Objectives:Type 1 diabetes (T1D) is a recognized risk factor for skeletal fragility in adults, but its impact on bone microstructure in children remains incompletely characterized. In particular, data on trabecular bone quality remain scarce. This study aimed to evaluate skeletal parameters in this group of children and examine their associations with clinical variables. Methods:This retrospective cross-sectional study evaluated children with T1D at the Hong Kong Children's Hospital from June 2023 to December 2024. Skeletal parameters, including trabecular bone score (TBS), bone health index (BHI), bone mineral density (BMD) by dual-energy x-ray absorptiometry, and serum vitamin D and HbA1c levels, were evaluated alongside fracture history. A parent-reported questionnaire measured participation in physical activity. Correlations between bone parameters and clinical variables were analyzed. Results:Sixty-eight children with T1D (male 42.6%, mean 12.7 ± 3.7 years, 44.1% prepubertal, mean HbA1c 7.3%) were included. A substantial proportion of children (19.6%) had low cortical bone density as reflected by BHI Z-score ≤ -2, whereas deficits in trabecular bone (TBS Z-score ≤ -2) were less common (4.8 %). Regression analysis confirmed that higher lean mass was associated with higher total body less head (TBLH), lumbar spine (LS) and TBS Z-scores (β=0.0001, p < 0.05), while disease duration had a negative association with these measurements (β=-0.1413; β =-0.1335, β=-0.2270, p < 0.05). Conclusion:In this cohort of children with T1D, a pattern of skeletal involvement was observed, characterized by a high prevalence of low BHI Z-scores and a relatively low prevalence of low TBS Z-scores. This may suggest differential involvement of cortical bone with relative preservation of trabecular microarchitecture. Whether these structural differences translate into fracture risk remains unknown. Longitudinal studies are needed to elucidate the evolution of bone alterations over time and to identify determinants underlying skeletal vulnerability in childhood-onset diabetes. Higher lean mass was associated with higher bone mass and microarchitectural indices, whereas longer disease duration may have a negative association with these parameters. These findings highlight modifiable and disease-related factors that may influence bone health, warranting confirmation in larger controlled studies.

BACKGROUND:Despite significant advancements in genetic diagnosis, there are still bottlenecks in DNA-level testing. Challenges to diagnosis include the inability to identify the causal variant, and the lack of functional evidence leading to an accumulation of variants of uncertain significance (VUS). Recently, there has been growing evidence demonstrating the diagnostic value of RNA sequencing (RNA-seq). METHODS:This diagnostic study implemented RNA-seq analysis of blood (and fibroblasts, if available) in 102 patients with genetically undiagnosed diseases. An outlier analysis for gene expression and splicing was adopted through a multi-modal machine learning algorithm (i.e., Detection of RNA Outliers Pipeline-DROP). FINDINGS:Our analysis aided the interpretation of 22/102 (21.6%) patients through both hypothesis-driven (i.e., with a prior genetic candidate; n = 10) and hypothesis-free (i.e., without a prior genetic candidate; n = 12) approaches. Not only did this workflow aid genetic diagnosis (n = 12), but it also provided additional information to known findings (n = 4) and guided the discovery of unestablished disease mechanisms (n = 6). INTERPRETATION:This study demonstrated the clinical and scientific value of blood transcriptomics through both hypothesis-driven and hypothesis-free approaches. We have proposed an initial framework for RNA-seq implementation into the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines using PVS1 (null variants) and PP4 (phenotypic specificity). However, other considerations are required, including further clarifications for thresholds, and detailed guidance on the incorporation of different aspects of RNA-seq results (e.g., degree of nonsense-mediated decay and completeness of splicing). FUNDING:This study was supported by grants from the Society for the Relief of Disabled Children, the Health and Medical Research Fund (HMRF) and Commissioned Paediatric Research at HKCH under HMRF both by the Health Bureau, The Government of the Hong Kong Special Administrative Region.

