Efficacy and Safety of Topical Corticosteroid Treatment under Occlusion for Severe Alopecia Areata in Children. A single-center retrospective analysis.

BACKGROUND: Alopecia areata (AA) has a poor clinical course in children. There are no reliable therapeutic options for children with severe AA, including alopecia totalis (AT) and alopecia universalis (AU). AIM: We evaluated the efficacy and adverse effects of a potent topical corticosteroid (TCS) under occlusion in pediatric patients with severe AA. METHODS: We reviewed records of 23 patients under the age of 10 years with AT or AU treated with a potent TCS (0.05% clobetasol propionate or 0.3% diflucortolone valerate) for 8 hours under occlusion with a plastic film. We used the Severity of Alopecia Tool (SALT) to measure clinical improvement. The primary endpoint was a Severity of Alopecia Tool (SALT) score of 20 or less at six months. We analyzed the change in cortisol levels to identify the long-term safety of TCS therapy on the hypothalamus-pituitary-adrenal axis. RESULTS: Nineteen patients reached SALT 20 or less at the 6-month treatment. Six patients relapsed over the 6-month follow-up period. Four patients were suspected of adrenal insufficiency. However, the cortisol level of the patients recovered to normal at least 1-month after lowering TCS potency or changing to non-steroidal treatments. LIMITATIONS: Retrospective design and small sample size. CONCLUSION: This study shows that a potent TCS occlusion may be a safe treatment option in pediatric patients with severe AA. Further long-term studies are required to evaluate the safety and recurrence of TCS occlusion therapy for pediatric AA.

Comparison of anthropometric, metabolic, and body compositional abnormalities in Korean children and adolescents born small, appropriate, and large for gestational age: a population-based study from KNHANES V (2010-2011).

PURPOSE: The impacts of growth restriction and programming in the fetal stage on metabolic and bone health in children and adolescents are poorly understood. Moreover, there is insufficient evidence for the relationship between current growth status and metabolic components. Herein, we compared the growth status, metabolic and body compositions, and bone mineral density in Korean children and adolescents based on birth weight at gestational age. METHODS: We studied 1,748 subjects (272 small for gestational age [SGA], 1,286 appropriate for gestational age [AGA], and 190 large for gestational age [LGA]; 931 men and 817 women) aged 10-18 years from the Korean National Health and Nutrition Examination Survey (KNHANES) V (2010-2011). Anthropometric measurements, fasting blood biochemistry, and body composition data were analyzed according to birth weight and gestational age. RESULTS: The prevalence of low birth weight (14.7% vs. 1.2% in AGA and 3.2% in LGA, p<0.001) and current short stature (2.237 [1.296-3.861] compared to AGA, p=0.004) in SGA subjects was greater than that in other groups; however, the prevalence of overweight and obesity risks, metabolic syndrome (MetS), and MetS component abnormalities was not. Moreover, no significant differences were found in age- and sex-adjusted lean mass ratio, fat mass ratio, truncal fat ratio, bone mineral content, or bone density among the SGA, AGA, and LGA groups in Korean children and adolescents. CONCLUSION: Our data demonstrate that birth weight alone may not be a determining factor for body composition and bone mass in Korean children and adolescents. Further prospective and longitudinal studies in adults are necessary to confirm the impact of SGA on metabolic components and bone health.

Exploring the Genetic Causes for Postnatal Growth Failure in Children Born Non-Small for Gestational Age.

The most common causes of short stature (SS) in children are familial short stature (FSS) and idiopathic short stature (ISS). Recently, growth plate dysfunction has been recognized as the genetic cause of FSS or ISS. The aim of this study was to investigate monogenic growth failure in patients with ISS and FSS. Targeted exome sequencing was performed in patients categorized as ISS or FSS and the subsequent response to growth hormone (GH) therapy was analyzed. We found 17 genetic causes involving 12 genes (NPR2, IHH, BBS1, COL1A1, COL2A1, TRPS1, MASP1, SPRED1, PTPTN11, ADNP, NADSYN1, and CERT1) and 2 copy number variants. A genetic cause was found in 45.5% and 35.7% of patients with FSS and ISS, respectively. The genetic yield in patients with syndromic and non-syndromic SS was 90% and 23.1%, respectively. In the 11 genetically confirmed patients, a gain in height from -2.6 to -1.3 standard deviations after 2 years of GH treatment was found. The overall diagnostic yield in this study was 41.7%. We identified several genetic causes involving paracrine signaling, the extracellular matrix, and basic intracellular processes. Identification of the causative gene may provide prognostic evidence for the use of GH therapy in non-SGA children.

