Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay.

BACKGROUND: The diagnostic yield of whole-exome sequencing (WES) varies from 30%-50% among patients with mild to severe neurodevelopmental delay (NDD)/intellectual disability (ID). Routine retrospective reanalysis of undiagnosed patients has increased the total diagnostic yield by 10-15%. Here, we performed proband-only WES of 1065 patients with NDD/ID and applied a prospective, daily reanalysis automated pipeline to patients without clinically significant variants to facilitate diagnoses. METHODS: The study included 1065 consecutive patients from 1056 nonconsanguineous unrelated families from 10 multimedical centers in South Korea between April 2018 and August 2021. WES data were analyzed daily using automatically updated databases with variant classification and symptom similarity scoring systems. RESULTS: At the initial analysis, 402 patients from 1056 unrelated families (38.0%, 402/1,056 families) had a positive genetic diagnosis. Daily prospective, automated reanalysis resulted in the identification of 34 additional diagnostic variants in 31 patients (3%), which increased our molecular diagnostic yield to 41% (433/1056 families). Among these 31 patients, 26 were diagnosed with 23 different diseases that were newly discovered after 2019. The time interval between the first analysis and the molecular diagnosis by reanalysis was 1.2 ± 0.9 years, which was shorter in the patients enrolled during the latter part of the study period. CONCLUSION: Daily updated databases and reanalysis systems enhance the diagnostic performance in patients with NDD/ID, contributing to the rapid diagnosis of undiagnosed patients by applying the latest molecular genetic information.

Association between ARID2 and RAS-MAPK pathway in intellectual disability and short stature.

BACKGROUND: ARID2 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. METHODS: The 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. RESULTS: The 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. DISCUSSION: ARID2 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.

Comparison of Initial Presentation of Pediatric Diabetes Before and During the Coronavirus Disease 2019 Pandemic Era.

BACKGROUND: Hospital visitation has become challenging during the coronavirus disease 2019 pandemic because of quarantine measures and fear of infection. Consequently, newly diagnosed patients may present with more severe diseases during the pandemic. The present study analyzed the differences in the initial clinical presentations of newly diagnosed patients with type 1 diabetes (T1D) and type 2 diabetes (T2D), comparing pre-pandemic and pandemic periods. METHODS: Newly diagnosed patients with T1D or T2D and aged < 18 years during 2018-2020 were included in the study. Data were collected retrospectively from four academic centers in Gyeonggi-do, South Korea. Initial clinical data were compared between the pre-pandemic (2018-2019) and pandemic (2020) periods. RESULTS: In the pre-pandemic and pandemic periods, 99 patients (41 T1D and 58 T2D patients) and 84 patients (51 T1D and 33 T2D patients) were identified, respectively. During the pandemic, the proportion of diabetic ketoacidosis (DKA) cases increased compared to the pre-pandemic period (21.2% during 2018-2019 vs. 38.1% in 2020; P = 0.012). In the pre-pandemic and pandemic periods, initial pH was 7.32 ± 0.14 and 7.27 ± 0.15, respectively (P = 0.040), and HbA1c values were 11.18 ± 2.46% and 12.42 ± 2.87%, respectively (P = 0.002). During the pandemic, there was an increased risk of DKA in patients with T1D (odds ratio, 2.42; 95% confidence interval, 1.04-5.62; P = 0.040). CONCLUSION: During the pandemic, the proportion of DKA in newly diagnosed patients with T1D increased and clinical parameters showed a deteriorating pattern. Increased awareness of pediatric diabetes, especially DKA, could facilitate visit to the hospital for an early diagnosis; thus, reducing the number of DKA cases during the pandemic era.

Efficacy of Triptorelin 3-Month Depot Compared to 1-Month Depot for the Treatment of Korean Girls with Central Precocious Puberty in Single Tertiary Center.

