Jong Seo Yoon

Luteinizing Hormone Secretion during Gonadotropin-Releasing Hormone Stimulation Tests in Obese Girls with Central Precocious Puberty.

Objective: Girls with precocious puberty have high luteinizing hormone (LH) levels and advanced bone age. Obese children enter puberty at earlier ages than do non-obese children. We analyzed the effects of obesity on LH secretion during gonadotropin-releasing hormone (GnRH) tests in girls with precocious puberty. Methods: A total of 981 subjects with idiopathic precocious puberty who had undergone a GnRH stimulation testing between 2008 and 2014 were included in the study. Subjects were divided into three groups based on body mass index (BMI). Auxological data and gonadotropin levels after the GnRH stimulation test were compared. Results: In Tanner stage 2 girls, peak stimulated LH levels on GnRH test were 11.9±7.5, 10.4±6.4, and 9.1±6.1 IU/L among normal-weight, overweight, and obese subjects, respectively (p=0.035 for all comparisons). In Tanner stage 3 girls, peak stimulated LH levels were 14.9±10.9, 12.8±7.9, and 9.6±6.0 IU/L, respectively (p=0.022 for all comparisons). However, in Tanner stage 4 girls, peak stimulated LH levels were not significantly different among normal, overweight, and obese children. On multivariate analysis, BMI standard deviation score was significantly and negatively associated with peak LH (β=-1.178, p=0.001). Conclusion: In girls with central precocious puberty, increased BMI was associated with slightly lower peak stimulated LH levels at early pubertal stages (Tanner stages 2 and 3). This association was not valid in Tanner stage 4 girls.

Predictors of transient congenital hypothyroidism in children with eutopic thyroid gland

Purpose Congenital hypothyroidism (CH) is the most common cause of preventable mental retardation. Recently, the detection of CH cases with eutopic thyroid gland has increased due to neonatal screening programs. In this study, we aimed to identify and evaluate predictive factors that could distinguish between permanent and transient CH in patients with eutopic thyroid gland. Methods We retrospectively reviewed 100 children diagnosed with CH and with eutopic thyroid gland. All subjects were treated with levothyroxine and underwent re-evaluation after 3 years of age. Results Of the 100 CH patients, 35 (35.0%) were diagnosed with permanent CH (PCH) and 65 (65.0%) were diagnosed with transient CH (TCH). The initial thyroid stimulating hormone levels were significantly lower in the TCH subjects than in PCH subjects. In addition, the mean doses of levothyroxine (µg/kg/day) at the 1st, 2nd, and 3rd year of treatment were significantly lower in subjects with TCH than in PCH subjects with eutopic thyroid gland. Based on the receiver operating characteristic (ROC) curve, the optimal cutoff dose of levothyroxine at 3 years of 2.76 µg/kg/day could predict TCH, and was associated with 87.3% sensitivity and 67.6% specificity, with an area under the ROC curve of 0.769. Conclusion The levothyroxine dose requirement during treatment period has a predictive role in differentiating TCH from PCH in CH patients with eutopic thyroid gland.

Changes in body mass index during gonadotropin-releasing hormone agonist treatment for central precocious puberty and early puberty

Gonadotropin-releasing hormone agonists (GnRHa) have been widely used for decades to treat patients with central precocious puberty (CPP). Several studies have investigated changes in body composition in patients with CPP following GnRHa treatment, but the results are inconsistent. The aim of this study was to investigate changes in body mass index (BMI) in children treated with GnRHa for 2 years. We also assessed whether BMI affects treatment outcomes. This study included 383 girls (214 girls with central precocious puberty and 169 girls who underwent early puberty) treated with depot leuprolide acetate monthly for at least 2 years. We analyzed changes in BMI standard deviation score (SDS). Furthermore, blood luteinizing hormone (LH) levels were determined 30 min after depot leuprolide acetate administration every 6 months to evaluate adequate suppression of the hypothalamic-pituitary-gonadal axis. Pretreatment mean BMI SDS values were 0.07 ± 0.69, 1.29 ± 0.16, and 1.95 ± 0.32 in the normal weight, overweight, and obese subjects, respectively. Mean BMI SDS values after 2 years of treatment increased significantly only in normal weight children (0.07 ± 0.69 vs. 0.25 ± 0.73, P < 0.001). LH levels 30 min after leuprolide injection after 2 years of treatment were not different among normal weight, overweight, and obese subjects. Although the difference in BMI SDS was relatively small, it standard deviation score increased significantly after 2 years of treatment in normal weight girls with early pubertal development.

