Context:Vosoritide, a C-type natriuretic peptide analogue, is the first approved therapy targeting the pathophysiology of achondroplasia. While clinical trials demonstrate efficacy, individuals with prior orthopedic surgeries are typically excluded, and real-world data remain limited. Objective:To evaluate real-world growth outcomes of vosoritide therapy in children with achondroplasia, including those with prior surgical interventions. Methods:This retrospective analysis included 25 children with achondroplasia (17 boys, age range 2.9-14.3 years) treated with vosoritide for a mean duration of 12.7 months at a multidisciplinary center. Z-scores were calculated using an AI-assisted growth assessment tool previously validated for children with achondroplasia. Δ z-scores for height, sitting height, arm span, and body mass index (BMI) were calculated from baseline to follow-up. Multiple linear regression analyses assessed predictors of response. Results:Mean height z-scores improved from -0.62 ± 1.09 to -0.24 ± 1.20 (P < .001). Mean arm span z-score increased from -1.28 ± 0.93 to -0.96 ± 0.91 (P = .007). Sitting height z-scores showed a non-significant trend toward improvement; BMI z-scores remained stable. Mean Δ height and Δ arm span z-score gains were +0.38 ± 0.45 and +0.32 ± 0.48, respectively. A subgroup analysis of 8 patients with vs 17 without prior limb-lengthening surgery showed no significant differences. Regression analyses adjusted for sex, age, BMI z-scores, and surgical history were likely underpowered to detect meaningful predictors of response. There were no serious treatment-related adverse events. Conclusion:Vosoritide therapy enhanced linear and appendicular growth in a real-world cohort of children with achondroplasia, including post-surgical patients. These findings align with clinical trial data and support the therapy's applicability across diverse clinical profiles.

X-linked hypophosphatemic rickets (XLH) is a rare inherited metabolic bone disorder caused by excess fibroblast growth factor 23 (FGF23), leading to hypophosphatemia and rickets. Burosumab, a human monoclonal antibody targeting FGF23, was approved for the treatment of XLH in April 2018. By 2022, the FDA extended its approval to include children as young as six months of age. To describe three infants with XLH who began burosumab therapy before one year of age and were monitored for at least one year. Case series. Clinical outcomes, including anthropometric measures, skeletal outcomes (Rickets Severity Score [RSS], mechanical axis deviation [MAD], and neck-shaft angle [NSA]), and laboratory parameters, were assessed in a real-world setting. Two patients demonstrated satisfactory linear growth, and one experienced growth faltering, possibly due to sleep-disordered breathing or phosphate imbalance. These patients received higher doses of burosumab than the current guideline recommendations for achieving treatment goals aimed at normalizing phosphate levels. The patient’s phosphate levels improved but did not normalize. Bone pain was not formally assessed, but parents reported improvements in their children’s conditions. Importantly, two patients with assessable mechanical axes demonstrated neutral mechanical axis deviations, indicating improved lower limb alignment and supporting the therapeutic efficacy of burosumab. All three patients had favorable RSS outcomes, and none developed long bone diaphyseal bowing or coxa vara following this early initiation of burosumab treatment. This case series demonstrated potential benefits of early initiation of burosumab treatment for XLH by showing improvements in growth, phosphate levels, and skeletal outcomes. Burosumab appears well tolerated in infancy, but further research is needed to refine dosing strategies and assess its long-term safety and therapeutic efficacy in young patients with XLH. Meticulous monitoring and individualized care are essential throughout treatment. This case series followed three infants with X-linked hypophosphatemic rickets (XLH) who initiated burosumab treatment at 6 months of age, filling a significant knowledge gap in early intervention. Despite requiring higher-than-recommended dosing, burosumab demonstrated favorable outcomes in terms of growth parameters and skeletal development over a minimum one-year follow-up. Two patients maintained normal growth trajectories, whereas one experienced temporary growth faltering, which resolved after adenoidectomy. Importantly, neutral mechanical axis deviation was achieved, indicating effective prevention of lower limb deformities. No significant adverse effects were observed. Despite limitations such as a small sample size and short follow-up, these findings suggest that early burosumab therapy can improve outcomes in infantile XLH patients. Further research is needed to refine dosing protocols and assess long-term safety and efficacy in this young population.