Natural History and Molecular Characteristics of Korean Patients with Mucopolysaccharidosis Type III.

BACKGROUND: Mucopolysaccharidosis type III (MPS III) is an autosomal recessive lysosomal storage disorder characterised by progressive neurocognitive deterioration. MPS III subtypes are clinically indistinguishable, with a wide range of symptoms and variable severity. The natural history of this disorder within an Asian population has not yet been extensively studied. This study investigated the natural history of Korean patients with MPS III. METHODS: Thirty-four patients from 31 families diagnosed with MPS III from January 1997 to May 2020 in Samsung Medical Centre were enrolled. Clinical, molecular, and biochemical characteristics were retrospectively collected from the patients' medical records and via interviews. RESULTS: 18 patients had MPS IIIA, 14 had IIIB, and two had IIIC. Twenty (58.9%) patients were male. Mean age at symptom onset was 2.8 ± 0.8 years and at diagnosis was 6.3 ± 2.2 years. All patients with MPS IIIA and IIIB were classified into the rapidly progressing (RP) phenotype. The most common symptom at diagnosis was language retardation (88.2%), followed by motor retardation (76.5%), general retardation (64.7%), and hyperactivity (41.2%). Language retardation was more predominant in IIIA, and motor retardation was more predominant in IIIB. The mean age of the 13 deceased patients at the time of the study was 14.4 ± 4.1 years. The age at diagnosis and lag time were significantly older and longer in the non-survivor group compared with the survivor group (p = 0.029 and 0.045, respectively). Genetic analysis was performed in 24 patients with MPS III and identified seven novel variants and three hot spots. CONCLUSION: This study is the first to analyse the genetic and clinical characteristics of MPS III patients in Korea. Better understanding of the natural history of MPS III might allow early diagnosis and timely management of the disease and evaluation of treatment outcomes in future clinical trials for MPS III.

Growth Responses During 3 Years of Growth Hormone Treatment in Children and Adolescents With Growth Hormone Deficiency: Comparison Between Idiopathic, Organic and Isolated Growth Hormone Deficiency, and Multiple Pituitary Hormone Deficiency.

BACKGROUND: The study aimed to compare the growth responses to 3 years of growth hormone (GH) treatment in children and adolescents with GH deficiency (GHD) according to idiopathic, organic, isolated (IGHD), and multiple pituitary hormone deficiency (MPHD). METHODS: Total 163 patients aged 2-18 years (100 males and 63 females; 131 idiopathic and 32 organic GHD; 129 IGHD and 34 MPHD) were included from data obtained from the LG Growth Study. Parameters of growth responses and biochemical results were compared during the 3-year GH treatment. RESULTS: The baseline age, bone age (BA), height (Ht) standard deviation score (SDS), weight SDS, mid-parental Ht SDS, predicted adult Ht (PAH) SDS, and insulin like growth factor-1 (IGF-1) SDS were significantly higher in the organic GHD patients than in the idiopathic GHD patients, but peak GH on the GH-stimulation test, baseline GH dose, and mean 3-year-GH dosage were higher in the idiopathic GHD patients than in the organic GHD patients. The prevalence of MPHD was higher in the organic GHD patients than in the idiopathic GHD patients. Idiopathic MPHD subgroup showed the largest increase for the ΔHt SDS and ΔPAH SDS during GH treatment, and organic MPHD subgroup had the smallest mean increase after GH treatment, depending on ΔIGF-1 SDS and ΔIGF binding protein-3 (IGFBP-3) SDS. The growth velocity and the parental-adjusted Ht gain were greater in the idiopathic GHD patients than the organic GHD patients during the 3-year GH treatment, which may have been related to the different GH dose, ΔIGF-1 SDS, and ΔIGFBP-3 SDS between two groups. Multiple linear regression analysis revealed that baseline IGF-1 SDS, BA, and MPH SDS in idiopathic group and baseline HT SDS in organic group are the most predictable parameters for favorable 3-year-GH treatment. CONCLUSION: The 3-year-GH treatment was effective in both idiopathic and organic GHD patients regardless of the presence of MPHD or underlying causes, but their growth outcomes were not constant with each other. Close monitoring along with appropriate dosage of GH and annual growth responses, not specific at baseline, are more important in children and adolescents with GHD for long-term treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01604395.

