Band 38, Heft 7 - Highlight: Vitamin D as a Tool for Pediatric Health Care

Objectives This review explores the relationship between physical activity and serum 25-hydroxyvitamin D (25(OH)D) levels in children and adolescents, highlighting the importance of vitamin D for bone health and muscle function. Content A narrative mini review was conducted by searching PubMed, Google Scholar, and Scopus for studies published from January 2000 to April 2024, focusing on children aged 5–18 years. Ten studies were reviewed, including five cross-sectional, three population-based, one longitudinal, and one randomized controlled trial. Overall, physically active children and teens were more likely to maintain sufficient 25(OH)D levels and demonstrated better physical fitness, especially in muscle strength, compared to their less active peers. One study linked higher vitamin D levels to increased bone mineral content in active adolescents, while another reported a positive connection between vitamin D and bone density. Risk factors for deficiency included limited sun exposure, low physical activity, sedentary behavior, and obesity, with the latter group being more prone to low vitamin D levels, which were negatively associated with fat mass. Interventions that increased physical activity were found to improve vitamin D levels. Summary and Outlook Regular physical activity, especially outdoor exercise, is associated with healthier vitamin D levels in children, supporting better bone health and physical fitness.

Objectives Previous studies have shown that vitamin D deficiency is a risk factor for obesity in children and adolescents, but most focus on school-age children and adolescents, with little attention paid preschoolers. The aim of the study was to explore the relationship between overweight or obesity in the context of vitamin D intake among preschool children in Beijing, and analyze the correlation. Methods A total of 51,640 preschoolers (26,775 boys; 24,865 girls), aged 1–6 years, were recruited for physical examination. Overweight or obesity was defined according to the World Health Organization Child Growth and Development Standards (2006 edition). Serum 25-hydroxy (OH) vitamin D levels were determined using standardized liquid chromatography-tandem mass spectrometry (LC-MS/MS), and vitamin D status was evaluated based on the Practice Guide on Clinical Issues Related to Vitamin D Nutrition in Chinese Children (2022). Results No significant change was observed in the incidence of overweight (7.72, 7.51, and 7.24 %) or obesity (2.75, 2.63, and 2.40 %) from 2021 to 2023. Among boys, 7.3 % were overweight and 2.8 % were obese. Among girls, 7.6 % were overweight and 2.3 % were obese. Vitamin D deficiency (2.10, 1.70, and 1.01 %) and insufficiency rate (24.09, 18.42, and 15.44 %) showed a decreasing trend. Deficiency or insufficiency was most common in children aged 36–59 months, and serum 25- (OH) vitamin D levels were significantly lower in winter compared to other seasons, with the highest levels in summer. Time spent outdoors was significantly less among children with vitamin D deficiency or insufficiency, and preschoolers who spent more than 2.94 h/day had higher serum vitamin D level. Serum 25- (OH) vitamin D levels were negatively correlated with body mass index (BMI), with overweight or obesity preschoolers showing significantly lower than their normal weight group. After adjusting for age, gender and season, family economic status, guardian educational level and time spent outdoors, the odds of vitamin D deficiency and insufficiency in overweight or obesity in preschoolers were 1.025 (95 % Cl: 1.002–1.174), 1.218 (95 % Cl: 1.099–1.708), respectively. Conclusions From 2021 to 2023, there was no significant change in the incidence of overweight or obesity among preschool children in Beijing. Furthermore, the rate of vitamin D deficiency or insufficiency decreased year by year. Vitamin D deficiency or insufficiency associates with factors such as age, season of the year, and time spent outdoors, and there is an association between overweight or obesity and vitamin D status among preschoolers.