BACKGROUND: Triptorelin depot is largely used to treat central precocious puberty (CPP) in children, and a 3-month depot has been introduced. However, data about the 3-month gonadotropin-releasing hormone use for treatment of CPP in Korean girls are not available. This study was conducted to compare the efficacy of a triptorelin 11.25 mg 3-month depot with that of a 3.75 mg 1-month depot in suppressing pubertal development for the treatment of CPP. METHODS: A retrospective study, including 106 girls with CPP treated with triptorelin, was conducted. Fifty patients were treated with a triptorelin 3-month depot, and 56 were treated with a triptorelin 1-month depot. Serum luteinizing hormone (LH), follicle-stimulating hormone, and estradiol levels were analysed every 6 months after the visit. The height and bone age of each patient was evaluated at the beginning of treatment, after 6 months, and one year after therapy. RESULTS: The baseline characteristics of the girls treated with a 3-month depot were similar to those of the girls treated with a 1-month depot. A suppressed levels of LH to the triptorelin injection (serum LH < 2.5 IU/L) at 6 months was seen in 90.0% and 98.2% of the girls treated with the 3-month and 1-month depots, respectively (P = 0.160). After 1 year of treatment, a suppressed levels of LH was seen in 93.5% and 100% of the girls treated with the 3-month and 1-month depots, respectively (P = 0.226). Height velocity showed no significant difference between the two groups. Degree of bone age advancement decreased from 1.22 ± 0.07 and 1.22 ± 0.08 years at baseline (P = 0.914) to 1.16 ± 0.07 and 1.17 ± 0.08 in the girls treated with the 3-month and 1-month depots after 1 year, respectively (P = 0.481). CONCLUSION: This study showed that the efficacy of long-acting triptorelin 3-month was comparable to 1-month depot regarding hormonal suppression and inhibition of bone maturation. The triptorelin 11.25 mg 3-month depot is an effective treatment for girls with CPP.

Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types.

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.

Serum Levels of Thyroid Stimulating Hormone and Luteinizing Hormone Are Decreased in Girls with Central Precocious Puberty after 12-Month GnRH Agonist Treatment.

Puberty is the transitional period from childhood to adult that leads to growth spurt, sexual maturation and attainment of reproductive capacity. Precocious puberty is defined when secondary sexual characteristics develop before the age of eight for girls and nine for boys. Central precocious puberty (CPP) is diagnosed when the process is driven by premature activation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion. Many factors promote CPP, and the thyroid function is thought to be one of them. In our previous study, thyroid stimulating hormone (TSH) was higher in the CPP group than that of the participants without CPP. This elevation of TSH in CPP is said to be associated with pubertal luteinizing hormone (LH) elevation. The aim of this study was to evaluate the causal relationship between TSH and LH in CPP patients. A total of 221 girls diagnosed with CPP and treated with GnRH agonists were included. All participants except one showed LH suppression (peak LH < 3 IU/L), and serum levels of follicle stimulating hormone (FSH) were also lower after the treatment. These results indicate that puberty has slowed down and that the patients were successfully treated for CPP. As for thyroid hormones, TSH was significantly lower and free thyroxine (fT4) levels were higher after 12 months of GnRH agonist treatment compared with baseline. With GnRH agonist treatment, the serum levels of LH and TSH were decreased, suggesting that the increase in serum TSH levels is associated with premature LH elevation in girls with CPP.

Lysinuric protein intolerance with homozygous SLC7A7 mutation caused by maternal uniparental isodisomy of chromosome 14.

Lysinuric protein intolerance (LPI) is caused by mutations in the SLC7A7 gene at 14q11.2. Its clinical presentation includes failure to thrive, protein intolerance due to a secondary urea cycle defect, interstitial lung disease, renal tubulopathy, and immune disorders. Maternal uniparental disomy 14 (UPD14mat) is the most common cause of Temple syndrome (TS14), which is characterized by severe intrauterine and postnatal growth failure. Here, we describe a severe form of LPI accompanied by TS14 in an 11-month-old girl, which presented as profound failure to thrive and delayed development. LPI was diagnosed by the detection of a homozygous mutation of c.713 C>T (p.Ser238Phe) in SLC7A7, which was eventually found to co-occur with UPD14mat. Despite receiving a protein-restricted diet with citrulline and lysine supplementation, the severe failure to thrive has persisted at follow-up of the patient at 4 years of age.

Fabry disease: characterisation of the plasma proteome pre- and post-enzyme replacement therapy.

