Vosoritide Therapy in Children with Achondroplasia: Early Experience and Practical Considerations for Clinical Practice.

INTRODUCTION: Vosoritide is the first precision medical therapy approved to increase growth velocity in children with achondroplasia. Sharing early prescribing experiences across different regions could provide a framework for developing practical guidance for the real-world use of vosoritide. METHODS: Two meetings were held to gather insight and early experience from experts in Europe, the Middle East, and the USA. The group comprised geneticists, pediatric endocrinologists, pediatricians, and orthopedic surgeons. Current practices and considerations for vosoritide were discussed, including administration practicalities, assessments, and how to manage expectations. RESULTS: A crucial step in the management of achondroplasia is to determine if adequate multidisciplinary support is in place. Training for families is essential, including practical information on administration of vosoritide, and how to recognize and manage injection-site reactions. Advocated techniques include establishing a routine, empowering patients by allowing them to choose injection sites, and managing pain. Patients may discontinue vosoritide if they cannot tolerate daily injections or are invited to participate in a clinical trial. Clinicians in Europe and the Middle East emphasized the importance of assessing adherence to daily injections, as non-adherence may impact response and reimbursement. Protocols for monitoring patients receiving vosoritide may be influenced by regional differences in reimbursement and healthcare systems. Core assessments may include pubertal staging, anthropometry, radiography to confirm open physes, the review of adverse events, and discussion of concomitant or new medications-but timing of these assessments may also differ regionally and vary across institutions. Patients and families should be informed that response to vosoritide can vary in both magnitude and timing. Keeping families informed regarding vosoritide clinical trial data is encouraged. CONCLUSION: The early real-world experience with vosoritide is generally positive. Sharing these insights is important to increase understanding of the practicalities of treatment with vosoritide in the clinical setting.

Left atrial remodelling among Turner syndrome patients: novel insights from non-invasive 3D echocardiography.

Background: To assess (I) the left atrial (LA) size, function and (II) the impact of excess weight on the LA and left ventricular (LV) performance in Turner syndrome (TS) patients. Methods: Twenty-five TS patients without congenital heart disease (CHD) and 19 healthy, age-matched controls underwent three-dimensional echocardiography (3DE) for LA volume measurements and two-dimensional speckle tracking echocardiography (2DSTE) for LA strain measurements. LV performance was measured through LV Tei-index, indexed isovolumetric contraction (ICT/√RR interval), indexed relaxation (IVRT/√RR interval) and indexed filling time (FT/√RR interval). Results: Compared to healthy controls, normal-weight TS patients (n=16) displayed significantly increased heart rate (92.88±16.66 vs. 76.53±15.65 bpm; P=0.005), reduced indexed LV filling time (11.67±2.55 vs. 15.16±5.07; P=0.018), reduced 3D maximum LA volume at LV end systole/BSA (16.74±5.00 vs. 19.89±4.32 mL/m2; P=0.05), reduced 3D LA total emptying volume/BSA [10.04 (5.05/18.46) vs. 13.11 (7.69/18.46) mL/m2; P=0.001] and reduced 3D LA active emptying volume/BSA [2.61 (0.1/3.82) vs. 3.44 (1.64/6.37) mL/m2; P=0.006]. Compared to normal-weight TS patients, overweight/obese TS patients (n=9) showed impaired LV Tei-index [0.38 (0.26/0.55) vs. 0.27 (0.07/0.41); P=0.009], prolonged indexed IVRT (2.04±0.72 vs. 1.30±0.64; P=0.015), prolonged indexed ICT [1.96 (1.57/2.73) vs. 1.29 (0.35/2.69); P=0.009] and increased 3D LA active emptying volume/BSA (3.38±1.21 vs. 2.29±1.07 mL/m2; P=0.032). Conclusions: Normal-weight TS patients with increased heart rate and reduced LV filling time display subtle LV diastolic dysfunction in the form of reduced LA reservoir and pump function. Manifested systolic and diastolic LV dysfunction among overweight TS patients is partially compensated through an increase in LA active pump function.

Cardiovascular safety of growth hormone treatment in Noonan syndrome: real-world evidence.

