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Background Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is one of the most common autoimmune encephalitis in children. Most children recovered well after anti-NMDA receptor encephalitis. However, the NMDA receptor network functions are critical for the developing brain in children. The long-term consequences in pediatric patients of anti-NMDA receptor encephalitis are very infrequently reported. Methods This case series study retrospectively enrolled 10 children aged below 18 years old with antibody-proved anti-NMDA receptor encephalitis in a tertiary medical center from 2010 to 2019. Long-term neurological consequences of anti-NMDA receptor encephalitis in children were followed. Results One boy and nine girls were enrolled with a median onset age of 3.6 years. The most common initial presentation was verbal reduction and psychiatric symptoms soon after some flu-like prodromal symptoms. Nearly all patients then developed decreased level of consciousness, mutism, seizures and orofacial-lingual dyskinesia. Autonomic instability occurred in 5 patients, particularly in pre-pubertal children. Only one adolescent patient had ovarian teratoma. All patients survived after immunotherapy and were followed for 5.8 ± 3.3 years after discharge. Four had epilepsy within 2 years after encephalitis, four had a cognitive deficit, one had mild psychiatric symptoms of hallucination, and none had residual involuntary movements. Moreover, two pre-pubertal children developed central precocious puberty about 3 years after encephalitis, and one required gonadotropin-releasing hormone agonist treatment. Conclusion Central precocious puberty could be a consequence of anti-NMDA receptor encephalitis in the pre-pubertal children. The pediatrician should pay attention to its occurrence at follow-up.

Thyroxine (T4) importantly regulates the growth of newborns. Compared to fetuses with equivalent gestational ages, very preterm infants (VPIs) often experience relatively low thyroxinemia, with a normal thyroid-stimulating hormone (TSH) concentration < 10 μIU/mL. However, there is continued debate regarding postnatal thyroxine supplementation for VPIs with normal TSH and transitionally low thyroxinemia. Little research has explored the role of the postnatal total T4 (TT4) serum concentration on the growth of VPIs. In this study, we aim to clarify whether the postnatal thyroxine concentration is associated with the short- and long-term growth outcomes of VPIs. A total of 334 surviving VPIs in our previously reported cohort, born in the period August 2007–July 2016, were enrolled. The exposure variable was the postnatal TT4 concentration at 1 month old. The primary outcomes were body weight increments over 28 days after the screening and anthropometric outcomes at the corrected age of 24 months old. Infants with any hormonal replacement, severe brain injury, congenital anomaly, or cerebral palsy were excluded. In total, 290 (86.8%) VPIs were included for analysis. In the 28 days after thyroid function screening, the TT4 concentration was found to have a significant association with positive increments in body weight (mean increment: 25.7 g per 1 μg/dL; p < 0.001) and a positive body weight z-score (mean increment: 0.039 per 1 μg/dL; p = 0.037), determined by generalized estimating equation analysis. At the corrected age of 24 months old, a higher postnatal TT4 concentration was associated with a lower body mass index (mean coefficient: −0.136; 95% CI: −0.231 to −0.041, p = 0.005) and lower body mass index z-score (mean coefficient: −0.097; 95% CI: −0.170 to −0.024, p = 0.009). Infants with a TT4 concentration > 6.4 ug/dL had significantly lower odds of overweight status (odds ratio: 0.365; 95% CI: 0.177 to 0.754, p = 0.006). We conclude that the postnatal TT4 concentration is associated with a positive increment in body weight in the short term. At the same time, the postnatal TT4 concentration is associated with lower odds of overweight status after long-term follow-up.

Previous studies have shown hypothyroidism was independently associated with nonalcoholic fatty liver disease (NAFLD) in adults, but few studies examined their relationships in pediatric populations. This study aimed to investigate the prevalence of NAFLD in pediatric congenital hypothyroidism (CHT) patients and to identify the association between CHT and NAFLD. This study enrolled pediatric CHT patients receiving levothyroxine treatment at one medical center from 2013 to 2014. Euthyroid subjects (ET) and transient hypothyroidism (THT) patients weaned off medication successfully after age 3 were selected for further comparison. Laboratory data including thyroid functions, liver functions, and metabolic profiles were obtained. The major outcome was the occurrence of NAFLD, diagnosed based on the findings of abdominal ultrasonography. One‐hundred and twenty‐nine subjects (47 in CHT, 47 in THT, and 35 in ET groups) were enrolled. The analysis showed higher fasting serum glucose, insulin, thyroxine (T4), and mean thyroid‐stimulating hormone (TSH) levels in the CHT group. NAFLD prevalence was higher in the CHT (23.4%) group than in the THT (8.5%) and the ET (5.7%) groups, demonstrating an increasing trend across three strata (X2linear‐by‐linear = 5.9, P

