Antonius Eduard van Herwaarden

Objective: To assess plasma renin levels, fludrocortisone dosing, and their relationships with electrolytes, blood pressure, and early growth in children with 21-hydroxylase deficiency (21OHD). Design: Retrospective single-centre longitudinal cohort study. Methods: Patients born 2013-2022 and followed until age 3 years were included. Serial plasma renin, fludrocortisone dose, sodium chloride supplementation, electrolytes, and blood pressure were extracted from clinical records. Fludrocortisone trajectories and repeated-measures associations were analysed using mixed-effects models. Plasma renin was categorized as below, within, or above the assay reference range. Growth at 1 and 3 years was assessed as height SD score relative to target height. Results: Twenty-eight children were included. Fludrocortisone dosing peaked around 3 months (estimated mean 130 µg/day, 95% CI: 115-144) and declined to a plateau after 1 year (84 µg/day, 95% CI: 72-96). Higher renin levels were associated with lower sodium (approximately 139.7 vs 136.9 mmol/L) and higher potassium (4.09 vs 4.81 mmol/L). Suppressed renin levels were associated with the highest predicted probability of hypertension. Renin levels did not affect linear growth. Conclusions: Renin suppression in early childhood is associated with increased hypertension risk, whereas higher renin was not associated with growth or electrolyte abnormalities. These findings emphasize the importance of avoiding mineralocorticoid overtreatment and monitoring blood pressure carefully.

Context: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is characterized by cortisol and aldosterone deficiency and hyperandrogenism. Historically, patients have been classified into salt-wasting (SW), simple-virilizing (SV), and the less severe nonclassic (NC) form. Standard treatment for patients with classic 21OHD (SW and SV) consists of glucocorticoid and sometimes mineralocorticoid replacement to prevent adrenal crises. Interestingly, some patients were untreated due to delayed diagnosis or stopped treatment and survived without overt signs of adrenal insufficiency. Objective: This work describes a cohort of patients with 21OHD who survived without glucocorticoid treatment, with particular focus on sickness, surgical interventions, and adrenal crises. Methods: A multicenter, retrospective, open cohort observational study was conducted. Patients with classic (SW, n = 29; SV, n = 23) and NC (n = 24) 21OHD, with a median age of 11.0 and 21.7 years, respectively, were included. Results: Patients with classic and NC 21OHD were untreated with glucocorticoid for 8.7 years (IQR 4.7-14.3) and 28.1 years (IQR 12.2-39.0), respectively (P < .001). Of patients with classic 21OHD, 48% never received glucocorticoid treatment. Remarkably, 71% of them did not experience adrenal crises during the untreated period, even during illness or surgical interventions. In the NC 21OHD group, 21% was never treated with glucocorticoid; 2 patients (8.3%) experienced an adrenal crisis, both had an I2 splice/P31L genotype. All adrenal crises, except 1, were reported before age 7 years. Conclusion: Study of untreated patients with 21OHD provides a valuable opportunity to further explore mechanisms that influence glucocorticoid activity and elucidate disease variability in 21OHD.

Introduction: Thyroidectomy is a fundamental therapeutic intervention for various thyroid disorders, yet it entails significant risks, including iatrogenic hypoparathyroidism. Since 2019, our institution has implemented a standardized post-thyroidectomy protocol using parathyroid hormone (PTH) and calcium measurements to stratify hypocalcemia risk and guide calcium and alfacalcidol supplementation. Objective: This study aimed to assess the effectiveness of this structured approach in reducing unscheduled referrals due to hypocalcemia within three weeks after total thyroidectomy and evaluate the utility of early postoperative PTH levels in predicting permanent hypoparathyroidism (PhP). Methods: A retrospective observational cohort study was conducted at Radboud UMC Nijmegen, including 373 adult patients who underwent total/completion thyroidectomy between January 2014 and April 2025. Patients were assigned to either the post-protocol cohort (PPC) (N = 154) or the historic cohort (N = 219), depending on whether surgery occurred after or before protocol implementation, and subsequently compared. Results: Unscheduled referrals were significantly more frequent in the historic cohort than in the PPC (19.2% vs. 11% respectively, p = 0.034), and the introduction of the protocol was associated with a significant reduction in the odds of these referrals. Early postoperative PTH levels were a significant predictor of unscheduled referrals (p = 0.003), postoperative hypocalcemia (p < 0.001) and PhP (p < 0.001). A postoperative PTH cutoff of 1.7 pmol/L was identified as a clinically meaningful threshold for PhP prediction, demonstrating 100% sensitivity. Conclusions: Subject to assay availability and workflow efficiency, implementation of this protocol may reduce post-thyroidectomy emergency consultations and readmissions, improving healthcare resource utilization and optimizing follow-up.

