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Thyroid hormone abnormalities have been linked to antiseizure medications (ASMs). Oxcarbazepine is considered safer than carbamazepine because it induces the hepatic cytochrome P450 metabolic enzymes less than the carbamazepine does. However, limited data exist for the influence of oxcarbazepine on thyroid function in children and adolescents. The objective of this study was to determine the effect of oxcarbazepine on thyroid function in these patients.A total of 162 pediatric patients with epilepsy who started oxcarbazepine for the first time between April 2003 and May 2020 were enrolled. The longitudinal effects of oxcarbazepine for thyroid functions were confirmed using general estimating equations.Serum triiodothyronine (T3), thyroxine (T4), and free thyroxine (fT4) levels decreased significantly during 5 years of follow-up (all p's .001). In particular, T3 and fT4 levels were reduced steeply in the first 2 years of oxcarbazepine treatment. There was no significant change in thyroid-stimulating hormone during oxcarbazepine treatment.Serum T3, T4, and fT4 levels decreased significantly during oxcarbazepine use, and this change was maintained during the treatment period. In patients receiving oxcarbazepine, it is recommended that periodic thyroid function testing should be performed, especially within the first 2 years after starting this ASM. Our results indicate that oxcarbazepine-induced hypothyroidism does not appear to be accompanied by a significant increase in TSH, and consequently might be missed if TSH alone is monitored as a measure of thyroid dysfunction.

Because of paucity of published data, we evaluated the 2-year major clinical outcomes between early invasive (EI) and delayed invasive (DI) strategies according to the stage of chronic kidney disease (CKD) in patients with non-ST-segment elevation myocardial infarction (NSTEMI), who underwent a successful newer-generation drug-eluting stent (DES) implantation.A total of 8241 NSTEMI patients were recruited from the Korea Acute Myocardial Infarction Registry (KAMIR). Based on baseline estimated glomerular filtration rate (eGFR; ≥90, 60-89, 30-59, and30 mL/min/1.73 mAfter multivariable-adjusted and propensity score-adjusted analyses, the cumulative incidence of MACE (group A, p = 0.139 and p = 0.103, respectively; group B, p = 0.968 and p = 0.608, respectively; group C, p = 0.111 and p = 0.196, respectively; group D, p = 0.882 and p = 0.571, respectively), all-cause death, re-MI, and any repeat revascularization was similar between the EI and DI groups in the 4 different renal function groups.In the era of newer-generation DES, EI and DI strategies showed comparable major clinical outcomes in patients with NSTEMI and CKD during a 2-year follow-up period. However, to confirm these results, further randomized, large-scale, long-term follow-up studies are needed.

Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 2 (ADH2) is caused by a heterozygous gain-of-function mutation in

Background Solid pseudopapillary tumors (SPTs) are rare, but they comprise the majority of pediatric pancreatic neoplasms. However, studies on these conditions in pediatric patients are lacking. The aim of this study was to investigate the clinical characteristics and treatment outcomes in children and adolescents with SPTs. Methods This retrospective study included 51 patients with SPTs who had undergone pancreatic tumor resection before the age of 19 years at Samsung Medical Center in Korea (from November 1994 to August 2020). We investigated the postoperative outcomes. Results Of the 51 patients with SPTs (female, 88.2%), the median age at diagnosis was 14 years (range, 8–19). The most common symptom was abdominal pain (60.8%), and 14 patients (27.5%) were asymptomatic. The median maximal tumor diameter was 7 cm (range, 1.4–14), and the pancreatic body and/or tail were involved in 68.6% of patients. The short-term complication rate was 21.5%, and the recurrence rate was 5.9%. New-onset diabetes mellitus (NODM) occurred in four patients. Conclusions The ideal treatment for SPTs is complete resection of the tumor; however, long-term postoperative complications including NODM should be monitored carefully, particularly in children and adolescents.

Objectives The purpose of this study was to evaluate the impact of recombinant human growth hormone (rhGH) on the development and progression of scoliosis in patients with idiopathic short stature (ISS). Methods Patients with ISS who underwent rhGH treatment from 1997 to 2017 and were followed up for scoliosis screening with serial radiographic examination were included. For assessing scoliosis development, patients who did not have scoliosis at the time of rhGH treatment were included and followed up to determine whether de novo scoliosis developed during the treatment. For evaluating scoliosis progression, patients who already had scoliosis were analyzed. Univariate and multivariate Cox regression analyses of demographic and radiographic variables were performed to determine the related factors in the development and progression of scoliosis. Results For assessing scoliosis development, 1093 patients were included. The average duration of rhGH treatment was about 2 years. De novo scoliosis developed in 32 patients (3.7%). The analysis revealed that sex (p=0.016) and chronological age (p=0.048) were statistically significant factors associated with scoliosis development. However, no relationship was observed between scoliosis development and rhGH treatment types or duration. Among 67 patients who already had scoliosis at the time of rhGH treatment, 11 (16.4%) showed scoliosis progression. However, the rhGH types and duration also did not affect scoliosis progression. Conclusions De novo scoliosis developed in 3.7% and scoliosis progressed in 16.4% of the patients during rhGH treatment. However, scoliosis development or progression was not affected by the types or duration of rhGH treatment in patients with ISS.

ObjectiveThis study aimed to determine the most appropriate age for height control treatment in patients with Marfan syndrome (MFS).Materials and MethodsThis retrospective study included patients with MFS who underwent height control treatment with estradiol valerate. The estrogen dose was increased according to the height change. The cut-off age for the maximum difference between the expected height and actual final height was evaluated.ResultsSeventeen patients were included in this study. The difference between the height predicted by the growth curve and the final height (gcHtD) and that predicted by the bone age and the final height (baHtD) was the largest in the 10.5 years age group (p=0.0045 and p=0.0237, respectively). The gcHtD was 10.6 (10.2, 13.5) cm for patients aged ≤10.5 years, whereas it was 0.6 (−3.65, 5.85) cm for patients aged >10.5 years. The baHtD was 10.1 (7.31, 11.42) cm for patients aged ≤10.5 years, while it was 3.83 (0.84, 6.4) cm for patients aged >10.5 years. When height change was observed for a minimum of 6 months after completion of estrogen treatment, the average growth was 0.6 (0.2, 2.1) cm.ConclusionInitiating height control treatment before the age of 10.5 years is effective in female patients with MFS.

Background Short stature is the most consistent characteristic feature of Turner syndrome (TS). To improve final heights of children with TS effectively, it is important to provide them with early and appropriate treatment using growth hormone (GH). The objective of this study was to assess the efficacy and safety of a new recombinant human GH, Growtropin®-II (DA-3002, Dong-A ST Co., Ltd) versus a comparator (Genotropin®, Pfizer Inc.) for Korean children with TS. Methods This open-label, active-controlled, parallel-group, randomized controlled phase III trial was conducted at 11 hospitals in Korea. Eligible patients (n = 58) were randomized to two groups: 1) DA-3002 group (administrated with DA-3002 at 0.14 IU [0.0450–0.050 mg] /kg/day); and 2) comparator group (administrated with the comparator at 0.14 IU [0.0450–0.050 mg] /kg/day). Results The change from baseline in annualized height velocity (HV) after a 52-week treatment period was 4.15 ± 0.30 cm/year in the DA-3002 group and 4.34 ± 0.29 cm/year in the comparator group. The lower bound of 95% two-sided confidence interval for group difference in the change of annualized HV (− 1.02) satisfied the non-inferiority margin (− 1.5). The change in height standard deviation score (HtSDS) at 52-week was 0.70 ± 0.23 for the DA-3002 group and 0.66 ± 0.39 for the comparator group, showing no significant (p = 0.685) difference between the two groups. The change of skeletal maturity defined as change in bone age/change in chronological age between the two groups was not significantly different (1.25 ± 0.58 for the DA-3002 group and 1.47 ± 0.45 for the comparator group, p = 0.134). Changes from baseline in serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after 52 weeks of treatment did not differ significantly between the two groups (p = 0.565 and p = 0.388, respectively) either. The occurrence of adverse events was not statistically different between groups. Conclusions This study demonstrates that the efficacy and safety of GH treatment with DA-3002 in children with TS are comparable with those of the comparator. It is expected to analysis the long-term effect of DA-3002 on the increase of final adult height in children with TS and possible late-onset complications in the future. Trial registration The study was registered at ClinicalTrials.gov. ClinicalTrials.gov identifier: NCT01813630 (19/03/2013).