OBJECTIVES:Despite proven benefits of diabetes technologies in children with type 1 diabetes (T1DM), utilization varies globally. In Hong Kong, continuous glucose monitoring system (CGMS) uptake was low (10.6 %) in 2018; however reimbursement programs have been implemented since then to enhance accessibility. This study examined trends in diabetes technology adoption and glycemic outcomes from 2018 to 2023. METHODS:The Hong Kong Childhood Diabetes Registry prospectively collected standardized data on all children with diabetes at age ≤18 years in public hospitals since 2018, and those with follow-up data between 2018 and 2023 were included. Regular CGMS use was defined as >80 % usage/year. Outcomes included mean HbA1c levels, incidence of diabetic ketoacidosis (DKA) and severe hypoglycemia. Clinical and psychosocial factors were compared between regular and non-regular CGMS users. RESULTS:Mean HbA1c significantly decreased from 8.3 % in 2018 to 8.0 % in 2023 (p<0.05), with fewer children having HbA1c >9 % and a reduced rate of DKA. Regular CGMS use increased from 10.7 to 41.7 %, with highest adoption among school-aged children and lowest among adolescents. Compared to non-regular users, regular CGMS users demonstrated better glycemic outcome (mean HbA1c 7.6 vs. 8.2 %, p<0.05). There were no significant differences in rates of micro/macrovascular complications or severe hypoglycemic events between the two groups. CONCLUSIONS:Despite improved glycemic outcomes and free access, CGMS adoption remained suboptimal in Hong Kong particularly among adolescents, indicating barriers beyond cost. Further research is needed to identify these barriers and develop targeted strategies to enhance technology use.

Purpose: 45,X/46,XY mosaicism is a rare subset of sex chromosome abnormalities within the spectrum of differences of sex development. This study aimed to evaluate the long-term outcomes in a group of individuals with 45,X/46,XY mosaicism over a 30-year period.Methods: A retrospective review was performed including 68 patients diagnosed from January 1990 to December 2023 at a tertiary unit. Cytogenetic analysis, patient demographics and various health outcomes were examined.Results: Thirty-five patients were raised as females and 33 were raised as males. Fifteen patients were found to have 45,X/46,XY mosaicism prenatally. The prevalence of gonadal tumor was 17.6% among phenotypic females and 38.5% in males with abnormal genitalia, whereas no tumors were detected in males with normal genitalia. The mean external genitalia score was significantly lower in males with gonadal tumors compared to those without (6.6 vs 10.4, P=0.002). For females, while most gonadal tumors were identified in those who had gonadectomy at pubertal age (5 of 6, 83.3%), gonadal tumors were also detected in very young children (1.3 years old). There was no significant improvement in height in those treated with growth hormone therapy and final adult height remained suboptimal (overall final adult height z-score -2.6±1.2). Adherence to surveillance for associated systemic comorbidities was inconsistent.Conclusion: Gonadal tumor risk is higher in less masculinized males, while females may develop tumors across a wide age range. The long-term efficacy of growth hormone therapy in these patients remains unclear. Our findings emphasized the need for individualized surveillance in this population.

Purpose:Children with chronic illness are vulnerable to compromised bone health. Dual-energy X-ray absorptiometry (DXA) is commonly used for assessment but has limitations related to body size adjustments and positioning, highlighting the need for accessible alternatives. This study evaluated the correlation between the Bone Health Index (BHI), derived from automated hand radiograph analysis, and areal bone mineral density (BMD) measured by DXA in Chinese children with chronic illness. Methods:In this retrospective study, Chinese children undergoing simultaneous DXA and hand radiography were included. Correlations between BHI metrics and DXA-derived BMD Z-scores were assessed. Results:A total of 327 patients were analyzed. Absolute BHI values showed negligible correlation with DXA-derived BMD at the lumbar spine (LS) (r = 0.10, p = 0.05) and total body less head (TBLH) (r = 0.00, p = 0.35). BHI standard deviation scores (SDS) exhibited moderate positive correlations with DXA BMD Z-scores (LS: r = 0.42, p <0.001; TBLH: r = 0.43, p <0.001). In steroid-treated patients, these correlations were weaker (LS: r = 0.30, p =0.007; TBLH: r = 0.30, p 0.001). Conversely, steroid-naïve patients exhibited stronger correlations (LS: r = 0.48, p<0.001; TBLH: r = 0.53, p<0.001). Conclusion:In steroid-treated patients, BHI SDS correlated weakly with DXA-derived BMD Z-scores, whereas steroid-naïve patients exhibited moderate correlations. This highlights that BHI and DXA BMD assess distinct bone properties that are differentially influenced by systemic treatment like glucocorticoids. Consequently, BHI should be regarded as a complementary tool rather than serving as a direct surrogate for DXA.