OBJECTIVES:Fibrodysplasia ossificans progressiva (FOP) is one of the most catastrophic forms of genetic heterotopic ossification (HO). FOP is characterized by severe, progressive inflammatory flare-ups, that often lead to HO. The flare-ups are associated with increased inflammatory cytokine production, suggesting auto-inflammatory features driven by IL-1β. This study describes the short- and long-term responses of FOP patients to anti-IL-1 therapy. METHODS:Previously, we reported that a patient with FOP treated with anti-IL-1 agents showed dramatically lower rates of flare-ups, improved flare-up symptoms, decreased use of glucocorticoids and apparently decreased size of residual lesions. Plasma analyses also showed marked elevation in IL-1β levels during a FOP flare, further supporting a role of IL-1β in the pathogenesis of FOP flares. Here, we report results from long-term therapy with IL-1 inhibitors in that patient and describe 3 additional patients, from two medical centres. RESULTS:All 4 patients showed persistent improvement in flare activity during treatment with IL-1 inhibitors, with minimal formation of new HO sites. Two patients who stopped therapy experienced a resurgence of flare activity that was re-suppressed upon re-initiation. These patients had IL-1β levels comparable to those in IL-1β-driven diseases. Child Health Assessment Questionnaires confirmed extensive subjective improvements in the pain and general health visual analogue scales. CONCLUSION:This case series demonstrates significant benefits from IL-1 inhibitors for reducing flare activity and improving the general health of patients with FOP. These data provide strong support for additional studies to better understand the function of IL-1 inhibition, primarily in reducing the formation of new HO. FUNDING:RH received support from the International FOP Association ACT grant; ECH received support from NIH/NIAMS R01AR073015 and the UCSF Robert Kroc Chair in Connective Tissue and Rheumatic Diseases III.

IntroductionX-linked hypophosphatemia (XLH) is caused by an inactivating mutation in the phosphate-regulating endopeptidase X-linked (PHEX) gene whose defective product fails to control phosphatonin fibroblast growth factor 23 (FGF23) serum levels. Although elevated FGF23 levels have been linked with detrimental cardiac effects, the cardiologic outcomes in XLH patients have been subject to debate. Our study aimed to evaluate the prevalence and severity of cardiovascular morbidity in pediatric XLH patients before, during, and after a 2-year treatment period with burosumab, a recombinant anti-FGF23 antibodyMethodsThis prospective observational study was conducted in a tertiary medical center, and included 13 individuals with XLH (age range 0.6–16.2 years) who received burosumab every 2 weeks. Clinical assessment at treatment initiation and after .5, 1, and 2 years of uninterrupted treatment included anthropometric measurements and cardiologic evaluations (blood pressure [BP], electrocardiogram, conventional echocardiography, and myocardial strain imaging).ResultsThe linear growth of all patients improved significantly (mean height z-score: from -1.70 ± 0.80 to -0.96 ± 1.08, P=0.03). Other favorable effects were decline in overweight/obesity rates (from 46.2% to 23.1%) and decreased rates of elevated BP (systolic BP from 38.5% to 15.4%; diastolic BP from 38.5% to 23.1%). Electrocardiograms revealed no significant abnormality throughout the study period. Cardiac dimensions and myocardial strain parameters were within the normative range for age at baseline and remained unchanged during the study period.ConclusionCardiologic evaluations provided reassurance that 2 years of burosumab therapy did not cause cardiac morbidity. The beneficial effect of this treatment was a reduction in cardiovascular risk factors, as evidenced by the lower prevalence of both overweight/obesity and elevated BP.