Background/purposeGraves’ disease (GD) is the most common cause of thyrotoxicosis in children and adolescents. There is some debate regarding the optimal treatment and predicting factors of remission or relapse in children and adolescents with GD. In this study, we report a retrospective study of 195 children and adolescents with GD treated at a single tertiary institution in Korea.MethodsThis study included children and adolescents with GD diagnosed before 19 years of age from January of 2000 to October of 2020. The diagnosis of GD was based on clinical features, high thyroxine (FT4), suppressed thyroid-stimulating hormone, and a positive titer of thyrotropin receptor antibodies. Remission was defined as maintenance of euthyroid status for more than six months after discontinuing antithyroid drug (ATD).ResultsA total of 195 patients with GD were included in this study. The mean age at diagnosis was 12.9 ± 3.2 years, and 162 patients (83.1%) were female. Among all 195 patients, five underwent thyroidectomy and three underwent radioactive iodine therapy. The mean duration of follow-up and ATD treatment were 5.9 ± 3.8 years and 4.7 ± 3.4 years, respectively. The cumulative remission rates were 3.3%, 19.6%, 34.1%, 43.5%, and 50.6% within 1, 3, 5, 7, and 10 years of starting ATD, respectively. FT4 level at diagnosis (P = 0.001) was predicting factors for remission [HR, 0.717 (95% CI, 0.591 – 0.870), P = 0.001]. Methimazole (MMI)-related adverse events (AEs) occurred in 11.3% of patients, the most common of which were rash and hematologic abnormalities. Of a total of 26 AEs, 19 (73.1%) occurred within the first month of taking MMI.ConclusionsIn this study, the cumulative remission rate increased according to the ATD treatment duration. Long-term MMI treatment is a useful treatment option before definite treatment in children and adolescents with GD.

Background Prader-Willi syndrome (PWS) is a rare complex genetic disorder and is characterized by short stature, muscular hypotonia, abnormal body composition, psychomotor retardation, and hyperphagia. Recombinant human growth hormone (rhGH) treatment improves the symptoms in children with PWS, and early treatment results in more favorable outcomes. However, systematic studies in infants and toddlers under 2 years of age are lacking. This multicenter, randomized, active-controlled, parallel-group, open-label, Phase III study aimed to evaluate the safety of rhGH (Eutropin, LG Chem, Ltd.) and its efficacy on growth, body composition, and motor and cognitive development in infants and toddlers with PWS compared with a comparator treatment (Genotropin, Pfizer, Inc.). Eligible Korean infants or toddlers with PWS were randomly assigned to receive Eutropin or comparator (both 0.24 mg/kg/week, 6 times/week) for 1 year. Height standard deviation score (SDS), body composition, and motor and cognitive development were measured. Results Thirty-four subjects (less than 24 months old) were randomized into either the Eutropin (N = 17) group or the comparator (N = 17) group. After 52 weeks of rhGH treatment, height SDS and lean body mass increased significantly from baseline in both groups: the mean height SDS change (SD) was 0.75 (0.59) in the Eutropin group and 0.95 (0.66) in the comparator group, and the mean lean body mass change (SD) was 2377.79 (536.25) g in the Eutropin group and 2607.10 (641.36) g in the comparator group. In addition, percent body fat decreased significantly: the mean (SD) change from baseline was − 8.12% (9.86%) in the Eutropin group and − 7.48% (10.26%) in the comparator group. Motor and cognitive developments were also improved in both groups after the 1-year treatment. The incidence of adverse events was similar between the groups. Conclusions rhGH treatment for 52 weeks in infants and toddlers with PWS improved growth, body composition, and motor and cognitive development, and efficacy and safety outcomes of Eutropin were comparable to those of Genotropin. Hence, Eutropin is expected to provide safe and clinically meaningful improvements in pediatric patients with PWS. Trial registration The study was registered at ClinicalTrials.gov (identifier: NCT02204163) on July 30, 2014. URL: https://clinicaltrials.gov/ct2/show/NCT02204163?term=NCT02204163&rank=1

We aimed to present a comprehensive assessment of the ophthalmic characteristics of genetically confirmed oculodentodigital dysplasia (ODDD) in 4 members of a single Korean family across 3 generations.The characteristics of 4 affected ODDD patients were evaluated. Comprehensive ophthalmic and medical examinations were performed in 3 patients including the proband, together with genetic analysis, and retrospective chart review was conducted for an affected ancestor. For genetic analysis, targeted gene panel sequencing was conducted using genomic DNA extracted from peripheral blood.All affected individuals in this family showed shared ophthalmic abnormalities of microcornea, microphthalmia, elevated intraocular pressure, and shallow anterior chamber, all of which have been reported as typical ocular features of ODDD. Myopic refractive error despite short axial length and thick cornea were highlighted as new findings of ODDD. Facial abnormalities were common in all affected members, but their fingers were normal. Severity of glaucoma was different among the affected individuals and seemed to depend on elevation of intraocular pressure, which occurred in narrow, but open-angle. Genetic analysis revealed the presence of c.119CT (p.Ala40Val) in GJA1, which is responsible for ODDD, but not found in the control population.This report describes detailed ocular characteristics in a genetically confirmed ODDD family, including unreported findings of thick cornea and myopic refractive error despite short axial length. The ocular features derived from the A40V mutation in GJA1 showed complete penetrance, suggesting a possible role of Cx43 in regulation of IOP and pathogenesis of glaucoma.

Multiple osteochondromas (MOs) or hereditary multiple exostoses is a rare autosomal-dominant disease characterized by growths of MOs, which are benign cartilage-capped bone tumors that grow away from the growth plates. Almost 90% of MOs have a molecular explanation and 10% are unexplained. MOs are genetically heterogeneous with two causal genes on 8q24.11 (EXT1) and 11p12 (EXT2), with a higher frequency in EXT1. MO is a very rare genetic disorder, and the genotype-phenotype of MO with EXT2 mutation has not been well investigated in Korea. We present the clinical radiographic and molecular analysis of a four-generation Korean family with 11 MO-affected members (seven males and four females). The affected members from the third generation available for molecular analysis and their detailed medical histories showed moderate-to-severe phenotypes (clinical classes II-III), including bony deformities and limb misalignment with pain requiring surgical correction. The x-rays showed MOs in multiple sites. A novel EXT2 frameshift mutation (c.590delC, p.P197Qfs*73) was revealed by targeted exome sequencing in the affected members of this family. In this article, we not only expand the phenotypic-genotypic spectrum of MOs but also highlight the phenotypic heterogeneity in a family with the same mutation. In addition, we compiled the mutation spectrum of EXT2 from a literature review and identified that exon 2 of EXT2 is a mutation hot spot. Early medical attention with diagnosis of MO through careful examination of the clinical manifestations and genetic analysis can provide the opportunity to establish coordinated multispecialty management of the patient.

