A Significant Association between Type 1 Diabetes and Helicobacter pylori Infection: A Meta-Analysis Study.

Background and Objectives: Type 1 diabetes mellitus (T1DM) is a chronic and serious condition that is characterized by inadequate pancreatic-ß-cells' insulin production. The connection between T1DM and Helicobacter pylori infection remains uncertain. This study aimed to conduct a systematic meta-analysis to examine the association between H. pylori infection, hemoglobin A1c levels, and the development of T1DM. Materials and Methods: The initial search identified 451 articles on the association between H. pylori infection and T1DM. Among them, 12 articles had 2797 participants who met the inclusion criteria for an advanced meta-analysis. Results: A significant association was observed between H. pylori infection and T1DM (OR 1.77, 95% CI 1.47-2.12, p < 0.0001), with heterogeneity: Tau2 = 0.47; Chi2 = 57.07, df = 11 (p < 0.0001); I2 = 81%. Subgroup analysis showed that H. pylori infection was significantly associated with a longer duration of T1DM and higher hemoglobin A1c levels (p < 0.001 for both) but not with age at T1DM diagnosis (p = 0.306). Conclusions: These findings contribute to the understanding of the association between H. pylori infection and T1DM and highlight the potential role of H. pylori in influencing the duration and glycemic control of diabetes. Therefore, pediatric patients who have longstanding T1DM and poor glycemic control should be screened for H. pylori infection.

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.

The effects of gonadotropin-releasing hormone agonist on final adult height among girls with early and fast puberty.

Introduction: This study aimed to explore the impact of gonadotropin-releasing hormone agonists (GnRHa) on final adult height (FAH) in girls with early and fast puberty. Methods: A retrospective study was conducted by reviewing data from the medical records of the Pediatric Endocrinology Clinics between January 1, 2010, and December 31, 2020, at MacKay Children's Hospital. The treatment group included 109 patients who received 3.75 mg monthly for at least 1 year, whereas the control group consisted of 95 girls who received no treatment. Results: The treatment group was significantly older at the time of inclusion(chronological age (CA1), treatment vs. control, 8.7 vs. 8.4 years, p < 0.001), had a more advanced bone age (BA) (BA1, 11.5 vs. 10.8 years, p < 0.001), BA1-CA1 (2.7 vs. 2.2 years, p < 0.001), and shorter predicted adult height (PAH1) (153.3 vs. 157.1 cm, p = 0.005) that was significantly lower than their target height (Tht)(PAH1-Tht, -3.9 vs. -1.3 cm, p = 0.039). The FAHs of the GnRHa and the control group were similar (157.0 vs. 156.7 cm, p = 0.357) and were not significantly different from their Tht (FAH vs. Tht in the GnRHa group, 157.0 vs. 157.0 cm; control group, 156.7 vs. 157.0 cm). In the subgroup analysis, FAH was significantly higher after GnRHa treatment in those with PAH1 less than 153 cm and Tht (154.0 vs. 152.0 cm, p = 0.041), and those whose CA1 was between 8 and 9 years (158.0 vs. 155.4 cm, p = 0.004). We defined satisfactory FAH outcome as FAH-PAH1≥5 cm and significant factors were GnRHa therapy, PAH1 shorter than their Tht, age younger than 9 years, and faster growth velocity during the first year. Discussion: GnRHa is effective in restoring the Tht in some early and fast pubertal girls, especially in those with poorly PAH (PAH lower than 153 cm and shorter than their target height). A younger age at initiation of treatment and a faster growth velocity during treatment are associated with a better height gain.

Application of Drug Testing Platforms in Circulating Tumor Cells and Validation of a Patient-Derived Xenograft Mouse Model in Patient with Primary Intracranial Ependymomas with Extraneural Metastases.