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, ß-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.

Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening.

BACKGROUND: Fatty acid oxidation disorders (FAODs) include more than 15 distinct disorders with variable clinical manifestations. After the introduction of newborn screening using tandem mass spectrometry, early identification of FAODs became feasible. This study describes the clinical, biochemical and molecular characteristics of FAODs patients detected by newborn screening (NBS) compared with those of 9 patients with symptomatic presentations. METHODS: Clinical and genetic features of FAODs patients diagnosed by NBS and by symptomatic presentations were reviewed. RESULTS: Fourteen patients were diagnosed with FAODs by NBS at the age of 54.8 ± 4.8 days: 5 with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, 5 with medium chain acyl-CoA dehydrogenase (MCAD) deficiency, 1 with primary carnitine deficiency, 1 with carnitine palmitoyltransferase 1A (CPT1A) deficiency, 1 with long-chain 3-hydroxyacyl-CoA dehydrogenase or mitochondrial trifunctional protein (LCAHD/MTP) deficiency, and 1 with short chain acyl-CoA dehydrogenase (SCAD) deficiency. Three patients with VLCAD or LCHAD/MTP deficiency developed recurrent rhabdomyolysis or cardiomyopathy, and one patient died of cardiomyopathy. The other 10 patients remained neurodevelopmentally normal and asymptomatic during the follow-up. In 8 patients with symptomatic presentation, FAODs manifested as LCHAD/MTP deficiencies by recurrent rhabdomyolysis or cadiomyopathy (6 patients), and VLCAD deficiency by cardiomyopathy (1 patient), and CPT1A deficiency by hepatic failure (1 patient). Two patients with LCHAD/MTP deficiencies died due to severe cardiomyopathy in the neonatal period, and developmental disability was noted in CPT1A deficiency (1 patient). CONCLUSIONS: NBS helped to identify the broad spectrum of FAODs and introduce early intervention to improve the clinical outcome of each patient. However, severe clinical manifestations developed in some patients, indicating that careful, life-long observation is warranted in all FAODs patients.

Mutation Spectrum of STAR and a Founder Effect of the p.Q258* in Korean Patients with Congenital Lipoid Adrenal Hyperplasia.

Congenital lipoid adrenal hyperplasia (CLAH) is the most severe form of congenital adrenal hyperplasia, caused by defects in the steroidogenic acute regulatory protein (STAR). The STAR p.Q258* mutation is the most common mutation in China, Japan, and Korea, suggesting a founder effect. This study aimed to investigate the phenotypic and mutation spectrum of STAR defects and identify a founder effect of the p.Q258* mutation in Korean patients with CLAH. For 45 patients from 42 independent pedigrees, haplotype analysis was performed in 10 unrelated trio families, including patients with the p.Q258* mutation whose DNA samples were available, using 1,972 single nucleotide polymorphism (SNP) and six short tandem repeat (STR) markers. An Illumina Infinium® Human Omni2.5-8 v1.3 performed the SNP genotyping. Among 84 alleles from 42 unrelated families, mutation p.Q258* was found in 74 alleles (88.1%) from 41 families. A shared haplotype was identified in 17 of 20 alleles from 10 patients (size, 198 kb). The age of the founder mutation was estimated as 4,875 years (95% credible set: 3,575-7,925 years) assuming an intergenerational time interval of 25 years. The STAR p.Q258* mutation is the most common in Korean patients with CLAH, suggesting a founder effect. The age of the mutation corresponded with the date when the Korean people settled in the Korean peninsula. The high prevalence of p.Q258* in Japan and China also suggests a founder effect in Asian countries.

DEND Syndrome with Heterozygous KCNJ11 Mutation Successfully Treated with Sulfonylurea.