Disorders (or differences) of sex development (DSD) represent a broad spectrum of rare congenital conditions characterized by atypical development of chromosomal sex, gonadal differentiation, or internal and/or external genital anatomy. Although some individuals are identified in early life, a substantial proportion first present during adolescence, frequently with delayed or absent pubertal development, primary amenorrhea, virilization, or questions regarding gender identity or fertility. This sensitive developmental phase is accompanied by increasing autonomy, necessitating a patient-centered approach with transparent communication and shared decision-making. In this paper, we describe our structured, stepwise diagnostic pathway for adolescents presenting with suspected DSD, embedded within a specialized multidisciplinary team including pediatric endocrinology, laboratory medicine, clinical genetics, psychology, radiology, and surgical expertise. Advances in biochemical profiling, imaging techniques, and genetic testing have improved diagnostic accuracy; nonetheless, psychosocial guidance remains essential throughout the process to support understanding, coping, and long-term well-being. To contextualize this approach, we present an illustrative adolescent case highlighting key clinical considerations, communication strategies, and the specific roles of each team member. Through this case-based framework, we aim to provide clinicians with clear and clinically applicable guidance for the coordinated evaluation and management of adolescents with DSD, emphasizing individualized, developmentally appropriate and gender-affirming care.

Background: Previous studies mainly investigated singular serum tumor marker (STM) measurements for the management of advanced cancer patients, resulting in differences between recommended cut-off points and associated accuracies in evaluating treatment outcomes. We aimed to determine which STM dynamics recur during treatment in advanced non-small cell lung cancer (NSCLC) patients with disease control three months after starting with immune checkpoint inhibitor (ICI)-containing treatment and explore whether these dynamics retain information on treatment outcomes. Methods: This real-world exploratory multi-center observational cohort study included advanced NSCLC patients with clinical and radiological disease control three months after starting with ICI-containing treatment and at least three STM measurements for at least one STM during treatment. STM dynamics visualized for all patients were subclassified into three serological response patterns by two investigators who were blinded for treatment outcomes. Results: Between March 2013 and January 2023, 256 patients were included at two thoracic oncology outpatient clinics in The Netherlands. Kaplan–Meier survival analyses showed a significant association between the serological response patterns and both progression-free survival (PFS) and overall survival (OS). Additionally, the serological response patterns could be used to distinguish a durable response versus secondary treatment resistance, and oligoprogression versus systemic progression. Conclusions: Our findings underscore the value of monitoring STM dynamics in advanced NSCLC patients during ICI-containing treatment to improve response classification and decision-making in clinical practice. Future studies should explore the value of the identified dynamics in other tumor- and systemic treatment-types and tumor cell analytes for assessing treatment outcomes across multiple indications.

Objectives: Male patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) are at risk of developing testicular adrenal rest tumors (TART), which are benign but an important cause of infertility. The limited medical infrastructure and lack of knowledge and awareness of 21OHD in Indonesia has contributed to missed or delayed diagnoses, leading to a reportedly low prevalence of 21OHD and an expected high rate of undiagnosed patients. In Indonesia, TART has not been widely reported, with only a single patient documented in a recent paper. This study aim was to define the potential risk factors for developing TART in Indonesian pediatric patients with 21OHD. Methods: This cross-sectional study was conducted in 20 boys with genetically proven 21OHD (0–18 years old). All had pathogenic variants associated with 0 % or 0–1% residual enzymatic activity. Medical history, clinical characteristics, genetic analysis results, biochemical measurements, bone age, and scrotal ultrasonography (US) data were evaluated. Results: In 5 of 20 patients (25 %), TART was detected by US. The patients with TART were mainly in puberty (p=0.014). Higher androstenedione levels and advanced bone age were associated with TART. Conclusions: TART is an important complication in Indonesian patients with 21OHD presenting before or during puberty. Factors associated with TART are pubertal age and longstanding poor hormonal control. Early diagnosis and optimization of treatment may help to prevent TART development and consequently improve fertility in these patients.