Objective: The study aims to assess the cardiovascular safety of growth hormone (GH) treatment in patients with Noonan syndrome (NS) in clinical practice. Design: The study design involves two observational, multicentre studies (NordiNet® IOS and the ANSWER Program) evaluating the long-term effectiveness and safety of GH in >38,000 paediatric patients, of which 421 had NS. Methods: Serious adverse events, serious adverse reactions (SARs) and non-serious adverse reactions (NSARs) were reported by the treating physicians. Cardiovascular comorbidities at baseline and throughout the studies were also recorded. Results: The safety analysis set comprised 412 children with NS (29.1% females), with a mean (s.d.) baseline age of 9.29 (3.88) years, treated with an average GH dose of 0.047 (0.014) mg/kg/day during childhood. Cardiovascular comorbidities at baseline were reported in 48 (11.7%), most commonly pulmonary valve stenosis (PVS) and atrial septal defects. Overall, 22 (5.3%) patients experienced 34 safety events. The most common were the NSARs: headache (eight events in seven patients) and arthralgia (five events in three patients). Two SARs occurred in one patient (brain neoplasm and metastases to spine). No cardiovascular safety events were recorded in patients with NS. Five cardiovascular comorbidities in five patients were reported after initiation of GH treatment: three cases of unspecified cardiovascular disease, one ruptured abdominal aortic aneurysm and one PVS. Conclusions: GH treatment had a favourable safety profile in patients with NS, including those with cardiovascular comorbidities. Prospective studies are warranted to systematically assess the safety of GH treatment in patients with NS and cardiovascular disease.

Age, American Thyroid Association Risk Group, and Response to Therapy Are Prognostic Factors in Children With Differentiated Thyroid Cancer.

CONTEXT: Against the background of increasing incidence, pediatric differentiated thyroid carcinoma (DTC) frequently presents with advanced disease and high recurrence rates while prognosis remains excellent. BACKGROUND: We investigated the use of a pediatric classification and an adult response to therapy risk stratification for pediatric DTC patients and their implications for adaptation of treatment and follow-up. METHODS: Data from patients aged <18 years with a diagnosis of primary DTC, registered with the German Pediatric Oncology Hematology-Malignant Endocrine Tumor registry since 1995, were analyzed. For risk prediction, patients were retrospectively assigned to the American Thyroid Association (ATA) risk groups and evaluated for response to therapy. RESULTS: By October 2019, 354 patients with DTC had been reported (median age at diagnosis 13.7 years, range 3.6-17.9) with lymph node and distant metastases in 74.3% and 24.5%. Mean follow-up was 4.1 years (range 0-20.6). Ten-year overall and event-free survival (EFS) rates were 98.9% and 78.1%. EFS was impaired for patients with lymph node and distant metastases (P < .001), positive postoperative thyroglobulin (P = .006), incomplete resection (P = .002), sequential surgeries to achieve total thyroidectomy (P = .042), invasion of capsule (P < .001) and lymph vessels (P = .005), infiltration of surrounding soft tissues (P < .001), tumor multifocality (P < .001), ATA intermediate- and high-risk group (P < .001), and age <10 years (P < .001). Multivariate analysis revealed age <10 years at diagnosis, ATA high-risk level, and poor response to therapy as significant negative prognostic factors for EFS. CONCLUSION: Age, ATA risk group, and response to therapy emerged as significant prognostic factors for EFS in pediatric patients with DTC, requiring risk-adapted individualized therapy and follow-up.

Long-Term Safety of Growth Hormone Treatment in Childhood: Two Large Observational Studies: NordiNet IOS and ANSWER.

CONTEXT: Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised. OBJECTIVE: This work aims to assess the long-term safety of GH treatment in clinical practice. METHODS: Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose. RESULTS: The combined studies comprised 37 702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130 476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P = .003 and P = .001, respectively) and the non-SGA subgroup (both P = .002), and for SAEs in the intermediate- and high-risk groups (P = .002 and P = .05, respectively). CONCLUSIONS: We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

Assessment of left ventricular myocardial work in Turner syndrome patients: insights from the novel non-invasive pressure-strain loop analysis method.