To translate the 26-item English version Problem Areas in Diabetes-Teen (PAID-T) into a Chinese version and then to examine its psychometrical properties for measuring diabetes distress in adolescents with type 1 diabetes (T1D).The 26-item English version PAID-T was translated into a Chinese version guided by the translation model for cross-cultural research. A cross-sectional design was used and 203 adolescents with T1D were recruited from four hospitals in Taiwan. Content validity, exploratory factor analysis, and item analysis were used to ensure the item quality and build the factor structure of the Chinese version PAID-T. Confirmatory factor analysis, concurrent validity, and reliability testing were also used to examine its psychometric properties.The three second-order factors of the 18-item Chinese version PAID-T were developed. The correlation coefficients of the three-factor Chinese version PAID-T with self-management and glycosylated hemoglobin levels were all significant and ranged from -0.32 to -0.45 and 0.18 to 0.33 respectively. Cronbach's α and the test-retest reliability of the three-factor Chinese version PAID-T ranged from 0.85 to 0.93 and from 0.89 to 0.94 respectively.The Chinese version PAID-T with good translation quality was a reliable and valid scale to screen and assess diabetes distress for adolescents with T1D.Nurses could use the Chinese version PAID-T to track diabetes distress and tailor interventions for adolescents with T1D; also, the Chinese version PAID-T could facilitate the conducting of research on diabetes distress for adolescents with T1D.

Background and Objectives: Insulin treatment may be initially required to stabilize patients presenting with metabolic crisis at type 1 and 2 diabetes mellitus (DM) onset. Some patients with type 2 DM may need persistent insulin treatment. This study aimed to examine the predictive performance of non-stimulated C-peptide level at the time of diagnosis for future insulin use in pediatric diabetic patients. Materials and Methods: We reviewed the medical charts of diabetic patients aged 18 years or younger in a medical center in southern Taiwan from January 2000 to December 2019. Clinical and individual data were collected at the time of DM diagnosis. Outcomes were persistent insulin use at the time of diagnosis, as well as at one and two years after diagnosis. Results: The final analysis included a total of 250 patients. The best cut-off point of non-stimulated C-peptide was 0.95 ng/mL, and the predictive indices for the insulin use were 0.84 for sensitivity and 0.94 for specificity at two years after DM diagnosis. Incorporating age at onset and presence of GAD antibodies can further increase the predictive power of non-stimulated C-peptide. Conclusions: The value of non-stimulated C-peptide at diabetic onset was feasible and effective for predicting future insulin treatment up to the time point of two years after diagnosis.

Primary congenital hypothyroidism is a disease associated with low serum thyroxine and elevated thyroid-stimulating hormone (TSH) levels. The processes of screening and treating congenital hypothyroidism, in order to prevent neurodevelopmental impairment (NDI) in newborns, have been well investigated. Unlike term infants, very preterm infants (VPIs) may experience low thyroxine with normal TSH levels (&lt, 10.0 μIU/mL) during long-stay hospitalization. In the current literature, thyroxine treatment has been evaluated only for TSH-elevated VPIs. However, the long-term impact of low thyroxine levels in certain VPIs with normal TSH levels deserves more research. Since July 2007, VPIs of this study unit received screenings at 1 month postnatal age (PNA) for serum TSH levels and total thyroxine (TT4), in addition to two national TSH screenings scheduled at 3–5 days PNA and at term equivalent age. This study aimed to establish the correlation between postnatal 1-month-old TT4 concentration and long-term NDI at 24 months corrected age among VPIs with serial normal TSH levels. VPIs born in August 2007–July 2016 were enrolled. Perinatal demography, hospitalization morbidities, and thyroid function profiles were analyzed, and we excluded those with congenital anomalies, brain injuries, elevated TSH levels, or a history of thyroxine treatments. In total, 334 VPIs were analyzed and 302 (90.4%) VPIs were followed-up. The postnatal TT4 concentration was not associated with NDI after multivariate adjustment (odd ratios 1.131, 95% confidence interval 0.969–1.32). To attribute the NDI of TSH-normal VPIs to a single postnatal TT4 concentration measurement may require more research.

Full genome analysis of a young girl with deafness, dystonia, central hypomyelination, refractory seizure, and fluctuating liver function impairment revealed a heterozygous, de novo variant in the BCAP31 gene on chromosome Xq28 (NM_001256447.2:c.92G>A), mutations of which caused the X-linked recessive severe neurologic disorder deafness, dystonia, and cerebral hypomyelination. Reverse transcription-polymerase chain reaction of the patient's white blood cells showed the absence of wild-type BCAP31 messenger RNA (mRNA) but the presence of two novel BCAP31 mRNAs. The major alternatively spliced mRNA is due to Exon 2 skipping and the utilization of a new initiation site in Exon 3 that leads to a frameshift and truncated transcript while the minor novel mRNA has a 110 nucleotide insertion to Exon 2. Phasing studies showed that the de novo variant arose in the paternal X chromosome. X chromosome inactivation assay was done and confirmed that the patient's maternal X chromosome was preferentially inactivated, providing evidence that the mutated BCAP31 gene was the one predominantly expressed. According to the American College of Medical Genetics and Genomics guideline, this variant is deemed "pathogenic" (PS2, PS3, PM2, PP3, and PP4) and deleterious. This is the first reported female patient in BCAP31-related syndrome resulted from skewed X-inactivation and a de novo mutation in the active X chromosome.