Objectives The aim of the current study was to assess the natural course of partial remission (PR) phase of type 1 diabetes (T1D) and to highlight the putative association between vitamin D receptor (VDR) ( Fok1 ) gene polymorphism and PR phase. Methods Ninety participants with newly diagnosed T1D were followed up for a total of 12 months. The VDR ( Fok1 ) rs2228570 gene polymorphism was genotyped using allelic discrimination (AD) assay. Results Fifty-four patients (60 %) reached PR with an average duration of 5.63 ± 2.9 months. Among remitters, the frequency of CC “FF” genotype and allelic frequency of C “F” were significantly higher (p<0.001). Furthermore, participants expressing “CC” genotype had earlier onset of PR and spent a significantly longer duration in remission (p<0.001). Younger age (p<0.001; OR 41.6; CI 12.12–142.99), absence of DKA (p<0.001; OR 16, CI 4.36–50.74), higher C-peptide levels (p<0.001; OR 19.55; CI 6.52–58.63), and presence of CC “FF” genotype of VDR (p<0.001; OR 6.74; CI 2.41–18.86) best predicted the overall occurrence of PR. Conclusions Younger age, less extent of metabolic derangements, and expression of a CC “FF” genotype were found to influence the occurrence of PR. Data from the current study showed that the “C” allele could have a protective role on preserving residual β-cell mass and could predict both onset and duration of PR among newly diagnosed T1D. These findings support the growing concept of future tailored precision medicine.

Objectives This study aimed to identify the 25-hydroxyvitamin D (25OHD) threshold that maximally suppressed parathyroid hormone (PTH) in a group of healthy Chinese Infants in Hong Kong. Methods Healthy infants detected to have low serum 25OHD less than 25 nmol/L in a population study on vitamin D status were referred to Hong Kong Children’s Hospital (HKCH) for further management. Their total 25OHD was repeated with serum calcium, phosphate, alkaline phosphatase and PTH. Three-phase segmented regression was used to identify the optimal breakpoint between 25OHD and PTH. Results Two hundred and twelve infants were included (59 % male). They were reassessed at a median age of 156 days (IQR: 111–247 days). Using unadjusted three-phase segmented regression, the estimated breakpoint of 25OHD on PTH suppression, after adjusting for factors including age, gender, history of vitamin D supplement and mode of feeding, was 20.0 nmol/L (95 % CI: 13.1 to 26.9). Conclusions The threshold of 25OHD that triggered the inflection point for PTH in our Hong Kong Chinese infants was lower than that reported in the Western literature. This might imply the cutoff for vitamin D deficiency is lower for Chinese infants. This could be explained by younger age and different ethnicity. Further study with larger sample size is needed to validate the observation.

Hypotonic polyuria, also known as the polyuria-polydipsia syndrome (PPS), caused by primary polydipsia (PP), arginine vasopressin deficiency (AVP-D or central diabetes insipidus), or uncommonly by AVP resistance (AVP-R), is diagnostically challenging due to overlapping symptoms and the need to conclusively diagnose or exclude AVP-D caused by serious organic lesions of the central nervous system. Diagnostic tests that stimulate AVP secretion by increasing plasma osmolality include the water deprivation test (WDT) and the hypertonic saline test (HST). The WDT, considered the gold standard for evaluating PPS in children, has suboptimal diagnostic accuracy, is burdensome, and requires hospitalization. The HST has been used rarely in children due to safety concerns and need for intensive monitoring. The finding that some anterior pituitary stimulating agents also stimulate the posterior pituitary, and the availability of a robust serum/plasma assay for copeptin as a reliable surrogate of AVP, has allowed development of nonosmotic, copeptin/AVP stimulation tests. In the present review, we focus on these new copeptin stimulation tests, which include single stimuli with intravenous (IV) arginine, IV insulin, intramuscular glucagon, oral levodopa, and double stimuli (IV arginine-insulin or AITT; IV arginine and oral Levodopa/carbidopa or ALD-ST), which we have previously shown to induce very robust copeptin secretion. Specifically, the ALD-ST differentiated AVP-D from PP in 20 children with high diagnostic accuracy at a cutoff stimulated copeptin of 9.3 pmol/L. We propose the utilization of the outpatient ALD-ST in the early stages of PPS evaluation in children, given its safety, cost-effectiveness, and limited side effects.

