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.
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.
X-linked hypophosphatemia (XLH) is caused by an inactivating mutation in the phosphate-regulating endopeptidase X-linked (
) 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 antibody.
This 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).
The linear growth of all patients improved significantly (mean height z-score: from -1.70 ± 0.80 to -0.96 ± 1.08,
=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.
Cardiologic 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.
Aims
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.
Methods
Case-scenarios and review of the literature.
Results
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.
Conclusion
Unraveling the precise genetic cause for the clinical manifestations led to the prediction of phenotypic manifestations, and enhanced the clinical outcomes.
Cyclical iv therapy with pamidronate improves the clinical course in children and adolescents with osteogenesis imperfecta (OI). In this study we evaluated the effect of this therapy on bone and ...mineral metabolism in 165 patients with OI types I, III, and IV (age, 2 wk to 17.9 yr; 86 girls and 79 boys). All patients received iv pamidronate infusions on 3 successive days, administered at age-dependent intervals of 2–4 months. During the 3 d of the first infusion cycle, serum concentrations of ionized calcium dropped by 0.14 ± 0.008 mmol (mean ± se; P < 0.001), and serum PTH levels transiently almost doubled (P < 0.001). At the same time, urinary excretion of the bone resorption marker type I collagen N-telopeptide related to creatinine (uNTX/uCr) decreased by 61–73% (P < 0.001). Two to 4 months later, ionized calcium had returned to pretreatment levels, and uNTX/uCr remained 30–35% lower than at baseline (P < 0.001). During 4 yr of pamidronate therapy (n = 40 patients), ionized calcium levels remained stable, but PTH levels increased by about 30% (P < 0.01). uNTX/uCr, expressed as a percentage of the age- and sex-specific mean value in healthy children, decreased from 132 ± 13% (mean ± se) at baseline to 49 ± 3% after 4 yr of therapy (P < 0.001). In conclusion, serum calcium levels can decrease considerably during and after pamidronate infusions, requiring close monitoring especially at the first infusion cycle. In long-term therapy, bone turnover is suppressed to levels lower than those in healthy children. The consequences of chronically low bone turnover in children with OI are unknown at present.
ObjectiveTo evaluate the efficacy and safety of zolmitriptan nasal spray (ZNS) in the acute treatment of migraine headache in patients aged 6 to 11 years.BackgroundTriptans have demonstrated efficacy ...in adults, but pediatric studies of these agents have largely failed and there are few triptan options for these patients. Because lack of response to 1 triptan does not necessarily preclude response to an alternate triptan, additional triptan options for pediatric patients are desirable.MethodsThis Phase 3, randomized, double‐blind, placebo‐controlled, multicenter crossover trial with an open‐label extension enrolled patients aged 6 to 11 years with a diagnosis of migraine for ≥6 months and ≥16 headache‐free days/month (N = 373). After a run‐in period to eliminate placebo responders, 186 patients were randomized within their body weight stratum to ZNS followed by matching placebo, or placebo followed by matching ZNS. Patients <50 kg who were randomly allocated to ZNS were randomized to 5:1 to ZNS 2.5 or 1.0 mg; those ≥50 kg were randomized 5:1 to ZNS 5.0 or 2.5 mg. Patients had 6 weeks to treat 1 moderate to severe migraine headache and then crossed over to the alternate arm, during which they had 6 weeks to treat a second migraine attack. Patients could participate in a subsequent 6‐month outpatient open‐label extension. The primary efficacy endpoint was pain‐free status at 2 h in patients treated with the high dose from each stratum.ResultsThe trial was terminated early due to slow enrollment. Three hundred patients (mean age, 9 years) entered the placebo run‐in period and 186 entered the double‐blind period. Pain‐free status at 2 h postdose was achieved by 45/133 (33.8%) and 30/128 (23.4%) of patients who received high‐dose ZNS and placebo, respectively (p = 0.0777; odds ratio OR 1.51; 95% confidence interval CI 0.96, 2.38). Several secondary endpoints achieved statistical significance. There were few treatment‐related adverse events and none led to discontinuation. ZNS retained efficacy and demonstrated a consistent safety profile throughout the 6‐month open‐label extension.ConclusionThe effect of high‐dose ZNS on the primary endpoint of pain‐free status at 2 h did not achieve statistical significance. ZNS was safe and well tolerated in this pediatric population.
Objective
To evaluate the efficacy and safety of zolmitriptan nasal spray (ZNS) in the acute treatment of migraine headache in patients aged 6 to 11 years.
Background
Triptans have demonstrated ...efficacy in adults, but pediatric studies of these agents have largely failed and there are few triptan options for these patients. Because lack of response to 1 triptan does not necessarily preclude response to an alternate triptan, additional triptan options for pediatric patients are desirable.
Methods
This Phase 3, randomized, double‐blind, placebo‐controlled, multicenter crossover trial with an open‐label extension enrolled patients aged 6 to 11 years with a diagnosis of migraine for ≥6 months and ≥16 headache‐free days/month (N = 373). After a run‐in period to eliminate placebo responders, 186 patients were randomized within their body weight stratum to ZNS followed by matching placebo, or placebo followed by matching ZNS. Patients <50 kg who were randomly allocated to ZNS were randomized to 5:1 to ZNS 2.5 or 1.0 mg; those ≥50 kg were randomized 5:1 to ZNS 5.0 or 2.5 mg. Patients had 6 weeks to treat 1 moderate to severe migraine headache and then crossed over to the alternate arm, during which they had 6 weeks to treat a second migraine attack. Patients could participate in a subsequent 6‐month outpatient open‐label extension. The primary efficacy endpoint was pain‐free status at 2 h in patients treated with the high dose from each stratum.
Results
The trial was terminated early due to slow enrollment. Three hundred patients (mean age, 9 years) entered the placebo run‐in period and 186 entered the double‐blind period. Pain‐free status at 2 h postdose was achieved by 45/133 (33.8%) and 30/128 (23.4%) of patients who received high‐dose ZNS and placebo, respectively (p = 0.0777; odds ratio OR 1.51; 95% confidence interval CI 0.96, 2.38). Several secondary endpoints achieved statistical significance. There were few treatment‐related adverse events and none led to discontinuation. ZNS retained efficacy and demonstrated a consistent safety profile throughout the 6‐month open‐label extension.
Conclusion
The effect of high‐dose ZNS on the primary endpoint of pain‐free status at 2 h did not achieve statistical significance. ZNS was safe and well tolerated in this pediatric population.
Purpose
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.
Methods
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.
Results
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.
Conclusion
Surgical treatment of severe spine deformity in OI patients with cementless posterior spinal fusion is safe and effective after applying a specific preoperative strategy.
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