Critical illnesses caused by undiagnosed genetic conditions are challenging in PICUs. Whole-exome sequencing is a powerful diagnostic tool but usually costly and often fail to arrive at a final diagnosis in a short period. We assessed the feasibility of our whole-exome sequencing as a tool to improve the efficacy of rare diseases diagnosis for pediatric patients with severe illness.Observational analysis.We employed a fast but standard whole-exome sequencing platform together with text mining-assisted variant prioritization in PICU setting over a 1-year period.A tertiary referral Children's Hospital in Taiwan.Critically ill PICU patients suspected of having a genetic disease and newborns who were suspected of having a serious genetic disease after newborn screening were enrolled.None.Around 50,000 to 100,000 variants were obtained for each of the 40 patients in 5 days after blood sampling. Eleven patients were immediately found be affected by previously reported mutations after searching mutation databases. Another seven patients had a diagnosis among the top five in a list ranked by text mining. As a whole, 21 patients (52.5%) obtained a diagnosis in 6.2 ± 1.1 working days (range, 4.3-9 d). Most of the diagnoses were first recognized in Taiwan. Specific medications were recommended for 10 patients (10/21, 47.6%), transplantation was advised for five, and hospice care was suggested for two patients. Overall, clinical management was altered in time for 81.0% of patients who had a molecular diagnosis.The current whole-exome sequencing algorithm, balanced in cost and speed, uncovers genetic conditions in infants and children in PICU, which helps their managements in time and promotes better utilization of PICU resources.

Background Hyperglycemia is common during treatment for pediatric acute lymphoblastic leukemia (ALL). Several risk factors have been proposed, but emergence of new evidence suggests conflicting results. In view of ethnic differences in the propensity for diabetes, this study aims to delineate the characteristics of pediatric patients at risk for hyperglycemia during chemotherapy in Taiwan. Methods This retrospective study involved chart review of consecutive patients younger than 18 years with diagnosis of ALL in a medical center in Taiwan from 1997 to 2008. Hyperglycemia was defined by random plasma glucose levels ≥200 mg/dL or fasting glucose levels ≥126 mg/dL in at least two separate samplings. Risk factors for hyperglycemia were described with crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) in the univariate and multivariate regression analysis. Results A total of 133 patients were included for analysis. Overall, 22 patients (16.5%) experienced hyperglycemia during ALL treatment. Most hyperglycemic episodes occurred within the first 8 days after prednisolone use. Age older than 10 years was the most important predictor of hyperglycemia (adjusted OR = 10.88, 95% CI 2.40–49.37). Patients with fasting glucose concentration ≥100 mg/dL were also 5.7-fold (95% CI 1.63–19.93) more likely to develop hyperglycemia, whereas the predictive significance of obesity was attenuated after adjustment. Conclusion Assessment of glucose concentration should be vigilant in the 1st week after prednisolone use during ALL treatment. Clinicians should be alert to the patient at risk of hyperglycemia, particularly obese adolescents with disarranged glucose homeostasis.

Prader-Willi syndrome (PWS) is a genetic disorder with obesity, developmental delay, short stature, and behavioral abnormalities. The study aimed to assess the functional independence in children with PWS. The Functional Independence Measure for Children (WeeFIM) was used to evaluate 81 children with PWS (44 boys and 37 girls) with a median age of 11 years 1 month (range 2 years 8 months to 20 years 2 months) were recruited between January 2013 and December 2016. The mean total WeeFIM score was 103.8 (maximum 126). Sixty-five patients (80%) had deletion type PWS, 16 (20.0%) had nondeletion type. The scores were 103.6 ± 18.5 for deletion and 104.8 ± 18.3 for nondeletion type (p = .405), 104.8 ± 19.3 in boys and 102.6 ± 17.3 in girls (p = .293). The mean self-care, mobility, and cognition scores were 47 (maximum 56), 33 (maximum 35), and 24 (maximum 35), respectively. All total scores and 18 subscores in the three functional domains were positively correlated with age (p < .05). Most children required assistance in problem-solving, comprehension, and expression. The WeeFIM identified the strengths and limitations of children with PWS and confirmed that support and supervision were needed in cognitive and self-care tasks.

Background Little is known about the metabolic factors associated with the health-related quality of life (HRQOL) among obese youths. The aim of this study is to assess metabolic correlates of HRQOL in a clinical sample of Taiwanese overweight and obese (OW/OB) adolescents. Methods OW/OB adolescents (age 11–19 years) were recruited and compared to their normal-weight counterparts in a tertiary hospital. HRQOL was assessed by the Pediatric Quality of Life Inventory (PedsQL). Student t tests and Cohen’s d were used to compare the differences in the PedsQL scores between normal-weight and OW/OB participants who were stratified by their cumulative number of cardiometabolic risk factors (CRF). Pearson’s correlation and multivariate linear regression analyses were applied to identify predictors of PedsQL. Results OW/OB adolescents (n = 60) reported lower PedsQL scores than those of normal-weight peers. The negative effects were even larger in OW/OB participants with more than one CRF. Body mass index z-scores and serum alanine aminotransferase (ALT) levels were negatively correlated with overall and subscales of PedsQL (r = − 0.283 to − 0.431). Multivariate linear models showed ALT to be the most salient factor associated with poor obesity-related HRQOL. Conclusion Taiwanese OW/OB adolescents, particularly those having additional CRF, reported worse HRQOL. Impaired liver functions may predispose OW/OB subjects to even worse HRQOL.