Primary intracranial ependymoma is a challenging tumor to treat despite the availability of multidisciplinary therapeutic modalities, including surgical resection, radiotherapy, and adjuvant chemotherapy. After the completion of initial treatment, when resistant tumor cells recur, salvage therapy needs to be carried out with a more precise strategy. Circulating tumor cells (CTCs) have specifically been detected and validated for patients with primary or recurrent diffused glioma. The CTC drug screening platform can be used to perform a mini-invasive liquid biopsy for potential drug selection. The validation of potential drugs in a patient-derived xenograft (PDX) mouse model based on the same patient can serve as a preclinical testing platform. Here, we present the application of a drug testing model in a six-year-old girl with primary ependymoma on the posterior fossa, type A (EPN-PFA). She suffered from tumor recurrence with intracranial and spinal seeding at 2 years after her first operation and extraneural metastases in the pleura, lung, mediastinum, and distant femoral bone at 4 years after initial treatment. The CTC screening platform results showed that everolimus and entrectinib could be used to decrease CTC viability. The therapeutic efficacy of these two therapeutic agents has also been validated in a PDX mouse model from the same patient, and the results showed that these two therapeutic agents significantly decreased tumor growth. After precise drug screening and the combination of focal radiation on the femoral bone with everolimus chemotherapy, the whole-body bone scan showed significant shrinkage of the metastatic tumor on the right femoral bone. This novel approach can combine liquid biopsy, CTC drug testing platforms, and PDX model validation to achieve precision medicine in rare and challenging tumors with extraneural metastases.

The effects of estrogen induction therapy on pubertal presentations in turner syndrome patients.

OBJECTIVE: In this study, we investigated various pubertal presentations and progressions before and after estrogen induction therapy and the correlations with Turner syndrome karyotypes. MATERIALS AND METHODS: We reviewed the medical records of patients with Turner syndrome diagnosed before the age of 18 years between 2000 and 2019. Sixty-six patients were enrolled and distributed into 45,X monosomy group, X chromosome structural abnormalities group and X mosaicism group. The pubertal presentations were classified into spontaneous puberty, arrested puberty and no spontaneous puberty. All patients' karyotypes, pubertal progressions and laboratory data were collected and analyzed. RESULTS: The karyotypes were highly correlated with pubertal presentations. No spontaneous puberty was noticed in 58.3% 45,X monosomy patients, 50% patients with X chromosome structural abnormalities had arrested puberty, whereas 70% patients with X mosaicism had spontaneous puberty. Estrogen induction therapy in patients with no spontaneous puberty could induce puberty and the tempo of puberty may approximate to the spontaneous puberty group (median, 2.3 vs. 2.2 years, P = 0.95). In both interventional groups, the FSH level was distinguishable before treatment (median, 65.1 vs. 100.4 mIU/mL, P = 0.02). After long term estrogen therapy, the FSH could be suppressed to similar level in both interventional groups (median, 37.5 vs 34.5 mIU/mL, P = 0.84). Neither LH nor E2 level provided valuable information before and after treatment. CONCLUSION: The karyotypes were highly correlated with pubertal presentations at Turner syndrome patients. The integrity of 2nd X chromosome plays an important role. Low dose estrogen could mimic the tempo of puberty even delay induction age at Taiwan. The FSH data could provide predictive information of pubertal induction for both interventional groups.

Effect of Oral Vitamin D3 Supplementation in Exclusively Breastfed Newborns: Prospective, Randomized, Double-Blind, Placebo-Controlled Trial.

Exclusively breastfed infants are at a high risk of vitamin D deficiency. Few studies have evaluated the effects of vitamin D supplementation. Hence, we conducted a prospective randomized controlled trial investigating the effects of oral vitamin D3 400 IU/d supplementation in exclusively breastfed newborns. Serum 25-hydroxy-vitamin D (25[OH]D) levels in pregnant women and their newborns were evaluated. Breastfed newborns were randomized to one of two regimens at age 10 days. One group received vitamin D3 supplementation at a dose of 400 IU/d (vD-400 group), whereas the placebo group received a liquid product without vitamin D3. Outcomes were assessed at 4 months of age. A total of 92 pregnant women and their infants were enrolled, and the data of 72 infants (37 in the vD-400 group and 35 in the placebo group) who completed the study at 4 months of age were assessed. The results showed severe vitamin D deficiency in 15.2% of mothers before delivery, while 54.3% had vitamin D deficiency. Moreover, 15.2% of newborns presented with severe vitamin D deficiency at birth, while 52.2% had vitamin D deficiency. Maternal vitamin D levels were significantly correlated with infant vitamin D levels at birth (r = 0.816, p < 0.001). At 4 months of age, weight, head circumference, serum 25(OH)D, phosphorus, and intact parathyroid hormone levels significantly differed between the vD-400 and placebo groups. However, the body length and bone mineral density of the two groups did not differ significantly. Regardless of vitamin D supplementation, participants with severe vitamin D deficiency had significantly higher intact parathyroid hormone levels and lower bone mineral content. In conclusion, among exclusively breastfed infants, oral supplementation with vitamin D3 at a dose of 400 IU/d from age 10 days increased 25(OH)D concentrations at 4 months of age, but it did not affect bone mineralization. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Graves disease is more prevalent than Hashimoto disease in children and adolescents with type 1 diabetes.