Permanent neonatal diabetes mellitus (PNDM) is caused by mutations in the ATP-sensitive potassium channel (KATP channel) subunits. Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome is the most severe form of PNDM and is characterized by various neurologic features. We report on a patient with DEND syndrome following initial misdiagnosis with type 1 DM, who was successfully switched from insulin to sulfonylurea therapy. A 50-day-old male presented with fever and seizure, complicated by persistent hyperglycemia. Insulin therapy was initiated. At 10 months of age, the patient was unable to hold his head up and make eye contact with others. At 17.9 years of age, direct sequencing of KCNJ11 identified a heterozygous mutation of c.602G>A (p.R201H). Since then, treatment with gliclazide was initiated and the insulin dose was gradually reduced. Following 3 months, insulin was discontinued with a gliclazide dose of 2.4 mg/kg. The patient continued to have excellent glycemic control with a glycated hemoglobin (HbA1c) level of 5.8% after 5 months. However, the patient's psychomotor retardation did not improve. This study reports the first case of DEND syndrome in Korea caused by a KCNJ11 mutation and emphasizes the necessity to screen mutations in KATP channel genes in patients with neonatal diabetes.

Long-term enzyme replacement therapy for Fabry disease: efficacy and unmet needs in cardiac and renal outcomes.

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 (<1 g per day) before ERT. The left ventricular mass index decreased or was stable throughout the ERT in male patients with or without left ventricular hypertrophy before ERT initiation. In female carriers and pediatric male patients, renal and cardiac functions remained stable with ERT. Arrhythmias were observed in 10 adult males and 1 female patient before ERT and persisted during ERT. One pediatric patient newly developed arrhythmia despite ERT. In conclusion, long-term ERT has beneficial effects on the renal and cardiac outcomes of Fabry patients but has limited effect in patients with irreversible organ damage. Identification of patients in the early disease stage and rapid ERT initiation might be the best strategy to improve the natural course of the disease.

Growth trajectories of children born preterm and full term with low birth weight to preschool ages: A nationwide study.

CONTEXT: Preterm (PT) and full term with low birth weight (FT-LBW) children are at a high-risk of poor growth outcomes. OBJECTIVE: To investigate the growth trajectories of PT and FT-LBW children from birth to preschool ages. METHODS: This study included 1,150,508 infants (PT, 41,454; FT-LBW, 38,250) who underwent the first three rounds (4-6, 9-12, and 18-24 months) of the National Health Screening Program for Infants and Children (NHSPIC). Growth measurements were obtained from the NHSPIC database and converted into Z-scores. Growth data at 2, 4, and 6 years old were measured as outcome variables. The impact of being born small on poor growth outcomes was investigated using a generalized estimating equation and Cox proportional-hazards regression analysis. RESULTS: The median birth weights of the PT, FT-LBW, and full term (FT) groups were 2.3, 2.4, and 3.2 kg, respectively. The incidence of short stature (height Z-score < -2 standard deviation score [SDS]) and failure to thrive (FTT) (body mass index (BMI) Z-score < -2 SDS) was the highest in the FT-LBW group, followed by the PT and FT groups. At 4 years old, the incidence rates were 6.0% vs. 5.2% vs. 1.9% for short stature and 4.6% vs. 3.9% vs. 1.7% for FTT. The ß estimate of height outcome was lower in both the PT (-0.326 SDS) and FT-LBW (-0.456 SDS) groups. CONCLUSIONS: The FT-LBW group was consistently shorter and lighter throughout the preschool period than the PT group, highlighting the significance of growth monitoring in high-risk populations.

Long-term efficacy of triptorelin 3-month depot in girls with central precocious puberty.

Purpose: Three-month gonadotropin-releasing hormone agonists (GnRHa) are expected to achieve better compliance in patients with central precocious puberty (CPP). However, 1-month depot remains the dominant choice for conventional treatment worldwide. Our study aimed to investigate the long-term efficacy of a 3-month GnRHa for CPP treatment. Methods: In this retrospective study, 69 Korean girls with CPP were prescribed with either triptorelin pamoate (TP) 3-month depot (n = 29) or triptorelin acetate (TA) 1-month depot (n = 40) and were followed up for 1 year after the end of treatment. Auxological, radiological, and biochemical data were collected every 6 months. Results: Baseline characteristics of the subjects were similar between the two groups. In the TP 3-month depot group, 27/29 (93.1 %) of patients exhibited suppressed LH levels (below 2.5 IU/L) after 6 months of treatment, and this suppression level was reserved until the final injection. The degree of bone age advancement in the TP 3-month depot group decreased from 1.8 ± 0.4 years at the start of treatment to 0.6 ± 0.5 years at 1 year post-treatment. The gain in predicted adult height (PAH) at 1 year after the end of treatment was similar between the TP 3-month and TA 1-month depot groups (5.2 ± 3.1 and 5.3 ± 2.4 cm, respectively; P = 0.875). Conclusion: The 3-month depot of triptorelin effectively inhibited gonadal and sex hormones, suppressed bone maturation, and increased PAH. For the patients' convenience, we suggest a 3-month GnRHa regimen as a promising CPP treatment option.