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is characterized by conjugated hyperbilirubinemia and increased plasma bile acid concentrations. However, the underlying mechanisms remain unclear. We established a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneously quantifying plasma bile acids and examined bile acid profiles in NICCD infants.We measured 15 bile acids within 15min and found a wide linear range for individual bile acids.The within-run and run-to-run CV of all bile acids was 1.2-10.9% and 3.1-10.8%, respectively, with a mean recovery of 90.5-112.6%. Compared to infants with citrullinemia without mutations in SLC25A13 (non-NICCD), NICCD infants showed increased plasma total bile acid concentrations (mean: 201 vs. 42μM, p0.001), with a distinct bile acid profile characterized by increased conjugated primary bile acid concentrations. The calculated ratios, including primary/secondary bile acid (714 vs. 235, p0.05) and conjugated/free bile acid (371 vs. 125, p0.05) ratios, were higher in NICCD infants. The area under receiver operating characteristic curve for conjugated/free bile acid ratio to identify infants with NICCD was 0.871 (95% confidence interval, 0.713-1.0).Together, our findings indicated plasma bile acid profile as a potential noninvasive diagnostic biomarker for NICCD.

study question: Is there an association between exposure to phthalates and the timing of female puberty? summaryanswer: Our study suggests that the early onset of puberty is related to increased kisspeptin secretion. what is known already: Girls are maturing earlier than in past decades and the quantity of phthalates used in consumer products has concurrently risen. The hypothesis that exposure to phthalates may increase kisspeptin secretion and thereby cause early-onset puberty is unexplored. studydesign,size,duration: This case– control study ran from 2006 to 2009. We enrolled 104 girls. Girls in the central precocious puberty (CPP) (case) group were recruited from a pediatric endocrinology policlinic in Taiwan; prepubescent controls were recruited from local elementary schools and all were categorized based on a pediatrician’s diagnosis. participants/materials, setting, methods: The physical characteristics of puberty were assessed and levels of LH, FSH estradiol and kisspeptin-54 in blood samples were evaluated using radioimmunoassay. Reversed-phase high-performance liquid chromatography-tandem mass spectrometry was used to analyze seven urinary phthalate metabolites. Non-parametric analyses, trend tests and linear regressions were performed on the data. main results and the role of chance: All seven urinary phthalate metabolites in the CPP group were significantly (P , 0.05) higher than in prepubescent controls. Serum kisspeptin-54 levels were higher (P ¼ 0.022) in the CPP group than controls and were still significantly higher after adjusting for age (P ¼ 0.03). There was a significant increasing trend (Ptrend ¼ 0.005) between levels of kisspeptin and the stages of puberty. The concentration of kisspeptin-54 did not change in girls treated with leuprorelin acetate. There was a significant positive correlation between kisspeptin-54 and urinary mono-n-butyl phthalate (ng/ml: R 2 ¼ 0.251, P , 0.001; mg/g-creatinine: R 2 ¼ 0.109, P ¼ 0.024). limitations, reasons forcaution: The study duration was short and the sample size relatively small; therefore, we were unable to collect sufficient evidence to support the temporality between exposure to phthalates and the subsequent occurrence of PP. wider implications of the findings: Kisspeptin may promote the onset of puberty in girls who are exposed to a high level of phthalates, especially di-n-butyl phthalate. These data suggest that developing a kisspeptin antagonist might be an alternative strategy for treating PP.

Background Earlier adiposity rebound (AR) is correlated with obesity. Our goal is to examine rates of obesity and AR in congenital hypothyroidism (CHT) and analyze the risk factors of obesity. Methods We retrospectively reviewed the cases with abnormal newborn screens of thyroid-stimulating hormone (TSH) from 1990 to 2005 and enrolled permanent CHT patients who continued to receive treatment after the 3 rd year of life. We determined subgroups of obesity/being overweight and normal body mass index (BMI) by the latest BMI at 6–7 years of age. BMI at each age and the age of AR were compared with the general population in Taiwan. The statistical correlation of obesity with the age and BMI at both AR and first peak, and thyroid function was calculated. Results A total of 90 cases of CHT were enrolled. The prevalence of obesity/being overweight was 32.2%. The age of AR was 4.94 ± 1.81 and 4.58 ± 1.86 years old in boys and girls, respectively. The age of AR in the girls with CHT was earlier than in girls in general, but no statistical significance was found in boys with CHT compared to the general population. Obesity was correlated with earlier age of AR, higher BMI at first peak and AR, and lower T4 after treatment, but not with the age of first peak of BMI, T4/TSH at diagnosis and AR, and TSH after treatment. Conclusion Children with CHT have a higher risk of obesity due to earlier age of AR. We recommend that supervision and intervention on weight control should be provided to prevent the occurrence of obesity later.