PurposePheochromocytoma (PCC) and paraganglioma (PGL) (PPGL) are rare neuroendocrine tumors, and data on managing these conditions in children and adolescents are lacking. The objective of this study was to demonstrate the clinical presentation and treatment outcomes in children and adolescents with PPGL in a single tertiary care center in Korea.MethodsThis retrospective study included 23 patients diagnosed with PCC (n = 14) and PGL (n = 9) before the age of 21 at Samsung Medical Center (from June 1994 to June 2019). We describe age, gender, family history, clinical characteristics, laboratory findings, pathologic findings, therapeutic approaches, and treatment outcomes.ResultsOf the 23 patients, 14 had PCC and nine had PGL. The median age at diagnosis was 16.8 years (range, 6.8–20.8 years). The common presenting symptoms were hypertension (n = 10), headache (n = 9), palpitation (n = 4), and sweating (n = 4). The plasma or 24-hour urine catecholamine and/or metabolite concentrations were markedly elevated in 22 patients with PPGL, but were normal in one patient with carotid body PGL. All tumors were visualized on computed tomography. Genetic tests were performed in 15 patients, and seven patients showed mutations in RET (n = 3), SDHB (n = 3), and VHL (n = 1). All patients underwent surgery, and complete excision was performed successfully. Three patients with metastasis underwent postoperative adjuvant therapy.ConclusionThis study suggests that pediatric PPGL tends to be extra-adrenal and bilateral and shows a higher potential for genetic mutations. Considering the hereditary predisposition of pediatric PPGL, genetic screening tests are strongly recommended, and lifelong follow-up is needed to detect recurrence and metastasis. Further research with a larger sample size and routine genetic screening is needed to better understand the genetic conditions and long-term prognosis of PPGL.

Baraitser-Winter Cerebro-fronto-facial syndrome (BWCFF, OMIM #243310, #614583) is caused by a heterozygous gain-of-function mutation of

Aarskog-Scott syndrome (AAS), also known as faciogenital dysplasia (FGD, OMIM # 305400), is an X-linked recessive inheritance, characterized by short stature, facial dysmorphism, and skeletal abnormalities. We report the clinical and molecular analysis of a family with ASS. A 31-month-old boy and his cousin were initially mistaken for having Noonan syndrome owing to short stature and facial dysmorphism. Considering the family history, we suspected the possibility of an X-linked genetic disease and performed targeted gene panel sequencing; a novel hemizygous variant c.1192-1 GA in

Coffin-Siris syndrome (OMIM #135900) is an autosomal dominant inherited disorder, characterized by dysmorphic features, congenital anomalies, and developmental delay. We report the clinical and molecular findings in a patient with Coffin-Siris syndrome. A 3-year-and-6-month-old boy presented with developmental delay, distinctive facial features, hypertrichosis, partial agenesis of the corpus callosum, fifth digit nail hypoplasia, congenital anomalies, and growth retardation. Targeted gene panel sequencing identified a novel heterozygous frameshift mutation c.2147_2148insAC in ARID1B which was predicted as a premature stop codon p. (Gln717Argfs*29). This is the second report of Coffin-Siris syndrome in Korea. Targeted gene panel sequencing can be used as an effective tool for the diagnosis of rare complex syndromes such as Coffin-Siris syndrome.

Background/Purpose: A prolactinoma is the most common pituitary adenoma, but it is relatively rare in childhood and adolescence. There is only limited research about the clinical spectrum, treatment, and outcomes of prolactinomas in childhood and adolescence. In this single-center cohort study, we assessed the clinical, hormonal, and neuroradiological characteristics and therapeutic outcomes of children and adolescents with prolactinomas. Methods: This retrospective cohort study included 25 patients with prolactinomas diagnosed before 19 years of age, who presented at Samsung Medical Center during a 15-year period (March 2005 to August 2019). Results: The median age at diagnosis was 16.9 (range 10.1–18.5) years, and 80% of the patients were female. The common clinical manifestations at diagnosis were galactorrhea (10/20, 50%) and amenorrhea (9/20, 45%) among females and visual field defects (3/5, 60%) and headaches (2/5, 40%) among males. In our cohort, macroadenomas accounted for 56% of cases, and the rate of overall responsiveness to dopamine agonists (DAs) was 56% (10/18). Male gender, the prolactin (PRL) level at diagnosis, and the presence of panhypopituitarism were positively correlated with maximum tumor diameter (r = 0.443, P = 0.026; r = 0.710, P < 0.001; and r = 0.623, P = 0.001, respectively). After the trans-sphenoidal approach (TSA), 53% (8/15) of patients showed normalization of the PRL level. Three patients, who underwent gamma knife surgery (GKS) owing to either resistance or intolerance to DAs or recurrence after the TSA, achieved a normal PRL level accompanied with marked tumor reduction and symptom remission. Conclusions: A macroprolactinoma is more prevalent than a microprolactinoma in children and adolescents than in adults. Male gender, increased PRL levels, and the presence of panhypopituitarism at diagnosis are closely related to macroprolactinomas in children and adolescents.

Rationale: Monosialotetrahexosylganglioside (GM1) gangliosidosis is a rare lysosomal storage disorder caused by the deficiency of ß-galactosidase. Because clinical symptoms of GM1 gangliosidosis overlap with other neurodevelopmental disorders, the diagnosis of this disease is not easy, specifically in late infantile GM1 gangliosidosis. This report described a case of late-infantile GM1 gangliosidosis mistaken for juvenile idiopathic arthritis. Patient concerns: A 16-year-old girl was referred to our hospital due to persistent multiple joint deformities and mental retardation, which could not be explained by juvenile idiopathic arthritis. Diagnosis: We made a diagnosis of late infantile GM1 gangliosidosis through enzyme assays and genetic testing after a skeletal survey. Interventions: The patient underwent cervical domeplasty and laminectomy for cord compression and received rehabilitation treatment. Outcomes: The patient is receiving multidisciplinary care at a tertiary center for variable skeletal disease and conditions associated with GM1 gangliosidosis. Lessons: Late infantile GM1 gangliosidosis should be considered in the differential diagnosis of progressive neurologic decline and skeletal dysostosis.

This study investigated the relationship between peak stimulated growth hormone (GH) and body mass index (BMI), as well as the impact of BMI on therapeutic response in patients with GH deficiency (GHD). A total of 460 patients were enrolled in the study. The patients were divided into four groups as per the etiology and peak GH values: idiopathic (n = 439), organic (n = 21), complete (n = 114), and partial (n = 325) GHD groups. Subsequently, they were classified as normal, overweight, or obese based on their BMI. There was no difference in BMI between complete and partial GHD. A significant negative relationship between peak GH and BMI were found. Moreover, obese GHD children had a considerably better therapeutic response in height increase and BMI decrease during 2 years of GH treatment compared to non-obese children with GHD. There was no difference between peak GH and type of GH stimulation test (GHST), except the clonidine test, which showed a much lower peak GH in obese GHD children. In conclusion, BMI had a negative impact on peak GH response, and therapeutic outcome was more favorable in the obese group. Despite no difference in GH response by type of GHST, the degree of obesity differentially affected the results.

Background/Aims: The SYNERGY (Saizen® for Your New Life and Brighter Tomorrow without Growth Deficiency) study is the first randomised multi-centre, open-label study to assess the short-term efficacy and safety of this recombinant human growth hormone (r-hGH) preparation for prepubertal children with idiopathic short stature in South Korea. Methods: The SYNERGY study (ClinicalTrials.gov NCT01746862) was conducted at 9 centres throughout South Korea between December 2012 and March 2015. The primary endpoint was difference in height velocity from baseline to 6 months in the treatment and control arms. Results: 97 children were screened; 90 were randomly assigned: 60 children to 0.067 mg/kg/day r-hGH for 12 months (treatment) and 30 children to 6 months of no treatment followed by 0.067 mg/kg/day r-hGH for 6 months (control). The 6-month mean height velocity in the treatment group increased from 5.63 cm/year (SD 1.62) to 10.08 cm/year (SD 1.92) (p < 0.0001) and from 4.94 cm/year (SD 1.91) to 5.92 cm/year (SD 2.01) (p = 0.0938) in the control group (between-group difference 3.47 cm/year, 95% CI 2.17–4.78; p < 0.0001). Adherence was > 90% throughout the study. The safety profile was consistent with that already known for r-hGH. Conclusion: Treatment with r-hGH in the SYNERGY study demonstrated a statistically significant increase in height velocity at 6 months.