Introduction: Autoimmune thyroid disease (AITD) is the most common associated autoimmune disorder in type 1 diabetes (T1D). Early detection of AITD is crucial to optimize glycemic control, growth, and intellectual development. In this prospective cohort study, we sought to characterize the prevalence, incident ages and risk factors of AITD in children and adolescents with T1D. Materials and methods: Patients with T1D diagnosed at ≤ 18 years at MacKay Children's Hospital, Taipei, from 1990 to 2019 underwent annual screening for AITD. Institutional Review Board-approved data on age, sex, and disease profile are collected. Statistical analysis was performed by using independent sample t test for continuous variables, chi-squared test for categorical variables, and Kaplan-Meier estimates of cumulative incidence of AITD were calculated. A p value of <0.05 was considered statistically significant. Results: We prospectively followed up 808 patients with T1D, 761 patients were included in the study. Of these patients, 197 (25.9%) of them had thyroid autoimmunity, meaning positivity of thyroid autoantibodies. Females had a higher prevalence of thyroid autoimmunity than males (59.9%, p = 0.012). Altogether, 5.5% patients developed AITD (4.1% had Graves disease; 1.4% had Hashimoto disease), at a mean age of 17.8 ± 8.5 years. The cumulative incidence of AITD at 30 years of disease duration was 0.29 in the total group and was significantly higher in females (0.39, n = 397) than in males (0.15, n = 364, p<0.001). Discussion: In Taiwan, the prevalence of AITD in pediatric population with T1D increases with age, a longer disease duration and female sex. For early detection of autoimmune thyroid disease in Taiwanese children and adolescents with T1D, an annual AITD screening program should be implemented.

Diagnostic evaluation of central precocious puberty in girls.

BACKGROUND: The gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for confirming the activation of the hypothalamic-pituitary-gonadal axis in central precocious puberty (CPP). However, it is time-consuming and costly. Our aim was to search for a simpler diagnostic modality for CPP by 1) evaluating the performance of basal serum luteinizing hormone (LH), 2) constructing a practical scoring system, and 3) determining the optimal single sampling time for serum LH in the GnRH stimulation test. METHODS: Data of girls aged between 3 and 9 years at the time of the GnRH stimulation test, who attended our endocrine clinic at the MacKay Children's Hospital for signs of puberty between July 2014 and June 2019, were analyzed retrospectively. We recorded patients' age, height, weight, breast Tanner stage (BS), bone age, serum LH, and follicle-stimulating hormone (FSH). Receiver operating characteristic (ROC) curves and the Youden index were used to obtain the optimal basal serum LH level. Binary logistic regression was employed to construct a practical scoring system. Cross-sectional, cumulative frequency, and ROC curves were used to simplify the GnRH stimulation test. RESULTS: Overall, 381 sets of GnRH stimulation tests were performed in 313 patients. Basal serum LH ≥ 0.2 IU/L demonstrated 70% sensitivity and 70% specificity for predicting positive GnRH stimulation test results. The practical scoring system (3 × BS + 3 × LH + 4 × FSH) showed 76% sensitivity and 72% specificity. The serum LH level at 30 min after intravenous gonadorelin exhibited 99% sensitivity and 100% specificity. CONCLUSION: Single sampling of serum LH at 30th minute post-injection of GnRH demonstrated a diagnostic performance equivalent to the traditional GnRH stimulation test in diagnosing CPP. Therefore, this approach could become the simplest diagnostic modality.

Acute kidney injury is a common complication in children and adolescents hospitalized for diabetic ketoacidosis.