Camurati-Engelmann disease (CED) is an autosomal dominant bone dysplasia characterized by progressive hyperostosis of the skull base and diaphyses of the long bones. CED is further divided into two subtypes, CED1 and CED2, according to the presence or absence of TGFB1 mutations, respectively. In this study, we used exome sequencing to investigate the genetic cause of CED2 in three pedigrees and identified two de novo heterozygous mutations in TGFB2 among the three patients. Both mutations were located in the region of the gene encoding the straitjacket subdomain of the latency-associated peptide (LAP) of pro-TGF-β2. Structural simulations of the mutant LAPs suggested that the mutations could cause significant conformational changes and lead to a reduction in TGF-β2 inactivation. An activity assay confirmed a significant increase in TGF-β2/SMAD signaling. In vitro osteogenic differentiation experiment using iPS cells from one of the CED2 patients showed significantly enhanced ossification, suggesting that the pathogenic mechanism of CED2 is increased activation of TGF-β2 by loss-of-function of the LAP. These results, in combination with the difference in hyperostosis patterns between CED1 and CED2, suggest distinct functions between TGFB1 and TGFB2 in human skeletal development and homeostasis.

BackgroundX-linked hypophosphatemic rickets (XLH) is associated with uninhibited FGF23 activity, which leads to phosphaturia, hypophosphatemia and depressed active vitamin D (1,25OH2D) levels. Conventional treatment with phosphate supplements and vitamin D analogs may lead to hypercalciuria (HC), nephrocalcinosis (NC) and hyperparathyroidism. We investigated the effects of burosumab treatment, an anti-FGF23 monoclonal antibody recently approved for XLH, on these complications.MethodsThis retrospective study included children with XLH who were treated with burosumab for at least one year at one of three referral centers. Clinical and biochemical potential treatment outcomes were regularly followed, including multiple urine calcium measurements and NC severity score (0 = no NC, 3 = worse NC).ResultsTwenty-six (13 male) children aged 7.6 ± 3.9 years were followed for 27.5 ± 9.6 months. Mean serum phosphate levels rapidly increased from 2.67 ± 0.61 at baseline to 3.57 ± 0.53 mg/dL after 3 months (p < 0.001) and remained stable thereafter. Concomitant decreases were observed in phosphaturia, serum alkaline phosphatase and parathyroid hormone. HC (U-Ca/Cr > 0.2 mg/mg) was detected in 2/26 (7.7%) patients before burosumab initiation, resolved in one and persisted, albeit improved, in the second. Two patients were newly diagnosed with HC, 15 and 3 months after therapy, which persisted in one of them despite dose reduction attempts. Seven patients had NC at baseline (mean score: 1.8 ± 0.34), but none showed deterioration or developed new NC.ConclusionIn children with XLH treated with burosumab, HC was an infrequent side effect and preexisting NC did not worsen.

To assess the long-term efficacy of burosumab for pediatric patients with X-linked hypophosphatemia, focusing on linear growth. This multi-center retrospective study included 35 pediatric patients who began treatment with burosumab between January 2018 and January 2021. We collected clinical data, anthropometric measurements, laboratory results, and Rickets Severity Score (RSS), from 2 years prior to treatment initiation and up to 4 years after. Burosumab was initiated at a mean age of 7.5 ± 4.4 years (range 0.6–15.9), with a mean initial dose of 0.8 ± 0.3 mg/kg, which was subsequently increased to 1.1 ± 0.4 mg/kg. The patients were followed for 2.9 ± 1.4 years (range 1–4) after initiating burosumab. Serum phosphorus levels increased from 2.7 ± 0.8 mg/dl at burosumab initiation to 3.4 ± 0.6 mg/dl after 3 months and remained stable (p < 0.001). Total reabsorption of phosphorus increased from 82.0 ± 6.8 to 90.1 ± 5.3