ObjectiveA firm diagnosis revealing the etiology of disorders/differences of sex development (DSD) is most helpful in guiding clinical management. The aim of this study is to investigate molecular genetic diagnoses and surgical treatment in a cohort of children with 46,XY DSD.MethodsA retrospective study was conducted on children with 46,XY DSD. They were referred to a tertiary surgical center during the period between 2011 and 2022 and were found to have genetic alterations, which were considered etiologies for their DSD. Data on clinical presentations, sex of rearing, genetic findings, surgical treatment, and comorbidities were collected and reviewed.ResultsA total of 21 patients were included in the study: 11 and 10 were reared as male and female, respectively. Genetic alterations were found as the causes for androgen insensitivity syndrome (n = 4), 5-alpha reductase type II deficiency (n = 5), 17-beta hydroxysteroid dehydrogenase III deficiency (n = 1), 17-alpha hydroxylase deficiency (n = 1), and gonadal dysgenesis (n = 10). Of those with gonadal dysgenesis, the genetic alterations were NR5A1 mutation/deletion (n = 3), DMRT1 deletion (n = 4), WT1 mutation (n = 2), and DAX1 duplication (n = 1). A total of 20/21 patients underwent one or more surgical procedures including hypospadias repair (n = 10), gonadectomy (n = 11), gonadal biopsy (n = 4), hernia repair (n = 4), orchidopexy (n = 1), and feminizing genitoplasty (n = 1). A total of 5/21 had germ cell neoplasms in one or both gonads. A total of 8/10 patients with gonadal dysgenesis had comorbidities involving other systems. Of the whole group, seven patients were found to inherit genetic alterations from their parents.ConclusionsMolecular genetic diagnosis enhances the understanding of etiology, improves diagnostic accuracy, and provides precise guidance in the counseling and surgical management of children with 46,XY DSD.

Thyroid dysfunction is a well-recognized complication following hematopoietic stem cell transplant, com-monly manifested as nonimmune hypothyroidism secondary to chemotherapy and total body irradiation. Autoimmune thyroid diseases, including Graves disease and Hashimoto thyroiditis, are uncommon. Sequential development of hypothyroidism and hyperthyroidism after hematopoietic stem cell transplant is extremely rare and has only been reported in isolated case reports. We present 2 pediatric cases of this transition and explore the possible pathophysiological mechanisms and implications for long-term endocrine surveillance in hematopoietic stem cell transplant survivors.

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.

Background:The significant association between blood pressure (BP) in children and young adulthood and risks of cardiovascular diseases in adulthood highlights the critical need for early BP control. While lifestyle modifications such as increased physical exercise have proven effective, traditional exercise forms always suffer from low motivation and adherence. Active video games (AVGs), combining exercise with engaging gameplay, may present a promising alternative for managing BP in children and young adults. Objective:This study aims to evaluate the effectiveness of AVGs in managing BP among the population aged 6 to 25 years. Methods:Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline, this study retrieved and screened publications archived in the 4 databases (Web of Science, Cochrane Library, PubMed, and Embase) and the registration (ClinicalTrials.gov) up to December 30, 2024. Eligible studies were defined as interventional trials involving participants aged 6 to 25 years, using AVGs as one of the intervention protocols, and reporting BP outcomes. Studies were excluded if they involved participants with heart diseases, combined AVGs protocol with other intervention components, limited outcomes to immediate postgame BP, or included only control groups that received additional physical activity interventions. Depending on the heterogeneity among included trials, random-effects or fixed-effects models were selected to pool the effect sizes of individual trials, with 95% CIs. The risk of bias was assessed using the Cochrane Risk of Bias tool for controlled trials and the Methodological Index for Non-Randomized Studies for prepost design. Sensitivity analyses were performed to evaluate result robustness, while Egger tests investigated publication bias. Results:A total of 17 trials from 16 studies, involving 503 participants who are normotensive, were included in this study. The analysis showed that AVGs significantly reduced systolic blood pressure (standardized mean difference=-0.50, P<.001, 95% CIs -0.80 to -0.20) and increased diastolic blood pressure (standardized mean difference=0.23, P=.03, 95% CIs 0.02 to 0.44) in children younger than 18 years, with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) indicating the certainties of evidence as low for systolic blood pressure and moderate for diastolic blood pressure. Conclusions:These findings shed light on the cardiovascular benefits of AVGs in children younger than 18 years, underscoring their potential to improve vascular elasticity while maintaining organ perfusion. However, considering the limitations arising from small sample sizes, as well as inadequate allocation concealment and blinding in the included studies, these findings should be interpreted with caution.