BACKGROUND: Turner syndrome (TS), a relatively rare chromosomal disease, is associated with multiple cardiovascular risk factors that possibly lead to increased left ventricular afterload and functional impairment. The aim of this study was to investigate whether alterations in myocardial work and work efficiency can be found in TS patients through left ventricular pressure-strain loop analysis (PSL). METHODS: Thirty-eight patients with TS and 19 healthy, age-matched controls were recruited for this study. Global peak systolic strain (GLPS) and PSL of the left ventricle was assessed in study participants. TS patients whose history included coarctation of the aorta or prior cardiac surgery were excluded from GLPS and PSL analyses (n=5). RESULTS: Median age was 16.00 years in the TS group and 16.35 years in the control group (P=0.236). GLPS did not show significant differences between both groups (P=0.524). TS patients demonstrated, compared to controls, a significantly higher global myocardial work index (BSA) (mean ± SD: 1,497±505 vs. 1,214±245 mmHg*%/m2; P=0.027). Heart rate was significantly increased in TS patients, compared to controls (mean ± SD: 90.08±14.79 vs. 73.95±15.05 bpm; P<0.001), and correlated significantly with global myocardial work index [body surface area (BSA)] within the TS cohort (r=0.558, P=0.001). CONCLUSIONS: TS patients showed signs of increased myocardial workload that were only detectable through the novel PSL analysis method and not through GLPS. Moreover, elevated resting heart rate was linked with increased myocardial workload in TS patients. Further studies will have to investigate whether TS patients may develop advanced left ventricular systolic dysfunction later in life.

Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome.

INTRODUCTION: Few data exist on long-term growth hormone (GH) treatment in patients with Noonan syndrome (NS). OBJECTIVE: To evaluate the effectiveness and safety of GH treatment in NS in clinical practice. METHODS: Height gain, near-adult height (NAH), and safety were assessed in 2 complementary non-interventional studies: NordiNet® IOS and ANSWER. The safety analysis included 412 patients, and the effectiveness analysis included 84 GH-treated patients (male, n = 67) with ≥4 years' height standard deviation score (HSDS) data. HSDS was determined using national reference (NR) and NS-specific (NSS) data. RESULTS: The mean (SD) baseline age was 8.38 (3.57) years; HSDS, -2.76 (1.03); GH dose, 41.6 (11.1) µg/kg/day. The mean (SD) HSDS increase from baseline (ΔHSDS) was 0.49 (0.37) (first year), 0.79 (0.58) (second year), and 1.01 (0.60) (third year) (NR). The mean (SD) HSDS at year 3 was -1.66 (1.00) (NR; 1.06 [1.12] [NSS]). Twenty-four patients achieved NAH. The mean (SD) NAH SDS (NR) was -1.51 (0.60) (154.90 [3.21] cm) in females and -1.79 (1.09) (165.61 [7.19] cm) in males; 70.8% (17/24) had NAH SDS ≥ -2. Adverse drug reactions and GH-unrelated serious adverse events (n = 34) were reported in 22/412 (5.3%) patients. Four neoplasms and 3 cases of scoliosis were reported; no cardiovascular adverse events occurred. CONCLUSIONS: GH-treated children with NS achieved substantial height gain during the first 3 years of follow-up. Overall, 24 patients achieved NAH, with 70.8% having NAH SDS ≥ -2. There was no evidence to support a higher prevalence of neoplasm, or cardiac or other comorbidities.

Diabetes mellitus in pediatric solid organ recipients without and with cystic fibrosis: An analysis from the German-Austrian diabetes database (Diabetes Patienten Verlaufsdokumentation).

INTRODUCTION: Posttransplantation diabetes mellitus (PTDM) increases the risk of cardiovascular disease, graft loss, and decreased survival. Follow-up treatment after solid organ transplantation (SOT) needs to focus on, inter alia, maintaining balanced glucose metabolism. This study aimed to ascertain the prevalence of PTDM and describe patient characteristics in the large DPV (Diabetes Patienten Verlaufsdokumentation) pediatric diabetes database. METHODS: DPV data of 71 902 patients from the January 01, 1995 to January 04, 2015 period were analyzed for patients with and without cystic fibrosis (CF) after SOT (kidney, liver, heart, and lung). Multivariable analysis served to assess differences between SOT patient groups at risk for developing diabetes. RESULTS: Out of 109 SOT patients, 51 had CF; 72.5% received steroids and 62% were additionally given tacrolimus. PTDM developed in 45% of CF patients and 12% of non-CF patients. SOT patients were older at diabetes onset (mean age, 12.50 ± 3.98 years), shorter (height z-score, -1.67 ± 1.25), and lighter (weight z-score, -1.59 ± 1.57) than non-SOT diabetes patients (P < 0.01). With transplantation, glycated hemoglobin (HbA1c) was significantly lower and treatment for hypertension and dyslipidemia was increased. Among SOT patients, weight and body mass index (BMI) z-scores were significantly lower in patients with CF-related diabetes (P < 0.05). CONCLUSIONS: SOT was present in 6.6% of children with diabetes, and this might aggravate the risk of cardiovascular disease in populations with already increased rates of hypertension and dyslipidemia. Dystrophy and short stature were also present, particularly in transplant recipients with CF and diabetes. Comorbidities and long-term consequences call for multidisciplinary collaboration.

