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Background The prevalence of monogenic diabetes is estimated to be 1.1–6.3% of patients with diabetes mellitus (DM) in Europe. The overlapping clinical features of various forms of diabetes make differential diagnosis challenging. Therefore, this study investigated the etiologic distribution and clinical characteristics of pediatric diabetes, including monogenic diabetes, who presented at a single tertiary center over the last 20 years. Methods This study included 276 consecutive patients with DM diagnosed before 18 years of age from January 2000 to December 2019 in Korea. Clinical features, biochemical findings, β-cell autoantibodies, and molecular characteristics were reviewed retrospectively. Results Of the 276 patients, 206 patients (74.6%), 49 patients (17.8%), and 21 patients (7.6%) were diagnosed with type 1 DM, type 2 DM, and clinically suspected monogenic diabetes, respectively. Among 21 patients suspected to have monogenic diabetes, 8 patients had clinical maturity-onset diabetes of the young (MODY), and the remaining 13 patients had other types of monogenic diabetes. Among them, genetic etiologies were identified in 14 patients (5.1%) from 13 families, which included MODY 5, transient neonatal DM, developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, Wolfram syndrome, Donohue syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, Fanconi-Bickel syndrome, Wolcott-Rallison syndrome, cystic fibrosis-related diabetes, and maternally inherited diabetes and deafness. Conclusions Genetically confirmed monogenic diabetes accounted for 5.1% of patients evaluated at a single tertiary center over 20-year period. Based on the findings for our sample, the frequency of mutations in the major genes of MODY appears to be low among pediatric patients in Korea. It is critical to identify the genetic cause of DM to provide appropriate therapeutic options and genetic counseling.

Background Neurofibromatosis type 1 (NF1) is a common human genetic disease with age-dependent phenotype progression. The overview of clinical and radiological findings evaluated by whole-body magnetic resonance imaging (WBMRI) in NF1 patients Methods This study included 70 clinically or genetically diagnosed NF1 patients who received WBMRI before 3 years old. Clinical, genetic, and radiologic features were collected by retrospective chart review. In NF1+, widely spread diffuse cutaneous neurofibromas, developmental delay, autism, seizure, cardiac abnormalities, hearing defect, optic pathway glioma, severe plexiform neurofibromas (> 3 cm in diameter, disfigurement, accompanying pain, bony destruction, or located para-aortic area), brain tumors, nerve root tumors, malignant peripheral nerve sheath tumors, moyamoya disease, and bony dysplasia were included. Results The age at WBMRI was 1.6 ± 0.7 years old, and NF1 mutations were found in 66 patients (94.3%). Focal areas of signal intensity (FASI) were the most common WBMRI finding (66.1%), followed by optic pathway glioma (15.7%), spine dural ectasia (12.9%), and plexiform neurofibromas (10.0%). Plexiform neurofibromas and NF1+ were more prevalent in familial case (28.7% vs 5.7%, p = 0.030; 71.4% vs 30.2%, p = 0.011). Follow-up WBMRI was conducted in 42 patients (23 girls and 19 boys) after 1.21 ± 0.50 years. FASI and radiologic progression were more frequent in patients with mutations involving GTPase activating protein-related domain (77.8% vs 52.4%, p = 0.047; 46.2% vs 7.7%, p = 0.029). Conclusions WBMRI provides important information for the clinical care for young pediatric NF1 patients. As NF1 progresses in even these young patients, and is related to family history and the affected NF1 domains, serial evaluation with WBMRI should be assessed based on the clinical and genetic features for the patients’ best care.

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).

BackgroundAmbroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with high-dose ABX and enzyme replacement therapy (ERT) in nGD.MethodsABX+ERT therapy was administered for 4.5 years in four patients with nGD. ABX was initiated at a dose of 1.5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The target plasma level was 10 µmol/L or less. The changes in glucocerebrosidase activity, biochemical, safety and neurocognitive findings were assessed.ResultsEnhanced residual GCcase activity was observed in all patients, as evidenced in both in vitro and in vivo studies. During the first 2 years of study with ABX (up to 21 mg/kg/day), mean seizure frequencies and neurocognitive function worsened. After ABX dosage was increased up to 27 mg/kg/day of ABX, its trough plasma concentration was 3.2–8.8 µmol/L. Drug-to-drug interaction, especially with antiepileptic drug significantly affected the pharmacokinetic parameters of ABX. Importantly, at 27 mg/kg/day of ABX, the seizure frequencies markedly decreased from the baseline, and the neurocognitive function was improved. In addition, Lyso-Gb1, a biomarker for the severity and progression of GD, was normalised in all patients. High-dose ABX was well-tolerated with no severe adverse events.ConclusionsLong-term treatment with high-dose ABX+ERT was safe and might help to arrest the progression of the neurological manifestations in GD.

Whole exome sequencing (WES) is an effective tool for the genetic diagnosis of mitochondrial disorders due to various nuclear genetic defects. In this study, three patients affected by extremely rare mitochondrial disorders caused by nuclear genetic defects are described. The medical records of each patient were reviewed to obtain clinical symptoms, results of biochemical and imaging studies, and muscle biopsies. WES and massive parallel sequencing of whole mtDNA were performed for each patient. The oxygen consumption rate (OCR) and complex activity I and IV was measured. Patients 1 and 2 had exhibited global developmental delay and seizure since early infancy. Blood lactate, the lactate-to-pyruvate ratio, and urinary excretion of Krebs cycle intermediates were markedly elevated. Patient 1 also was noted for ophthalmoplegia. Patient 2 had left ventricular hypertrophy and ataxia. Patient 3 developed dysarthria, gait disturbance, and right-side weakness at age 29. Brain magnetic resonance imaging demonstrated abnormal signal intensity involving the bilateral thalami, midbrain, or pons. Based on WES, patient 1 had p.Glu415Gly and p.Arg484Trp variants in MTO1. In patient 2, p.Gln111ThrfsTer5 and RNA mis-splicing were identified in TSFM. Patient 3 carried p.Met151Thr and p.Met246Lys variants in AARS2. Skin fibroblasts of three patients exhibited decreased OCRs and complex 1 activity, and mitochondrial DNA was normal. These results demonstrate the utility of WES for identifying the genetic cause of extremely rare mitochondrial disorders, which has implications for genetic counseling.

Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder caused by mutations in the HPRT1 gene. The clinical features and mutation spectrum of 26 Korean LNS patients from 23 unrelated families were retrospectively reviewed. The HPRT1 gene was analyzed by direct sequencing of genomic DNA. The median age at diagnosis was 2.3 years (range, 4 months-22.6 years) and the initial presenting features included developmental delay, orange colored urine, and self-injurious behaviors. Most patients were wheelchair-bound and suffered from urinary complications and neurologic problems such as self-mutilation and developmental delay. Twenty different mutations in HPRT1 were identified among 23 independent pedigrees, including six novel mutations. The most common mutation type was truncating mutations including nonsense and frameshift mutations (45%). Large deletions in the HPRT1 gene were identified in exon 1, exons 5-6, exons 1-9, and at chr X:134,459,540-134,467,241 (7702 bp) including the 5'-untranslated region, exon 1, and a portion of intron 1. In conclusion, this study describes the phenotypic spectrum of LNS and has identified 20 mutations from 23 Korean families, including six novel mutations in Korean patients with LNS.

We evaluated trajectories of glycated hemoglobin (HbA1c) levels and body mass index z-scores (BMIz) for 5 years after diagnosis among Korean children and adolescents with type 1 diabetes (T1D) or type 2 diabetes (T2D) using the common data model. From the de-identified database of three hospitals, 889 patients p p p

BackgroundDue to remarkable progress in cancer treatment, endocrine complications are now the major medical issues facing childhood cancer survivors. Although non-central nervous system solid tumors (NCSTs) account for approximately 40% of all pediatric cancers, there have been few studies on endocrine complications associated with NCSTs. This study investigated endocrinopathies following the treatment of pediatric NCSTs.Design and settingRetrospective study in a single academic center.MethodsThis study analyzed 253 survivors of childhood NCSTs who were diagnosed between January of 2000 and December of 2018. The medical charts were reviewed regarding the frequency of endocrinopathies and treatment modalities. The hazard ratios were assessed by multivariable Cox regression analysis. The final height-SDS were analyzed by multivariable linear regression analysis.ResultsThere were 76 patients (30%) that developed at least one endocrine complication. Forty-four patients (17.4%) experienced endocrine complications within five years of their cancer diagnosis. The most common endocrine complication was growth failure (n = 35), followed by obesity (n = 18), and primary gonadal failure (n = 16). High cumulative doses of alkylating agents increased the risk of developing at least one endocrine complication. Hematopoietic stem cell transplantation was an important risk factor for primary gonadal failure.ConclusionsThis study described the comprehensive endocrine outcomes, including growth failure, obesity, primary gonadal failure, primary hypothyroidism, dyslipidemia, and osteoporosis, following the treatment of childhood NCSTs. As endocrinopathies occurred within five years of primary tumor diagnosis, surveillance for endocrine dysfunction is required for early intervention and management.

BackgroundEndocrine complications such as impaired growth, delayed puberty, and low bone mineral density (BMD) can be associated with inflammatory bowel disease (IBD) in children and adolescents. This study was performed to investigate the frequency, characteristics, and outcomes of endocrine complications of IBD in children and adolescents.MethodsThis study included 127 patients with IBD diagnosed before 18 years of age [117 with Crohn disease (CD) and 10 with ulcerative colitis (UC)]. Growth profiles, pubertal status, 25-hydroxyvitamin D3[25(OH)D3] levels, and BMD were reviewed retrospectively.ResultsShort stature was observed in 14 of 127 (11.0 %) with a mean height-SDS of -2.31 ± 0.72. During a 2-year follow-up period, height-SDS did not significantly improve, while weight-SDS significantly improved. Among 109 patients who were older than 13 (girls) or 14 (boys) years of age during the study period, 11 patients (10.1 %) showed delayed puberty, which was associated with low weight-SDS. Vitamin D deficiency was documented in 81.7 % (94/115) with the average 25(OH)D3level of 14.5 ± 7.0 ng/mL. Lumbar BMD Z-score was below − 2 SDS in 25 of 119 patients (21.0 %). Height-SDS, weight-SDS, and body mass index (BMI)-SDS were lower in patients with osteoporosis than those without osteoporosis. When pediatric CD activity index scores were high (≥ 30), weight-SDS, BMI-SDS, insulin-like growth factor 1 (IGF-1)-SDS, and testosterone levels were significantly decreased.ConclusionsVitamin D deficiency and osteoporosis are common in pediatric IBD patients. As disease severity deteriorates, weight-SDS, IGF-1-SDS, and testosterone levels were decreased. Optimal pubertal development is necessary for bone health.

Background Gaucher disease (GD) is caused by a deficiency of β-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.

BackgroundARID2 belongs to the Switch/sucrose non-fermenting complex, in which the genetic defects have been found in patients with dysmorphism, short stature and intellectual disability (ID). As the phenotypes of patients with ARID2 mutations partially overlap with those of RASopathy, this study evaluated the biochemical association between ARID2 and RAS-MAPK pathway.MethodsThe phenotypes of 22 patients with either an ARID2 heterozygous mutation or haploinsufficiency were reviewed. Comprehensive molecular analyses were performed using somatic and induced pluripotent stem cells (iPSCs) of a patient with ARID2 haploinsufficiency as well as using the mouse model of Arid2 haploinsufficiency by CRISPR/Cas9 gene editing.ResultsThe phenotypic characteristics of ARID2 deficiency include RASopathy, Coffin-Lowy syndrome or Coffin-Siris syndrome or undefined syndromic ID. Transient ARID2 knockout HeLa cells using an shRNA increased ERK1 and ERK2 phosphorylation. Impaired neuronal differentiation with enhanced RAS-MAPK activity was observed in patient-iPSCs. In addition, Arid2 haploinsufficient mice exhibited reduced body size and learning/memory deficit. ARID2 haploinsufficiency was associated with reduced IFITM1 expression, which interacts with caveolin-1 (CAV-1) and inhibits ERK activation.DiscussionARID2 haploinsufficiency is associated with enhanced RAS-MAPK activity, leading to reduced IFITM1 and CAV-1 expression, thereby increasing ERK activity. This altered interaction might lead to abnormal neuronal development and a short stature.

Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are the most common subtypes of RASopathy. As an effector of Ras, BRAF is one of the molecules responsible for RASopathy. We investigated the phenotypic and genotypic features of 26 patients with BRAF-associated RASopathy. The clinical diagnoses were CFC (n = 21, 80.8%), NS (n = 3, 11.5%), NS/CFC (n = 1, 3.8%), and undefined syndromic intellectual disability (ID) (n = 1, 3.8%). The mostly shared phenotypes were ID (90.5%), cutaneous manifestations (84.6%), congenital heart defects (76.9%), short stature (76.9%), and dysmorphic features such as short neck (65.4%) and low-set ears (65.4%). Importantly, moderate to severe ID (57.1%) and epilepsy (26.9%) were noted. Eighteen different missense mutations were found, including a novel mutation, p.Phe498Tyr. p.Gln257Arg (n = 9, 34.6%) was the most common mutation, and the mutations were clustered in the cysteine-rich domain or protein kinase domain. A review of previously reported cases along with our findings revealed the existence of multiple sub-phenotypes of RASopathy within a single genotype, indicating that BRAF-associated RASopathy is not variant-specific. Our study further delineated the diverse and expanded clinical phenotypes of BRAF-associated RASopathy with their molecular genetic characteristics.