Objective To identify health needs, preferred sources of health information and associated factors in Taiwanese adolescents. Design Cross-sectional questionnaire-based survey conducted in Taiwanese adolescents aged 12–18 years in 2010. Outcome measures Adolescents were queried about their health needs, healthcare service utilisation and preferred sources of health information. We compared differences in reported health needs and available sources among gender groups and grade levels. Demographic correlates of adolescent health needs were further examined using multiple ordinal logistic regression analysis. Results Participants (n=5018) needed weight and height information most, followed by dietary health advice. Academic stress was emphasised more than behavioural issues. Perceived needs for health information varied by age and gender. General high school programme, suburban location and chronic illness were associated with higher need. Only a small proportion (4.3%) of adolescents used healthcare services for mental and emotional concerns. Parents were the primary sources of health information, although students also turned to teachers, particularly for sensitive issues. Moreover, the mass media and internet were increasingly popular sources of information. Conclusions To achieve continuous care from childhood through adolescence to adulthood, paediatricians should understand adolescents’ diverse views of health needs and preferred sources of health information. Several demographic variables were shown to influence their health needs, reflecting the East Asian cultural context. Anticipatory guidance on body image, dietary health and academic stress should be emphasised while caring for these adolescents. We therefore advocate the development and effective delivery of culturally relevant adolescent-friendly health services.

Campomelic dysplasia (CD) is a rare autosomal dominant skeletal malformation with or without sex reversal. About 10% of cases that present with milder skeletal features are referred to as acampomelic campomelic dysplasia (ACD). CD and ACD are caused by mutations in SOX9. We report a patient of homozygous SOX9 deletion with minimal skeletal anomaly and female external genitalia in the presence of a male karyotype. The mechanisms explaining the homozygous deletion include a de novo mutation followed by gene conversion, uniparental disomy, or somatic crossing over. Our report highlights the possibility of ACD in XY sex-reversed patients with minimal skeletal presentation.

Monosomy 9p syndrome, also known as Alfi syndrome, has been described as a contiguous syndrome characterized by mental retardation, developmental delay, and facial dysmorphisms. Males with monosomy 9p often express variable degrees of feminization, although the genitalia of females will be normal. In the present report, we describe a case of ambiguous genitalia and intra-abdominal testicular development, with a derivative chromosome 9 arising from a translocation between 9p23 and Yq heterochromatin. Pathologic examination of the testes showed germ cell hypoplasia of the seminiferous tubules. fluorescence in situ hybridization, spectral karyotyping, and array comparative genomic hybridization were used to characterize the genetic changes.

G protein–coupled receptors (GPCRs) are ubiquitous mediators of signaling of hormones, neurotransmitters, and sensing. The old dogma is that a one ligand/one receptor complex constitutes the functional unit of GPCR signaling. However, there is mounting evidence that some GPCRs form dimers or oligomers during their biosynthesis, activation, inactivation, and/or internalization. This evidence has been obtained exclusively from cell culture experiments, and proof for the physiological significance of GPCR di/oligomerization in vivo is still missing. Using the mouse luteinizing hormone receptor (LHR) as a model GPCR, we demonstrate that transgenic mice coexpressing binding-deficient and signaling-deficient forms of LHR can reestablish normal LH actions through intermolecular functional complementation of the mutant receptors in the absence of functional wild-type receptors. These results provide compelling in vivo evidence for the physiological relevance of intermolecular cooperation in GPCR signaling.

Phthalates are developmental and reproductive toxicants for the fetus in pregnant rodents, and the ability of phthalates to penetrate the placenta have been reported. The aims of this study were to evaluate the association between maternal urine excretion, the exposure of fetus to phthalates in amniotic fluid, and the health of newborns. Amniotic fluid and urine samples from pregnant women were collected to measure five phthalate monoesters using liquid chromatography/tandem mass spectrometry (LC/MS-MS) and the newborns' birth weight, gestational age, and anogenital distance (AGD) were collected. The median levels of three phthalate monoesters in urine and amniotic fluid were 78.4 and 85.2 ng/mL monobutyl phthalate (MBP); 24.9 and 22.8 ng/mL mono-(2-ethylhexyl) phthalate (MEHP); 19.8 and Not Detected monoethyl phthalate (MEP). We found a significant positive correlation only between creatinine adjusted urinary MBP and amniotic fluid MBP (R2=0.156, p

Background Propionyl-CoA carboxylase (PCC) is a mitochondrial enzyme involved in the catabolism of several essential amino acids and odd chain fatty acids. Previous PCC assays have involved either a radiometric assay or have required mitochondria isolation and/or enzyme purification. Methods We developed an enzymatic method to analyze PCC activity in phytohemagglutinin (PHA) stimulated lymphocytes that involves high performance liquid chromatography. Results The method shows good linearity and sensitivity. PCC activity was unaffected even when lymphocytes were isolated and PHA stimulated after a whole blood sample had been stored at 4 °C for 5 days. This indicates that this method is suitable for analyzing samples from distant medical centers. The PCC activity of patients with propionic acidemia was found to be much lower than that of normal individuals and carriers. However, this PCC assay is significantly affected by the red blood cell contamination. In conclusion, this is a reliable method for performing PCC assays and only requires 0.5 to 1.0 ml of whole blood from newborns. Conclusions The PCC assay established in this study is useful for the confirmation of PA in individuals, and prenatal diagnosis and genetic counseling for the affected families.