Association of Early Pubertal Onset in Female Rats With Inhalation of Lavender Oil.

BACKGROUND: Central precocious puberty (CPP) is caused by early activation of the hypothalamic-pituitary-gonadal axis but its major cause remains unclear. Studies have indicated an association between chronic environmental exposure to endocrine-disrupting chemicals and pubertal onset. Essential oil is widely used in homes worldwide for relief of respiratory symptoms, stress, and/or sleep disturbance. METHODS: To evaluate this association, we compared the hormone levels and timing of vaginal opening (VO) in female rats exposed to lavender oil (LO) through different routes (study groups: control, LO nasal spray [LS], and indoor exposure to LO [LE]) during the prepubertal period. The body weights of the animals were also compared every 3 days until the day of VO, at which time gonadotropin levels and internal organ weights were assessed. RESULTS: The LS group showed early VO at 33.8 ± 1.8 days compared with the control (38.4 ± 2.9 days) and LE (36.6 ± 1.5 days) groups. Additionally, luteinizing hormone levels were significantly higher in the LE and LS groups than those in the control group. Body weights did not differ significantly among the groups. CONCLUSION: Inhalation exposure to an exogenic simulant during the prepubertal period might trigger early pubertal onset in female rats. Further evaluation of exposure to other endocrine-disrupting chemicals capable of inducing CPP through the skin, orally, and/or nasally is warranted.

Clinical Significance of Pancreatic Fat in Children: A Single-Center Experience.

OBJECTIVES: Recently, interest in pancreatic fat has increased, and fatty pancreas is considered to be related to nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. We aimed to evaluate the prevalence of echogenic pancreas in children and its related factors. METHODS: We retrospectively analyzed the data of patients aged 5 to 18 years who had undergone abdominal sonography between January 2020 and December 2020. Patients with chronic or pancreatic diseases were excluded. RESULTS: Of 102 patients, 27 (26.5%) had echogenic pancreas and 55 (53.9%) had NAFLD. Among the 55 patients with NAFLD, 18 (32.7%) had an echogenic pancreas. Patients with echogenic pancreas had significantly higher fasting glucose, low-density lipoprotein cholesterol, and triglyceride levels than those without echogenic pancreas. The proportion of NAFLD and obesity was higher in the echogenic group; however, only the proportion of obese subjects showed a significant difference. In multivariate analysis, family history of diabetes mellitus (DM) and/or dyslipidemia and presence of DM and/or dyslipidemia were factors related to the presence of echogenic pancreas. CONCLUSIONS: Echogenic pancreas is relatively common in children. Echogenic pancreas, typically observed in patients with a family history of DM and/or dyslipidemia, was strongly associated with metabolic syndrome, even in the absence of fatty liver.

Temporal Trends for Diabetes Management and Glycemic Control Between 2010 and 2019 in Korean Children and Adolescents with Type 1 Diabetes.