Vascular risk factors in children, adolescents, and young adults with type 1 diabetes complicated by celiac disease: results from the DPV initiative.

OBJECTIVE: Celiac disease (CD) is a common comorbidity of type 1 diabetes (T1D). Long-term consequences of CD are not completely understood, and adhering to a gluten-free diet is a burden for many patients. We investigated the effect of CD on vascular risk factors in a large cohort of T1D patients aged <20 yr. RESEARCH DESIGN AND METHODS: Within the longitudinal Diabetes Patienten Verlaufsdokumentation (DPV)-diabetes registry, data were analyzed from 59,909 < 20-yr-old T1D patients treated at 392 centers in Germany and Austria. A total of 974 patients with biopsy-proven celiac disease (BPCD) were compared with 28,398 patients without CD with respect to blood pressure (BP), lipids, glycohemoglobin (HbA1c ), body mass index (BMI), and reported smoking behavior. RESULTS: Patients with T1D and BPCD showed significantly lower high-density lipoprotein (HDL) cholesterol levels [median (interquartile range): 53.0 (43.0-62.6) mg/dL] than patients without CD [55.0 (45.0-66.0) mg/dL; p < 0.01; p < 0.001 after adjustment for confounding variables]. Systolic BP was lower in patients with CD [105.5 (100.0-112.5) mmHg] than in patients without CD [110.0 (102.0-117.0) mmHg; p < 0.0001; p < 0.001 after adjustment]. There were no significant differences regarding smoking behavior, BMI, or HbA1c . In a subgroup of 335 patients with BPCD, HDL cholesterol was measured 1 yr after diagnosis of CD:HDL increased by 8% (p < 0.01). CONCLUSION: Young people with T1D and CD have lower HDL cholesterol values than patients without CD. As low HDL cholesterol is associated with vascular risk, our findings support screening for CD and monitoring of HDL cholesterol in young people with T1D.

Hyperthyroidism in 276 Children and Adolescents with Type 1 Diabetes from Germany and Austria.

BACKGROUND/AIMS: Little is known about the incidence and clinical consequences of hyperthyroidism in pediatric patients with type 1 diabetes mellitus (T1DM). METHODS: We analyzed the DPV database (Diabetes Prospective Follow-Up Registry) to investigate the rate of hyperthyroidism in pediatric T1DM patients, its impact on metabolic control, and potential associations with organ-specific autoantibodies. RESULTS: Hyperthyroidism was found in 276/60,456 patients (0.46%) and was associated with younger age, shorter diabetes duration, female sex, and reduced body mass index. Diabetic ketoacidosis (DKA) and hypoglycemia were more frequent in T1DM with comorbid hyperthyroidism, while long-term metabolic control (HbA1c) was similar in both groups. Absolute blood pressure and arterial hypertension rate were elevated in the hyperthyroid patients. Rates of microalbuminuria and diabetic retinopathy were not different. Thyroid-specific antibodies (thyroid peroxidase, thyroglobulin, thyroid receptor) were associated with hyperthyroidism. Thyroid volume and rates of cysts and nodules were higher, and echogenicity was decreased. CONCLUSION: Prevalence of hyperthyroidism is low in diabetic children with T1DM but increased compared to children <18 years without diabetes. Hyperthyroidism is primarily associated with acute diabetes complications (DKA and hypoglycemia) and affects blood pressure regulation. Long-term metabolic control or insulin requirement were not different.

Microvascular Complications in Childhood-Onset Type 1 Diabetes and Celiac Disease: A Multicenter Longitudinal Analysis of 56,514 Patients From the German-Austrian DPV Database.