Children in Taiwan seem to be exposed to higher concentrations of phthalates than do children in Western countries. We developed intervention strategies to reduce the exposure of phthalates in Taiwanese girls. Thirty girls 4-13 years old who had been exposed to high levels of phthalates were selected from prior studies. To reduce their phthalate-exposure sources, we developed seven intervention strategies: handwashing, not using plastic containers, not eating food with a plastic bag/plastic-wrap cover, not microwaving food, not taking nutrition supplements, and reducing use of cosmetics/personal care products. Pre- and post-intervention urine samples were collected during a one-week study. HPLC-MS/MS was used to analyze urinary phthalate metabolites. The dominant urinary phthalate metabolite was mono-n-butyl phthalate (MBP), followed by mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP). Post-intervention concentrations of eight urinary phthalate metabolites were significantly lower. Girls in the high-frequency handwashing group had significantly lower urinary MBP (p=0.009) and mono-methyl phthalate (MMP) (p=0.07) than did girls in the low-frequency handwashing group. Girls who drank fewer beverages from plastic cups had significantly lower urinary MBP (p=0.016), MEHHP (p=0.038), and MECPP (p=0.012). Girls who used less shampoo and shower gel also had marginally significantly lower urinary MBP (p=0.06) and mono-ethyl phthalate (MEP) (p=0.06). The intervention strategies that we set up in this study were effective for reducing exposure to phthalates in children. Handwashing and drinking fewer beverages from plastic cups were the most effective strategies for reducing phthalate metabolites in urine, especially MBP and di(2-ethylhexyl) phthalate (DEHP) metabolites. Education and voluntary self-restraint were useful for reducing the body burden of phthalates.

There have been few reports about adolescent experiences with and expectations of health service utilization in an Asian societal setting. The aim of this study is to analyze the use of healthcare services in relation to health status and explore adolescents' preferences for youth-friendly service among Taiwanese high school students. A cross-sectional questionnaire-based survey was conducted on Taiwanese adolescents aged 12–18 years in 2010. We invited participants to rate their health status, report their previous healthcare service use, and rank their health service preferences. We used logistic regression analysis to investigate the association between self-rated health status and healthcare utilization and used nonparametric analysis to compare health service preferences among sociodemographic subgroups. A total of 4,907students (97.2 % response rate) returned valid questionnaires for analysis. Poor health status and chronic illness were most salient factors independently associated with frequent healthcare service use. Only 40 % of respondents reported having a regular doctor, and pediatrics (57.7 %) was the most commonly identified professional source of medical care. A great majority (86.2 %) of respondents made clinical visits with parents. For characteristics of youth-friendly clinician, the top-ranked items included competency and patience, while having helpful and friendly personnel was highlighted for clinical setting. Conclusion: Family participation is critical in healthcare for adolescents in Asian cultures. Health service use is significantly influenced by health status and chronic illness in the general health insurance system. Understanding these background influences on expectations for healthcare may help to create youth-friendly health services that are more culturally appropriate.

Background Citrin, encoded by SLC25A13 gene, is a mitochondrial solute transporter with a crucial role in urea, nucleotide and protein synthesis. SLC25A13 mutations cause two phenotypes, adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). This study aimed to develop a high resolution melting (HRM) analysis for SLC25A13 mutation scanning and determine the carrier rate in Taiwan. Methods DNAs from healthy subjects (n = 479), and patients with hepatocellular carcinoma (HCC, n = 100) and NICCD (n = 5) were scanned in exons 6, 9, 11, 16, and 17 and parts of introns of SLC25A13 using HRM analysis. All mutations detected by HRM analysis were further confirmed by TaqMan method and/or direct sequencing. Results In healthy subjects, seventeen carriers with mutants c.851_854del (n = 10), c.1638_1660dup, c.615 + 5G > A (n = 4), and two novel mutants, c.475C > T and c.1658G > A, were detected. The frequency of carriers was about 1/28. In patients with HCC, there were only 2 carriers with c.851_854del mutant. Patients with NICCD (n = 5) diagnosed during 2007 and 2008, harbored compound heterozygous mutations c.851_854del/c.1177 + 1G > A, c.851_854del/c.1638_1660dup (n = 2), c.851_854del/c.615 + 5G > A, and c.1638_1660dup/c.615 + 5G > A. Conclusions HRM analysis is a simple, rapid and robust method for detecting SLC25A13 mutations in clinical laboratories. SLC25A13 mutations may not be a major contributor to the pathogenesis of HCC in Taiwan.