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of inherited metabolic disorders with highly variable clinical presentations caused by deficient glycosylation of proteins and/or lipids. CDG-IIh is a very rare subgroup of CDG caused by mutations in the conserved oligomeric Golgi (COG) complex gene, COG8, and so far, only two cases have been reported in the medical literature. Here, we describe an 8-year-old Korean boy with psychomotor retardation, hypotonia, failure to thrive, elevated serum liver enzymes, microcephaly, and talipes equinovarus. A liver biopsy of the patient showed only interface hepatitis with mild lobular activity, and brain magnetic resonance imaging revealed cerebellar atrophy. Compared with the previous two reported cases, our patient showed relatively mild psychomotor retardation without a seizure history. The transferrin isoelectric focusing profiles in the patient showed a CDG type II pattern with increased disialo- and trisialo-transferrin. Targeted exome sequencing was performed to screen all CDG type II-related genes, and two novel frameshift mutations were found: c.171dupG (p.Leu58Alafs*29) and c.1656dupC (p.Ala553Argfs*15) in COG8. The parents were heterozygous carriers of each variant. CDG should be included in the initial differential diagnosis for children with a suspected unknown syndrome or unclassified inherited metabolic disorder or children with diverse clinical presentations, such as psychomotor retardation, hypotonia, skeletal deformity, microcephaly, cerebellar atrophy, and unexplained transient elevated liver enzyme.

The aim of this study was to evaluate the efficacy and tolerability of rosuvastatin/ezetimibe combination therapy in Korean patients with high cardiovascular risk.This was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 337 patients were screened. After a 4-week run-in period, 245 of these patients with high or moderately high risk as defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines were randomly assigned. Patients received 1 of 6 regimens for 8 weeks as follows: (1) rosuvastatin 5 mg, (2) rosuvastatin 5 mg/ezetimibe 10 mg, (3) rosuvastatin 10 mg, (4) rosuvastatin 10 mg/ezetimibe 10 mg, (5) rosuvastatin 20 mg, or (6) rosuvastatin 20 mg/ezetimibe 10 mg. The primary outcome variable was percentage change in the level of LDL-C at week 8 of drug treatment. Secondary outcome variables included percentage changes of other lipid variables and achievement rates of LDL-C targets. Tolerability analyses were also performed.The percentage change of LDL-C ranged from -45% to -56% (mean, -51%) in the monotherapy groups and from -58% to -63% (mean, -60%) in the combination therapy groups. The percentage change was greater in the pooled combination therapy group than in the counterpart (P0.001 for the pooled groups); this difference was more obvious for regimens with a lower statin dose. The percentage reductions of total cholesterol and triglycerides were greater in the combination groups than in the monotherapy groups. The LDL-C target achievement rates were 64% to 87% (mean, 73%) in the monotherapy groups and 87% to 95% (mean, 91%) in the combination groups (P = 0.01 for the pooled groups). The rates were significantly greater in patients receiving the combination therapy than in the monotherapy at lower doses of rosuvastatin. The proportions of patients with various adverse events were not significantly different between the groups.Rosuvastatin/ezetimibe combination therapy has better efficacy and target achievement rates than rosuvastatin monotherapy in patients with high cardiovascular risk.

Background Successful percutaneous coronary intervention (PCI) of the occluded infarct-related artery (IRA) in latecomers may improve long-term survival mainly by reducing left ventricular remodeling. It is not clear whether inhibition of renin–angiotensin system (RAS) brings additional better clinical outcomes in this specific population subset. Methods Between January 2008 and June 2013, 669 latecomer patients with acute ST-segment elevation myocardial infarction (STEMI) (66.2 ± 12.1 years, 71.0% males) in Korea Acute Myocardial Infarction Registry (KAMIR) who underwent a successful PCI were enrolled. The study population underwent a successful PCI for a totally occluded IRA. They were divided into two groups according to whether they were prescribed RAS inhibitors at the time of discharge: group I (RAS inhibition, n = 556), and group II (no RAS inhibition, n = 113). Results During the one-year follow-up, major adverse cardiac events (MACE), which consist of cardiac death and myocardial infarction, occurred in 71 patients (10.6%). There were significantly reduced incidences of MACE in the group I (hazard ratio = 0.34, 95% confidence interval 0.199–0.588, p = 0.001). In subgroup analyses, RAS inhibition was beneficial in patients with male gender, history of hypertension or diabetes mellitus, and even in patients with left ventricular ejection fraction (LVEF) ≥40%. In the baseline and follow-up echocardiographic data, benefit in changes of LVEF and left ventricular end-systolic volume was noted in group I. Conclusions In latecomers with STEMI, RAS inhibition improved long-term clinical outcomes after a successful PCI, even in patients with low risk who had relatively preserved LVEF.

Objective The purpose of the study was to evaluate audiologic findings according to mucopolysaccharidosis (MPS) subtypes and to estimate hearing changes as the disease progressed, as well as the therapeutic effect of enzyme replacement therapy on the hearing apparatus. Methods A total of 124 patients who were diagnosed with MPS between September 1994 and December 2016 were retrospectively analyzed. Play audiometry or pure-tone audiometry was performed for hearing assessment, and auditory brainstem response was conducted in patients with poor compliance. Results In total 124 patients were identified, ranging in age at diagnosis from 0 to 33 years. Fourteen of the patients had been diagnosed with type I, while 91 had type II, 2 had type III, 14 had type IV, and 3 had type VI. Mean bone conduction and air conduction for the better ear were 26.13±16.95 dB and 34.77 ± 20.00 dB in all patients, and 34.20±7.64 dB and 40.70±9.67 dB in patients with MPS II. The average auditory brainstem response threshold was 68.96 ±21.93 dB nHL. The most common type of hearing loss was pure sensorineural hearing loss in all subtypes, and the degree of hearing loss was variable mostly within the mild to severe range. The increase in the hearing threshold was also significantly correlated with the disease duration. However, the change in hearing level was not correlated with the duration of enzyme replacement therapy. Conclusions Hearing impairment in MPS patients is common and is aggravated as the disease progresses. Thus, adequate intervention and hearing rehabilitation might play an important role in managing hearing disabilities in MPS patients.

