GBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher disease.

BACKGROUND: Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations. METHODS: We selected 8115 patients with osteoporosis (T-score ≤ - 2.5) and 55,942 healthy individuals (T-score > - 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient's cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period. RESULTS: The GBA1 gene variant rs11264345 was significantly associated [P < 0.002, Odds Ratio (OR) = 1.06] with an increased risk of bone disease. Upregulation of Calnexin, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) was positively associated with osteoclastogenesis in patients with GD. In vitro AAV9-GBA1 treatment of GD patient cells led to enhanced GBA1 enzyme activity, reduced chitotriosidase activity, diminished ER stress, and decreased osteoclast differentiation. Long-term bone density data suggests that initiating ERT earlier in GD leads to greater improvements in bone density. CONCLUSIONS: Elevated ER stress and inflammasome activation are indicative of osteoporosis development, suggesting the need for clinical monitoring of patients with GD. Furthermore, disease-associated variant in the GBA1 gene may constitute a risk factor predisposing specific populations to osteoporosis.

Quantitative DNA Methylation Analysis and Epigenotype-Phenotype Correlations in Taiwanese Patients with Silver-Russell Syndrome.

Background: Silver-Russell syndrome (SRS; OMIM #180860) is a clinically and genetically heterogeneous imprinting disorder characterized by prenatal and postnatal growth failure. The aim of this study was to identify the epigenotype-phenotype correlations in these patients using quantitative DNA methylation analysis. Methods: One hundred and eighty-three subjects clinically suspected of having SRS were referred for diagnostic testing by the methylation profiling of H19-associated imprinting center (IC) 1 and imprinted PEG1/MEST regions using methylation-specific high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between quantitative DNA methylation status and clinical manifestations of the subjects according to the Netchine-Harbison (N-H) clinical scoring system for SRS were analyzed. Results: Among the 183 subjects, 90 had a clinical diagnosis of SRS [N-H score ≥ 4 (maximum = 6)] and 93 had an SRS score < 4. Molecular lesions were detected in 41% (37/90) of the subjects with a clinical diagnosis of SRS, compared with 3% (3/93) of those with an N-H score < 4. The IC1 methylation level was negatively correlated with the N-H score. The molecular diagnosis rate was positively correlated with the N-H score. Thirty-one subjects had IC1 hypomethylation (IC1 methylation level <35% by the MassARRAY assay), seven had maternal uniparental disomy 7, and two had pathogenic copy number variants. Among the 90 subjects with an N-H score ≥ 4, the IC1 methylation level was significantly different between those with or without some clinical SRS features, including birth length ≤ 10th centile, relative macrocephaly at birth, normal cognitive development, body asymmetry, clinodactyly of the fifth finger, and genital abnormalities. Conclusions: This study confirmed the suitability of the N-H clinical scoring system as clinical diagnostic criteria for SRS. Quantitative DNA methylation analysis using the MassARRAY assay can improve the detection of epigenotype-phenotype correlations, further promoting better genetic counseling and multidisciplinary management for these patients.

The Long-term Lung and Respiratory Outcomes of Acid Sphingomyelinase Deficiency: A 10- and 20-year Follow-up Study.

BACKGROUND/AIM: Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder characterized by sphingomyelin accumulation causing progressive lung disease, respiratory failure, and death. PATIENTS AND METHODS: This retrospective observational study used the TriNetX database of electronic health records for 15,108 patients with ASMD from 2000-2020. After exclusions, 8,980 individuals were followed for 10 or 20 years. Outcomes included incidence and prevalence of respiratory disorders. Associations of age, sex and race were assessed. RESULTS: Nearly all respiratory outcomes increased significantly over 20 versus 10 years. Other respiratory disorders, specified respiratory disorders and secondary pulmonary hypertension exhibited the greatest increases, reflecting progressive lung damage in ASMD. While outcomes were poor overall, older age, male sex, and racial minority status associated with greater risks, indicating differences in disease progression or care. CONCLUSION: This study confirms the progressive nature of ASMD and need for close monitoring and treatment of pulmonary complications to reduce long-term morbidity and mortality. Genetic testing enabling diagnosis even for milder, adult-onset forms is critical to optimize outcomes.

Spectrum of PHEX Mutations and FGF23 Profiles in a Taiwanese Cohort With X-Linked Hypophosphatemia Including 102 Patients.