BACKGROUND:Diabetic ketoacidosis (DKA) is a life-threatening complication in children with diabetes mellitus. There are considerable differences in the management approaches for DKA between different countries. One of the main areas of differences between guidelines is the administration of fluid, with most guidelines adopting a restrictive approach. The British Society of Paediatric Endocrinology updated its guideline in 2020 to adopt a more permissive approach to fluid administration, which has sparked controversy among some paediatricians. OBJECTIVES:The purpose of this article is to provide a narrative review on the management of DKA. METHODS:A PubMed search was performed with clinical queries using the key term "diabetic ketoacidosis". The search strategy included randomized controlled trials, clinical trials, meta-analyses, observational studies, guidelines, and reviews. The search was restricted to English literature and the age range of 18 years and younger. Moreover, we reviewed and compared major guidelines. RESULTS:Selected international guidelines for DKA, namely International Society for Pediatric and Adolescent Diabetes (ISPAD), National Institute for Health and Care Excellence (NICE), British Society for Paediatric Endocrinology and Diabetes (BSPED), and South Thames Retrieval Service (STRS) were reviewed. There are considerable differences in the management approaches for DKA between different countries. One of the main areas of differences between guidelines is the administration of fluid, with most guidelines adopting a restrictive approach. This is based on the concern over cerebral oedema, a lethal sequela allegedly to be caused by excessive fluid administration. However, recent new clinical studies suggest that there is no causal relationship between intravenous fluid therapy and DKA-related cerebral injury. The British Society of Paediatric Endocrinology updated its guideline in 2020 to adopt a more permissive approach to fluid administration, which has sparked controversy among some paediatricians. CONCLUSION:The management of DKA involves early recognition, accurate diagnosis, meticulous fluid and insulin treatment with close monitoring of blood glucose, ketones, electrolytes, renal function, and neurological status. There is still limited clinical evidence to support either a restrictive or permissive approach in the fluid management of paediatric DKA patients. Clinicians should exercise caution when applying different guidelines in their clinical practice, considering the specific circumstances of individual paediatric patients.

IntroductionVaccine-related myocarditis is recognized as a rare but important complication, especially after mass-scale mRNA COVID-19 vaccination. Knowledge regarding how to minimize the risk is limited. As NK cells can mediate acute myocarditis after mRNA COVID-19 vaccination and vitamin D may inhibit NK cells via cytokine modulation, we hypothesize that the myocarditis side effect is related to a hypovitaminosis D – mRNA vaccine – hypercytokinemia – NK cell axis, which is amendable to clinical intervention.MethodsBiochemical, immunophenotypic and genotyping assays were performed to examine vitamin D status and immune profiles in 60 patients who had BNT162b2 vaccine-related acute myocarditis.ResultsA high incidence of hypovitaminosis D (73.3%) was observed in these individuals with vaccine-related myocarditis, particularly in those presented with chest pain or intensive care unit (ICU) admission. Moreover, vitamin D level was negatively associated with peak serum cardiac troponin T level during vaccine-related myocarditis. Genotypically, the GC (vitamin D binding protein) rs4588T allele which encoded the GC2 isoform of vitamin D binding protein was a risk allele, whereas the GC1S isoform was protective. Mechanistically, hypovitaminosis D was associated with higher levels of cytokines pivotal for natural killer (NK) cells (particularly interleukin-1β (IL-1β), IL-12, Interferon-γ (IFN-γ), and IL-8) and higher percentage of CD69+ NK cells in blood, which in turn correlated with chest pain presentation.ConclusionThese data support the hypothesis that vitamin D plays a crucial role in mitigating mRNA vaccine-related myocarditis by modulating proinflammatory cytokine milieu and subsequent unfavorable NK cell activation, laying a groundwork for preventive and treatment strategies.

Introduction: Type 2 diabetes mellitus (T2DM) is becoming increasingly common among children and adolescents worldwide, including those in Hong Kong. This study analysed the characteristics and prevalence of microvascular complications among paediatric T2DM patients in Hong Kong at diagnosis and 2 years after diagnosis. Methods: All patients aged <18 years who had been diagnosed with DM at public hospitals in Hong Kong were recruited into the Hong Kong Childhood Diabetes Registry. Data collected at diagnosis and 2 years after diagnosis were retrospectively retrieved from the Registry for patients diagnosed from 2014 to 2018. Results: Median haemoglobin A1c (HbA1c) levels were 7.5% (n=203) at diagnosis and 6.5% (n=135) 2 years after diagnosis; 59.3% of patients achieved optimal glycaemic control (HbA1c level <7%) at 2 years. A higher HbA1c level at diagnosis was associated with worse glycaemic control at 2 years (correlation coefficient=0.39; P<0.001). The presence of dyslipidaemia (adjusted odds ratio [aOR]=3.19; P=0.033) and fatty liver (aOR=2.50; P=0.021) at 2 years were associated with suboptimal glycaemic control. Diabetic neuropathy and retinopathy were rare in our cohort, but 18.6% of patients developed microalbuminuria (MA) within 2 years after diagnosis. Patients with MA had a higher HbA1c level at 2 years (median: 7.2% vs 6.4%; P=0.037). Hypertension was a risk factor for MA at 2 years, independent of glycaemic control (aOR=4.61; P=0.008). Conclusion: These results highlight the importance of early diagnosis and holistic management (including co-morbidity management) for paediatric T2DM patients.