Diabetic ketoacidosis (DKA) is associated with dehydration and which can cause acute kidney injury (AKI). The proportion of AKI in children and adolescents with DKA has not been reported in East Asian population. This study aimed to identify the prevalence of AKI and to determine whether there is an association between AKI severity and recovery time from metabolic acidosis in children and adolescents with DKA. Medical records of children and adolescents (aged <18 years) presenting with type 1 or type 2 diabetes mellitus and DKA between 2000-2017 at the MacKay Children's Hospital were retrospectively reviewed. AKI was defined by an admission creatinine level >1.5 times the calculated expected baseline creatinine level. Patients were divided into three groups based on AKI severity: no AKI, mild AKI, and severe AKI. In total, 170 (56.5%) patients with DKA presented AKI (mild AKI, 116 [38.5%]; severe AKI, 54 [18.0%]). Heart rate and laboratory parameters related to dehydration, such as corrected sodium level and blood urea nitrogen, were strongly associated with AKI development (P<0.01). Blood pH, plasma glucose, and potassium levels were also associated with AKI. A negative correlation with borderline significance between the estimated glomerular filtration rate (eGFR) and recovery time from metabolic acidosis was observed in the severe AKI group. AKI was highly prevalent in children and adolescents with DKA. An association between AKI and biomarkers indicating dehydration was noted. The recovery time from metabolic acidosis following treatment may be longer in children with a decreased eGFR who present with severe AKI. AKI is a common complication in children with DKA.

HLA-DQ genotype and biochemical characterization of anti-transglutaminase 2 antibodies in patients with type 1 diabetes mellitus in Taiwan.

Human Leukocyte Antigen (HLA)-DQ2 and HLA-DQ8 are genetic risk factors for Type 1 Diabetes Mellitus (T1DM) and Celiac disease (CD) in Caucasians, but their association with Taiwanese Han population is unknown. We screened 532 Taiwanese T1DM patients for CD biomarkers including anti-tissue transglutaminase (TGM2), anti-gliadin and anti-neoepitope antibodies (Abs), sequencing DQB1 genotypes, and characterized the TGM2 Abs. We report that 3.76% of Taiwanese patients had TGM2-Abs and all had no CD's symptoms. In contrast to Caucasian's CD patients, DQ2/DQ8 only constituted ~4/5 of TGM2-Abs positive patients, while the other ~1/5 patients belonged to different HLA genotypes. Either anti-gliadin or anti-neoepitope Abs coexisted with ~3/4 of TGM2-Abs positive patients that were likely due to gluten-ingestion, while the cause of TGM2-Abs production for other ~1/4 of patients was unknown. Purified anti-TGM2 IgA (TGA) and anti-TGM2 IgG (TGG) could bind on endothelial cells surface, recognized native better than denatured forms of TGM2, and TGA inhibited TGM2's transamidation activity by up to 80% but TGG had no effects. Epitope mapping of all TGM2-Abs positive sera demonstrated that TGM2-Abs had heterogeneity in specificities. This is the first study on the differences between Taiwanese Han group and Caucasian in HLA genotypes and properties of TGM2-Abs.

Long-term outcomes of graves disease in children treated with anti-thyroid drugs.

BACKGROUND: Graves disease (GD) is the most common cause of thyrotoxicosis in children and adolescents, accounting for 15% of all thyroid diseases during childhood. Anti-thyroid drugs (ATD) are recommended as the first-line treatment in children and adolescents. However, the remission rate is lower in children than in adults, and the optimal treatment duration and favorable factors associated with remission remain unknown. We aimed to investigate long-term outcomes of pediatric GD patients receiving ATD. METHODS: We retrospectively reviewed medical charts of 396 GD subjects from 1985 to 2017 at MacKay Children's Hospital. Ninety-six patients were excluded from the analyses, including 71 patients followed for less than one year, 6 patients who received radioactive therapy and 19 patients who received surgery. The remaining 300 patients initially treated with ATD and followed up for more than 1 year constituted our study population. RESULTS: The 300 patients comprised 257 (85.7%) females and 43 (14.3%) males. Their median age at diagnosis was 11.6 (range 2.7-17.8) years with 11 patients (3.7%) younger than 5 years. Their median follow-up period was 4.7 (range 1.1-23.9) years. Overall, 122 patients achieved the criteria for discontinuing ATD treatment, and seventy-nine (39.9%) patients achieved remission, with a median follow-up period of 5.3 (range 1.5-20.1) years. Patients in the remission group were more likely to be aged <5 years (remission vs. relapse vs. ongoing ATD; 11.4 vs. 0 vs. 2.6%, P = 0.02), less likely to have a family history of thyroid disease (24.1 vs. 42.1 vs. 52.6%, P = 0.001), and had lower TSH receptor antibody (TRAb) levels (42.8 vs. 53.6 vs. 65.1%, P = 0.02) at the time of diagnosis. CONCLUSION: Long-term ATD remains an effective treatment option for GD in children. Pediatric GD patients aged <5 years, having no family history of thyroid disease and having initial lower TRAb levels were more likely to achieve remission.