As survival rates have improved owing to advances in management strategies for pediatric brain tumors, long-term complications such as endocrine dysfunction, have emerged as a major issue. This study investigated the long-term endocrine effects of childhood-onset brain tumors in a large number of patients. This study included 151 patients with brain tumors diagnosed between January 1995 and December 2016. The following data were retrospectively reviewed: tumor location, tumor histology, endocrine abnormalities, hypothalamic involvement on brain imaging, treatment modalities, and trends in body mass index. The mean age at diagnosis of patients with sellar/suprasellar (SE/SUP-SE) tumors and supra/infratentorial (ST/IT) tumors was 9.9 ± 4.5 and 6.5 ± 4.2 years, respectively. In patient with prepubertal age at diagnosis, height standard deviation score was lower in patients with SE/SUP-SE tumors at diagnosis (P = 0.031), which was lower in patients with ST/IT tumors at the final visit (P

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.

Background As syndromic short stature and overgrowth are heterogeneous and the list of causative genes is rapidly expanding, there is an unmet need for identifying genetic causes based on conventional gene testing or karyotyping. Early diagnosis leads to the proper management of the patient and providing genetic counseling for family members at risk in a timely manner. Materials and methods We conducted targeted exome sequencing to identify the genetic causes of undiagnosed syndromic short stature or overgrowth in 15 pediatric patients from 13 families in Korea. We applied targeted exome sequencing using the Next Seq platform and a TruSight One panel. Results Among the 13 families, 6 different disorders in 8 patients with short stature or overgrowth were identified, and the diagnostic yield was 46.2%. One boy with overgrowth had a TGFB3 gene mutation. In the short stature group, Coffin-Lowry syndrome (CLS), trichorhinophalangeal syndrome, DYRK1A haploinsufficiency syndrome, short stature with optic atrophy and Pelger-Huet anomaly syndrome with recurrent hepatitis, and type 4 Meier-Gorlin syndrome were identified. One CLS patient had a co-existing monogenic disease, congenital glaucoma, caused by the compound heterozygote mutations of the CYP1B1 gene. Conclusion Targeted exome sequencing is a powerful method for diagnosing syndromic growth disorders. It enables us to understand molecular pathophysiology and investigate new treatments for growth disorders.

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.

PURPOSE Congenital hypopituitarism is caused by mutations in pituitary transcription factors involved in the development of the hypothalamic-pituitary axis. Mutation frequencies of genes involved in congenital hypopituitarism are extremely low and vary substantially between ethnicities. This study was undertaken to compare the clinical, endocrinological, and radiological features of patients with an isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD). MATERIALS AND METHODS This study included 27 patients with sporadic IGHD and CPHD. A mutation analysis of the POU1F1, PROP1, LHX3, LHX4, and HESX1 genes was performed using genomic DNA from peripheral blood leukocytes. RESULTS IGHD and CPHD were observed in 4 and 23 patients, respectively. Mean age at diagnosis was 8.28±7.25 years for IGHD and 13.48±10.46 years for CPHD (p=0.37). Serum insulin-like growth factor-1 and peak growth hormone (GH) levels following GH stimulation tests were significantly lower in patients with CPHD than in those with IGHD (p

This study was to develop tablet personal computer-based cognitive training programs for children with developmental disabilities whose cognitive age is less than 4 years. Twelve cognitive training programs (named Injini) were designed comprising cognitive domains that included attention, visual and auditory perception, memory, executive function, language, and reasoning. In addition, programs related to learning experiences, such as self-regulation, role play, learning of number, and letter/shape concepts, comparison, classification, and pattern matching, were included. Six of 12 programs comprised approximately 10 levels for each program, with different difficulty levels. Other programs consisted of universal tasks that did not have a difficulty level. To ensure that the difficulty level was appropriate, we pre-tested the pilot version of Injini among 80 children with typical development aged 18 to 41 months. After modifying the pilot version, we developed the final version and tested it among 80 children with cognitive impairment whose cognitive age was 18 to 41 months. All children were assessed using the Bayley Scales of Infant and Toddler Development to determine their development and cognitive age. The difficulty level analyses in children with typical development revealed several inappropriate results wherein the success rate did not decrease with increase in level in some programs. After adjusting the difficulty level, the analyses in children with cognitive impairment demonstrated that the success rate gradually decreased with increasing level in all programs. Cognitive training programs for children with developmental disabilities were successfully developed.

Neurofibromatosis type 1 (NF1) is caused by heterozygous mutation in the NF1 gene. NF1 is one of the most common human genetic diseases. However, the overall genotype–phenotype correlation has not been known, due to a wide spectrum of genotypic and phenotypic heterogeneity. Here we describe the detailed clinical and genetic features of 427 Korean NF1 patients from 389 unrelated families. Long range PCR and sequencing of genomic DNA with multiplex ligation-dependent probe amplification analysis identified 250 different NF1 mutations in 363 families (93%), including 94 novel mutations. With an emphasis on phenotypes requiring medical attention (classified and termed: NF1+), we investigated the correlation of NF1+ and mutation types. NF1+ was more prevalent in patients with truncating/splicing mutations and large deletions than in those with missense mutations (59.6%, 64.3% vs. 36.6%, p = 0.001). This difference was especially significant in the patients younger than age 19 years. The number of items in NF1+ was a higher in the former groups (0.95 ± 0.06, 1.18 ± 0.20 vs. 0.56 ± 0.10, p = 0.002). These results suggest that mutation types are associated not only with higher prevalence of severe phenotypes in NF1 but also with their earlier onset.