Oculodentodigital dysplasia (ODDD; MIM #164200), a rare genetic disorder characterized by abnormal craniofacial, dental, ocular, and digital features, is caused by mutations in the gap junction alpha-1 (

Mucolipidosis III alpha/beta (ML III alpha/beta) is an autosomal recessive lysosomal storage disorder caused by N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) deficiency. It is characterized by coarse facial features, developmental delay, short stature, and skeletal deformities. Its cardiovascular symptoms include valvular thickening or hypertrophic cardiomyopathy. A 32-year-old female patient received heart transplantation due to end-stage heart failure caused by dilated cardiomyopathy (DCM). We performed whole exome sequencing to determine the etiology of DCM and/or skeletal deformities. The test revealed c.2715+1GA and c.3173CG mutations in the

Background Mutations in Proline-rich Transmembrane Protein 2 (PRRT2) have been primarily associated with individuals presenting with infantile epilepsy, including benign familial infantile epilepsy, benign infantile epilepsy, and benign myoclonus of early infancy, and/or with dyskinetic paroxysms such as paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, and exercise-induced dyskinesia. However, the clinical manifestations of this disorder vary widely. PRRT2 encodes a protein expressed in the central nervous system that is mainly localized in the pre-synaptic neurons and is involved in the modulation of synaptic neurotransmitter release. The anomalous function of this gene has been proposed to cause dysregulation of neuronal excitability and cerebral disorders. Case presentation We hereby report on a young child followed-up for three years who presents with a spectrum of clinical manifestations such as congenital microcephaly, dysmorphic features, severe intellectual disability, and drug-resistant epileptic encephalopathy in association with a synonymous variant in PRRT2 gene (c.501C > T; p.Thr167Ile) of unknown clinical significance variant (VUS) revealed by diagnostic exome sequencing. Conclusion Several hypotheses have been advanced on the specific role that PRRT2 gene mutations play to cause the clinical features of affected patients. To our knowledge, the severe phenotype seen in this case has never been reported in association with any clinically actionable variant, as the missense substitution detected in PRRT2 gene. Intriguingly, the same mutation was reported in the healthy father: the action of modifying factors in the affected child may be hypothesized. The report of similar observations could extend the spectrum of clinical manifestations linked to this mutation.

Mucolipidoses II and III (ML II and ML III) are lysosomal disorders in which the mannose 6-phosphate recognition marker is absent from lysosomal hydrolases and other glycoproteins due to mutations in GNPTAB, which encodes two of three subunits of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase. Both disorders are caused by the same gene, but ML II represents the more severe phenotype. Bone manifestations of ML II include hip dysplasia, scoliosis, rickets and osteogenesis imperfecta. In this study, we sought to determine whether a recombinant adeno-associated viral vector (AAV2/8-GNPTAB) could confer high and prolonged gene expression of GNPTAB and thereby influence the pathology in the cartilage and bone tissue of a GNPTAB knock out (KO) mouse model. The results demonstrated significant increases in bone mineral density and content in AAV2/8-GNPTAB-treated as compared to non-treated KO mice. We also showed that IL-6 (interleukin-6) expression in articular cartilage was reduced in AAV2/8-GNPTAB treated ML II mice. Together, these data suggest that AAV-mediated expression of GNPTAB in ML II mice can attenuate bone loss via inhibition of IL-6 production. This study emphasizes the value of the MLII KO mouse to recapitulate the clinical manifestations of the disease and highlights its amenability to therapy.

This study evaluated the efficacy of a stepwise regimen of estradiol valerate for height control in girls with Marfan syndrome. Eight girls with Marfan syndrome who had completed estrogen treatment for height control were included. Estradiol valerate was started at a dose of 2 mg/day, and then was increased. The projected final height was estimated using the initial height percentile (on a disease-specific growth curve for Korean Marfan syndrome [gcPFHt]), and the initial bone age (baPFHt). After the estrogen treatment, the projected final height was compared to the actual final height (FHt). The median baseline chronological and bone age were 10.0 and 10.5 years, respectively. After a median of 36.5 months of treatment, the median FHt (172.6 cm) was shorter than the median gcPFHt (181.0 cm) and baPFHt (175.9 cm). In the six patients who started treatment before the age of 11 years, the median FHt (171.8 cm) was shorter than the median gcPFHt (181.5 cm) and baPFHt (177.4 cm) after treatment. The median differences between the FHt and gcPFHt and baPFHt were 9.2 and 8.3 cm, respectively. In two patients started treatment after the age of 11, the differences between FHt and gcPFHt, and baPFHt after treatment were -4 and 1.4 cm, and -1.2 and 0 cm for each case, respectively. A stepwise increasing regimen of estradiol valerate may be an effective treatment for height control in girls with Marfan syndrome, especially when started under 11 years old., Graphical Abstract

Renpenning syndrome is a rare X-linked disorder characterized by mental retardation, leanness, microcephaly, facial dysmorphism, short stature, and small testes. This disease is caused by

Background Mucopolysaccharidosis I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a lack of the lysosomal enzyme α-L-iduronidase (IDUA). To date, more than 200 IDUA mutations have been reported. However, only a few types of mutations are recurrent and the frequencies of mutations differ from country to country. Methods We performed the IDUA mutation analysis in seven patients who were biochemically diagnosed with MPS I in the Department of Pediatrics, Samsung Medical Center, from 2009 to 2014. Here, we describe the results of the IDUA mutation analysis in seven patients with MPS I and the IDUA mutational spectrum in Korean patients with MPS I, including previous data. Results The IDUA mutations were found in all 14 alleles of 7 patients, and 11 kinds of IDUA mutations were identified. The detected mutations were five missense mutations (p.A79V, p.L346R, p.T388K, p.P496R, and p.C577Y), two nonsense mutations (p.Y618* and p.R628*), two deletions (c.683delC and c.1591delC), one splice site mutation (c.972+1G>A), and one duplication (c.613_617dup). Among these, p.T388K, p.C577Y, c.683delC, c.1591delC, and c.972+1G>A were novel mutations that have not previously been reported. After taking everything into consideration, including IDUA mutation analysis of the previously reported 10 unrelated Korean patients with MPS I, p.L346R and c.704ins5 were most commonly found in Korean patients with MPS I. However, p.W402* and p.Q70*, which have mainly been found in Caucasian patients, were not found. Conclusion As a result, p.L346R and c.704ins5, which were the most common in Korea, which is geographically situated midway between China and Japan, were some of the most common mutations in China and Japan, respectively. These results are especially worthy of notice. Electronic supplementary material The online version of this article (doi:10.1186/s12881-016-0319-x) contains supplementary material, which is available to authorized users.

Background/Aims: To determine the optimal dose of LB03002, a sustained-release, once-weekly formulation of recombinant human growth hormone (rhGH), and to compare its efficacy and safety with daily rhGH in children with idiopathic short stature (ISS). Methods: This multicenter, randomized, open-label, phase II study included GH-naïve, prepubertal children with ISS, randomized to receive daily rhGH 0.37 mg/kg/week (control, n = 16), LB03002 0.5 mg/kg/week (n = 14), or LB03002 0.7 mg/kg/week (n = 16). The primary endpoint was height velocity (HV) change at week 26. Results: At week 26, the least square (LS) means for HV change (cm/year) with control, LB03002 0.5 mg/kg/week, and LB03002 0.7 mg/kg/week were 5.08, 3.65, and 4.38, and the LS means for the change in height standard deviation score were 0.65, 0.49, and 0.58, respectively. The lower bound of the 90% confidence interval for the difference between LB03002 0.7 mg/kg/week and the control in the LS mean for HV change (–1.72) satisfied the noninferiority margin (–1.75). Adverse events were generally mild and short-lived. Conclusion: A once-weekly regimen of LB03002 0.7 mg/kg demonstrated noninferiority to the daily regimen of rhGH 0.37 mg/kg/week in terms of HV increments. LB03002 was well tolerated and its safety profile was comparable with that of daily rhGH.