BACKGROUND/AIM: X-linked hypophosphatemia (XLH), the most common form of hereditary rickets, results from loss-of-function mutations in the phosphate-regulating PHEX gene. Elevated fibroblast growth factor 23 (FGF23) contributes to hypophosphatemia in XLH. This study aimed to characterize PHEX variants and serum FGF23 profiles in Taiwanese patients with XLH. PATIENTS AND METHODS: We retrospectively reviewed the records of 102 patients clinically suspected of having hypophosphatemic rickets from 2006 to 2022. Serum intact Fibroblast growth factor-23 (iFGF23) levels were measured on clinic visit days. PHEX mutations were identified using Sanger sequencing, and negative cases were analyzed using whole-exome sequencing. RESULTS: The majority (92.1%) of patients exhibited elevated FGF23 compared with normal individuals. Among 102 patients, 44 distinct PHEX mutations were identified. Several mutations recurred in multiple unrelated Taiwanese families. We discovered a high frequency of novel PHEX mutations and identified variants associated with extreme FGF23 elevation and tumorigenesis. CONCLUSION: Our findings revealed the PHEX genotypic variants and FGF23 levels in Taiwanese patients with XLH. These results are crucial given the recent approval of burosumab, a monoclonal FGF23 antibody, for XLH therapy. This study provides key insights into the clinical management of XLH in Taiwan.

Elucidating the Cancer Phenotype in Turner Syndrome: A 20-Year Observational Cohort Study.

BACKGROUND/AIM: Turner syndrome confers increased cancer susceptibility; however, large-scale epidemiological evidence is lacking. This study aimed to analyze the incidence and prevalence of various malignancies in patients with Turner syndrome over 20 years of age to inform screening strategies. PATIENTS AND METHODS: We performed a retrospective cohort analysis of 11,502 patients with Turner syndrome from 2000 to 2020 utilizing the TriNetX research network database. The outcomes encompassed the incidence and prevalence of 20 cancers. Stratified analyses were used to evaluate variations in age, sex, and race. RESULTS: Key findings demonstrated markedly elevated risks of breast (1.7%), colon (1.0%), renal (0.4%), gonadoblastoma (0.4%), and other cancers. Significant demographic variations were observed in the incidence of cancers, such as gonadoblastoma, renal, and colon cancer. CONCLUSION: This large real-world study offers novel insights into the spectrum of cancer risk across adulthood in Turner syndrome. Our findings elucidate Turner syndrome's complex cancer phenotype to inform clinical decision-making, prognostication, and tailored screening strategies to ultimately advance patient care.

Prevalence of Kidney and Urinary Tract Complications in Fabry Disease from 2000 to 2020: A Global Cohort Study Including 10,637 Patients.

BACKGROUND/AIM: Fabry disease, an X-linked lysosomal storage disorder, causes progressive globotriaosylceramide accumulation in cells throughout the body. Characteristic multiorgan manifestations include renal dysfunction (Fabry nephropathy) and associated urinary tract complications. Enzyme replacement therapy (ERT) has been available since 2001, but contemporary real-world data are lacking regarding Fabry nephropathy risks and treatment outcomes. PATIENTS AND METHODS: This retrospective cohort study analyzed electronic medical records data for 10,637 Fabry disease patients from the TriNetX research database. Kidney and urinary tract outcomes were evaluated over two decades, 2000-2010 and 2011-2020. Outcomes assessed included chronic kidney disease (CKD), urinary tract infections, urinary incontinence, obstruction, renal insufficiency, and end-stage renal disease (ESRD). RESULTS: The prevalence of stage 4-5 CKD nearly doubled between 2000-2010 and 2011-2020, while ESRD prevalence rose over 4-fold. Incidence rates showed similar marked elevations across renal and urologic complications. Females and Black patients experienced disproportionate escalations in kidney and urinary tract morbidity. CONCLUSION: This large cohort study revealed significantly increased Fabry nephropathy and associated urologic complications over the past two decades, contradicting expectations of reduced morbidity with ERT availability. The findings highlight needs to optimize screening, treatment strategies, monitoring practices, and address disparities to curb rising disease burden and improve patient outcomes.

Long-Term Non-Congenital Cardiac and Renal Complications in Down Syndrome: A Study of 32,936 Patients.