Background & Aims Both existing clinical criteria and genetic testing have significant limitations for the diagnosis of Wilson disease (WD), often creating ambiguities in patient identification and leading to delayed diagnosis and ineffective management. ATP7B protein concentration, indicated by direct measurement of surrogate peptides from patient dried blood spot samples, could provide primary evidence of WD. ATP7B concentrations were measured in patient samples from diverse backgrounds, diagnostic potential is determined, and results are compared with biochemical and genetic results from individual patients. Methods Two hundred and sixty-four samples from biorepositories at 3 international and 2 domestic academic centers and 150 normal controls were obtained after Institutional Review Board approval. Genetically or clinically confirmed WD patients with a Leipzig score >3 and obligate heterozygote (carriers) from affected family members were included. ATP7B peptide measurements were made by immunoaffinity enrichment mass spectrometry. Results Two ATP7B peptides were used to measure ATP7B protein concentration. Receiver operating characteristics curve analysis generates an area under the curve of 0.98. ATP7B peptide analysis of the sequence ATP7B 887 was found to have a sensitivity of 91.2%, specificity of 98.1%, positive predictive value of 98.0%, and a negative predictive value of 91.5%. In patients with normal ceruloplasmin concentrations (>20 mg/dL), 14 of 16 (87.5%) were ATP7B-deficient. In patients without clear genetic results, 94% were ATP7B-deficient. Conclusions Quantification of ATP7B peptide effectively identified WD patients in 92.1% of presented cases and reduced ambiguities resulting from ceruloplasmin and genetic analysis. Clarity is brought to patients with ambiguous genetic results, significantly aiding in noninvasive diagnosis. A proposed diagnostic score and algorithm incorporating ATP7B peptide concentrations can be rapidly diagnostic and supplemental to current Leipzig scoring systems.

RASopathies are a group of syndromes caused by germline mutations of the RAS/MAPK pathway. They include Noonan syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, and Noonan syndrome with multiple lentigines, which share many characteristic features including cardiac abnormalities. Here, we retrospectively reviewed the clinical manifestations and evaluated the genotype-phenotype associations with special focus on cardiac lesions of the patients with RASopathies. Cardiac symptoms were the most common initial presentation (27 %), except for admission to neonatal intensive care. Although there was a significant gap between the first visit to the hospital and the diagnosis of the genetic syndrome (19.9 ± 39.1 months), the age at the clinical diagnosis of the genetic syndrome was significantly lower in patients with CHD than in patients without CHD (47.26 ± 67.42 vs. 86.17 ± 85.66 months, p = 0.005). A wide spectrum of cardiac lesions was detected in 76.1 % (118/155) of included patients. The most common lesion was pulmonary stenosis, followed by atrial septal defect and hypertrophic cardiomyopathy (HCMP). About half of the pulmonary stenosis and HCMP patients progressed during the median follow-up period of 109.9 (range 9.7-315.4) months. Early rapid aggravation of cardiac lesions was linked to poor prognosis. MEK1, KRAS, and SOS1 mutations tend to be highly associated with pulmonary stenosis. Cardiologists may play important roles in early detection and diagnosis of RASopathies as well as associated CHDs. Due to the variety of clinical presentations and their progression of severity, proper management with regular long-term follow-up of these patients is essential.

Background Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is classified either as Kallmann syndrome (KS) with anosmia or normosmic idiopathic hypogonadotropic hypogonadism (nIHH) and caused by mutations in more than 30 different genes. Recent advances in next-generation sequencing technologies have revolutionized the identification of causative genes by using massively parallel sequencing of multiple samples. This study was performed to establish the genetic etiology of IGD using a targeted gene panel sequencing of 69 known human IGD genes. Methods This study included 28 patients with IGD from 27 independent families. Exomes were captured using customized SureSelect kit (Agilent Technologies) and sequenced on the Miseq platform (Illumina, Inc.), which includes a 163,269 bp region spanning 69 genes. Results Four pathogenic and six likely pathogenic sequence variants were identified in 11 patients from 10 of the 27 families (37%) included in the study. We identified two known pathogenic mutations in CHD7 and PROKR2 from two male patients (7.4%). Novel sequence variants were also identified in 10 probands (37%) in CHD7, SOX3, ANOS1, FGFR1, and TACR3. Of these, while eight variants (29.6%) were presumed to be pathogenic or likely pathogenic, the remaining two were classified as variants of uncertain significance. Of the two pre-pubertal males with anosmia, one harbored a novel heterozygous splice site variant in FGFR1. Conclusions The overall diagnostic yield was 37% of the patients who had undergone targeted gene panel sequencing. This approach enables rapid, cost-effective, and comprehensive genetic screening in patients with KS and nIHH.

Syndromes of reduced sensitivity to thyroid hormone can be caused by innate resistance to thyroid hormone (RTH), thyroid hormone cell transporter defects, or thyroid hormone metabolism defects. This study was performed to describe clinical, endocrinological, and molecular characteristics of patients with disorders associated with impaired sensitivity to thyroid hormone due to THRB or SLC16A2 mutations.This study included 5 probands (1 male and 4 females) with RTH and 6 patients with Allan-Herndon-Dudley syndrome (AHDS). Clinical features and endocrine findings were reviewed retrospectively. Molecular analysis of two candidate genes, THRB or SLC16A2, confirmed the diagnosis.Among RTH patients, median age at diagnosis was 5.6 years. Three patients were classified as having generalized RTH, whereas the other 2 patients were regarded as having isolated pituitary RTH. Three novel heterozygous mutations and 2 known mutations in THRB were identified from 5 independent pedigrees. All mutations were located in the major ligand-binding domain. In AHDS patients, delayed development was apparent between 3 and 6 months of age. Direct sequencing of SLC16A2 identified 6 hemizygous missense mutations in each patient: p.I188N, p.G221R, p.A224V, p.G276R, p.W398R, and p.G401R.This study identified 3 novel mutations in THRB in RTH patients and 1 novel mutation in SLC16A2 in AHDS patients. Routine neonatal screening based on the TSH assay has a limited role in detecting RTH or AHDS. Therefore, genetic testing of the candidate genes THRB and SLC16A2 should be performed for diagnosis of RTH and AHDS in patients with the suggestive clinical phenotype.

SummaryContext Hypoparathyroidism is characterised by hypocalcaemia, hyperphosphataemia, and low or inappropriately normal parathyroid hormone (PTH) levels. Idiopathic or genetic drivers are the predominant causes of hypoparathyroidism in paediatric-age patients. Objective This study investigated the aetiology and clinical course of primary hypoparathyroidism in infancy and childhood. Subjects and measurements This study included 37 patients (23 males, 14 females) with primary hypoparathyroidism diagnosed prior to 18 years of age. We analysed aetiologies, initial presentation, age at diagnosis, endocrine and radiological findings, and outcomes. Results The median age at presentation was 1.7 months (range 1 day–17 years), and the mean follow-up duration was 7.0 ± 5.3 years (range 0.5–16.8 years). Our cohort included 22 cases (59.5%) of 22q11.2 microdeletion syndrome. Other aetiologies included hypoparathyroidism-deafness-renal dysplasia syndrome (5/37, 13.5%) and one patient each with autoimmune polyglandular syndrome type 1, Kearns–Sayre syndrome, and Kenny–Caffey syndrome. The remaining 7 (18.9%) patients were classified as idiopathic hypoparathyroidism cases. Among the 15 patients who underwent brain imaging, 5 (33.3%) had basal ganglia calcification. Among the 26 patients examined by renal imaging, 5 (19.2%) had either nephrocalcinosis or a renal stone. After 11 months of calcium or calcitriol supplementation, 16 patients (43.2%) discontinued medication. The final PTH levels were significantly higher in patients with transient hypoparathyroidism than those with permanent hypoparathyroidism. Conclusions Identification of the genetic aetiologies of hypoparathyroidism makes it possible to predict patient outcomes and provide appropriate genetic counselling. Long-term treatment with calcium and calcitriol necessitates monitoring for renal complications. This article is protected by copyright. All rights reserved.

