Ped endo journal scan

Enhancing accuracy of newborn screening for 21-hydroxylase deficiency (21OHD): Strategic use of 21-deoxycortisol in a large-scale Tokyo cohort

Yamano H, Watanabe K, Komatsu M, Hashimoto A, Suzuki Y, Kirino S, et al. J Clin Endocrinol Metab. 2026 Feb 20;111(3):689-697. doi: 10.1210/clinem/dgaf506. PMID: 40922648.

Objective: The present study aimed to derive and validate a newborn screening algorithm for congenital adrenal hyperplasia (CAH) due to 21OHD, by utilizing novel and specific biochemical markers, such as 21DOC, 11-deoxycortisol (11DOC)/17-hydroxyprogesterone (17OHP) ratio, and (17OHP+androstenedione [4AD])/cortisol (F) ratio, with the levels of the said metabolites assessed using liquid chromatography–tandem mass spectrometry (LC-MS/MS).

Study Methodology and Results: The study comprised a prospective cohort of 326,006 newborns who underwent first-tier screening at a tertiary institute in Tokyo, Japan, between April 2021 and January 2025. A total of 10,916 infants had an initial 17OHP ≥97^th centile when assessed by an immunoassay. When the dried blood spots of these infants were subjected to second-tier screening with LC-MS/MS, eleven turned out to be “screen positive” by virtue of fulfilling either criteria A (17OHP >5 ng/mL and 21DOC >1 ng/mL) or criteria B (17OHP >5 ng/mL, 11DOC/17OHP <0.1 and [17OHP + 4AD]/F >2); while 133 participants were called for retesting as they met criteria C (17OHP >1.5 ng/mL, 11DOC/17OHP <0.3 and [17OHP + 4AD]/F >0.3). Finally, all 11 participants (screen positive) and 2 of those subjected to retesting were later confirmed to have CAH due to 21-OHD. The positive predictive value (PPV) of this algorithm was, thus, estimated to be 13 of 144, i.e., 9%. On analyzing all 144 participants, it was noted that 109 (75.7%) of these were low birth weight (LBW), and samples from each of these patients had yielded false positive results. To identify biochemical parameters that would discern LBW infants from those with proven enzyme deficiency, steroid profiles of the 109 LBW infants (without disease) and those of 17 patients (19 samples) with subsequently proven 21OHD were analyzed. As compared to LBW infants, infants with confirmed disease had higher 21DOC (P < 0.001) and lower 11DOC/17OHP (P < 0.001). On the other hand, (17OHP + 4AD)/F showed poor discriminatory ability.

Based on these findings, a refined algorithm was drawn that entailed determining initial 17OHP through immunoassay, subjecting samples with values ≥97^th centile to LC-MS/MS, and finalizing those with 21DOC >0.3 ng/mL and 11DOC/17OHP <0.2 as screen positive, and those with 21DOC >0.2 ng/mL and 11DOC/17OHP <0.3 as warranting retesting. When the proposed algorithm was applied to a larger cohort of 946,246 participants (326,006 from the current prospective cohort, and 620,240 from a retrospective cohort of infants screened between 2015 and 2021), the PPV of “first positive” increased markedly to 87.2% (41 confirmed to have disease, of a total of 47 with first LC-MS/MS positivity). The overall sensitivity was 100%, and LBW infants accounted for a mere 2.1% of the retest cases.

Critical Review: This is a pivotal study, as it clearly establishes the role of biochemical markers such as 21DOC and 11DOC/17OHP in newborn screening for 21OHD. Given the generally high rates of false positivity with 17OHP assessment, even when estimated through LC-MS/MS, and especially in those born preterm and LBW, the introduction and validation of markers such as these offer promise for improving sensitivity and lowering unnecessary recall rates.

Once-weekly navepegritide in children with achondroplasia: the approach randomized clinical trial

Savarirayan R, McDonnell C, Bacino CA, Hoernschemeyer DG, Legare JM, Abuzzahab MJ, et al. JAMA Pediatr. 2026 Jan 1;180(1):18-25. doi: 10.1001/jamapediatrics.2025.4771. PMID: 41247754.

Objective: The study was aimed at determining whether navepegritide, a once-weekly C-type natriuretic peptide analog, was superior to placebo in improving annualized height velocity in children with achondroplasia.