Increased final adult height by gonadotropin-releasing hormone agonist in girls with idiopathic central precocious puberty

Objective Gonadotropin-releasing hormone agonists (GnRHa) are the treatment of choice for central precocious puberty (CPP) and have been widely used for several decades. We determined the effect of GnRHa treatment on the auxological outcomes of girls with idiopathic CPP. Methods This study included 84 girls treated monthly with depot leuprolide acetate who had reached adult height. We compared their final adult height (FAH) with their initial predicted adult height (PAH). We performed a multivariate analysis of the factors associated with FAH on all girls diagnosed with CPP. Results We performed the final evaluations at a mean age of 14.1 ± 0.8 years after a mean treatment duration of 2.98 ± 0.73 years (ranging from 1.5–4.8 years). Menarche had occurred at 12.6 ± 0.6 years of age, which was 16.5 ± 6.1 months after discontinuation of GnRHa therapy. Mean FAH was 160.1 ± 5.0 cm, which was significantly higher than the initial PAH (156.1 ± 5.7 cm; P < 0.001). To investigate whether growth outcomes were influenced by the age at initial treatment, we divided all patients into two groups, those treated between 6 and 8 years (n = 23) and those treated after 8 years (n = 61); no significant differences were observed in FAH between the two groups. FAH was significantly and positively correlated with the height standard deviation score (SDS) at the end of treatment and with the target height, whereas the difference between bone age and chronological age at the start and end of treatment was negatively correlated with FAH. Conclusion FAH was significantly higher than the initial PAH in girls with CPP who were treated with GnRHa. Also, GnRHa treatment was still effective even after 8 years of age in girls with CPP.

The prevalence of brain abnormalities in boys with central precocious puberty may be overestimated

Brain magnetic resonance imaging (MRI) is routinely performed to identify brain lesions in boys with central precocious puberty (CPP). We investigated the prevalence of CPP in Korean boys and the necessity for routine brain MRI examinations. This retrospective cross-sectional study was conducted from April 2003 to December 2016 at a Korean university hospital. Among 151 boys who were diagnosed with CPP, the data of 138 boys who underwent sellar MRI were evaluated. The mean age of the study subjects was 9.51 ± 0.56 years (<8 years [n = 4] and ≥8 years [n = 134]). We excluded patients who had been previously diagnosed with brain tumors and those who did not undergo a sellar MRI because of refusal or the decision of the pediatric endocrinologist. The main outcome measure was the prevalence of intracranial lesions among boys with CPP. Normal sellar MRI findings were observed in 128 of the 138 boys (93%). Mild brain abnormalities were found in 10 boys (7%), while none of the patients had pathological brain lesions. The prevalence (7%) of intracranial lesions among boys who were healthy, did not have neurological symptoms, and were diagnosed with CPP was different from that previously reported. None of the identified lesions necessitated treatment. Although this was a single country study, we found that the previously reported prevalence of brain lesions in boys with CPP is much higher than the prevalence observed in Korea. This study suggests the need to globally reevaluate the prevalence of pathological brain lesions among male pediatric patients with CPP.

Glycated hemoglobin A1c as a screening test for detecting type 2 diabetes mellitus in obese children and adolescents

Abstract Background: The diagnostic cutoff points for indicators of type 2 diabetes mellitus (T2DM) in the pediatric population have not been defined thus far. Methods: A retrospective, single-center study was conducted from April 2003 to May 2016. We enrolled 236 overweight or obese children and adolescents aged 4–17 years. Thirty-nine (26.9%) of 145 patients had T2DM according to the oral glucose tolerance test results. Results: A glycated hemoglobin (HbA1c) level of 6.5% had a sensitivity and specificity of 87.2% and 98.5%, respectively, for detecting T2DM. The optimal HbA1c cutoff level for T2DM was >6.2% (94.7% sensitivity, 95.5% specificity). Conclusions: We observed that the use of an HbA1c level of 6.5% had a lower sensitivity for detecting T2DM than an HbA1c level of >6.2%.

Prevalence of autoimmune thyroiditis in patients with type 1 diabetes: a long-term follow-up study

Purpose Type 1 diabetes mellitus (DM) is associated with autoimmune diseases such as thyroiditis. Therefore, we aimed to investigate the prevalence of autoimmune thyroiditis in patients with type 1 DM. Methods A total of 102 patients who were diagnosed and followed up (mean age, 8.1±4.0 years) in Ajou University Hospital were enrolled in this study. All the patients were evaluated for beta cell autoimmunity, including insulin autoantibody, glutamic acid decarboxylase antibodies (GADA), and islet cell antibody. Moreover, autoantibodies to thyroid peroxidase and thyroglobulin were assessed at initial diagnosis and annually thereafter. Results The mean patient age (49 men and 53 women) was 19.2±4.8 years. The prevalence of at least one thyroid antibody was 30.4%. Patients with thyroid antibodies had a significantly higher frequency of GADA at the time of the diagnosis. Autoimmune thyroiditis was more prevalent in the older age group. GADA was a significant risk factor for development of thyroid autoantibodies after diagnosis of type 1 DM (odds ratio, 4.45; 95% confidence interval, 1.399–14.153). Conclusions In patients with type 1 DM, the prevalence of autoimmune thyroiditis was higher than in the general population. Moreover, GADA positivity at diagnosis was associated with thyroid autoimmunity.