Prolactinoma is a benign tumor of the pituitary gland that rarely occurs in children and adolescents; thus, the clinical spectrum and long-term prognosis in these patients remain unknown. This study was performed to investigate the long-term outcomes of medical treatment and the prognostic factors for remission and relapse in children and adolescents with prolactinoma. Three male subjects and four female subjects between the ages of 7- and 17-years-old were included in this study. The mean initial serum prolactin level was 443 ± 251.8 ng/mL (range, 152-946 ng/mL). During the follow-up period (range, 0.6-20 years), a dopamine agonist was administered, and surgery or radiotherapy was performed in cases of resistance to medical treatment or relapse. Unlike female subjects with macroadenoma who often exhibit a good clinical course, two male subjects with early onset macroadenoma presented with visual disturbances. These subjects showed resistance to medical therapy and relapsed, eventually requiring surgical removal and radiotherapy; one of the subjects manifested a metastatic thrombus in the internal jugular vein. In conclusion, pediatric prolactinoma exhibits a broad clinical spectrum, a relatively high incidence of macroadenoma, resistance to medical therapy, and frequent tumor relapses. In addition, a poor prognosis appears to be correlated with male sex, age at disease onset, and histopathological characteristics.

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.

Supplemental Digital Content is available in the text, 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 ± 19 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 ± 3.6 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.

Background Fabry disease is characterised by the progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in vascular endothelial cells. Enzyme replacement therapy (ERT) clears this accumulation. We analysed plasma proteome profiles before and after ERT to characterise its molecular pathology. Methods Two-dimensional electrophoresis and matrix-assisted laser desorption/ionisation-time of flight tandem mass spectrometry (MALDI-TOF MS) and tandem mass spectrometry (MS/MS) were done using plasma samples before and after ERT in eight patients with classical Fabry disease Results After short-term ERT (4–12 months), the levels of 15 plasma proteins involved in inflammation, oxidative and ischaemic injury, or complement activation were reduced significantly. Among them, β-actin (ACTB), inactivated complement C3b (iC3b), and C4B were elevated significantly in pre-ERT Fabry disease plasma compared with control plasma. After longer-term ERT (46–96 months), iC3b levels gradually decreased, whereas the levels of other proteins varied. The gradual reduction of iC3b was comparable to that of Gb3 levels. In addition, iC3b increased significantly in pre-ERT Fabry disease mouse plasma, and C3 deposits were notable in renal tissues of pre-enzyme replacement therapy patients. Conclusion These results indicated that C3-mediated complement activation might be altered in Fabry disease and ERT might promote its stabilisation.

KBG syndrome is a very rare genetic disorder characterized by macrodontia of upper central incisors, global developmental delay, distinctive craniofacial features, short stature, and skeletal anomalies. Ankyrin repeat domain 11 gene (ANKRD11) has recently been identified as a causal factor of this syndrome. We describe a 6-yr-old Korean boy with features of KBG syndrome. The patient had a short stature, macrodontia, dysmorphic facial features, speech and motor delay with intellectual disability, and partial seizures as indicated by the electroencephalogram, but he was neither autistic nor had autism spectrum disorders. Using high-resolution oligonucleotide array comparative genomic hybridization, we identified a heterozygous 240-kb deletion at 16q24.3 corresponding to ANKRD11. This patient provided additional evidence on the influence of ANKRD11 in KBG syndrome and suggested that deletion limited to ANKRD11 is unlikely to cause autism.

Plasma chitotriosidase activity is used for diagnosis and monitoring of Gaucher disease. However, homozygous duplication of a 24 bp region in exon 10 of the chitotriosidase gene (CHIT1) abolishes enzyme activity, limiting its use as a biomarker in Gaucher disease. This study investigates the allele frequency of the 24 bp duplication, in both the general Korean population and in patients with Gaucher disease. Fifteen Korean patients with Gaucher disease and 231 Korean normal individuals were enrolled. Genotyping was performed to identify the 24 bp duplication in exon 10 of CHIT1 using DNA extracted from peripheral leukocytes or dried blood spots. Two patients with Gaucher disease (13.3%) had normal plasma chitotriosidase activity, and carried a homozygous 24 bp duplication of exon 10 of the CHIT1 gene. Nine patients were heterozygote carriers (60.0%). Of the normal 231 Korean individuals, heterozygous duplication was detected in 109 individuals (47.2%) and homozygous duplication in 75 (32.5%). The allele frequency was 56.1% (95% confidence interval, 49.4-62.7%). The frequency of the 24 bp duplication was remarkably high in both Korean patients with Gaucher disease and in the normal population, limiting the efficacy of chitotriosidase as a biomarker in Gaucher disease in Korea. New biomarkers are required that consider the genetic characteristics of different populations.

N-acetylglutamate synthase (NAGS) deficiency is a rare inborn error regarding the urea cycle, however, its diagnosis is important as it can be effectively treated by N-carbamylglutamate. We evaluated a patient with NAGS deficiency who harbored two novel NAGS mutations and who showed excellent responsiveness during 1 year of N-carbamylglutamate treatment.

Objective: Angelman syndrome is a genetic syndrome resulted from a lack of UBE3A gene expression of the maternally inherited abnormalities of chromosome 15q11-q13. About 90% of patients with Angelman syndrome experience epilepsy and its distinctive electroencephalographic changes. Epilepsy predominates in childhood, but may persist in adulthood. The seizure types may be quite varied and sometimes difficult to control. Methods: We retrospectively reviewed and analyzed data of 18 patients with genetically and clinically confirmed Angelman syndrome at Asan Medical Center. Results: An analysis of 53 electroencephalography (EEG) records from 18 patients showed that diffuse slow-wave background patterns were significantly associated with uncontrolled periods of epilepsy. Moreover, epileptiform discharges tended to shift from posterior to anterior head regions over time after an initial normal pattern at a young age. Conclusions: Children with Angelman syndrome follow general developmental patterns, with specific patterns of EEG reflecting the maturational pattern of the brain and epileptic activity.