The current recombinant human growth hormone (rhGH) therapy requires daily subcutaneous (sc) injections, which results in poor patient compliance, especially in young children. To reduce the dosing frequency, we generated a chimeric protein of rhGH and the Fc-domain of immunoglobulin G (IgG) (rhGH-Fc). The pharmacokinetics and pharmacodynamics of sc-injected rhGH-Fc were assessed in male Sprague-Dawley rats and hypophysectomized rats, respectively. A single sc injection of rhGH-Fc at a dose of 0.2 mg/kg slowly reached a Cmax of 16.80 ng/mL and remained for 7 days with a half-life of 51.1 h. Conversely, a single sc injection of rhGH 0.2 mg/kg rapidly reached a Cmax of 46.88 ng/mL and declined with a half-life of 0.55 h to baseline values in 4 h. In the efficacy study, the sc-injected rhGH-Fc induced rapid weight gain and tibial width growth at a dose of 240 μg/animal. The effect of two injections of rhGH-Fc separated by 1 week was comparable to that of the same dose of 14 daily injections of rhGH. The rhGH-Fc is a novel candidate for long-acting rhGH therapy with more convenient weekly administration, as it reduces glomerular filtration and receptor-mediated clearance while allowing for the rapid reversal of potential adverse events.

CYP21A2 mutation analysis of congenital adrenal hyperplasia (CAH) is challenging because of the genomic presence of a homologous CYP21A2 pseudogene and the significant incidence of pseudogene conversion and large deletions. The objective of this study was to accurately analyze the CYP21A2 genotype in Korean CAH patients using a combination of complementary methods. Long-range PCR and restriction fragment length polymorphism analyses were performed to confirm valid amplification of CYP21A2 and to detect large gene conversions and deletions before direct sequencing. Multiple ligation-dependent probe amplification (MLPA) analysis was conducted concurrently in 14 CAH-suspected patients and six family members of three patients. We identified 27 CYP21A2 mutant alleles in 14 CAH-suspected patients. The c.293-13A>G (or c.293-13C>G) was the most common mutation, and p.Ile173Asn was the second, identified in 25% and 17.9% of alleles, respectively. A novel frame-shift mutation of c.492delA (p.Glu 164Aspfs*24) was detected. Large deletions were detected by MLPA in 10.7% of the alleles. Mutation studies of the six familial members for three of the patients aided in the identification of haplotypes. In summary, we successfully identified CYP21A2 mutations using both long-range PCR and sequencing and dosage analyses. Our data correspond relatively well with the previously reported mutation spectrum analysis.

Patients with Marfan syndrome (MFS) presents with primary skeletal manifestations such as tall stature, chest wall abnormality, and scoliosis. These primary skeletal manifestations affect the growth pattern in MFS. Therefore, it is not appropriate to use normal growth charts to evaluate the growth status of MFS. We aimed to develop disease-specific growth charts for Korean MFS patients and to use these growth charts for understanding the growth patterns in MFS and managing of patients with MFS. Anthropometric data were available from 187 males and 152 females with MFS through a retrospective review of medical records. Disease-specific growth charts were generated and 3, 25, 50, 75, and 97 percentiles were calculated using the LMS (refers to λ, μ, and σ, respectively) smoothing procedure for height and weight. Comparisons between MFS patients and the general population were performed using a one-sample t-test. With regard to the height, the 50th percentile of MFS is above the normative 97th percentile in both genders. With regard to the weight, the 50 percentile of MFS is above the normative 75th percentile in male and between the normative 50th percentile and the 75th percentile in female. The disease-specific growth charts for Korean patients with MFS can be useful for monitoring growth patterns, planning the timing of growth-reductive therapy, predicting adult height and recording responses to growth-reductive therapy.

Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome) is caused by deficient activity of the enzyme, N-acetylgalactosamine-4-sulfatase, resulting in impaired degradation of the glycosaminoglycan dermatan sulfate. Patients experience a range of manifestations including joint contractures, short stature, dysostosis multiplex, coarse facial features, decreased pulmonary function, cardiac abnormalities, corneal clouding and shortened life span. Recently, clinicians from institutions in the Asia-Pacific region met to discuss the occurrence and implications of delayed diagnosis and misdiagnosis of MPS VI in the patients they have managed. Eighteen patients (44% female) were diagnosed. The most common sign presented by the patients was bone deformities in 11 patients (65%). Delays to diagnosis occurred due to the lack of or distance to diagnostic facilities for four patients (31%), alternative diagnoses for two patients (15%), and misleading symptoms experienced by two patients (15%). Several patients experienced manifestations that were subtler than would be expected and were subsequently overlooked. Several cases highlighted the unique challenges associated with diagnosing MPS VI from the perspective of different specialties and provide insights into how these patients initially present, which may help to elucidate strategies to improve the diagnosis of MPS VI.

Schmid-type metaphyseal chondrodysplasia (MCDS) is characterized by short stature with short legs, bowing of the long bones, coxa vara, and waddling gait. MCDS is a relatively common form of MCD. Most mutations that cause MCDS occur within the carboxyl-terminal non-collagenous domain (NC1) of the COL10A1 gene. We performed mutational analysis of the COL10A1 genes in 4 unrelated Korean patients with diagnosed MCDS. Mutational analysis of COL10A1 identified c.1904_1915delinsT (p.Gln635LeufsX10) and c.1969dupG (p.Ala657GlyfsX10), 2 novel frameshift mutations, and c.2030T>A (p.Val677Glu) and c.862G>C (p.Gly288Arg) at unusual mutational sites, which could be pathogenic. We present the first report of the molecular characteristics of MCDS in 4 Korean patients. Our findings suggest that a novel sequence variation involving an unusual mutational site of the COL10A1 gene can cause mild MCDS.

Idursulfase beta (Hunterase®) has been used for enzyme replacement therapy (ERT) of patients with mucopolysaccharidosis II (MPS II, Hunter syndrome) aged 6 years or older since 2012 in Korea. The objective of this study was to evaluate the safety and efficacy of ERT with idursulfase beta in Hunter syndrome children younger than 6 years. This study was a 52-week, single center, single arm, open-label clinical trial (NCT01645189). Idursulfase beta (0.5mg/kg/week) was administered intravenously for 52 weeks. The primary endpoint was safety assessed by adverse events (AEs). Secondary endpoints included vital signs, physical examination, ECG, laboratory tests, anti-idursulfase antibodies, and efficacy represented by changes in urinary glycosaminoglycan (GAG) at week 53 from baseline. In addition, growth indices and developmental milestones (Denver II test) were evaluated as exploratory variables. All six patients experienced at least one AE. A total of 109 AEs were reported. One patient experienced a serious AE (hospitalization due to gastroenteritis) that was considered not to be treatment related. One patient (16.7%) experienced infusion-related adverse drug reactions (ADRs), developing urticaria six times and a cough five times. There were no serious ADRs and no clinically significant changes in vital signs, physical exam, laboratory parameters, or ECG. Of the six patients, four (66.7%) showed anti-idursulfase antibodies and neutralizing antibodies on at least one occasion during the study. At week 53, urinary GAG was significantly reduced by -35.1±30.6mgGAG/g creatine from baseline (P=0.038). This study indicates that the safety and efficacy of idursulfase beta are similar to those reported in Hunter syndrome patients aged 6 years or older.