Evaluation of bone mineral status in prepuberal children with newly diagnosed type 1 diabetes

Purpose Many studies have reported that patients with type 1 diabetes have reduced bone mineral density (BMD). We assessed bone status in prepubertal children with type 1 diabetes mellitus (type 1 DM) at initial diagnosis and investigated factors associated with BMD. Methods Prepubertal children (n=29) with newly diagnosed type 1 diabetes from 2006 to 2014 were included. Dual-energy X-ray absorptiometry measured regional and whole-body composition at initial diagnosis. BMD was compared with healthy controls matched for age, sex, and body mass index (BMI). Results The mean age of all subjects (16 boys and 13 girls) was 7.58±1.36 years (range, 4.8–11.3 years). Initial mean glycosylated hemoglobin (HbA1c) level was 12.2%±1.9%. The mean BMD z-scores of lumbar spine, femur neck, and total body were not significantly different between patients and controls. Three patients (10.3%) had low bone density (total body BMD standard deviation score [SDS] < -2.0). To identify determinants of lumbar spine BMD z-score, multivariate regression analysis was performed with stepwise variable selection of age, pubertal status, BMI SDS, insulin like growth factor-1, and HbA1c. Only BMI SDS was significantly correlated with lumbar spine BMD z-score (β=0.395, P=0.023). Conclusions Prepubertal children with newly diagnosed type 1 DM had similar bone mass compared to healthy peers. However, patients with low BMI should be carefully monitored for bone density in type 1 DM.

Successful switching from insulin to sulfonylurea in a 3-month-old infant with diabetes due to p.G53D mutation in KCNJ11

Permanent neonatal diabetes mellitus is most commonly caused by mutations in the ATP-sensitive potassium channel (KATP) subunits. Prompt initiation of sulfonylurea treatment can improve glycemic control in children with KCNJ11 mutation. In this report, we present a case of permanent neonatal diabetes caused by a mutation in the KCNJ11 gene that was successfully treated via early switching of insulin to sulfonylurea treatment. A 53-day-old female infant presented with diabetic ketoacidosis. Insulin was administered for the ketoacidosis and blood glucose regulation. At 3 months of age, using genomic DNA extracted from peripheral lymphocytes, direct sequencing of KCNJ11 identified a heterozygous mutation of c.158G>A (p.G53D) and confirmed the diagnosis of permanent neonatal diabetes mellitus. Subsequently, treatment with sulfonylurea was initiated, and the insulin dose was gradually tapered. At 4 months of age, insulin therapy was discontinued, and sulfonylurea (glimepiride, 0.75 mg/kg) was administered alone. At 6 months after initiation of administration of sulfonylurea monotherapy, blood glucose control was stable, and no hypoglycemic events or developmental delays were reported. C-peptide levels increased during treatment with sulfonylurea. Early switching to sulfonylurea in infants with permanent diabetes mellitus owing to a KCNJ11 mutation could successfully help regulate glycemic control, which suggests the need for early genetic testing in patients presenting with diabetes before 6 months of age.

No association between estrogen receptor gene polymorphisms and premature thelarche in girls

Abstract Objective: Premature thelarche (PT) is a benign, nonprogressive condition defined as isolated breast development. While the pathophysiology of PT remains unclear, increased sensitivity to estrogen may cause PT. The aim of this study was to investigate the association between polymorphisms in the estrogen receptor alpha (ERα) gene and PT in girls. Methods: In this case–control study, we examined 96 girls referred for early breast development (before the age of 8 years). The control group included healthy Korean females with normal pubertal progression. Anthropometric and hormonal parameters were measured and PvuII and XbaI ERα gene polymorphisms were evaluated by PCR. Out of the 96 girls, all coding exon and exon-intron boundaries of ERα were sequenced from the DNA of 46 girls. Results: There was no significant difference in the distribution of PvuII and XbaI polymorphisms between patients and controls. However, the carriers of XbaI polymorphisms had more advanced Tanner stage than did the non-carriers. Also, four ERα gene polymorphisms were previously identified, but these polymorphisms had no clinical significance. Conclusion: No association was found between the ERα gene polymorphisms and PT in girls. However, XbaI polymorphisms may contribute to early breast budding.