The aim of this review is to summarize recent advances regarding the genetic components of the complex and coordinated process of puberty, an update of the genes implicated in disorders of puberty, the endocrinologic changes of puberty, and influences of environment in the light of our current understanding of the mechanism of the onset of puberty.The timing of puberty varies greatly in the general population among ethnic groups throughout the world, suggesting the genetic control of puberty. Several studies on the pathological conditions of pubertal onset provide unique information about the interactions of either the genetic susceptibility of or environmental influences on hypothalamic control of pubertal onset. However, these findings suggested that no isolated pathway or external factor is solely responsible for the neuroendocrine control of puberty.Puberty is initiated by gonadotropin-releasing hormone from the hypothalamus followed by a complex sequence of endocrine changes and is regulated by both genetic and environmental factors. New attempts to use genetics and genomics might enhance our understanding of the spectrum of pubertal development.

Early diagnosis is a key objective in clinical medicine, and early detection of pathological short stature has tangible benefits for growth prognosis and the well-being of the child. Despite late diagnosis being common in growth disorders, programmes of height screening in primary care are not universal in developed countries and may be random or non-existent. A notable exception is automated growth monitoring in Finland, where an algorithm to detect abnormal growth is integrated into children's electronic health records, resulting in increased diagnoses of pathological short stature. Evidence-based anthropometric criteria for referral of short stature to secondary or tertiary care are now published, due largely to excellent studies in the Netherlands. Following referral of the short child, the protocol for laboratory investigations remains somewhat controversial because in healthy children their diagnostic yield can be too low for cost-effectiveness. However, outside of tertiary academic paediatric endocrinology centres, baseline screening tests are considered worthwhile and may speed up diagnosis and treatment. Finally, auxological cut-offs cannot replace good clinical practice, and the understanding that early and effective management depends on commitment to a diagnosis and individualisation of therapy in the short child cannot be overemphasised.

Short-chain acyl-CoA dehydrogenase (SCAD) catalyzes the first step in mitochondrial short-chain β-oxidation, and its deficiency is caused by mutations in the ACADS We sought to investigate the spectrum ACADS mutations and associated clinical manifestations in Korean patients with SCAD deficiency. The study included ten patients with SCAD deficiency from 8 unrelated families as diagnosed by biochemical profile and mutation analyses. Clinical features, biochemical data, growth, and neurodevelopmental state were reviewed retrospectively. Eight patients were found during newborn screening, and two were diagnosed by family screening. During follow-up ranging from 2 months to 4.5 years, no hypoglycemic event was noted, and the development and growth of the patients were normal, except in two siblings. One exhibited hypotonia and gross motor delay, while one girl showed cyclic vomiting until the age of two years. We identified seven different mutations of ACADS Of these, p.E344G was the most frequent mutation with an allele frequency of 50%, followed by p.P55L with 18.8%. p.G108D and four novel mutations were identified: p.L93I, p.E228K, p.P377L, and p.R386H. Korean patients with SCAD deficiency showed heterogenous clinical features and ACADS genotype. Our data contributes to a better understanding of the distinct molecular genetic characteristics and clinical manifestations of SCAD deficiency.

Fabry disease is a progressive lysosomal storage disease caused by alpha-galactosidase A deficiency. This condition is characterized by progressive accumulation of glycosphingolipids with functional impairment in various organs, including the kidney, heart and cerebrovascular system. Enzyme replacement therapy (ERT) is essential because it attenuates the disease progression. The present study investigated the long-term efficacy of ERT in 19 Korean Fabry patients (11 adult males, 4 symptomatic female carriers and 4 pediatric males) who had received ERT for 8.1±2.2 years (range, 5.3–10.5 years). In the 11 adult males, the mean reduction in the estimated glomerular filtration rate (eGFR) was −3.8±4.5 ml−1 min 1.73 m–2. The rate of eGFR decline was significantly lower in patients with lower proteinuria (

X-linked adrenal hypoplasia congenita with hypogonadotropic hypogonadism and adrenal insufficiency is a rare disorder caused by mutations of DAX-1. In this study, we investigated the functional defects of DAX-1 caused by mutations identified in 3 unrelated Korean patients with adrenal hypoplasia congenita. The DAX-1 gene was directly sequenced using genomic DNA isolated from peripheral blood leukocytes. The functional defects of DAX-1 caused by mutations were evaluated using an in vitro promoter assay. After mutagenesis of DAX-1 complementary DNA in the pcDNA3.1 vector, steroidogenic factor 1 and the promoter region of steroidogenic acute regulatory protein (StAR) genes in pGL4.10[luc2] were transiently cotransfected into human embryonic kidney 293 cells, followed by luminometry measurements of the luciferase activity of StAR. Mutation analysis of 3 patients revealed p.L386delfsX2, p.W105X, and p.Q252X mutations of the DAX-1 gene. The mutant DAX-1 proteins showed lower repressive activity on the StAR gene promoter when compared with normal DAX-1. Nonsense and frameshift mutations of the DAX-1 gene partially eliminated the ability of DAX-1 to repress the transcription of StAR in an in vitro assay.

Progressive familial intrahepatic cholestasis (PFIC) is a group of severe genetic disorders, inherited in an autosomal recessive manner, causing cholestasis of hepatocellular origin, later progressing to biliary cirrhosis and liver failure. This is the first report of PFIC type 1 with novel compound heterozygous mutations in Korea. The patient was presented with intrahepatic cholestasis, a normal level of serum γ-glutamyl transferase, steatorrhea, and growth failure. Genetic testing of this patient revealed novel compound heterozygous mutations (p.Glu585Ter and p.Leu749Pro) in the ATP8B1 gene. After a liver transplantation at age 19 months, the patient developed severe post-transplant steatohepatitis.