Mutations in glucokinase and other genes detected in neonatal and type 1B diabetes patient using whole exome sequencing may lead to disease-causing changes in protein activity.

Monogenic diabetes is caused by mutations that reduce ß-cell function. While Sanger sequencing is the standard method used to detect mutated genes. Next-generation sequencing techniques, such as whole exome sequencing (WES), can be used to find multiple gene mutations in one assay. We used WES to detect genetic mutations in both permanent neonatal (PND) and type 1B diabetes (T1BD). A total of five PND and nine T1BD patients were enrolled in this study. WES variants were assessed using VarioWatch, excluding those identified previously. Sanger sequencing was used to confirm the mutations, and their pathogenicity was established via the literature or bioinformatic/functional analysis. The PND and T1BD patients were diagnosed at 0.1-0.5 and 0.8-2.7 years of age, respectively. Diabetic ketoacidosis was present at diagnosis in 60% of PND patients and 44.4% of T1BD patients. We found five novel mutations in five different genes. Notably, patient 602 had a novel homozygous missense mutation c.1295C > A (T432 K) in the glucokinase (GCK) gene. Compared to the wild-type recombinant protein, the mutant protein had significantly lower enzymatic activity (2.5%, p = 0.0002) and Vmax (1.23 ±â€¯0.019 vs. 0.33 ±â€¯0.016, respectively; p = 0.005). WES is a robust technique that can be used to unravel the etiologies of genetically heterogeneous forms of diabetes. Homozygous inactivating mutations of the GCK gene may have a significant role in PND pathogenesis.

Autoantibodies against islet cell antigens in children with type 1 diabetes mellitus.

We investigated the prevalence of glutamic acid decarboxylase 65 autoantibody (GADA), insulinoma-associated protein 2 autoantibody (IA2A), and insulin autoantibody (IAA) in 750 children with type 1 diabetes (T1D) living in Taiwan. GADA, IA2A, and IAA were measured by radioimmunoassay. The data were assessed by χ2 test, binary logistic regression, and Spearman rank correlation. Of the 750 T1D patients, 66.3% had GADA, 65.3% IA2A, 35.7% IAA, and 17.2% no autoantibodies. The prevalence of GADA and IA2A significantly decreased along T1D duration. The positivity of either GADA or IA2A was 89.4% within the first year of disease and decreased to 36.7% after 9 years (P = 1.22 × 10-20). Female patients had significantly higher prevalence of GADA compared with male patients (72.3% vs. 59.7%, P = 0.00027). The patients diagnosed before 12 years of age had a positive rate of 92.2% for either GADA or IA2A. Patients diagnosed at age 12 or above had a significantly lower positive rate of 81.6% (P = 0.011). GADA and IA2A significantly correlated with each other (rs = 0.245, P = 1.09 × 10-11). We concluded that autoantibodies were detectable in 89.4% of T1D patients within one year after diagnosis. Their prevalence declined with disease duration. GADA was more prevalent in female patients. GADA and IA2A weakly correlated with each other.

Factors associated with diabetic nephropathy in children, adolescents, and adults with type 1 diabetes.

BACKBROUD/PURPOSE: Microalbuminuria and macroalbuminuria are markers of diabetic nephropathy (DN). The purpose of this study was to unravel the risk factors for DN in the young patients with type 1 diabetes (T1D). METHODS: 341 patients (160 males) with T1D diagnosed at the age 7.6 ± 4.0 years with disease duration 11.5 ± 6.5 years were assessed. Among them, 185 were young adults (aged 18.0-36.2 years). Urinary albumin creatinine ratio (UACR) was checked on morning spot urine. Microalbuminuria and macroalbuminuria were defined as a UACR of 30-300 mg/g and >300 mg/g, respectively, in at least 2 consecutive specimens. RESULTS: 50 (14.7%) patients were classified as microalbuminuria and 13 (3.8%) as macroalbuminuria. In all patients, multivariate logistic regression revealed that the most significant risk factors were average HbA1c (%), OR (95% CI) = 1.76 (1.37-2.25), P = 0.002); and male sex, OR = (odd ratio 2.31 (1.19-4.46), P = 0.013). In adult patients, the most significant factors were average HbA1c, OR = 1.74 (1.32-2.31), P = 0.003; and systolic blood pressure, OR = 1.06 (1.01-1.11), P = 0.011. Survival analysis showed average HbA1c levels significantly influenced the development of DN. CONCLUSION: The most important risk factors for DN were average HbA1c and age. When microalbuminuria is detected, proper treatment with ACEIs or ARBs and improving glycemic control can delay progression of DN.