ContextMutations of the FSHβ gene, causing in women isolated FSH deficiency and hypogonadism, are very rare and only a few have been described.ObjectiveTo describe the phenotype and response to recombinant human (rh) FSH of a female patient with a novel homozygous loss-of-function mutation of FSHβ, and to characterize in vitro the molecular mechanisms responsible for the FSH inactivation.PatientA 29-year-old woman with primary amenorrhea and impaired pubertal development associated with isolated FSH deficiency.Methods and resultsSequencing of the FSHβ gene revealed a homozygous 1 bp (G) deletion at codon 79 (c.289delG) of exon 3 which produced a frameshift at codon 79 (A79fs108X) and a premature stop codon at codon 109. The wild-type and mutant FSHβ cDNAs inserted into expression vector were cotransfected into Chinese hamster ovary cells with the α-subunit. Wild-type FSH was readily detectable in culture medium, whereas no mutant FSH was detectable by either immunoassay or in vitro bioassay. Mutant FSHβ protein could not be detected in western blot.In response to a 15-day treatment with rhFSH, sonography revealed multifollicular development in the ovaries. Circulating levels of estradiol and inhibin B were dramatically increased, whereas anti-Mullerian hormone decreased. Serum LH first decreased and then increased, inducing multiovulation associated with supraphysiologic progesterone and inhibin A levels.ConclusionA novel FSHβ mutation was detected in a hypogonadal woman. rhFSH was effective in ovulation induction in the patient but with signs of ovarian hyperstimulation. The high pretreatment LH levels could contribute to this excessive ovarian response to rhFSH.

The aim of this study was to determine the levels of phthalate ester metabolites in girls in early puberty, and the associated environmental factors for phthalate exposure. A case-control study was conducted in which we recruited girls in early puberty, including 30 girls with premature thelarche (PT) and 26 with central precocious puberty (CPP), and 33 normal controls. The mean urine levels of monomethyl phthalate (MMP) were significantly higher in the PT group (96.5 +/- 134.0 ng/ml) than in the control group (26.4 +/- 30.0 ng/ml; p = 0.005). The levels of monobutyl phthalate (MBuP) correlated with the intake of seafood, drink and the use of plastic cups. The levels of mono-(2-ethylhexyl) phthalate (MEHP) correlated with the intake of seafood and meat and exposure plastic handi-wrap. Significantly higher MMP in the PT girls revealed that phthalate may be one of the environmental causes of early puberty in Taiwanese girls.

Birth size is associated with long-term morbidity. Insulin-like growth factor (IGF) system is the most important endocrine factor influencing fetal growth. During rapid somatic growth, free-to-total IGF-I ratio is increased, resulting in higher IGF-I bioavailability. The purpose of this study was to investigate the association of free-to-total IGF-I ratios, IGF-II, and IGF-binding protein (IGFBP)-3 umbilical cord levels with anthropometric data of term neonates.Umbilical venous plasma samples were obtained from 95 term neonates and analyzed by enzyme-linked immunosorbent assay.The large-for-gestational age (LGA) neonates had higher free IGF-I, total IGF-I, and IGFBP-3 levels than small-for-gestational age (SGA) neonates (P0.01, 0.001, 0.01, respectively) and higher total IGF-I and IGFBP-3 levels than appropriate-for-gestational age (AGA) neonates (P0.05, 0.01, respectively). The free-to-total IGF-I ratios and IGF-II levels were not different among SGA, AGA, and LGA neonates. Free IGF-I, total IGF-I, and IGFBP-3 levels were positively correlated with birth weight (r = 0.34, P0.001; r = 0.41, P0.001; r = 0.25, P0.05, respectively). Multiple linear regression analyses revealed that only total IGF-I levels was the independent predictive variable for birth weight.Our data suggest total IGF-I is the most important factor in the IGF system for determining fetal growth, at least near term gestation. Free-to-total IGF-I ratios may mostly be determined by total IGF-I. If birth size is associated with adult chronic metabolic diseases, total IGF-I may be involved in the pathogenesis.

The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked multisystem disorder characterized by congenital cataracts, mental retardation, and renal tubular dysfunction. The OCRL1 gene responsible for Lowe syndrome has been mapped to chromosome Xq24-q26. We analyzed two Taiwanese OCRL patients and their families. In Case 1, a splicing mutation (889-11 G --A) was identified in intron 10 of the OCRL1 gene. The mother is a heterozygous carrier. The 889-11 G --A mutation results in an abnormal splicing and predicts premature termination of translation. In Case 2, a novel de novo missense mutation (1373G --A, P458H) was identified in exon 14 of the OCRL1 gene. The missense mutation predicts a substitution in a domain highly conserved among the inositol-5-phosphatase family.

This report presents the case of a 7-year-old girl with gonadotrophin-independent precocious puberty treated with cetrorelix [gonadotrophin-releasing hormone (GnRH) antagonist] after poor response to GnRH agonist therapy was observed in the endocrinology outpatient clinic. Uterine and ovarian morphology returned to within the normal prepubertal range after GnRH antagonist was injected subcutaneously. Vaginal bleeding stopped completely. The effects of GnRH antagonist treatment were comparable to those of GnRH agonist. The potential advantage of GnRH antagonists would be a clinically significant direct effect on the ovary, if it exists, and GnRH antagonists should be available for use in such children.