Supplemental Digital Content is available in the text, Marfan syndrome (MFS) and Loeys–Dietz syndrome (LDS) are the connective tissue disorders characterized by aortic root aneurysm and/or dissection and various additional features. We evaluated the correlation of these mutations with the phenotypes and determined the clinical applicability of the revised Ghent criteria. The mutation spectrum and phenotypic heterogeneities of the 83 and 5 Korean patients with suspected MFS and LDS were investigated as a retrospective manner. In patients with suspected MFS patients, genetic testing was conducted in half of 44 patients who met the revised Ghent criteria clinically and half of 39 patients who did not meet these criteria. Fibrillin1 gene (FBN1) variants were detected in all the 22 patients (100%) who met the revised Ghent criteria and in 14 patients (77.8%) who did not meet the revised Ghent criteria (P = .0205). Patients with mutations in exons 24–32 were diagnosed at a younger age than those with mutations in other exons. Ectopia lentis was more common in patients with missense mutations than in patients with other mutations. Aortic diameter was greater in patients with missense mutations in cysteine residues than in patients with missense mutations in noncysteine residues. Five LDS patients had either TGFBR1 or TGFBR2 variants, of which 1 patient identified TGFBR1 variant uncertain significance. The revised Ghent criteria had very high clinical applicability for detecting FBN1 variants in patients with MFS and might help in selecting patients with suspected MFS for genetic testing.

Background: Camurati–Engelmann disease is an extremely rare disease characterized by hyperostosis of multiple long bones. This condition is caused by heterozygous mutations in the TGFB1 gene. Methods: We describe the clinical and genetic characteristics of 4 Korean patients with this rare disease diagnosed at Asan Medical Center in Korea between June 2012 and May 2016, to increase awareness about this condition among general physicians and orthopedists. The presenting features, biochemical findings, radiographic and nuclear imaging findings, molecular analysis, and treatment outcomes of 4 patients were reviewed retrospectively. Results: Two patients had sporadic disease, whereas the other 2 were familial cases. The average age at symptom onset was 8.8 ± 5.5 (4–14) years. Symptoms included waddling gait or leg pain. Bone pain and easy fatigability were documented in all patients. Skeletal deformities such as osteoporosis, genu valgum, and severe scoliosis were observed. Visual and otologic manifestations presenting as exophthalmos, retinal detachment, and vestibulopathy were found in 3 patients. Skeletal survey showed diaphyseal expansion with diffuse cortical thickening of long bones in all patients. Bone scintigraphy images showed increased uptake of radioactive material in the calvarium and diaphysis of long bones. The mean erythrocyte sedimentation rate was 46.5 ± 22.2 (20–72) mm/h. Sequence analysis of TGFB1 revealed the previously reported mutations p.Arg218His, p.Arg218Cys, and p.Glu169Lys. Corticosteroid was effective in relieving pain, and losartan was used as maintenance therapy. Conclusions: Our experience suggests that this rare condition can be suspected in patients with characteristic symptoms and skeletal findings. Considering the presence of effective medical treatment, efforts are needed to identify more cases.

Summary Objective Recombinant human growth hormone (GH) can achieve final adult height gain in girls with Turner syndrome (TS), but its efficacy varies widely across individuals. The exon 3-deleted polymorphism of growth hormone receptor (d3-GHR) has been reported to be associated with responsiveness to GH therapy. The short-term growth response of Turner patients to GH therapy was analysed according to their GHR-exon 3 polymorphism genotype. Design and patients This was a retrospective study of 175 TS patients. Auxological and endocrine parameters were measured, and the GHR-exon 3 genotype was analysed. Allelic frequencies of GHR-exon 3 genotype were compared between patients with TS and control individuals. GH had been administered to 147 patients, 115 of which remained pre-pubertal after the first follow-up year. Changes in height standard deviation score (SDS), height velocity (HV), body mass index (BMI), IGF-1 and IGF binding protein-3 (IGFBP-3) concentrations were compared between these patients, grouped according to genotype, after the first follow-up year. Results There was no difference in GHR-exon 3 genotype frequency between the TS and control groups of Koreans. According to the GHR-exon 3 genotype (fl/fl group vs. d3/fl and d3/d3 group), HV gain and height SDS gain did not differ significantly at the first year of GH therapy. Moreover, changes in IGF-1, IGFBP-3 concentration and BMI showed no significant difference between the groups with and without d3-GHR after 1 year of GH therapy. Conclusion The distribution of the GHR-exon 3 genotype was similar in the TS and control groups in a Korean population. The growth promotion efficacy of GH therapy did not differ significantly between TS patients with and without the d3-GHR allele. These findings indicate that the GHR-exon 3 genotype may not be a major factor to affect the GH response in Korean Turner patients.

Summary Objective A human GH receptor (GHR) gene exon 3 polymorphism (d3-GHR) has been reported to be associated with responsiveness to GH therapy. We assessed the frequencies of this polymorphism in Korean control and idiopathic short stature (ISS) populations, and analysed short-term growth response to GH therapy according to GHR-exon 3 genotypes in Korean children with ISS. Design and patients This was a retrospective study in 158 ISS children. Auxological and endocrine parameters were measured, and the GHR-exon 3 genotype was analysed. Allelic frequencies of GHR-exon 3 genotype were compared between the ISS group and a control group. GH had been administered for 62 patients, 52 of whom remained prepubertal after the first follow-up year. Changes in height velocity (HV) and IGF-1 and IGFBP-3 concentrations following GH therapy were compared in patients with these genotypes. Results There was no difference in GHR-exon 3 genotype frequency between ISS and control groups of Koreans. However, the fl/fl genotype was more frequent in Koreans than in Caucasians. ISS children with d3-GHR showed a significantly higher increment in HV (P = 0·002) and a marginally significant increment in IGF-1 concentration (P = 0·064) at the first year of GH therapy. Conclusion fl-GHR was more frequently detected in a Korean population than in Caucasians. The growth promotion efficacy of GH therapy differed significantly between ISS patients with and without the d3-GHR allele. These findings indicate that the GHR-exon 3 polymorphism can affect the growth promoting efficacy of short-term GH therapy in Korean children with ISS.

After 2006, germline mutations in the KRAS, SOS1, and RAF1 genes were reported to cause Noonan syndrome (NS), in addition to the PTPN11 gene, and now we can find the etiology of disease in approximately 60-70% of NS cases. The aim of this study was to assess the correlation between phenotype and genotype by molecular analysis of the PTPN11, SOS1, KRAS, and RAF1 genes in 59 Korean patients with NS. We found disease-causing mutations in 30 (50.8%) patients, which were located in the PTPN11 (27.1%), SOS1 (16.9%), KRAS (1.7%), and RAF1 (5.1%) genes. Three novel mutations (T59A in PTPN11, K170E in SOS1, S259T in RAF1) were identified. The patients with PTPN11 mutations showed higher prevalences of patent ductus arteriosus and thrombocytopenia. The patients with SOS1 mutations had a lower prevalence of delayed psychomotor development. All patients with RAF1 mutations had hypertrophic cardiomyopathy. Typical facial features and auxological parameters were, on statistical analysis, not significantly different between the groups. The molecular defects of NS are genetically heterogeneous and involve several genes other than PTPN11 related to the RAS-MAPK pathway.