BACKGROUND: Individuals with Down syndrome are at a higher risk of cardiac, renal, and other health issues due to a complex disease physiology. However, few data exist on long-term disease risks to guide prevention and care. We aimed to determine the 10-year incidence of cardiac, renal, and urinary tract complications in Down syndrome versus matched controls. METHODS: This retrospective cohort study utilized a large collaborative database. We identified 32,444 patients with Down syndrome and matched controls, excluding those with pre-follow-up target events. Covariates included demographics, lifestyle factors, and comorbidities. Outcomes were ischemic heart disease, hypertension, hypothyroidism, epilepsy, urinary tract infections and chronic kidney disease. We calculated unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox regression and plotted Kaplan-Meier survival curves. FINDINGS: Over 10 years, Down syndrome patients showed a 3.7-fold higher ischemic heart disease risk (95% CI: 3.0-4.6) and a 1.6-fold higher hypertension risk (95% CI: 1.4-1.8) versus controls. Hypothyroidism (HR = 2.0; 95% CI: 1.7-2.4), epilepsy (HR = 4.5; 95% CI: 3.5-5.8), and urinary tract infection (HR = 3.9; 95% CI: 3.4-4.6) risks were also higher. Chronic kidney disease risk was 2.7-fold greater (95% CI: 2.1-3.5). Survival analysis confirmed a significantly higher incidence of all outcomes in Down syndrome (p < 0.0001). INTERPRETATION: This large study found major health challenges in Down syndrome, with risks 3- to 5-fold higher for chronic conditions versus matched controls over 10 years. Though survival remains high with proper care, focusing resources on the prevention and management of complications in this high-risk group can optimize well-being across the lifespan. Future research accounting for limitations here would provide definitive estimates of disease risk in Down syndrome to guide targeted health strategies.

Incidence of Pulmonary and Respiratory Conditions in Gaucher Disease from 2000 to 2020: A Multi-institutional Cohort Study.

BACKGROUND/AIM: Gaucher disease (GD) is a rare lysosomal storage disorder that can involve the lungs and pulmonary vasculature. The long-term effects of GD on respiratory health remain unclear due to limited data on the natural history of this disease. We analyzed electronic health records for 11,004 patients with GD over 10-20 years to determine the incidence of pulmonary hypertension (PH), lung disease, and other respiratory comorbidities and better understand disease course to guide management. PATIENTS AND METHODS: We conducted a retrospective cohort study using the TriNetX research database of 130 million international patients. The incidence of primary/secondary PH, pulmonary heart disease, interstitial/obstructive/restrictive lung disease, pulmonary hemorrhage, and pulmonary embolism was assessed in patients with GD from 2000-2020. RESULTS: Incidence rates of all conditions assessed increased from 10 to 20 years of follow-up. Excess risk of PH, lung disease, and pulmonary hemorrhage was significantly higher in GD patients after 20 versus 10 years. CONCLUSION: Extended follow-up in GD is associated with substantially higher risks of PH, lung disease and other respiratory comorbidities, highlighting the need for close monitoring and early intervention to mitigate long-term pulmonary decline. Improved understanding of mechanisms driving respiratory deterioration can support the development of novel treatments to optimize outcomes in this population at high risk of pulmonary morbidity and mortality.

Combining polygenic risk scores and human leukocyte antigen variants for personalized risk assessment of type 1 diabetes in the Taiwanese population.

AIMS: To analyse the genome-wide association study (GWAS) data of patients with type 1 diabetes mellitus (T1D) in order to develop a risk score for the genetic effects on T1D risk and age at diagnosis in the Taiwanese population. MATERIALS AND METHODS: We selected 610 patients with T1D and 2511 healthy individuals from an electronic medical record database of more than 300 000 individuals with genetic information, analysed their GWAS data, and developed a polygenic risk score (PRS). RESULTS: The PRS, based on 149 selected single-nucleotide polymorphisms, could effectively predict T1D risk. A PRS increase was associated with increased T1D risk (odds ratio [OR] 2.09, 95% confidence interval [CI] 1.72-2.55). Moreover, a 1-unit increase in standardized T1D PRS decreased the age at diagnosis by 0.74 years. Combined PRS and human leukocyte antigen (HLA) DQA1*03:02-DQA1*05:01 genotypes could accurately predict T1D risk. In multivariable models, HLA variants and PRS were independent risk factors for T1D risk (OR 3.76 [95% CI 1.54-9.16] and 1.71 [95% CI 1.37-2.13] for HLA DQA1*03:02-DQA1*05:01 and PRS, respectively). In a limited study population of those aged ≤18 years, PRS remained significantly associated with T1D risk. The association between T1D PRS and age at diagnosis was more obvious among males and patients aged ≤18 years. CONCLUSIONS: Polygenic risk score and HLA variations enable personalized risk estimates, enhance newborn screening efficiency for ketoacidosis prevention, and addresses the gap in data on T1D prediction in isolated Asian populations.