Cholestasis caused by panhypopituitarism and acquired cytomegalovirus infection in a 2-month-old male infant: A case report.

RATIONALE: Septo-optic dysplasia (SOD) is a rare congenital disorder that may cause jaundice in infants. However, it is usually prone to neglect and misdiagnosis in infants with cholestasis because endocrine disorder such as panhypopituitarism is rare in the cause of infantile cholestasis. We report a case of SOD concurrent with acquired cytomegalovirus (CMV) infection, who presented with prolonged jaundice as the first clinical sign. PATIENT CONCERNS: The patient was a 2-month-old male infant who presented with cholestasis, combined with fever and panhypopituitarism. DIAGNOSES: He was diagnosed with SOD and acquired CMV infection. INTERVENTIONS: He was treated with hormone replacement therapy and ganciclovir. OUTCOMES: After correction of the pituitary hormone deficiency and ganciclovir treatment, significant improvements of cholestasis, retinal lesions, and growth rate were seen in our patient. LESSONS: Although an endocrine disorder such as panhypopituitarism is rare in the cause of neonatal or infantile cholestasis, we must keep this reason in mind.

Helicobacter pylori infection is not associated with failure to thrive: a case control study.

PURPOSE: The long-term impact of Helicobacter pylori infection is complex, and concerns about the need for eradication exist. We conducted this case control study to investigate the association between H. pylori infection and failure to thrive (FTT). PATIENTS AND METHODS: From January 2009 to December 2011, 53 children with FTT group and matched children with the same sex and age and similar socioeconomic status without FTT (control group) were enrolled. A questionnaire was administered to the parents/guardian, and a 13C-urea breath test was performed to detect H. pylori infection. RESULTS: We found that the total prevalence of H. pylori infection was 29.2% and that there was no association between FTT and H. pylori infection (FTT group: 32%; control group: 26.4%; P=0.67). Short stature was more common in the FTT group and abdominal pain in the control group (FTT group: 37.7%; control group: 11.3%; P=0.003). In a comparison between the H. pylori-positive and -negative groups, abdominal pain (87.1% vs 64%; P=0.032) and the frequency of endoscopy (74.2% vs 32%; P<0.001) were significantly more common in the H. pylori-positive group. CONCLUSION: We found that children with H. pylori infection are at an increased risk for abdominal pain and that FTT is not associated with H. pylori infection. The decision for eradication should be evaluated carefully and individualized.

Association of Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) Gene Polymorphisms with Autoimmune Thyroid Disease in Children and Adults: Case-Control Study.

Autoimmune thyroid disease (AITD), including Graves disease (GD) and Hashimoto disease (HD), is an organ-specific autoimmune disease with a strong genetic component. Although the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) polymorphism has been reported to be associated with AITD in adults, few studies have focused on children. The aim of our study was to investigate whether the CTLA4 polymorphisms, including -318C/T (rs5742909), +49A/G (rs231775), and CT60 (rs3087243), were associated with GD and HD in Han Chinese adults and children. We studied 289 adult GD, 265 pediatric GD, 229 pediatric HD patients, and 1058 healthy controls and then compared genotype, allele, carrier, and haplotype frequencies between patients and controls. We found that CTLA4 SNPs +49A/G and CT60 were associated with GD in adults and children. Allele G of +49A/G was significantly associated with GD in adults (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.21-1.84; corrected P value [Pc] < 0.001) and children (OR, 1.42; 95% CI, 1.15-1.77; Pc = 0.002). Allele G of CT60 also significantly increased risk of GD in adults (OR, 1.63; 95% CI, 1.27-2.09; Pc < 0.001) and GD in children (OR, 1.58; 95% CI, 1.22-2.04; Pc < 0.001). Significant linkage disequilibrium was found between +49A/G and CT60 in GD and control subjects (D' = 0.92). Our results showed that CTLA4 was associated with both GD and HD and played an equivalent role in both adult and pediatric GD in Han Chinese population.

Successful treatment of a newborn with congenital hyperinsulinism having a novel heterozygous mutation in the ABCC8 gene using subtotal pancreatectomy.

