 1, 3, 6, and 12 months were preplanned and included whole-body bone mineral content, lumbar spine bone mineral content, and bone mineral density using dual-energy x-ray absorptiometry, and serum 25(OH)D3 using liquid chromatography tandem mass spectrometry. Results: Of 139 included infants, 81 (58.3%) were male, and the median (IQR) gestational age at birth was 39.6 (38.9-40.6) weeks. A total of 49 infants were included in the 1000 IU per day group, 49 infants in the 400 IU per day group, and 41 in the reference group. Mean (SD) whole-body bone mineral content was not different between trial groups over time (1000 IU per day, 173.09 [2.36] g; 400 IU per day, 165.94 [66.08] g). Similarly, no differences were observed in lumbar spine bone mineral content or density. Mean (SD) serum 25(OH)D3 concentrations were significantly higher in the 1000 IU per day group from age 3 to 12 months (3 months, 115.2 [35.3] nmol/L; 6 months, 121.6 [34.4] nmol/L; 12 months, 99.6 [28.8] nmol/L) compared with the 400 IU per day trial group (3 months, 77.4 [23.3] nmol/L; 6 months, 85.1 [18.6] nmol/L; 12 months, 82.3 [14.3] nmol/L). Conclusions and Relevance: In this study, a higher dose of vitamin D supplementation in infants born with 25(OH)D concentrations less than 50 nmol/L did not present advantages to bone mass in infancy. This study supports a standard dose of 400 IU per day of vitamin D supplementation for breastfed infants in Montreal. Trial Registration: ClinicalTrials.gov Identifier: NCT02563015.