Study Methodology and Results: In this double-blinded, randomized, placebo-controlled phase 2b trial conducted at 10 hospitals across 7 countries (Australia, Canada, Denmark, Ireland, New Zealand, Spain, and the US) between March and August 2023, 84 treatment-naïve children aged 2–11 years with genetically confirmed achondroplasia were enrolled. They were subsequently randomized in a 2:1 ratio to receive either once-weekly navepegritide (n = 57, mean [standard deviation (SD)] age 5.6 [2.6] years, 54% males) or placebo (n = 27, mean [SD] 6.0 [2.7] years, 52% males). The drug/placebo was administered subcutaneously at a dose of 100 μg/kg/week for 52 weeks. At baseline, the mean (SD) height SDS (Centers for Disease Control and Prevention [CDC]-based) was –5.0 (1.0) across both groups, with a disease-specific Z-score of 0.1 (0.9), and a baseline annualized growth velocity (AGV) of 3.9 cm/year. At the end of 52 weeks, the least-squares mean (LSM) difference in AGV between the drug and placebo groups was 1.49 cm/year; 95% confidence interval (CI) 1.05, 1.93; P < 0.001. The respective values were 1.02 (0.29, 1.74) cm in children <5 years (n = 31), 1.41 (0.65, 2.17) cm in children aged 5–7 years (n = 36), and 2.48 (1.39, 3.57) cm in children ≥8 years old (n = 17). The LSM difference between the intervention and placebo arms with respect to CDC height Z-score was 0.30 (0.14, 0.45), and that with respect to disease-specific height Z-score was 0.28 (0.18, 0.39). Other secondary end points included changes in upper to lower body segment ratio (LSM difference –0.02 [–0.07, 0.03]), fibula to tibia length ratio (LSM difference –0.016 [–0.024, –0.008]), tibial-femoral angle (LSM difference –1.81° [–3.16°, –0.47°]) and mechanical axis deviation (LSM difference –2.78 [–4.71, –0.86] mm). In addition, health-related quality of life as assessed by the achondroplasia child experience measures physical functioning, daily living functioning, and observable signs measures, also showed improvement in the navepegritide group as compared with the control group. The proportion of children developing treatment-related adverse events (AEs) was similar in the intervention (21.1%) and placebo (25.9%) groups, and no AEs led to treatment discontinuation or withdrawal from the trial.

Critical Review: With its convenient once-weekly dosing, which circumvents the effects of high peak drug concentrations (e.g., hypotension), and an efficacy similar to that of vosoritide, navepegritide is a promising alternative for managing children with achondroplasia. Besides increasing AGV, the study establishes its superiority in improving limb misalignment and quality of life in these patients. However, the lack of data on the impact of navepegritide on the final adult height in affected children remains a key limitation, necessitating additional follow-up studies.

Efficacy and safety of Inclisiran in adolescents with heterozygous familial hypercholesterolaemia (ORION-16): a two-part, randomised, multicenter clinical trial

Wiegman A, Peterson AL, Bruckert E, Defesche JC, Schweizer A, Bergeron J, et al. Lancet Diabetes Endocrinol. 2026 Mar;14(3):233-242. doi: 10.1016/S2213-8587(25)00351-1. PMID: 41616799.

Objective: The present study aimed to assess the efficacy and safety of inclisiran, a small interfering RNA targeting Proprotein convertase subtilisin/kexin type 9 (PCSK9), in adolescents with heterozygous familial hypercholesterolemia (HeFH).

Study Methodology and Results: In this multicenter, randomized, two-part, phase 3 trial conducted at 51 centers across 26 countries in Europe, North America, South America, the Middle East, Asia and Africa; patients aged 12–<18 years with clinically suspected or genetically proven HeFH (according to the European Atherosclerosis Society Consensus Panel) with a fasting low-density lipoprotein (LDL)-cholesterol >130 mg/dL on stable (≥30 days) maximally tolerated statin treatment (with or without other lipid-lowering therapy) were enrolled. Previous lipid-lowering therapy was continued throughout the study. Between February 2021 and December 2022, 141 enrolled patients were randomized in a 2:1 ratio to receive either inclisiran (n = 93) or placebo (n = 48). The median (interquartile range [IQR]) age was 15.1 (13.4, 16.8) years, 53% patients were female, and 91% were White. The median (IQR) LDL-cholesterol was 174 (150.8, 208.8) mg/dL, 93% patients were on statins, whereas 23% were on ezetimibe. A genetic diagnosis of HeFH was available for 135 (96%) participants, among whom the most common genotypes were low-density lipoprotein receptor (LDLR) null (51%), LDLR defective (46%), LDLR unclassified (<1%), and ApoB (4%) defect. In part 1, all randomized participants received the drug/placebo (inclisiran sodium 300 mg subcutaneously) on days 1, 90, and 270. The LSM percent change in LDLcholesterol from baseline to day 330 was –27.1% (95% CI −32.0, −22.2) in the inclisiran group versus 1.4% (95% CI −4.0, 6.9) in the placebo group, with a between-group difference of −28.5% (95% CI −35.8, −21.3; P < 0.001). Similar reductions were noted in secondary endpoints such as absolute change in LDL-cholesterol (–50.3 [95% CI –61.9, –38.7] mg/dL; P < 0.001) and percentage change in ApoB (−25.7% [95% CI −31.7, −19.7%]; P <0.001).