OBJECTIVE: To investigate whether celiac disease (CD) associated with type 1 diabetes increases the risk of microvascular complications. RESEARCH DESIGN AND METHODS: Patients (n = 56,514) aged >10 years with diabetes duration <20 years from 392 centers in Germany and Austria were assigned to one of three categories (n): no CD (50,933), biopsy-confirmed CD (812), or suspected CD (4,769; clinical diagnosis or positive antibodies). The confirmed and suspected groups were combined and analyzed for retinopathy or nephropathy. Cox proportional hazards regression was used to adjust for potential confounders (glycated hemoglobin [HbA1c], age at diabetes onset, sex, smoking, dyslipidemia, and hypertension). RESULTS: Kaplan-Meier analysis revealed that retinopathy and nephropathy occurred earlier in the presence versus absence of CD: retinopathy at age 26.7 years (95% CI 23.7-30.2) in 25% of patients with CD vs. age 33.7 years (33.2-34.4) in 25% without CD and microalbuminuria at age 32.8 years (29.7-42.5) vs. 42.4 years (41.4-43.3). The adjusted risk for both retinopathy (hazard ratio 1.263 [95% CI 1.078-1.481]) and nephropathy (1.359 [1.228-1.504]) was higher in patients with diabetes and CD versus those without CD. Cox regression revealed CD as an independent risk factor for microvascular complications after adjustment for confounders. CONCLUSIONS: CD is an independent risk factor for retinopathy and nephropathy in patients with type 1 diabetes. Our study therefore supports the recommendation for regular serologic testing for CD, even in the absence of clinical CD. Further prospective studies are required to investigate whether a gluten-free diet might reduce the risk of microvascular disorders in patients with diabetes and CD.

Liver abscess complicated by diaphragm perforation and pleural empyema leads to the discovery of interleukin-1 receptor-associated kinase 4 deficiency.

Interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency predisposes to severe invasive bacterial infections in infancy and early childhood, often with a fatal course caused by a defect in Toll-like receptor and interleukin-1 receptor signaling. Despite severe invasive infections, acute phase responses are often diminished. We report the successful treatment of a child with multiple liver abscesses, diaphragm perforation and pleural empyema, accompanied by strong acute phase responses as a unique presentation of IRAK-4 deficiency.

Blood biomarkers of methylation in Down syndrome and metabolic simulations using a mathematical model.

SCOPE: The study tests the metabolites of the methylation cycle in individuals with Down syndrome (DS) and applies a mathematical model in order to change this cycle by nutritional factors. METHODS AND RESULTS: We measured concentrations of the metabolites related to the methylation cycle in the blood of 35 young individuals with DS and 47 controls of comparable age. Moreover, we applied a mathematical model to learn more about the regulation of the methylation cycle in DS. Concentrations of cystathionine, cysteine, betaine, choline, dimethylglycine, S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), and holotranscobalamin were significantly higher in DS compared to the controls. The median SAM/SAH ratio was lower in DS and that of methionine and reduced glutathione did not differ significantly between the groups. The mathematical model showed that enhanced methionine turnover and accelerated Hcy-remethylation might explain the shift in the methylation cycle in DS. CONCLUSION: In addition to the DS-related excess of cystathionine beta synthase (CBS) activity, increases in the activities of MS and betaine homocysteine methyl transferase, and in methionine input were necessary to account for the changes in metabolite levels observed in DS. A low-methionine diet might offer a perspective for reversing the metabolic imbalance in DS, but this awaits clinical investigations.

Growth hormone therapy and the risk of tumor recurrence after brain tumor treatment in children.

To assess the effect of human growth hormone (hGH) therapy and other factors on tumor recurrence after treatment of pediatric brain tumors (BTs), we retrospectively analyzed data from 108 craniopharyngioma, medulloblastoma, and ependymoma patients. Risk factors were identified using multifactorial univariate regression analysis. Recurrences occurred in 41 and second malignant neoplasms in 4 patients. There were significant correlations for completeness of tumor removal and recurrence-free survival (RFS). 13/44 hGH-treated and 28/59 non-hGH-treated children relapsed. This difference was found only for medulloblastomas and accounted for by higher rates of incomplete tumor removal in non-hGH patients. Craniopharyngioma recurrence correlated only with RFS. Malignant BT recurrence correlated with completeness of tumor removal, chemotherapy, and RFS. 4 children developed SMNs, 3/4 after hGH therapy. Our regression model yielded accurate within-sample prediction of recurrence for 90% of the study population. We conclude that hGH therapy after treatment of pediatric BTs does not increase tumor recurrence risk.