Purpose: There is increasing use of modern devices in the management of patients with type 1 diabetes (T1D). We investigated temporal trends for diabetes management and outcomes in Korean pediatric T1D patients over 10 years. Methods: We retrospectively collected the data from 752 participants (boys: 311, 41.4%) diagnosed with T1D and aged ≤18 years, with ≥1 year of follow-up between 2010 and 2019 in any of the seven study hospitals in Korea. Results: Over the 10-year study period, use of continuous glucose monitoring (CGM) increased from 1.4% to 39.3%. From 2010 to 2019, there was an increased use of multiple daily insulin injections (MDI; 63.9%-77.0%, respectively) and continuous subcutaneous insulin infusion (CSII; 2.1%-14.0%, respectively), but decreased use of conventional insulin therapy (CIT, 33.9%-9.0%, respectively). Mean glycated hemoglobin (HbA1c) decreased from 8.56% to 8.01% (P < 0.001) and was lower in younger patients, boys, and CGM users (P < 0.001). MDI and CSII users had lower mean HbA1c levels than CIT users (P = 0.003). Regarding the acute complications of T1D, CGM use was associated with lower incidences of diabetic ketoacidosis (P = 0.015); CSII users were likely to experience less severe hypoglycemia (P = 0.008). Conclusions: The use of CSII and CGM increased ∼7- and 30-fold, respectively, over the 10-year study period. The glycemic control of pediatric T1D patients in Korea improved from 2010 to 2019, probably because of increased use of T1D technologies.

Single random measurement of urinary gonadotropin concentration for screening and monitoring girls with central precocious puberty.

PURPOSE: The gold standard for assessing pubertal activation is the gonadotropinreleasing hormone (GnRH) stimulation test (GnRHST), which is invasive, timeconsuming, and inconvenient. This study evaluated whether a single random measurement of urinary luteinizing hormone (LH) concentration could substitute for the GnRHST in diagnosing and monitoring central precocious puberty (CPP) in girls. METHODS: Fifty-five girls with breast buds before 8 years of age were assessed by both the GnRHST and urinary gonadotropin assays. Based on the GnRHST results, 29 girls were assigned to the CPP group (peak LH≥5 IU/L), and 26 were placed in the premature thelarche (PT) group (peak LH<5 IU/L). Auxological data and urine and serum samples were collected at baseline and after treatment with a GnRH agonist for 12 and 24 weeks. RESULTS: Although the auxological data did not differ between the 2 groups, the serum levels of insulin-like growth factor-1, basal LH, follicle-stimulating hormone (FSH), estradiol, and peak LH; urinary LH; and peak serum LH/FSH and urinary LH/FSH ratios were higher in the CPP group than in the PT group. Pearson correlation analysis showed a positive correlation between the urinary and serum LH concentrations (r=0.660, P<0.001). Receiver-operating characteristic curve analyses showed that a urinary LH concentration of 0.725 IU/L was a cutoff that significantly predicted positivity on the GnRHST. Urinary LH and FSH concentrations declined significantly during GnRH agonist treatment. CONCLUSION: A single, random measurement of urinary gonadotropin concentration could be a reliable tool for initial screening and therapeutic monitoring of CPP in girls.

Pancreatic involvement in patients with inborn errors of metabolism.

BACKGROUND: Repeated inflammation of the pancreas can cause pancreatitis or diabetes. It is well recognized that the organic acidemias may be complicated by pancreatitis but less recognized are other metabolic disorders in which pancreatitis can occur. This study shows that long-term follow-up of patients with various metabolic disorders in Korea revealed several with episodes of isolated pancreatitis or diabetes concomitantly with pancreatitis. RESULTS AND DISCUSSION: In this study, two patients with methylmalonic aciduria (MMA), two with propionic acidemia (PPA), one with fatty acid oxidation disorder (FAOD), and one with hyperornithinemia, gyrate atrophy, and juvenile onset diabetes mellitus (DM) were clinically followed for up to 10 - 21 years. Two Korean siblings with MMA showed recurrent pancreatitis from the age of 15 and 19, respectively. The frequency of admission due to pancreatitis was up to 11 times. One patient with MMA developed diabetes mellitus at the age of 20. The other patient with MMA developed recurrent pancreatitis at 4 years and diabetes at 8 years of age. One of the patients with PPA presented with diabetic ketoacidosis. The other PPA patient died of cardiac arrest at age 10. The patient with FAOD presented with pancreatitis at 10 years and died at the age of 15 years due to cardiac arrest. A 35-year-old woman with hyperornithinemia/gyrate atrophy was diagnosed with juvenile onset diabetes at the age of 7 years. No pancreatitis occurred during the follow-up period. CONCLUSIONS: We conclude that various metabolic disorders can trigger acute or chronic pancreatitis. Proper and prompt multidisciplinary management of metabolic derangement is crucial for preventing pancreatic damage. Further clinical and investigational studies are required to elucidate the pathogenesis of pancreatitis and diabetes mellitus in patients with inborn errors in metabolism.