Introduction Assessing pubertal stage can be challenging, particularly in large-scale settings, due to the sensitive nature of Tanner staging by healthcare providers (HCP) or self-reported Tanner stage through photographs or line drawings. The self-reported Pubertal Development Scale (PDS) avoids sensitive issues like genitalia or nudity, is adaptable to various settings, reduces time and cost burdens on researchers. This study aimed to explore the agreement between self-reported PDS and HCP-assessed Tanner staging. Content Papers for the meta review were retrieved from Pubmed, Embase, Fang Wan, CNKI, and Cochrane Library before January 15, 2025. Quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Pooled estimates and 95 % confidence intervals (CI) were calculated using random-effects models. Summary and Outlook Five studies with 6024 participants met inclusion criteria. Among stage 1–5, substantial agreement was found among girls (Wk: 0.63 [0.62–0.65]) and overall participants (Wk: 0.68 [0.67–0.69]), while moderate agreement was observed in boys (Wk: 0.58 [0.56–0.61]). Broadening puberty criteria to stages I-III showed substantial agreement for girls (Wk: 0.66 [0.64–0.68]), boys (Wk: 0.64[0.61–0.67]), and overall participants (Wk: 0.69 [0.67–0.70]). For pubertal onset, using Tanner stage as the gold standard, girls showed that the area under the receiver operating characteristic curve (AUC) was 0.86 (0.85–0.87), the sensitivity and positive predictive value (PPV) of self-reported PDS were 0.85 and 84.2 % respectively. Similarly, among boys, the AUC was 0.89 (95 % CI: 0.87–0.92), the sensitivity and PPV were 0.91 and 97.8 % respectively. Our findings indicate moderate to substantial agreement between the two methods, with high sensitivity and PPV for self-reported PDS in assessing puberty onset, PDS may be a reliable and cost-effective method for large-scale epidemiological studies.

Objectives To investigate how four different prediabetes definitions (by fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c), FPG-or-HbA1c, or FPG-and-HbA1c) affect prediabetes prevalence estimates and their association with cardiometabolic risk in Danish children and adolescents referred for tertiary obesity treatment. Methods This cross-sectional study included 5–18-year-olds with BMI SDS above 1.28 and blood samples taken within 30 days of obesity treatment initiation. Anthropometric measurements, blood pressure, and blood samples were analysed to determine prediabetes prevalence and calculate odds ratios for hypertension, dyslipidaemia, abdominal obesity, high alanine aminotransferase (ALT), and BMI SDS ≥99th percentile. Results Among 2,849 children and adolescents, prediabetes prevalence was 12.8 %, 6.6 %, 17.2 %, and 2.2 % when applying the FPG, HbA1c, FPG-or-HbA1c, and FPG-and-HbA1c definitions, respectively. Hypertension, dyslipidaemia, abdominal obesity, high ALT, and BMI SDS ≥99th percentile phenotypes were common, with increased prevalence among individuals with prediabetes defined from FPG-or-HbA1c. The FPG-derived definition of prediabetes was associated with hypertension and abdominal obesity, while the HbA1c-derived definition of prediabetes was associated with dyslipidaemia, high ALT, and BMI SDS ≥99th percentile. The strongest association was between the FPG-derived definition and hypertension. Conclusions The FPG-derived definition identified more individuals with prediabetes than the HbA1c-derived definition. Children and adolescents with prediabetes defined from FPG-or-HbA1c exhibited a high burden of hypertension, dyslipidaemia, abdominal obesity, high ALT, and BMI SDS ≥99th percentile. No single diagnostic test proved superior, as each associated with different cardiometabolic risk factors.