Effectiveness of the triptorelin stimulation test compared with the classic gonadotropin-releasing hormone stimulation test in diagnosing central precocious puberty in girls.

PURPOSE: The gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for diagnosing central precocious puberty (CPP). Gonadorelin (Relefact) is used for the test but is not always readily available; triptorelin is used as an alternative. The purpose of this study was to evaluate the diagnostic validity of the triptorelin test compared with the GnRH test in the diagnosis of CPP in girls. METHODS: This retrospective study included 100 girls with premature thelarche (PT) who underwent a hypothalamic-pituitary-gonadal axis evaluation. In the overall group, 50 girls were tested with intravenous gonadorelin (Relefact) and 50 girls were tested with subcutaneous triptorelin acetate (Decapeptyl). Luteinizing hormone (LH) and follicle-stimulating hormone levels were measured at baseline and 30, 45, 60, and 90 minutes after gonadorelin injection or 30, 60, 90, and 120 minutes after triptorelin injection. RESULTS: Clinical characteristics of age, height, weight, body mass index, and bone age were similar between the 2 groups. The highest LH level was reached 60 minutes after stimulation in both groups. Approximately 20% of the gonadorelin group and 24% of the triptorelin group were diagnosed with CPP (P=0.52). Among those diagnosed with CPP, the mean peak LH concentrations were 8.15 mIU/mL and 9.73 mIU/mL in the gonadorelin and triptorelin groups, respectively. CONCLUSION: The triptorelin test showed similar trends of LH elevation and diagnostic rate compared with the traditional GnRH test for diagnosing CPP. This suggests that the triptorelin test may be a valid alternative to the GnRH test for differentiating CPP from self-limiting PT. Our study also demonstrated that a triptorelin stimulation test for up to 120 minutes was sufficient to diagnose CPP.

Obesity in Children and Adolescents: 2022 Update of Clinical Practice Guidelines for Obesity by the Korean Society for the Study of Obesity.

The prevalence of obesity in children and adolescents has been gradually increasing in recent years and has become a major health problem. Childhood obesity can readily progress to adult obesity. It is associated with obesity-related comorbidities, such as type 2 diabetes mellitus, hypertension, obstructive sleep apnea, non-alcoholic fatty liver disease, and the risk factor for cardiovascular disease. It is important to make an accurate assessment of overweight and obesity in children and adolescents with consideration of growth and development. Childhood obesity can then be prevented and treated using an appropriate treatment goal and safe and effective treatment strategies. This article summarizes the clinical practice guidelines for obesity in children and adolescents that are included in the 8th edition of the Clinical Practice Guidelines for Obesity of the Korean Society for the Study of Obesity.

Brain magnetic resonance imaging (MRI) findings in central precocious puberty patients: is routine MRI necessary for newly diagnosed patients?