The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects.

BACKGROUND: Gaucher disease (GD) is caused by a deficiency of ß-glucocerebrosidase, encoded by GBA. Haplotype analyses previously demonstrated founder effects for particular GBA mutations in Ashkenazi Jewish and French-Canadian populations. This study aimed to investigate the clinical characteristics and mutation spectrum of GBA in Korean GD patients and to identify founder effect of GBA p.G85E in non-neuronopathic GD patients. RESULTS: The study cohort included 62 GD patients from 58 unrelated families. Among them, 18 patients from 17 families harbored the p.G85E mutation. Haplotype analysis was performed for 9 probands and their parents for whom DNA samples were available. In 58 unrelated probands, the GBA mutation p.L483P was the most common (30/116 alleles, 26%), followed by p.G85E (16%), p.F252I (13%), and p.R296Q (9%). The median age at diagnosis of the 18 patients harboring the p.G85E mutation was 3.8 (range 1.2-57) years. No patients developed neurological symptoms during follow-up periods of 2.2-20.3 (median 13.9) years. The size of the shared haplotype containing GBA p.G85E was 732 kbp, leading to an estimated age of 3075 years. CONCLUSION: The GBA p.G85E mutation, which appears to be neuroprotective despite producing distinctive visceromegaly and skeletal symptoms, exhibited a potential founder effect in Korean GD patients.

The Effect of Combined Growth Hormone and a Gonadotropin-Releasing Hormone Agonist Therapy on Height in Korean 3-M Syndrome Siblings.

3-M syndrome is a rare autosomal recessive growth disorder characterized by severe growth retardation, low birth weight, characteristic facial features, and skeletal anomalies, for which three causative genes (CUL7, OBSL1, and CCDC8) have been identified. We herein report two Korean siblings with 3-M syndrome caused by two novel OBSL1 mutations, and describe the effect of a combined treatment with growth hormone (GH) and a gonadotropin-releasing hormone (GnRH) agonist. A 7-year-old girl with short stature (-3.37 standard deviation score, SDS) and breast budding presented with subtle dysmorphic features, including macrocephaly, frontal bossing, a triangular face, prominent philtrum, full lips, a short neck, and fifth-finger clinodactyly. GnRH stimulation test revealed a pubertal pattern and advanced bone age of 8 years and 10 months. Her older sister, aged 10 years and 9 months, had experienced an early menarche, and had an advanced bone age (13.5 years) and predicted adult height of 142 cm (-4.04 SDS). Targeted exome sequencing identified that the siblings had two heteroallelic mutations in OBSL1. Both siblings underwent a combination therapy with GH and a GnRH agonist. A height gain was noted in both siblings even after short-term treatment. To fully elucidate the effects of the combined therapy, a larger cohort should be analyzed following a longer treatment period. However, such an analysis would be challenging due to the rarity of this disease.

First Case of Peroxisomal D-bifunctional Protein Deficiency with Novel HSD17B4 Mutations and Progressive Neuropathy in Korea.

Peroxisomal D-bifunctional protein (DBP), encoded by the HSD17B4 gene, catalyzes ß-oxidation of very long chain fatty acids (VLCFAs). The deficiency of this peroxisomal enzyme leads to the accumulation of VLCFAs, causing multisystemic manifestations including the brain, retina, adrenal gland, hearing, and skeletal system. Herein, we report the first Korean neonatal case of peroxisomal DBP deficiency and the clinical prognosis over 2 years. This patient showed craniofacial dysmorphism, club foot, and seizures with cyanosis one day after birth. Elevated VLCFAs levels were indicative of a peroxisomal disorder. Targeted exome sequencing was performed and two missense mutations p.Asp117Val and p.Phe279Ser in the HSD17B4 gene were identified. The patient had type III DBP deficiency; therefore, docosahexaenoic acid and non-soluble vitamins were administered. However, progressive nystagmus, optic nerve atrophy, and bilateral hearing defects were observed and follow-up brain imaging revealed leukodystrophy and brain atrophy. Multiple anti-epileptic drugs were required to control the seizures. Over two years, the patient achieved normal growth with home ventilation and tube feeding. Hereby, the subject's parents had support during the second pregnancy from the proven molecular information. Moreover, targeted exome sequencing is an effective diagnostic approach, considering genetic heterogeneity of Zellweger spectrum disorders.