Objectives Inborn errors of immunity (IEI) are a diverse group of genetically inherited disorders. We aimed to summarize and discuss endocrinopathies in children with IEI. Methods This study included 84 IEI patients evaluated between September 2019 and September 2023. Results We found that 15.6 % of the 32 patients with 22q11.2 deletion syndrome had permanent hypoparathyroidism. Hypergonadotropic hypogonadism was identified in one of four female patients with ataxia-telangiectasia (AT) and in all four females with severe congenital neutropenia (SCN) due to HAX1 deficiency. Additionally, hypergonadotropic hypogonadism was observed in one of nine males with common variable immunodeficiency (CVID). Among the CVID patients, one presented with autoimmune thyroiditis (AIT), type 1 diabetes mellitus (T1DM), hypoparathyroidism, and primary adrenal insufficiency. Of the 307 patients followed for selective IgA deficiency (sIgAD), 26 also received care in pediatric endocrinology. Among the sIgAD cases, 3.2 % had AIT and 4.5 % had T1DM. A patient with a STAT1 gain-of-function (GOF) variant was diagnosed with T1DM, AIT, and growth hormone deficiency, while a patient with a novel STAT3-GOF variant developed neonatal DM and interstitial lung disease. When the whole group was evaluated, thyroid disease was the most common endocrinopathy affecting 30.9 % of individuals, followed by DM, which was observed in 20.2 % of cases. Conclusions We have determined that AIT and T1DM were the most prevalent endocrine disorders in IEI patients. Pubertal development and gonadal functions should be monitored in the children with IEI. Early diagnosis and individualized treatment of endocrinopathies are crucial for a better quality of life and reduction of IEI-related complications.

Objectives A prospective study was conducted examining the association between blood lipid levels and bone mineral density in preschool-aged children. Methods Healthy preschool-aged children (n=411) were included in this 12-month cohort study. The bone mineral density and bone mineral content of the non-dominant forearm and calcaneus were measured using dual-energy X-ray absorptiometry (DXA). Additionally, the children’s fasting blood was drawn at baseline to measure blood lipids. Results The sample comprised 411 healthy preschool-aged children, 208 girls and 203 boys, with a mean age of 4.80±0.70 years. After one year of observation, the bone mineral density of the non-dominant calcaneus in preschool children increased by 30.37 mg/cm 2 , bone mineral content increased by 29.85 mg, and triglyceride levels increased by 0.05 mmol/L. A significant inverse assocation was observed between serum triglyceride levels within the normal physiological range and the changes in bone mineral density (BMD) at the non-dominant calcaneus in preschool children, whereas no such association was detected with BMD changes in the non-dominant forearm. A 1 mmol/L increase in triglycerides within the physiological normal range was associated with a 6.73 mg/cm 2 decrease in bone mineral density (95 % CI: −12.90, −0.56) and a 5.98 mg decrease in bone mineral content (95 % CI: −11.77, −0.19). There was no significant relationship between other lipids and bone mineral density. Conclusions Serum triglyceride concentrations within the physiological normal range showed a significant negative correlation with the 12-month increment of calcaneal bone mineral density in preschool children (p<0.05).

Objectives Endocrine disrupting chemicals (EDCs) interfere with hormonal homeostasis, and have been observationally linked to altered pubertal timing, defined by the age of menarche (AAM) in girls and the age at voice change (AVC) in boys. However, the causality of these associations remains unclear. We used Mendelian randomization (MR) to investigate if genetically altered serum EDC levels affect pubertal timing. Methods We performed univariate MR to assess the effects of 22 EDCs on AAM and AVC, using the largest GWAS for EDCs as well as European and multi-ethnic GWAS on AAM and AVC. Multivariate MR (MVMR) and two-step MR were conducted to examine mediating effects of body mass index (BMI). Results We found causal MR associations with AAM for three polychlorinated biphenyls (PCBs): PCB 74 (β IVW : −0.015, 95 % CI [−0.028, −0.003], p=0.014), PCB 194 (β IVW : −0.015, 95 % CI [−0.024, −0.007], p=3.27×10 −4 ), and PCB 206 (β IVW : −0.024, 95 % CI [−0.041, −0.006], p=0.0068) and for dibutyl phthalate (DBP, β IVW : 0.006, 95 % CI [0.001, 0.010], p=0.013). One MR association was found with AVC for bisphenol A (BPA, β Wald ratio = −0.032, 95 % CI [−0.044, −0.019], p=2.62×10 −7 ). Mediation analyses by MVMR or Two-Step MR suggested BMI’s mediating role in the associations of EDCs with AAM and AVC. Conclusions Our findings indicate that exposure to specific PCBs leads to earlier AAM whereas exposure to DBP delays AAM. Exposure to BPA leads to earlier AVC, with BMI potentially acting as a mediator.