A model based on the soluble Fms-like tyrosine kinase-1/placental growth factor ratio, gestational age, and the urinary protein-to-creatinine ratio (PRERISK calculator) has been developed to predict preeclampsia-related maternal-fetal complications. Here, we tested whether this model can reduce hospital admissions without increasing complication rates among women with suspected or confirmed preeclampsia. In this multicenter, open-label, randomized controlled trial conducted at 5 Dutch medical centers, women with suspected or confirmed preeclampsia were randomly assigned to the intervention group, where admission was guided by the PRERISK score using a 5% cutoff, or to the control group receiving routine care with a concealed PRERISK score. Two co-primary outcomes were the incidence of maternal-fetal preeclampsia-related complications (noninferiority) and the proportion of women with a hospitalization ratio (=admission days/inclusion days) ≤0.05 (superiority). The intervention and control groups included 442 and 435 women, respectively. In the intention-to-treat analysis, complications occurred in 41.6% of the intervention group versus 39.5% of the control group (adjusted relative risk 1.06 [95% CI, 0.92–1.22]; P=0.43). The proportion of women achieving a hospitalization ratio ≤0.05 was 23.6% in the intervention group and 26.3% in the control group (adjusted relative risk, 0.89 [95% CI, 0.71–1.13]; P=0.34). The latter was comparable in the per-protocol analysis (adjusted relative risk, 0.87 [95% CI, 0.64–1.19]; P=0.38), while in this analysis, complications occurred in 47.8% of the intervention group (n=251) versus 41.7% of the control group (n=365; adjusted relative risk 1.19 [95% CI, 1.03–1.38]; P=0.02). Routine screening with the PRERISK score and a 5% cutoff in patients with suspected or confirmed preeclampsia does not decrease hospitalization and is therefore not recommended. URL: https://onderzoekmetmensen.nl/nl/trial/48687; Unique identifier: NL63386.078.17, NL-OMON48687.

Introduction: Maturity-onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM) are the most prevalent causes of monogenic diabetes. MODY is an autosomal dominant condition with onset in childhood and young adulthood, while NDM is defined with diabetes onset within 6 months of age and can be caused by dominant, recessive, X-linked genes or by chromosomal abnormalities. Here, we describe a rare case of monogenic diabetes in a patient who is homozygous for an INS gene variant. Research design and methods: The index patient, a male diagnosed with type 2 diabetes, was treated with low-dose insulin and metformin. Blood plasma was collected under fasting conditions for analysis. MODY screening was performed using a next-generation sequencing panel. In silico analysis of the insulin variant’s three-dimensional structure and its interaction with the insulin receptor was conducted. Insulin receptor affinity and downstream signaling potency were evaluated in vitro. Results: Auto-immune diabetes was excluded. A homozygous missense variant of the INS gene (c.130G>A, p.Gly44Arg) was identified in the patient. The combination of three different insulin assays showed that the biosynthesis of proinsulin into insulin was intact. In silico analysis of the mutant insulin 3D structure revealed that the INS variant is likely to affect insulin receptor binding and subsequent in vitro analysis suggested reduced potency in downstream signaling. Conclusions: The homozygous c.130G>A variant in the INS gene results in reduced insulin receptor binding and signaling potency. This, combined with pancreatic β-cell apoptosis or dedifferentiation supposedly, has contributed in the late-onset of monogenic diabetes in the index patient.

Context Some patients with classic congenital adrenal hyperplasia (CAH) survive without glucocorticoid treatment. Increased precursor concentrations in these patients might lead to higher free (biological active) cortisol concentrations by influencing the cortisol-protein binding. In 21-hydroxylase deficiency (21OHD), the most common CAH form, accumulated 21-deoxycortisol (21DF) may further increase glucocorticoid activity. Both mechanisms could explain the low occurrence of symptoms in some untreated classic CAH patients. Objective Develop and validate an LC-MS/MS method for free cortisol and free 21DF to quantify these steroids in untreated patients with classic CAH (n=29), non-classic CAH (NCCAH, n=5), other forms of adrenal insufficiency (AI, n=3), and controls (n=11) before and 60 minutes after Synacthen® administration. Results Unstimulated total cortisol concentrations of untreated classic CAH patients (median 109 nmol/L) were lower than in untreated NCCAH patients (249 nmol/L, p=0.010) and controls (202 nmol/L, p=0.016), but free cortisol concentrations were similar. Basal free 21DF concentrations were high in 21OHD patients (median 5.32 nmol/L) and undetectable in AI patients and controls (<0.19 nmol/L). After Synacthen® administration, free 21DF concentrations increased in 21OHD patients, while free cortisol concentrations did not change. Conclusions Free cortisol concentrations in classic CAH patients were similar to those in controls and NCCAH patients, indicating comparable cortisol availability. Additionally, 21OHD patients produce high concentrations of 21DF, possibly explaining the low occurrence of symptoms in some classic 21OHD patients. Free cortisol and 21DF levels should be considered in evaluating adrenal insufficiency in patients with CAH.