Mucopolysaccharidosis type II (Hunter syndrome) is an X-linked lysosomal storage disorder. A novel gross deletion in the iduronate-2-sulfatase (IDS) gene was found in a 6-year-old boy with Hunter syndrome. The phenotype of the patient was severe, including joint stiffness, kyphosis, hepatomegaly, hypertrophic cardiomyopathy, moderate mental retardation, and bilateral hearing loss. The 38.8 kb gross deletion involves exons 1-7, the proximal breakpoints lying in intron 7, at position 1307880 (GenBank NT:019686), and the distal deletion breakpoint was located at position 1346697. The large deletion correlated with the severe phenotype of this Hunter syndrome patient.

Hypophosphatemic rickets is a genetic disorder commonly associated with renal phosphate wasting and bone deformities. The PHEX gene (phosphate regulating gene with homologies to endopeptidases on the X chromosome) encodes a 749-amino acid protein that putatively consists of an intracellular, transmembrane, and extracellular domain. PHEX mutations have been observed in 60-80% of hypophosphatemic rickets patients. In this study, we report 2 de novo novel mutations in 2 Taiwanese girls with clinical characteristics of hypophosphatemic rickets. The presenting phenotype of lower extremity deformities and short stature was suggestive of the diagnosis. Primers flanking 22 exons were used to amplify DNA by polymerase chain reaction. The results by direct DNA sequencing of case 1 revealed a C to T transition changing glutamine at codon 224 in exon 6 to a stop codon (Q224X). The result of case 2 showed a 2-base pair deletion (2090delGA) and resulted in a frameshift and premature termination of codon (PTC+19aa). Both mutations presumably result in a truncated protein, leading to loss of function of PHEX. This is the first report of PHEX gene mutation in the Taiwanese population.

The association of hypophosphatemic rickets and epidermal nevus or giant hairy nevus is rare. We report two patients with hypophosphatemic rickets, one associated with epidermal nevus syndrome and the other with giant hairy nevus, and describe their clinical features and variable response to treatment. The abnormal nevus tissue may have contributed to the pathogenesis of hypophosphatemic rickets. We did not find a PHEX gene mutation in these two patients, and the mechanism for their rickets may be different from that in X-linked hypophosphatemic rickets.

Russell-Silver syndrome (RSS) should be suspected in patients with prenatal and postnatal growth retardation. Because there is no clinical feature specific for RSS, molecular analysis is necessary to confirm the diagnosis. Recently, maternal uniparental disomy of chromosome 7 (mUPD7) has been reported in approximately 10% of RSS patients. We describe a 10-year-old Taiwanese RSS girl with prenatal and postnatal growth retardation, relative macrocephaly, a triangular face, frontal bossing, and mild fifth finger clinodactyly. Molecular diagnosis of mUPD7 was confirmed by use of methylation-specific polymerase chain reaction and haplotype analysis with single nucleotide polymorphisms (SNPs) genotyping. Analyzing the methylation status of the PEG1/MEST gene is a cost-effective screening method for mUPD7 molecular diagnosis. However, positive cases should be subsequently confirmed by haplotype analysis using SNPs genotyping or short tandem repeat markers.

The 5α-reductase type 2 deficiency is a rare autosomal recessive 46,XY disorder of sex development caused by the mutated 5α-reductase type 2 (SRD5A2) gene. In this disease, defective conversion of testosterone to dihydrotestosterone leads to variable presentations of male ambiguous genitalia during fetal development. The most crucial clinical decision for the affected individual is proper gender assignment; therefore, a prompt and correct diagnosis is important. In this present study, we report a normal male karyotype manifesting microphallus, bifid scrotum/labia majora with bilateral palpable gonads, and a blind-ended pseudovagina. The mutation analysis of the SRD5A2 gene revealed one novel C to T transition changing glutamine to a stop codon at codon 71 (p.Q71X) in exon 1 and one known G to A transition changing arginine to glutamine at codon 227 (p.R227Q) in exon 4. The p.Q71X mutation presumably results in a truncated protein, while the p.R227Q mutation is conceived to impair enzyme function and has been reported in patients of East Asian descent. This report demonstrates the essential role of hormonal and molecular studies for genetic counseling and gender assignment in males with pseudovaginal disorder of sex development, and our report helps identify a novel SRD5A2 gene mutation in the Taiwanese population.

Background Mucopolysaccharidosis type II (MPS II) is an X-linked recessive, multisystemic lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase. MPS II has a variable age of onset and variable rate of progression. In Asian countries, there is a relatively higher incidence of MPS II compared to other types of MPS. Methods A retrospective analysis was carried out of 34 Taiwanese MPS II patients who died between 1995 and 2012. The clinical characteristics, medical records, age at death, and cause of death were evaluated to better understand the natural progression of this disease. Results The mean age at death of 31 of the patients with a severe form of the disease with significant cognitive impairment was 13.2 ± 3.2 years, compared with 22.6 ± 4.3 years in the three patients with a mild form of the disease without cognitive involvement (n = 2) or the intermediate form (n = 1) (p