Successful rapid weight reduction and the use of liraglutide for morbid obesity in adolescent Prader-Willi syndrome.

Prader-Willi syndrome (PWS), an imprinting disorder, results from the loss of expression of a paternal gene on chromosome 15q11-q13. Progressive obesity and its associated complications lead to increased morbidity and early death in PWS patients. The management techniques available for morbid obesity in adolescents and adults with PWS are limited. Herein, we report successful weight reduction in an adolescent PWS case showing morbid obesity and respiratory failure. An 18-year-old girl with PWS presented with diffuse cellulitis and dyspnea due to severe obesity. Her body weight had increased from 146 to 161 kg despite dietary restriction to 800 kcal/day, and a mechanical ventilator was required for dyspnea. During mechanical ventilation, the patient was managed using diuretics and by restricting fluid intake; her daily calorie intake was reduced to 200 kcal. This aggressive calorie and water restriction continued for 3 weeks and reduced her body weight to 118.6 kg. After transfer to the general ward, the patient was provided with growth hormone therapy and intensive aquatic rehabilitation and was administered liraglutide; as a result, her weight further decreased to 104 kg (body mass index [BMI], 50.8 kg/m2), and she was discharged. Following discharge, she maintained her BMI and adapted to 1,000 kcal/day for 1 year. Aggressive water and calorie restriction were observed as an effective method for rapid weight reduction in PWS patients, and liraglutide appeared useful in maintaining weight reduction in adolescent and adult PWS.

Sleep duration independently influences metabolic body size phenotype in children and adolescents: a population-based study.

BACKGROUND: Epidemiologic studies have found an association between sleep duration and obesity. However, the relationship between sleep duration and metabolic body size phenotype in children and adolescents remains unknown. METHODS: In this cross-sectional study, 3650 participants (1946 boys and 1704 girls) from the Korean National Health and Nutrition Examination Survey 2007-2012 were classified into four phenotypes according to body mass index and metabolic heath status based on the definition of metabolic syndrome by NCEP-ATP III or the International Diabetes Federation. The four phenotypes were: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHO), and metabolically unhealthy overweight (MUO). The associations between the four metabolic body size phenotypes and sleep duration, categorized as very short (≤5 h), short (6-7 h), normal (8-10 h), or long (≥11 h), were evaluated. RESULTS: Sleep duration was shorter in the MUO group (7.0 ± 1.5 h) than in the MHNW (7.3 ± 1.4 h) or MUNW (7.8 ± 1.6 h) groups. After adjusting for age, sex, household income, and physical activity, compared with a normal sleep duration, very short sleep duration (≤5 h) was associated with a higher prevalence of being overweight/obese (26.4% vs 17.4%, p = 0.001), lower risk of being MHNW (0.711 (0.538-0.940), p = 0.017) or MUNW (0.478 (0.237-0.962), p = 0.039), and higher risk of being MHO (1.702 (1.193-2.428), p = 0.003). By contrast, long sleep duration (≥11 h) was associated with a higher risk of being MUNW (2.581 (1.124-5.928), p = 0.025). CONCLUSIONS: Sleep duration may be independently associated with metabolic body size phenotype in children and adolescents.

Korean pediatric reference intervals for FT4, TSH, and TPO Ab and the prevalence of thyroid dysfunction: A population-based study.