Asia-Pacific Consensus Recommendations on X-Linked Hypophosphatemia: Diagnosis, Multidisciplinary Management, and Transition From Pediatric to Adult Care.

X-linked hypophosphatemia (XLH) is a rare, inherited, multisystem disorder characterized by hypophosphatemia that occurs secondary to renal phosphate wasting. Mutations in PHEX gene (located at Xp22.1) in XLH alter bone mineral metabolism, resulting in diverse skeletal, dental, and other extraskeletal abnormalities that become evident in early childhood and persist into adolescence and adult life. XLH impacts physical function, mobility, and quality of life, and is associated with substantial socioeconomic burden and health care resource utilization. As the burden of illness varies with age, an appropriate transition of care from childhood and adolescence to adulthood is necessary to meet growth-related changes and minimize long-term sequelae of the condition. Previous XLH guidelines that encompassed transition of care have focused on Western experience. Regional differences in resource availability warrant tailoring of recommendations to the Asia-Pacific (APAC) context. Hence, a core expert panel of 15 pediatric and adult endocrinologists from nine countries/regions across APAC convened to formulate evidence-based recommendations for optimizing XLH care. A comprehensive literature search on PubMed using MeSH and free-text terms relevant to predetermined clinical questions on diagnosis, multidisciplinary management, and transition of care of XLH revealed 2171 abstracts. The abstracts were reviewed independently by two authors to shortlist a final of 164 articles. A total of 92 full-text articles were finally selected for data extraction and drafting the consensus statements. Sixteen guiding statements were developed based on review of evidence and real-world clinical experience. The GRADE criteria were used to appraise the quality of evidence supporting the statements. Subsequently, a Delphi technique was utilized to rate the agreement on statements; 38 XLH experts (15 core, 20 additional, 3 international) from 15 countries/regions (12 APAC, 3 EU) participated in the Delphi voting to further refine the statements. Statements 1-3 cover the screening and diagnosis of pediatric and adult XLH; we have defined the clinical, imaging, biochemical, and genetic criteria and raised red flags for the presumptive and confirmatory diagnosis of XLH. Statements 4-12 tackle elements of multidisciplinary management in XLH such as therapeutic goals and options, composition of the multidisciplinary team, follow-up assessments, required monitoring schedules, and the role of telemedicine. Treatment with active vitamin D, oral phosphate, and burosumab is discussed in terms of applicability to APAC settings. We also expound on multidisciplinary care for different age groups (children, adolescents, adults) and pregnant or lactating women. Statements 13-15 address facets of the transition from pediatric to adult care: targets and timelines, roles and responsibilities of stakeholders, and process flow. We explain the use of validated questionnaires, desirable characteristics of a transition care clinic, and important components of a transfer letter. Lastly, strategies to improve XLH education to the medical community are also elaborated in statement 16. Overall, optimized care for XLH patients requires prompt diagnosis, timely multidisciplinary care, and a seamless transfer of care through the coordinated effort of pediatric and adult health care providers, nurse practitioners, parents or caregivers, and patients. To achieve this end, we provide specific guidance for clinical practice in APAC settings. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Phthalates exposure and pubertal development in a 15-year follow-up birth cohort study in Taiwan.