Long-term outcomes are imperative to confirm safety of drug-eluting stents. There have been 2 randomized controlled trials comparing everolimus-eluting stents (EESs) and Resolute zotarolimus-eluting stents (ZES-Rs). To date, long-term clinical outcomes of these stents were limited to only 1 report, which has recently reported 4-year comparisons of these stents. Therefore, more evidence is needed regarding long-term clinical outcomes of the second-generation stents. This study compared the long-term clinical outcomes of EES with ZES-R in "all-comer" cohorts up to 3-year follow-up. The EXCELLENT and RESOLUTE-Korea registries prospectively enrolled 3,056 patients treated with EES and 1,998 with ZES-R, respectively, without exclusions. Stent-related composite outcomes (target lesion failure) and patient-related composite events up to 3-year follow-up were compared in crude and propensity score-matched analyses. Of 5,054 patients, 3,830 patients (75.8%) had off-label indication (2,217 treated with EES and 1,613 treated with ZES-R). The stent-related outcome (189 [6.2%] vs 127 [6.4%], p = 0.812) and the patient-related outcome (420 [13.7%] vs 250 [12.5%], p = 0.581) did not differ between EES and ZES-R, respectively, at 3 years, which was corroborated by similar results from the propensity score-matched cohort (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.70 to 1.20, p = 0.523 and 0.85, 95% CI 0.70 to 1.02, p = 0.081, for stent- and patient-related outcomes, respectively). The rate of definite or probable stent thrombosis up to 3 years (22 [0.7%] vs 10 [0.5%], p = 0.370) was also similar. The rate of very late definite or probable stent thrombosis was very low and comparable between the 2 stents (3 [0.1%] vs 1 [0.1%], p = 0.657). In multivariate analysis, chronic renal failure (adjusted HR 3.615, 95% CI 2.440 to 5.354, p 0.001) and off-label indication (adjusted HR 1.782, 95% CI 1.169 to 2.718, p = 0.007) were the strongest predictors of target lesion failure at 3 years. In conclusion, both stents showed comparable safety and efficacy at 3-year follow-up in this robust real-world registry with unrestricted use of EES and ZES-R. Overall incidences of target lesion failure and definite stent thrombosis, including very late stent thrombosis, were low, even in the patients with off-label indications, suggesting excellent long-term safety and sustained efficacy of both types of second-generation drug-eluting stents.

Background Hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome, also known as Barakat syndrome, is a rare genetic disorder with high phenotypic heterogeneity caused by haploinsufficiency of the GATA3 gene on chromosome 10p14-p15. For these reasons, the diagnosis of HDR syndrome is challenging and requires a high index of suspicion as well as genetic analysis. Case presentation A 14-month-old boy, with sensorineural hearing loss in both ears, showed typical radiological features of X-linked stapes gusher on preoperative temporal bone computed tomography (CT) for cochlear implantations. Then after his discharge from hospital, he suffered a hypocalcemic seizure and we discovered a renal cyst during investigation of hypocalcemia. He was finally diagnosed with HDR syndrome by clinical findings, which were confirmed by molecular genetic testing. Direct sequencing of the GATA3 gene showed a heterozygous 2-bp deletion (c.1201_1202delAT), which is predicted to cause a frameshift of the reading frame (p.Met401Valfs*106). Conclusions To our knowledge, this is the first case of HDR syndrome with a novel de novo variant mimicking a congenital X-linked stapes gusher syndrome. Novel mutations and the diversity of clinical manifestations expand the genotypic and phenotypic spectrum of HDR syndrome. Diagnosis of HDR syndrome is still challenging, but clinicians should consider it in their differential diagnosis for children with a wide range of clinical manifestations including hypocalcemia induced seizures and deafness. We hope that this case will contribute to further understanding and studies of HDR-associated GATA3 mutations. Electronic supplementary material The online version of this article (10.1186/s12881-017-0484-6) contains supplementary material, which is available to authorized users.

Background Prader–Willi syndrome (PWS) is often related to severe obesity and type-2 diabetes mellitus (T2DM). However, few studies, and none in Korea, have examined prevalence of T2DM and other variables in PWS. The aim of this study was to identify the prevalence and associated risk factors for T2DM in Korean patients with PWS. Methods We performed a retrospective cohort study of the 84 PWS patients aged 10 or over (10.3–35.8 years of age) diagnosed with PWS at Samsung Medical Center from 1994 to 2016. We estimated occurrence of T2DM according to age (10–18 years versus >18 years), body mass index (BMI), genotype, history of growth hormone therapy, homeostasis model of assessment-insulin resistance (HOMA-IR), and the presence of dyslipidemia, hypogonadism, or central precocious puberty. Additionally, we investigated cutoff values of risk factors for development of T2DM. Results Twenty-nine of a total 211 patients, diagnosed with PWS over the study period, were diagnosed as having T2DM (13.7%, mean age 15.9 ± 3.6 years). In the >18 years group, obesity, HOMA-IR, and presence of dyslipidemia, hypogonadism, or central precocious puberty were associated with the occurrence of T2DM in univariate analysis. In multivariate logistic regression analysis, only obesity (p = 0.001) and HOMA-IR (p 2.7 and >28.49 kg/m2, respectively. Of the 29 patients, seven had ≥1 microvascular complication, with non-proliferative diabetic retinopathy in 6 of 7 cases. Advanced age and HOMA-IR were positively correlated with diabetic microvascular complications (p

Objective Mucopolysaccharidosis IVA (MPS IVA, or Morquio A syndrome) and VI (MPS VI, or Maroteaux–Lamy syndrome) are autosomal recessive lysosomal storage disorders. Skeletal abnormalities are common initial presenting symptoms and, when recognized early, may facilitate timely diagnosis and intervention, leading to improved patient outcomes. Patients with slowly progressing disease and nonclassic phenotypes can be particularly challenging to diagnose. The objective was to describe the radiographic features of patients with a delayed diagnosis of MPS IVA or VI. Materials and Methods This was a retrospective study. The records of 5 MPS IVA and 3 MPS VI patients with delayed diagnosis were reviewed. Radiographs were evaluated by a radiologist with special expertise in skeletal dysplasias. Results An important common theme in these cases was the appearance of multiple epiphyseal dysplasia (MED) with epiphyseal changes seemingly confined to the capital (proximal) femoral epiphyses. Very few patients had the skeletal features of classical dysostosis multiplex. Conclusions Radiologists should appreciate the wide phenotypic variability of MPS IVA and VI. The cases presented here illustrate the importance of considering MPS in the differential diagnosis of certain skeletal dysplasias/disorders, including MED, some forms of spondylo-epiphyseal dysplasia (SED), and bilateral Perthes-like disease. It is important to combine radiographic findings with clinical information to facilitate early testing and accurate diagnosis.

The natural progression of the severe form of mucopolysaccharidosis II in children is a rapid decline of neurodevelopmental function with hydrocephalus. Recombinant human iduronate-2-sulfatase enzyme replacement therapy (ERT) under a standard regimen seems to have limited effect. Therefore, we determined whether early, high-dose ERT attenuated ventriculomegaly and histologic abnormalities in the brains of IdS-knockout mice. IdS-knockout mice received saline or recombinant human IdS (0.5/1.0/2.0 mg kg(-1)) intravenously once weekly, starting at 4 weeks of age and continuing until 20 weeks. ERT with 2.0 mg kg(-1), but not 0.5 or 1.0 mg kg(-1), significantly attenuated enlarged ventricles, as confirmed by in vivo 7-teslar brain magnetic resonance image (MRI) at 20 weeks. However, neuronal cytoplasmic vacuolization and morphological alteration in the purkinje cells on brain histology and glycosaminoglycan (GAG) levels in brain homogenates were reduced in mice receiving ERT at lower dose than 2.0 mg kg(-1). Additionally, GAG levels significantly correlated with the percent volume ratio of ventricle to whole brain. These results suggested that high-dose systemic ERT started early in life could be a promising therapeutic modality for improving neurologic dysfunction including ventriculomegaly in children with severe Hunter syndrome.

Osteogenesis imperfecta (OI) type V is a specific OI phenotype with interosseous membrane calcification of the forearm and hyperplastic callus formation as typical features. The causative gene mutation for OI type V has been recently discovered. The purpose of this report is to review the clinical and radiographic characteristics of mutation confirmed OI type V in detail. Sixteen (nine familial and seven sporadic) patients were enrolled in the study. Blue sclera and dentinogenesis imperfecta were not evident in any patient. However, hypodontia in the permanent teeth, ectopic eruption, and short roots in molars were additionally observed in 11 patients. Of the radiographic abnormalities, cortical thickening and bony excrescence of interosseous margin of the ulna was the most common finding, followed by overgrowth of the olecranon and/or coronoid process of the ulna. Slender ribs and sloping of the posterior ribs with or without fractures were also a consistent finding. Hyperplastic callus was detected in 75% of patients and was commonly encountered at the femur. Heterotopic ossification in the muscles and tendon insertion sites were noted in four patients, which resulted in bony ankylosis or contracture of joints. The current study confirms common clinical and radiographic findings of OI type V and reports additional phenotypic information. These observations provide clues to recognize OI type V more promptly and guide to direct targeted molecular study. © 2013 Wiley Periodicals, Inc.

Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disorder (LSD) caused by abnormalities of the enzyme α-N-acetylglucosaminidase (NAGLU) that is required for degradation of heparan sulfate. The patient in this study was a 4-yr-old boy. He presented with normal height and weight, pectus carinatum, and multiple persistent Mongolian spots on his back. He had mild dysmorphic features with prominent speech developmental delays and, to a lesser extent, motor developmental delays. The cetylpyridinium chloride precipitation test revealed excessive mucopolysacchariduria (657.2 mg glycosaminoglycan/g creatinine; reference range, C (p.L67P) and c.1444C>T (p.R482W). The c.200T>C mutation was a novel finding. This is the first report of a Korean patient with MPS IIIB who was confirmed by molecular genetic analyses and biochemical investigation.

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome (OMIM 309900), is a rare, X-linked lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS; EC 3.1.6.13), which is involved in the lysosomal degradation of glycosaminoglycans (GAG). Although intermittent intrathecal (IT) injection of the enzyme has been introduced as a method to overcome the blood-brain barrier, continuous IT infusion of the enzyme would be more physiologic. This study was performed to investigate responses in the brain of MPS II mice to varying doses of continuous IT infusion of recombinant human IDS (rh-IDS) in MPS II mice by osmotic pump in three different doses (2.4, 4.8, and 12 µg/day) of rh-IDS for 3 weeks. The results showed that the group treated with 12 µg/day doses of rh-IDS demonstrated decreased GAG concentrations compared to the untreated KO mice group (P = 0.003). After 3 weeks of continuous IT ERT, the brain tissues of the high-dose IT-treated KO mice showed a reduction of vacuolation in the cerebral cortex, thalamus and cerebellar cortex, which was not observed in the low- and medium-dose KO mice groups. Moreover, the anti-NeuN signal representing intact neuron was restored in the cortexes of the high-dose group. In conclusion, continuous IT infusion of the deficient enzyme was effective in improving CNS defects in the MPS II mice, and could be a valuable therapeutic method for treating neurological deterioration in patients with MPS II.

Mucopolysaccharidosis IVA (MPS IVA; OMIM #253000) is caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), a lysosomal enzyme involved in the catabolism of keratan and chondroitin sulfate. In this study, we examined biochemical and genetic data from 6 Korean patients presenting with classic MPS IVA by measuring GALNS activity in peripheral blood leukocytes and skin fibroblasts. We initially identified Korean patients with MPS IVA by clinical, biochemical, and genetic analyses. We performed PCR-direct sequencing to identify molecular defects of the GALNS gene in patients and assessed the mutational statuses of family members as well as 50 healthy unrelated subjects. In silico analyses were performed to check for novel mutations. The mean age of the six female patients was 8.0 ± 5.2 years (range: 2-17 years), and were all found to have severe reductions of GALNS enzyme. A total of 12 mutant alleles were identified, corresponding to 7 different mutations. Five novel mutations were c.218A>G (p.Y73C), c.451C>A (p.P151T), c.725C>G (p.S242C), c.752G>A (p.R251Q), and c.1000C>T (p.Q334X). Two other mutations were c.1156C>T (p.R386C) and c.1243-1G>A. Two mutations, c.451C>A and c.1000C>T, accounted for 58% of all mutations in this sample.

Objectives Citrullinemia type I is a rare metabolic disorder and the distribution of mutations in the ASS1 gene varies among ethnic groups. We aimed to determine the molecular characteristics of citrullinemia type I in Korean patients. Design and methods Biochemical and clinical findings were investigated and mutations in the ASS1 gene were identified using direct sequencing method in five patients with high citrulline levels. We also reviewed previous genotypes reported for Korean patients with citrullinemia type I. Results We identified five mutations in 10 mutant alleles from the five patients. The most common mutation was the Gly324Ser mutation, which was present in 40% of the mutant alleles, followed by the c.421-2A > G mutation (30% of the mutant alleles). The other mutations (c.1128-6_1188dup67, Arg127Gln, and Arg279Gln) were identified in one mutant allele each. A comprehensive review of previous Korean reports revealed that Gly324Ser, c.421-2A > G, and c.1128-6_1188dup67 mutations accounted for 80.8% of the total mutations reported to date. In terms of genotype–phenotype correlations, a patient homozygous for the c.421-2A > G mutation had fatal clinical manifestations and two patients who were compound heterozygous for the Gly324Ser and c.1128-6_1188dup67 mutations presented with a mild clinical course. Conclusion We provided important information about the mutational spectrum of ASS1 gene in Korean patients with citrullinemia type I and demonstrated a difference in common mutations in the ASS1 gene according to ethnic and geographic backgrounds.

Mucopolysaccharidosis (MPS) III has 4 enzymatically distinct forms (A, B, C, and D), and MPS IIIC, also known as Sanfilippo C syndrome, is an autosomal recessive lysosomal storage disease caused by a deficiency of heparan acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT). Here, we report a case of MPS IIIC that was confirmed by molecular genetic analysis. The patient was a 2-yr-old girl presenting with skeletal deformity, hepatomegaly, and delayed motor development. Urinary excretion of glycosaminoglycan (GAG) was markedly elevated (984.4 mg GAG/g creatinine) compared with the age-specific reference range (A (IVS2+1G>A) and c.1150C>T (p.Arg384*). To the best of our knowledge, this is the first case of MPS IIIC to be confirmed by clinical, biochemical, and molecular genetic findings in Korea.

Background McCune–Albright syndrome (MAS) is a rare disease defined by the triad of fibrous dysplasia (FD), café au lait spots, and peripheral precocious puberty (PP). Because of the rarity of this disease, only a few individuals with MAS have been reported in Korea. We describe the various clinical and endocrine manifestations and genetic analysis of 14 patients with MAS in Korea. Methods Patients’ clinical data—including peripheral PP, FD, and other endocrine problems—were reviewed retrospectively. In addition, treatment experiences of letrozole in five patients with peripheral PP were described. Mutant enrichment with 3′-modified oligonucleotides - polymerase chain reaction (MEMO-PCR) was performed on eight patients to detect mutation in GNAS using blood. MEMO-PCR is a simple and practical method that enables the nondestructive selection and enrichment of minor mutant alleles in blood. Results The median age at diagnosis was 5 years 2 months (range: 18 months to 16 years). Eleven patients were female, and three were male. Thirteen patients showed FD. All female patients showed peripheral PP at onset, and three patients subsequently developed central PP. There was a significant decrease in estradiol levels after two years of letrozole treatment. However, bone age was advanced in four patients. Two patients had clinical hyperthyroidism, and two patients had growth hormone (GH) excess with pituitary microadenoma. c.602G > A (p.Arg201His) in GNAS was detected in two patients in blood, and c.601C > T (p.Arg201Cys) in GNAS was detected in one patient in pituitary adenoma. Conclusions This study described the various clinical manifestations of 14 patients with MAS in a single center in Korea. This study first applied MEMO-PCR on MAS patients to detect GNAS mutation. Because a broad spectrum of endocrine manifestations could be found in MAS, multiple endocrinopathies should be monitored in MAS patients. Better treatment options for peripheral PP with MAS are needed.