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in newborns and infants. CHI is characterized by unregulated secretion of insulin from pancreatic ß: cells. Here, we reported the case of a large-for-gestational-age, full-term newborn that suffered from CHI and developed severe and persistent hypoglycemia at an early stage of life. The infant was nearly unresponsive to medical treatment, which included continuous intravenous glucagon infusion, oral diazoxide, and nifedipine. After medical treatment had failed, an 18-fluoro L-3,4-dihydroxyphenylalanine positron emission tomography scan of the patient showed a focal lesion at the neck of the pancreas. The patient received subtotal pancreatectomy, and shortly after the procedure, the patient's blood sugar returned to the normal range. The patient was confirmed to have a novel heterozygous mutation at position c.2475+1G>A of the ABCC8 gene. This is the first report of a focal form of CHI in a patient in Taiwan, which had preoperatively been confirmed using 18-fluoro L-3,4-dihydroxyphenylalanine positron emission tomography.

Mutations in pseudohypoparathyroidism 1a and pseudopseudohypoparathyroidism in ethnic Chinese.

An inactivating mutation in the GNAS gene causes either pseudohypoparathyroidism 1a (PHP1A) when it is maternally inherited or pseudopseudohypoparathyroidism (PPHP) when it is paternally inherited. We investigated clinical manifestations and mutations of the GNAS gene in ethnic Chinese patients with PHP1A or PPHP. Seven patients from 5 families including 4 girls and 2 boys with PHP1A and 1 girl with PPHP were studied. All PHP1A patients had mental retardation. They were treated with calcitriol and CaCO3 with regular monitoring of serum Ca levels, urinary Ca/Cr ratios, and renal sonography. Among them, 5 patients also had primary hypothyroidism suggesting TSH resistance. One female patient had a renal stone which was treated with extracorporeal shockwave lithotripsy. She had an increased urinary Ca/Cr ratio of 0.481 mg/mg when the stone was detected. We detected mutations using PCR and sequencing as well as analysed a splice acceptor site mutation using RT-PCR, sequencing, and minigene construct. We detected 5 mutations: c.85C>T (Q29*), c.103C>T (Q35*), c.840-2A>G (R280Sfs*21), c.1027_1028delGA (D343*), and c.1174G>A (E392K). Mutations c.840-2A>G and c.1027_1028delGA were novel. The c.840-2A>G mutation at the splice acceptor site of intron 10 caused retention of intron 10 in the minigene construct but skipping of exon 11 in the peripheral blood cells. The latter was the most probable mechanism which caused a frameshift, changing Arg to Ser at residue 280 and invoking a premature termination of translation at codon 300 (R280Sfs*21). Five GNAS mutations in ethnic Chinese with PHP1A and PPHP were reported. Two of them were novel. Mutation c.840-2A>G destroyed a spice acceptor site and caused exon skipping. Regular monitoring and adjustment in therapy are mandatory to achieve optimal therapeutic effects and avoid nephrolithiasis in patients with PHP1A.

The IL18 gene and Hashimoto thyroiditis in children.

Interleukin 18 (IL18) stimulates interferon-γ production in Th1 cells which are prominent in the thyroid of Hashimoto thyroiditis (HT). We investigated the association between the IL18 gene and HT. There were 116 children with HT and 1272 controls. rs187238 and rs1946518 in the promoter region of the IL18 gene were genotyped. Differences in genotype, allele, carrier, and haplotype distributions between patients and controls were compared. A Pc value <0.05 was considered significant. The frequency of the C/G genotype of rs187238 was significantly higher in patients and conferred a risk of HT (OR, 1.96; 95% CI, 1.30-2.95; Pc, 0.0021). So did the frequencies of allele C (OR, 1.73; 95% CI, 1.22-2.44; Pc, 0.0035) and carrier C (OR, 1.96; 95% CI, 1.31-2.92; Pc, 0.0017), however the frequency of the G/G genotype was significantly lower in patients than in controls (OR, 0.51; 95% CI, 0.34-0.76; Pc, 0.0034). There was no association between HT and rs1946518. The CT haplotype was significantly more frequent in patients than in controls and conferred a risk of HT (OR, 1.76; 95% CI, 1.24-2.49; Pc, 0.0049). We concluded that the IL18 gene was associated with HT in children. The rs187238C allele and CT haplotype conferred a risk of HT.