The aim of this study was to assess the clinical and endocrinological features, and to analyze AR and SRD5A2 genes in patients with 46,XY disorders of sex development (DSD). This study included 20 patients from 19 families showing clinical features of 46,XY DSD. Molecular analysis was performed of the AR and SRD5A2 genes, as well as endocrinological evaluations, such as 17a-hydroxyprogesterone, plasma renin activity, aldosterone, adrenocorticotropic hormone and hCG stimulation test. Out of 20 patients with 46,XY DSD, only one (5%) displayed androgen insensitivity syndrome (AIS), and four (20%) were Sa-reductase deficient by mutation analysis. The patient with AIS revealed significant elevation of serum testosterone following hCG stimulation. The patient with Sa-reductase deficiency with a homozygous p.R246Q mutation had a low basal dihydrotestosterone level. The patient with p.Q6X/p.R246Q mutations showed a moderately elevated testosterone/ dihydrotestosterone ratio following hCG stimulation. Endocrinological tests are not reliable for the etiological diagnosis of AIS and Sa-reductase deficiency due to variable reference ranges of hormonal profiles according to the age and the severity of the enzyme defect. DNA analysis may be employed as a tool for the early and precise diagnosis of patients with 46,XY DSD, and genetic counseling can be used for families at risk.

The aim of the present study was to determine whether the clinical presentation of patients with central precocious puberty (CPP) permits differentiation between idiopathic and organic forms and to examine whether luteinizing hormone (LH) determination in single blood sample after gonadotropin-releasing hormone (GnRH) administration is sufficient to diagnose CPP. Potential clinical and laboratory predictors for the presence of central nervous system (CNS) abnormalities were assessed. Sensitivities and specificities of LH and follicle-stimulating hormone (FSH) levels at 0 15 30 60 90 and 120 min were compared after GnRH stimulation. In 45 girls with signs of breast development 26 were diagnosed as having CPP. The age of onset in patients with organic CPP was 4.75 plus or minus 2.01 years (range 1.2 - 7.1 years median 5.0 years) whereas the age in patients with idiopathic CPP was 7.09 plus or minus 0.87 years (range 5.0 - 7.9 years median 7.0 years). This parameter is the only one showing statistical significance. In addition the specimen at 30 min after GnRH stimulation yielded highest sensitivity for the diagnosis of CPP. The earlier the onset of disease the higher the possibility of presence of CNS lesion. According to the mean GnRH-stimulated LH levels and sensitivity at each time a single blood sample obtained for LH determined after GnRH administration at 30 min can be used to diagnose CPP. (authors)

Wilson disease (WND), an autosomal recessive disorder of copper transport, is characterized by excessive accumulation of intracellular copper in liver and extrahepatic tissues because of impaired biliary copper excretion and disturbed incorporation of copper into ceruloplasmin. Hepatic cirrhosis and neuronal degeneration are the major symptoms of WND, and mutations in the ATP7B gene are associated with WND. We have identified 28 different mutations in the ATP7B gene, including six novel variations, in 120 unrelated Korean patients with WND. Molecular defects in ATP7B were present in only 75.0% of Korean WND patients, with the most common mutation, p.Arg778Leu, having an allele frequency of 39.2%. To evaluate the functional defects of ATP7B caused by novel mutations, we used a yeast complementation system, and we used confocal microscopy to localize each mutation after transient expression in mammalian cells. Six novel variations were cloned into a yeast expression vector and two into a mammalian expression vector for confocal analysis. We found that c.2785A>G (p.Ile929Val) and c.3316G>A (p.Val1106Ile) were rare polymorphisms, whereas the others were novel variations disturbing ATP7B function.

We evaluated the efficacy of a monthly infusion of pamidronate on the frequency of fractures, biochemical effects, and bone mineral density in children with osteogenesis imperfecta. Eleven patients from 0.9 to 13.8 yr of age were included in this study. The patients were administered pamidronate intravenously (30 mg/m(2)) over a 4-hr period monthly for a period ranging from 6 to 37 months. Height and weight Z-scores did not change significantly. The frequency of fractures was decreased from 2.3+/-1.01 times per year before treatment to 0.6+/-0.69 times per year during treatment. There were no long-term changes in biochemical markers during pamidronate therapy. The mean bone mineral density of the spine and femur increased significantly. Monthly intravenous pamidronate therapy decreased frequencies of fracture and increased bone mineral density without significant adverse events in Korean patients with osteogenesis imperfecta.

OBJECT Moyamoya disease (MMD) is an idiopathic cerebrovascular occlusive disorder prevalent in East Asia. In the pathogenesis of MMD, the important role of genetic factors is being elucidated, and RNF213 has recently been identified as a susceptibility gene for MMD. The aim of this retrospective study was to investigate the RNF213 genotype in patients with MMD and to determine their genotype-phenotype associations. METHODS The study involved 165 Korean MMD patients from 155 unrelated families who were diagnosed with MMD at a single center from 1995 to 2013. Their demographic, radiological, and clinical findings were evaluated. Direct sequencing of the major RNF213 single nucleotide polymorphisms was performed. The association of the common RNF213 variant with MMD risk was evaluated using historical controls for comparison. Correlations between RNF213 genotype and phenotype were statistically analyzed. RESULTS The c.14429G>A (p.R4810K) variant was identified in 125 (75.8%) of 165 MMD patients. Most patients (112) were heterozygous, and 13 patients had 2 copies of the c.14429G>A variant. A novel heterozygous variant, c.12086A>G (p.Q4029R), was found in 1 additional patient. The minor allele frequency of the c.14429G>A variant was significantly higher in the MMD group (138 [41.8%] of 330 patients) than in the control group (8 [1.36%] of 588 subjects; p < 0.001). The c.14429G>A (p.R4810K) variant significantly increased the risk of MMD in Korean patients, with an OR of 52.11 (p < 0.001) compared with controls. Moreover, c.14429G>A (p.R4810K) genotypes occurred more frequently in patients with a family history of MMD. The homozygous variant was highly associated with early-onset MMD (age at onset < 5 years), cerebral infarction at diagnosis, and cognitive impairment in long-term outcome. CONCLUSIONS The findings indicate that the c.14429G>A (p.R4810K) allele of RNF213 is strongly associated with Korean patients with MMD. The homozygous c.14429G>A (p.R4810K) variant is particularly related to early-onset MMD, severe symptomatic manifestations at diagnosis, and poor prognosis. This genotypic variant may be a useful biomarker for early-onset MMD or unstable MMD with cerebral infarction, which requires early diagnosis and revascularization treatment.