Objectives Vitamin D dependent rickets type 2A (VDD2A) is a rare autosomal recessive disorder due to mutation in vitamin D receptor ( VDR ) gene leading to hypocalcemia, secondary hyperparathyroidism and signs of rickets. We are reporting case series of two siblings with VDDR2A who were managed in a non-conventional manner (oral calcium and oral vitamin D) in a tertiary care hospital of resource limited country. Case presentation Two male siblings presented at the age of 10 years (case 1) and 11.5 years (case 2) with the complaints of short stature and walking difficulty since 4 and 1.5 year of age respectively. They were born to consanguineous parents with a history of two maternal cousins having the same complaints. The investigations showed frank rickets findings on imaging with biochemical evidence of hypocalcemia, hypophosphatemia, raised levels of alkaline phosphatase and raised parathyroid hormone with normal 25-OH vitamin D levels and raised 1,25(OH) 2 D 3 levels confirming the diagnosis of calcipenic rickets. The whole exome sequencing (WES) of case 1 (younger sibling) showed that he was carrying a novel homozygous variant in VDR gene c.1354C>T, p(Arg452Cys). They both are being managed on high doses of oral calcium supplements and activated form of vitamin D. Conclusions VDDR2A can present with or without alopecia.It can be managed with high doses of oral calcium and vitamin D supplements in resource limited areas.

Objectives Bone morphogenetic protein 2 ( BMP2 ) is essential for endochondral ossification, skeletal development, and bone homeostasis. Monoallelic loss-of-function variants in BMP2 have been linked to short stature, facial dysmorphism, and skeletal anomalies, often accompanied by cardiac involvement. Here, we describe a 10-year-old girl with a novel heterozygous truncating BMP2 variant, presenting with distinct facial features, short stature, and skeletal abnormalities, notably osteolysis in the phalanges. Case presentation The patient was initially evaluated at six months of age due to hypotonia and dysmorphic facial features. At 10 years old, she presented with short stature and skeletal radiographs revealed osteolysis in multiple phalanges. Additional clinical evaluations, including echocardiography and metabolic studies, were unremarkable. Whole-exome sequencing identified a de novo heterozygous truncating variant (c.440C>G; p.Ser147*) in  BMP2 . Conclusions This report identifies a novel BMP2 nonsense variant and introduces osteolysis as a previously unrecognized phenotype. These findings highlight the necessity of longitudinal skeletal monitoring in BMP2-related conditions and underscore the importance of genetic evaluation in patients with subtle skeletal dysplasias to facilitate early diagnosis and management.

Objectives To describe the clinical course, diagnosis, and management of a rare pediatric case of ACTH-independent Cushing syndrome (CS), associated with developmental delay. Case presentation A three-year-old boy with global developmental delay, was referred for evaluation of rapid weight gain over the preceding three months, accompanied by increased body hair, a moon-shaped face, and sleep disturbances. Biochemical testing revealed undetectable ACTH levels and elevated cortisol levels, leading to the diagnosis of ACTH-independent CS. Abdominal magnetic resonance imaging demonstrated adrenal asymmetry, with a larger left adrenal gland, and further investigation using PET scan excluded the presence of adrenal adenomas/carcinomas. The patient was initially treated with metyrapone, which effectively reduced cortisol levels. However, after two months, a left adrenalectomy was performed. Pathological examination confirmed micronodular non-pigmented adrenal hyperplasia. One year later, cortisol levels increased again with undetectable ACTH, prompting the re-initiation of metyrapone. Due to intolerance to this medication, osilodrostat, an off-label treatment, was introduced. At the time of follow-up, 15 months after initiation of osilodrostat, both serum and urinary cortisol levels remained within normal ranges, ACTH levels remained undetectable, and the clinical symptoms of CS were well controlled. Conclusions This case underscores the diagnostic and therapeutic challenges associated with rare pediatric cases of ACTH-independent CS. The treatment course, which included metyrapone, adrenalectomy, and off-label use of osilodrostat, resulted in significant improvement in cortisol control and clinical symptoms. Ongoing genetic analysis is being conducted to explore potential underlying genetic factors contributing to the patient’s non-pigmented micronodular adrenal hyperplasia and developmental delay.