Purpose: Phthalates are ubiquitous endocrine disruptors that can affect pubertal development in children. The association of fetal and childhood levels of phthalates with pubertal development were explored. Methods: We conduct a population-based birth cohort study to investigate the association between prenatal and childhood exposure to phthalates and pubertal development. Initially, a total of 445 children were recruited from 2000 to 2001, of which 90 children were followed for 15 years which measurements of urine and development assessed at 2, 5, 8, 11, and 14 years. We defined higher Tanner stage as the 14-year-old Tanner stage ≥ 4 and 5 for boys and girls, respectively. A logistic regression analysis was conducted to estimate the crude and adjusted odds ratio of a higher Tanner stage at 14 years old. The Pearson correlation coefficient and multiple linear regression were used to estimate the association of testicular volume, uterine volume, ovarian volume, and blood hormones at 14 years of age with the log-transformed concentration of phthalates at 2, 5, 8, 11, and 14 years. Results: In boys, a significantly different geometric mean of mono-benzyl phthalate (MBzP) was observed in 11-year-olds; 6.82 and 2.96 in the lower Tanner stage group and higher Tanner stage group. In girls, a significant difference in the geometric mean of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) in 11-year-olds and mono-ethyl phthalate (MEP) in 2-year-olds was observed; MEHHP was 32.97 and 18.13 in the lower Tanner stage group and higher Tanner stage group, and MEP was 26.54 and 65.74 in the lower Tanner stage group and higher Tanner stage group, respectively. Uterine volume at 14 years old was negatively associated with several phthalate metabolites (MEHP at 8 years old, MnBP at 8 years old, MBzP at 14 years old, MMP prenatally, MMP at 8 years old, and MEP at 8 years old) after adjusting for covariates. However, no significant correlations were found between phthalate metabolites and ovarian or testicular volume. Conclusion: Phthalate exposure at certain time points may influence the reproductive development of children during puberty; however, further studies should be conducted to determine the causal nature of this association.

Maternal diabetes mellitus and birth defects in Taiwan: A 5-year nationwide population-based cohort study.

BACKGROUND: Birth defects (BDs) are the main causes of mortality and disability in infants and children. Associations between maternal diabetes mellitus (DM), including gestational DM (GDM) and pregestational DM (type 1 or type 2), and the risk of BDs have been reported. This study aims to determine the relationship between maternal DM and BDs and to investigate whether reducing the incidence of DM can decrease the incidence of BDs. METHODS: We identified all births in Taiwan from the National Birth Defects Surveillance Program between January 1, 2010, and December 31, 2014. Information on the infants' characteristics (sex, gestational age, and birth weight) and mothers' characteristics (age, parity, and associated diseases, including DM) were obtained from the National Birth Registry and National Health Insurance Research Database (NHIRD) in Taiwan. BDs were coded according to the International Classification of Diseases, 9th Revision-Clinical Modification (ICD-9-CM) codes 740-759. RESULTS: Multiple logistic regression analysis with adjusted odds ratio (aOR) and 95% confidence interval (95% CI) for all BDs showed that the aOR (95% CI) was 1.002 (0.965-1.041), and the p -value was 0.9139 in the GDM group. In the type 1 DM group, the aOR (95% CI) was 1.748 (1.110-2.754), and the p -value was 0.016. In the type 2 DM group, the aOR (95%CI) was 1.175 (1.005-1.375), 1.331 (1.196-1.482), and 1.391 (1.216-1.592), and the p -value was 0.0437, <0.0001, and <0.0001 for the duration of mothers with type 2 DM <2, 2 to 5, >5 years, respectively. CONCLUSION: Mothers with pregestational DM (type 1 or type 2) increase the incidence of BD. Appropriate maternal glycemic control may achieve good pregnancy and perinatal outcomes.

CD3+CD56+ T Lymphocytes Are Associated With ER Stress and Inflammasome Activation in Type 1 Diabetes.

BACKGROUND/AIM: The T cell's flexibility of the immune system to be regulated affects the onset of type 1 diabetes (T1D). However, the mechanisms of endoplasmic reticulum (ER) stress and inflammasome activation in the circulating CD3+CD56+ T cells of patients with T1D remain unclear. This study evaluated the role of CD3+CD56+ T cells in T1D and their correlations with ER stress, inflammasome activation and disease characteristics. MATERIALS AND METHODS: The frequency of circulating CD3+CD56+ T cells was determined using flow cytometry in healthy individuals and patients with T1D. Calnexin, NLR family pyrin domain containing 3 (NLRP3), ASC, caspase-1 (Casp1), cleaved caspase-3 (C-Casp3), and annexin V (AnnV) expression and propidium iodide staining in CD3+/CD56+ T cells were analyzed using flow cytometry. RESULTS: The frequency of CD3+CD56+ T cells was reduced in patients with T1D relative to that in healthy individuals. In addition, high calnexin, NLRP3, ASC and Casp1 expression in CD3+CD56+ T cells was negatively correlated with the percentage of CD3+CD56+ T cells in patients with T1D. CONCLUSION: ER stress, inflammasome activation, and a lower peripheral frequency of circulating CD3+CD56+ T cells might indicate disease progression and necessitate clinical T1D immunological self-tolerance monitoring.