The purpose of this study is to present the outcomes all patients with osteogenesis imperfecta (OI) who underwent cementless posterior spinal fusion for the treatment of severe spine deformity in our institution. All patients with OI who underwent surgical correction of their spine deformity in our institution between 2003 and 2020 were enrolled. The collected data included demographics, operative and follow-up findings, medical history, bisphosphonate therapy, HGT protocol, pre- and post-HGT and postoperative scoliosis and kyphosis curve measurements, hospitalization length, complications, and revision surgeries. General treatment strategies included cessation of bisphosphonate therapy around the surgery, 30-day HGT protocol, titanium rods, cementless screw technique, and a high implant density policy. Eleven consecutive patients with OI who underwent surgery for spine deformity in our institution were identified. The mean age at surgery was 15.6 ± 2.3. Mean follow-up period was 6.6 ± 5.8 years. The mean pre- and postoperative scoliosis curves were 85.4 ± 19.3° and 43.1 ± 12.5°, respectively, representing a 49.5% correction rate. Five patients underwent HGT and achieved a mean correction of 27.6 ± 7.1° (31.6%) preoperatively. Implant density ratio was 1.5 (screw or hook/level). Mean postoperative hospitalization length was 5.9 ± 1.6 days. One patient had deep wound infection which resolved following treatment according to our protocol for surgical site infection, and one patient had skull penetration by one of the halo pins. Surgical treatment of severe spine deformity in OI patients with cementless posterior spinal fusion is safe and effective after applying a specific preoperative strategy.

An inactivating PHEX gene mutation with the resultant accumulation of several mineralization-inhibiting proteins (e.g., FGF23) causes skeletal and dental morbidity in X-linked hypophosphatemia (XLH). This prospective case-control study explored the effect of burosumab, an anti-FGF23 antibody, on dental health of children with XLH. Ten children (age 4.3-15 years) with XLH underwent burosumab treatment per protocol. Assessment of their dental status at treatment initiation and after 1 and 3 years of treatment included clinical, laboratory and radiographic evaluation of rickets and dentition. Orthopantomographic examinations of ten healthy sex- and age-matched controls were selected for comparison. Coronal and pulp dimensions of a selected permanent mandibular molar were measured with Planmeca Romexis® software. One year of treatment led to improvement of height z-score (p=0.019) and healing of the rickets (p<0.001) in the XLH patients, and those achievements were maintained after three years of treatment. Dental morphology of XLH patients, distinguished by increased pulp-coronal ratios compared to controls (p=0.002), remained larger after the first year of treatment (p<0.001) and did not attain the decrease expected with age after three years of treatment. Five patients had a history of recurrent dental abscesses, with three having undergone at least one episode during the year before burosumab initiation. One patient sustained recurrent abscesses throughout three years of treatment. The persistence of the unique dental morphology of XLH patients undergoing burosumab therapy, as evidenced by excessively larger pulp dimensions, supports the role of other PHEX gene-related local mineralization inhibitors, such as osteopontin, in the pathogenesis of dental morbidity.

The precision medicine approach of tailoring treatment to the individual characteristics of each patient has been a great success in monogenic diabetes subtypes, highlighting the importance of accurate clinical and genetic diagnoses of the type of diabetes. We sought to describe three unique cases of childhood-onset diabetes in whom skeletal manifestations led to the revelation of a rare type of diabetes. Case-scenarios and review of the literature. Case 1: A homozygous mutation in TRMT10A, a tRNA methyltransferase, was identified in a 15-year-old boy with new-onset diabetes, developmental delay, microcephaly, dysmorphism, short stature and central obesity. The progressive apoptosis of pancreatic beta cells required insulin replacement therapy, with increased demand due to an unfavorable body composition. Case 2: Congenital generalized lipodystrophy type 1 was suspected in an adolescent male with an acromegaloid facial appearance, muscular habitus, and diabetes who presented with a pathological fracture in a cystic bone lesion. A homozygous mutation in AGPAT2, an acyl transferase which mediates the formation of phospholipid precursors, was identified. Leptin replacement therapy initiation resulted in a remarkable improvement in clinical parameters. Case 3: A 12-year-old boy with progressive lower limb weakness and pain was diagnosed with diabetic ketoacidosis. Diffuse diaphyseal osteosclerosis compatible with the diagnosis of Camurati-Engelmann disease and a heterozygous mutation in TGFβ1 were identified. Preservation of euglycemia by insulin replacement relieved pain, suggesting that the diabetic milieu may have augmented TGFβ1 overexpression. Unraveling the precise genetic cause for the clinical manifestations led to the prediction of phenotypic manifestations, and enhanced the clinical outcomes.