BACKGROUND: The appropriate age-related reference intervals for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are important in interpreting the results of thyroid function tests in children and adolescents. However, these reference intervals are scanty. This study aimed to establish the reference intervals for FT4, TSH, and thyroid peroxidase antibody (TPO Ab), and identify the epidemiological prevalence of thyroid dysfunction in a Korean pediatric population. METHODS: The data from a sample of 2042 children and adolescents aged 10-18years who underwent a nationwide Korean representative sampling and cross-sectional survey with blood collection for a thyroid function test using an electrochemiluminescence immunoassay were evaluated. RESULTS: Based on the National Academy of Clinical Biochemistry (NACB) criteria, the median and range (2.5th - 97.5th percentile) for FT4 and TSH in total were 16.47pmol/L (12.61-21.49pmol/L) and 2.48mIU/L (0.63-7.03mIU/L), respectively. Positive TPO Ab (3.1%) by NACB was >19.16kIU/L (boys) and >29.30kIU/L (girls) for adolescents aged 10-18years. FT4 and TSH were associated with increasing and decreasing age, respectively. Boys' FT4 and girls' TPO Ab levels were greater than for the other sex, respectively. Using the new reference interval, overt hypothyroidism, subclinical hypothyroidism, subclinical hyperthyroidism, and overt hyperthyroidism were found in 0.5%, 2.1%, 1.3%, and 1.2%, respectively, of Korean children and adolescents. CONCLUSIONS: This study provides evidence-based age- and sex-specific reference intervals for thyroid hormones and autoantibodies, and identifies the current prevalence of thyroid dysfunction in a Korean pediatric group.

A pilot study on using rapamycin-carrying synthetic vaccine particles (SVP) in conjunction with enzyme replacement therapy to induce immune tolerance in Pompe disease.

A major obstacle to enzyme replacement therapy (ERT) with recombinant human acid-α-glucosidase (rhGAA) for Pompe disease is the development of high titers of anti-rhGAA antibodies in a subset of patients, which often leads to a loss of treatment efficacy. In an effort to induce sustained immune tolerance to rhGAA, we supplemented the rhGAA therapy with a weekly intravenous injection of synthetic vaccine particles carrying rapamycin (SVP-Rapa) during the first 3 weeks of a 12-week course of ERT in GAA-KO mice, and compared this with three intraperitoneal injections of methotrexate (MTX) per week for the first 3 weeks. Empty nanoparticles (NP) were used as negative control for SVP-Rapa. Co-administration of SVP-Rapa with rhGAA resulted in more durable inhibition of anti-rhGAA antibody responses, higher efficacy in glycogen clearance in skeletal muscles, and greater improvement of motor function than mice treated with empty NP or MTX. Body weight loss was observed during the MTX-treatment but not SVP-Rapa-treatment. Our data suggest that co-administration of SVP-Rapa may be an innovative and safe strategy to induce durable immune tolerance to rhGAA during the ERT in patients with Pompe disease, leading to improved clinical outcomes.

Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey: Underdiagnosis of late-onset phenotype.

Fabry disease is a rare X-linked lysosomal storage disorder caused by an α-galactosidase A deficiency. The progressive accumulation of globotriaosylceramide (GL-3) results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. This study investigated the phenotypic and molecular spectra of GLA mutations in Korean patients with Fabry disease using a nationwide survey.This study included 94 patients from 46 independent pedigrees: 38 adult males, 46 symptomatic females, and 10 pediatric males. Each diagnosis was based on an enzyme assay and GLA gene mutation analysis.The mean age at presentation was 24 years (range, 5-65 years); however, the diagnoses were delayed by 21 ±â€Š19 years after the onset of symptoms. Those patients with late-onset Fabry disease were diagnosed by family screening or milder symptoms at a later age. Forty different mutations were identified: 20 missense (50%), 10 nonsense (25%), 8 frameshift (20%), and 2 splice site (5%) mutations. Five of them were novel. IVS4+919G>A (c.936+919 G>A) was not detected among the 6505 alleles via newborn screening using dried blood spots. Enzyme replacement therapy (ERT) was performed in all the males and pediatric patients, whereas 75% of the symptomatic females underwent ERT for 4.2 ±â€Š3.6 years.This study described the demographic data, wide clinical spectrum of phenotypes, and GLA mutation spectrum of Fabry disease in Korea. Most of the patients had classical Fabry disease, with a 4 times higher incidence than that of late-onset Fabry disease, indicating an underdiagnosis of mild, late-onset Fabry disease.