T Cells Mediate Kidney Tubular Injury via Impaired PDHA1 and Autophagy in Type 1 Diabetes.

CONTEXT: Nephropathy is a severe complication of type 1 diabetes (T1DM). However, the interaction between the PDHA1-regulated mechanism and CD4+ T cells in the early stage of kidney tubular injury remains unknown. OBJECTIVE: To evaluate the role of PDHA1 in the regulation of tubular cells and CD4+ T cells and further to study its interaction in tubular cell injury in T1DM. METHODS: Plasma and total RNA were collected from T cells of T1DM patients (n = 35) and healthy donors (n = 33) and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, PDHA1, and biomarkers of CD4+ T cells including T helper 1 cells (Th1) and regulatory T cells (Treg) markers. HK-2 cells cocultured with CD4+ T cells from T1DM patients or healthy donors (HDs) to evaluate the interaction with CD4+ T cells. RESULTS: Increased PDHA1 gene expression levels in CD4+ T cells were positively associated with the plasma level of NGAL in T1DM patients and HDs. Our data demonstrated that the Th1/Treg subsets skewed Th1 in T1DM. Knockdown of PDHA1 in kidney tubular cells decreased ATP/ROS production, NAD/NADH ratio, mitochondrial respiration, and cell apoptosis. Furthermore, PDHA1 depletion induced impaired autophagic flux. Coculture of tubular cells and T1DM T cells showed impaired CPT1A, upregulated FASN, and induced kidney injury. CONCLUSION: Our findings indicate that Th1 cells induced tubular cell injury through dysregulated metabolic reprogramming and autophagy, thereby indicating a new therapeutic approach for kidney tubular injury in T1DM.

Investigating the Impact of the TUITEK® Patient Support Programme, Designed to Support Caregivers of Children Prescribed Recombinant Human Growth Hormone Treatment in Taiwan.

Purpose: Poor adherence to recombinant human growth hormone (r-hGH) treatment presents a significant barrier to achieving optimal growth outcomes. It is important to identify and address the treatment adherence-related needs of children prescribed r-hGH treatment, and develop new approaches to improve adherence. We aimed to measure the impact of the TUITEK® patient support programme, a multi-component personalized service intervention, on caregivers' knowledge, beliefs, and perceptions of short stature and adherence to its treatment. Patients and Methods: The evaluation of the TUITEK® patient support programme was conducted among 31 caregivers of children with short stature and receiving r-hGH treatment via the easypod™ auto-injector device in Taiwan. Caregivers within the 'high risk' category for knowledge, beliefs and perception factors influencing adherence to r-hGH treatment (disease and treatment coherence, emotional burden, self-administration, and treatment-related anxiety) were identified via the TUITEK® personalization questionnaire and followed up with bi-weekly telephone calls by a nurse practitioner over a 3-month period. A Wilcoxon signed-rank test was used to compare changes in questionnaire-based scoring patterns between baseline and follow-up. Results: Between baseline and follow-up, the percentage of caregivers scoring as 'high risk' for emotional burden reduced by 37%; there was an improvement in confidence of self-administration by 57% and the percentage of caregivers scoring as 'high risk' for treatment-related anxiety reduced by 52%. At follow-up, all caregivers classified as 'high risk' within the disease and treatment coherence item at baseline moved into the 'low risk' category. Statistically significant changes in questionnaire scores between baseline and follow-up for disease and treatment understanding, emotional burden, self-administration, and treatment-related anxiety were also observed. Conclusion: These findings indicate that the TUITEK® patient support programme can positively address disease and treatment-related barriers amongst caregivers regarding optimal adherence of their children to r-hGH treatment, which has the potential to positively impact on adherence levels and patient clinical health outcomes.

A Comparative Prevalence of Birth Defects between Newborns of Immigrant and Native-Born Mothers in Taiwan: Ten Years of Population-Based Data.