Phase 2 of the study was an open-label extension phase in which both groups received inclisiran on days 450 and 630, with the erstwhile placebo group receiving an additional dose on day 360 (in order to preserve masking, the former intervention arm received a placebo on day 360). The mean percentage change in LDL-cholesterol from baseline to day 720 was −33.7% (SD 24.0), with similar reductions in patients treated with inclisiran from day 1 (−32.3% [24.8]) and patients switching from placebo to inclisiran on day 360 (−36.4% [22.3]). At the end of phase 2, the proportion of patients achieving LDL-cholesterol targets of <130 mg/dL and <100 mg/dL were 65% and 38%, respectively. In addition, consistent LDL reductions were observed regardless of age, sex, body mass index (BMI), region, baseline statin use, baseline LDL-cholesterol, and PCSK9. Consistent efficacy was also noted across genotypes.

In part 1, treatment-related AEs were recorded in 17% of inclisiran- and 8% of placebo-treated participants; in part 2, such events were noted in 10% of patients, chiefly injection-site reactions.

Critical Review: This is the first study to assess the efficacy and safety of inclisiran in adolescents with HeFH. Given its reduced frequency of administration and the favorable efficacy and safety profile, inclisiran may not only find a place in the routine management of adolescent HeFH, but the present research may also pave the way for studies assessing the efficacy of inclisiran in children with HoFH. However, long-term benefits on atherosclerotic cardiovascular disease risk reduction, and in predominantly non-White populations, remain to be determined.

Body roundness index is a stronger predictor of cardiometabolic risk than body mass index in children between ages 8 to 17 years

Jahan A, Abdullah MM, Frank R, Castellanos LJ, Singer P, Shen CL, et al. J Pediatr. 2026 Jan;288:114826. doi: 10.1016/j. jpeds.2025.114826. PMID: 40972710.

Objective: The study aimed to determine whether the BRI, which takes into account height and waist circumference, is a stronger predictor of cardiovascular outcomes (blood pressure [BP] and metabolic parameters) than BMI in children aged 8–17 years.

Study Methodology and Results: In this cross-sectional study conducted in the US, data from the National Health and Nutrition Examination Survey were collected. These included BP, anthropometric (weight, height, waist circumference), and biochemical (blood glucose, insulin, triglycerides) records for a total of 3,996 children aged 8–17 years, enrolled between 2015 and 2020. The estimation of BMI, and the definitions of obesity and hypertension were as per standard guidelines, whereas BRI was calculated as follows:

In addition, BP index, estimated as the measured BP divided by the 95^th centile for age, sex, and height or 130/80 mm Hg in children ≥13 years, was determined. Values ≥1 were representative of hypertensive records.

The mean (standard error [SE]) age of the study sample was 12.7 (0.06) years, 50.6% of the participants were boys, the prevalence of obesity (BMI >95^th centile for age and sex) was 13%, that of hypertension was 3.6%, and the mean (SE) BMI Z-score, BRI Z-score, fasting glucose, insulin and triglycerides were 0.7 (0.03), –0.04 (0.03), 97.8 (1.1) mg/dL, 13.9 (0.7) uIU/mL and 70.7 (2.1) mg/dL, respectively. Patients with hypertensive records had higher BMI (P = 0.06) and BRI (P = 0.01) Z-scores, alongside higher average insulin (P = 0.03) and triglycerides (P = 0.04). In adjusted linear regression models, BMI and BRI Z-scores were significant predictors of systolic and diastolic BP indices, wherein each unit increase in BRI Z-score was associated with a 0.013 unit increase in systolic BP index and a 0.018 unit increase in diastolic BP index, whereas respective values for BMI Z-scores were 0.012 and 0.010 units. In the adjusted logistic regression model, however, BMI Z-scores were not associated with hypertensive records (odds ratio [OR] 1.32, 95% CI 0.93, 1.89; P = 0.10), whereas BRI Z-scores were (OR 1.49, 95% CI 1.18, 1.91; P < 0.01).

For secondary outcomes assessed in 2,189 children with adequate data points, BMI and BRI Z-scores were individually strongly associated with insulin and triglyceride levels, but not with glucose levels. A one-unit increase in BMI and BRI Z-scores combinedly predicted a 1.71 mg/dL increase in glucose (β = 1.71, 95% CI 0.54, 2.88; P = 0.005), a 6.87 uIU/mL increase in insulin (β = 6.87, 95% CI 4.92, 8.83; P < 0.001), and an 11.28 mg/dL increase in triglycerides (β = 11.28, 95% CI 6.39, 16.17; P < 0.001).

Critical Review: The present study suggests that BRI, a measure that accounts for central adiposity, may be superior to BMI as a predictor of cardiovascular risk in adolescents. More long-term follow-up studies are nonetheless required to determine whether an increased BRI truly translates into increased cardiovascular risk in the future.