Background: Burosumab, a recombinant anti-FGF23 monoclonal antibody, was recently introduced as a treatment for X-linked hypophosphatemia (XLH). Burosumab normalizes blood phosphate levels, thereby healing rickets, decreasing leg bowing, and reducing pain. We aimed to explore the body composition and cardiometabolic health of pediatric patients with XLH treated with burosumab. Methods: This observational real-life study was conducted on growing children and adolescents. The outcome measures included changes in sex- and age-adjusted anthropometric and body composition parameters [fat mass (FM), fat-free mass (FFM), appendicular skeletal muscle mass (ASMM), muscle-to-fat ratio (MFR)], blood pressure, laboratory evaluation, and radiographic rickets severity [Thacher Rickets Severity Score (TRSS)]. Body composition was assessed by bioelectrical impedance analysis (BIA). Percentiles for FFM% and ASMM% were calculated according to BIA pediatric reference curves. The delta variable was calculated as the variable at 12 months minus the variable at baseline. Results: A total of 15 pediatric patients with XLH are treated in our clinic; included in the analyses were 7 children and adolescents (3 males, mean age 8.7 ± 3.2 years) with XLH without comorbidities. Baseline BIA revealed an unfavorable physique, with increased body fat percentage in five patients and decreased muscle mass in six. Indices of lean body mass significantly increased after 6 and 12 months of treatment: FFM(kg) ( p = 0.001, p = 0.046, respectively) and ASMM(kg) ( p = 0.012, p = 0.034, respectively), without any significant change in FM(kg). The percentile of ASMM% increased significantly after 6 months of treatment ( p = 0.006) and stabilized thereafter. TRSS improved significantly after 12 months of therapy ( p = 0.005). Age was positively correlated with delta TRSS ( r = 0.814, p = 0.026), and delta TRSS was negatively correlated with delta MFR ( r = −0.826, p = 0.022). Conclusions: There was a heretofore unrecognized improvement in body composition of growing children and adolescents with XLH who were treated with burosumab. These findings highlight the need to initiate burosumab treatment at a younger age when rickets is less severe.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal malformations including short stature, cone-shaped phalangeal epiphyses and Perthes-like changes of the hip. We describe the response to growth hormone (GH) treatment in a boy with TRPS. The patient presented at age 3.5 years for evaluation of short stature (-3.2SD). On physical examination, the characteristic facial phenotype of TRPS was noted. Radiographs showed cone-shaped phalangeal epiphyses and bilateral small and fragmented femoral heads. The diagnosis was confirmed by Sanger sequencing of the TRPS1 gene. Two GH stimulation tests revealed GH deficiency, and GH treatment was initiated. Subsequently, growth velocity improved, as did the radiographic appearance of the femoral epiphyses, as seen on sequential pelvis radiographs. This observation suggests the possibility of a beneficial effect of GH treatment on both height and epiphyses status in TRPS patient with GH deficiency. Further studies are needed to support the observation.

Variants in genes encoding ribosomal proteins have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. Here, we report one de novo missense variant and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13 (also called eL13), in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G>T, c.477+1G>A, and c.477+2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion. In contrast to observations from Diamond-Blackfan anemia, we detected no evidence of significant pre-rRNA processing disturbance in cells derived from two affected individuals. Consistently, we showed that the insertion-containing protein is stably expressed and incorporated into 60S subunits similar to the wild-type protein. Erythroid proliferation in culture and ribosome profile on sucrose gradient are modified, suggesting a change in translation dynamics. We also provide evidence that RPL13 is present at high levels in chondrocytes and osteoblasts in mouse growth plates. Taken together, we show that the identified RPL13 variants cause a human ribosomopathy defined by a rare skeletal dysplasia, and we highlight the role of this ribosomal protein in bone development.

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin-one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy-and the other for 18years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection. In both patients, FOP progressed despite the use of rapamycin. This report highlights the real-world use of rapamycin in two FOP patients and provides insight into the use of rapamycin in clinical trials for the management of FOP.