In recent years, newborns born to immigrant mothers have accounted for about 10% of the total births in Taiwan. However, little is known about whether there are differences between newborns of immigrant and native-born mothers regarding the prevalence and the possible causes of birth defects. By combining four nationwide databases and assessing all newborns between 2005 and 2014 in Taiwan as research subjects, this study determined the prevalence of birth defects stratified into nine categories (neuronal, facial, cleft, circulatory, respiratory, digestive, urogenital, musculoskeletal and chromosomal abnormalities) in the newborns of immigrant mothers and native-born mothers. We found that the prevalence of any birth defects in newborns of immigrant mothers (ranging from 0.98 to 1.24%) was lower than that of native-born mothers (2.86%). Skeletomuscular system defects are the most common among newborns of women from the main immigrant countries (0.24-0.42%), while circulatory system defects were the most common among newborns of Taiwanese women (0.92%). The risks of all defects remained lower for newborns of immigrant mothers (AORs ranged from 0.37 to 0.47) after controlling for possible confounding variables. The higher rates of birth defects among newborns of native-born mothers may be attributed to an older maternal age at childbirth and a higher prevalence of diabetes than that of immigrant mothers. The findings from this study imply that the prevalence of birth defects between newborns of immigrant and native-born mothers is not similar, as evidenced by a decade of population-based data.

Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver-Russell Syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder characterized by severe intrauterine growth retardation, poor postnatal growth, characteristic facial features, and body asymmetry. Hypomethylation of the imprinted genes of the chromosome 11p15.5 imprinting gene cluster and maternal uniparental disomy of chromosome 7 (mUPD7) are the major epigenetic disturbances. The aim of this study was to characterize the epigenotype, genotype, and phenotype of these patients in Taiwan. METHODS: Two hundred and six subjects with clinically suspected SRS were referred for diagnostic testing, which was performed by profiling the methylation of H19-associated imprinting center (IC) 1 and the imprinted PEG1/MEST region using methylation-specific multiplex ligation-dependent probe amplification and high-resolution melting analysis with a methylation-specific polymerase chain reaction assay. We also applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Clinical manifestations were recorded and analyzed according to the SRS scoring system proposed by Bartholdi et al. Results: Among the 206 referred subjects, 100 were classified as having a clinical diagnosis of SRS (score ≥ 8, maximum = 15) and 106 had an SRS score ≤ 7. Molecular lesions were detected in 45% (45/100) of the subjects with a clinical diagnosis of SRS, compared to 5% (5/106) of those with an SRS score ≤ 7. Thirty-seven subjects had IC1 hypomethylation, ten subjects had mUPD7, and three subjects had microdeletions. Several clinical features were found to be statistically different (p < 0.05) between the "IC1 hypomethylation" and "mUPD7" groups, including relative macrocephaly at birth (89% vs. 50%), triangular shaped face (89% vs. 50%), clinodactyly of the fifth finger (68% vs. 20%), and SRS score (11.4 ± 2.2 vs. 8.3 ± 2.5). CONCLUSIONS: The SRS score was positively correlated with the molecular diagnosis rate (p < 0.001). The SRS subjects with mUPD7 seemed to have fewer typical features and lower SRS scores than those with IC1 hypomethylation. Careful clinical observation and timely molecular confirmation are important to allow for an early diagnosis and multidisciplinary management of these patients.

Prenatal Exposure to Endocrine-Disrupting Chemicals and Subsequent Brain Structure Changes Revealed by Voxel-Based Morphometry and Generalized Q-Sampling MRI.

Previous studies have indicated that prenatal exposure to endocrine-disrupting chemicals (EDCs) can cause adverse neuropsychiatric disorders in children and adolescents. This study aimed to determine the association between the concentrations of prenatal EDCs and brain structure changes in teenagers by using MRI. We recruited 49 mother-child pairs during the third trimester of pregnancy, and collected and examined the concentration of EDCs-including phthalate esters, perfluorochemicals (PFCs), and heavy metals (lead, arsenic, cadmium, and mercury)-in maternal urine and/or serum. MRI voxel-based morphometry (VBM) and generalized q-sampling imaging (GQI) mapping-including generalized fractional anisotropy (GFA), normalized quantitative anisotropy (NQA), and the isotropic value of the orientation distribution function (ISO)-were obtained in teenagers 13-16 years of age in order to find the association between maternal EDC concentrations and possible brain structure alterations in the teenagers' brains. We found that there are several specific vulnerable brain areas/structures associated with prenatal exposure to EDCs, including decreased focal brain volume, primarily in the frontal lobe; high frontoparietal lobe, temporooccipital lobe and cerebellum; and white matter structural alterations, which showed a negative association with GFA/NQA and a positive association with ISO, primarily in the corpus callosum, external and internal capsules, corona radiata, superior fronto-occipital fasciculus, and superior longitudinal fasciculus. Prenatal exposure to EDCs may be associated with specific brain structure alterations in teenagers.

Long, Noncoding RNA SRA Induces Apoptosis of ß-Cells by Promoting the IRAK1/LDHA/Lactate Pathway.

Long non-coding RNA steroid receptor RNA activators (LncRNA SRAs) are implicated in the ß-cell destruction of Type 1 diabetes mellitus (T1D), but functional association remains poorly understood. Here, we aimed to verify the role of LncRNA SRA regulation in ß-cells. LncRNA SRAs were highly expressed in plasma samples and peripheral blood mononuclear cells (PBMCs) from T1D patients. LncRNA SRA was strongly upregulated by high-glucose treatment. LncRNA SRA acts as a microRNA (miR)-146b sponge through direct sequence-structure interactions. Silencing of lncRNA SRA increased the functional genes of Tregs, resulting in metabolic reprogramming, such as decreased lactate levels, repressed lactate dehydrogenase A (LDHA)/phosphorylated LDHA (pLDHA at Tyr10) expression, decreased reactive oxygen species (ROS) production, increased ATP production, and finally, decreased ß-cell apoptosis in vitro. There was a positive association between lactate level and hemoglobin A1c (HbA1c) level in the plasma from patients with T1D. Recombinant human interleukin (IL)-2 treatment repressed lncRNA SRA expression and activity in ß-cells. Higher levels of lncRNA-SRA/lactate in the plasma are associated with poor regulation in T1D patients. LncRNA SRA contributed to T1D pathogenesis through the inhibition of miR-146b in ß-cells, with activating signaling transduction of interleukin-1 receptor-associated kinase 1 (IRAK1)/LDHA/pLDHA. Taken together, LncRNA SRA plays a critical role in the function of ß-cells.

Monitoring Adherence Rate to Growth Hormone Therapy and Growth Outcomes in Taiwanese Children Using Easypod Connect: Observational Study.

BACKGROUND: Adherence to growth hormone therapy is difficult to detect reliably. Devices such as easypod have been developed for electronic recording of injections. The easypod connect observational study (ECOS) was an open-label, observational, multinational, phase IV study conducted in 24 countries around the world. The final results from ECOS in the Taiwanese cohort are reported in this paper. OBJECTIVE: This study aimed to evaluate the adherence and long-term outcomes of growth hormone therapy in pediatric subjects using the easypod electromechanical device. METHODS: Subjects (aged 2-18 years or >18 years without fusion of growth plates) who received Saizen (recombinant human growth hormone, somatropin) via the easypod device were enrolled in this study. The primary objective was to assess the level of adherence in subjects receiving Saizen via easypod. RESULTS: In Taiwan, a total of 35 and 13 children fulfilled the criteria of full analysis set and complete analysis set, respectively. The mean (SD) age of the complete analysis set was 12.08 (2.72) years. All subjects were growth hormone-naïve, with 38% (5/13) females. The mean adherence rates of 13 subjects were 87.6% at 3 months and 84.3% at 6 months, that of 8 subjects was 81.0% at 9 months, and that of 4 subjects was 91.6% at 1 year. After 1 year of treatment, subjects had a median (Q1:Q3) change in height SD score of 0.30 (0.06:0.48), median height velocity of 6.50 (4.33:8.24) cm/year, and median change in height velocity SD score of 1.81 (-0.04:3.52). CONCLUSIONS: With the easypod device, patients with inadequate adherence and poor response to treatment can be identified. Adherence to growth hormone therapy administered via easypod was generally high in the first year of treatment but the adherence gradually decreased over time. Overall, growth outcomes after 1 year indicated a positive growth response to growth hormone treatment. Future efforts should be focused on personalized management of adherence by using the easypod system.