PURPOSE: The overall incidence of central precocious puberty (CPP) has increased in recent decades, and brain magnetic resonance imaging (MRI) evaluations are recommended in cases of suspected brain lesions. This study aimed to investigate the prevalence of MRI abnormalities and to evaluate the need for routine brain MRI in patients with newly diagnosed CPP. METHODS: This retrospective study reviewed the data of patients newly diagnosed with CPP who underwent routine pituitary MRI at Korea University Anam Hospital from March 2020 to September 2021. A total of 199 girls and 24 boys was enrolled in this study. Positive MRI findings were categorized as abnormal pituitary, nonpituitary incidental, and pathological. In addition, we investigated the incidence of MRI abnormalities and evaluated their associations with clinical and biochemical factors. RESULTS: Positive brain MRI findings were observed in 84 patients (37.7%). Pituitary abnormalities were found in 54 patients (24.2%), with Rathke cleft cysts being the most common (16.1%). Incidental nonpituitary findings were observed in 29 patients (13.0%), while a pathological brain lesion (diagnosed as hypothalamic hamartoma) was observed in only 1 female patient (0.4%). No significant differences in sex or age were found in incidence of pituitary abnormalities or nonpituitary incidental findings. Compared with headache controls, significant associations were observed between abnormal pituitary findings on MRI and CPP (unadjusted odds ratio, 3.979; 95% confidence interval, 1.726-9.173). CONCLUSION: True pathological findings were rare, even though the prevalence of abnormalities on pituitary MRI in patients with CPP was relatively high. Considering its cost-effectiveness, MRI screenings should be carefully considered in patients with CPP.

2022 Clinical practice guidelines for central precocious puberty of Korean children and adolescents.

The Committee of Central Precocious Puberty of Korean Pediatrics and Adolescents of the Korean Society of Pediatric Endocrinology has newly developed evidence-based 2022 clinical practice guidelines for central precocious puberty in Korean children and adolescents. These guidelines provide the grade of recommendations, which includes both the strength of recommendations and the level of evidence. In the absence of sufficient evidence, recommendations are based on expert opinion. These guidelines have been revised and supplement the previous guidelines "Clinical Guidelines for Precocious Puberty 2011," and are drawn from a comprehensive review of the latest domestic and international research and the grade of recommendation appropriate to the domestic situation. This review summarizes the newly revised guidelines into 8 key questions and 27 recommendations and consists of 4 sections: screening, diagnosis, treatment, and long-term outcome of central precocious puberty.

Evaluation and Treatment of Obesity and Its Comorbidities: 2022 Update of Clinical Practice Guidelines for Obesity by the Korean Society for the Study of Obesity.

The goal of the 8th edition of the Clinical Practice Guidelines for Obesity is to help primary care physician provide safe, effective care to patients with obesity by offering evidence-based recommendations to improve the quality of treatment. The Committee for Clinical Practice Guidelines comprised individuals with multidisciplinary expertise in obesity management. A steering board of seven experts oversaw the entire project. Recommendations were developed as the answers to key questions formulated in patient/problem, intervention, comparison, outcomes (PICO) format. Guidelines underwent multi-level review and cross-checking and received endorsement from relevant scientific societies. This edition of the guidelines includes criteria for diagnosing obesity, abdominal obesity, and metabolic syndrome; evaluation of obesity and its complications; weight loss goals; and treatment options such as diet, exercise, behavioral therapy, pharmacotherapy, and bariatric and metabolic surgery for Korean people with obesity. Compared to the previous edition of the guidelines, the current edition includes five new topics to keep up with the constantly evolving field of obesity: diagnosis of obesity, obesity in women, obesity in patients with mental illness, weight maintenance after weight loss, and the use of information and communication technology-based interventions for obesity treatment. This edition of the guidelines features has improved organization, more clearly linking key questions in PICO format to recommendations and key references. We are confident that these new Clinical Practice Guidelines for Obesity will be a valuable resource for all healthcare professionals as they describe the most current and evidence-based treatment options for obesity in a well-organized format.

Single Point Insulin Sensitivity Estimator for predicting type 2 diabetes mellitus in obese adolescents.

PURPOSE: The prevalence of adolescents with type 2 diabetes mellitus (T2DM) has rapidly increased in Korea over the past few decades with the increase in the number of obese adolescents. The single point insulin sensitivity estimator (SPISE) was recently introduced as a surrogate marker for insulin sensitivity to predict T2DM in adults. We aimed to determine risk factors for T2DM in obese adolescents, including SPISE. METHODS: This retrospective study included 104 adolescents diagnosed with T2DM at Korea University Hospital between January 2010 and December 2020. We compared clinical and biochemical parameters and the SPISE of normoglycemic overweight and obese individuals with those of prediabetic and diabetic adolescents to determine risk factors for T2DM. Receiver operating characteristic analysis was performed with the Youden index to determine the cutoff point of SPISE. RESULTS: Frequency of fatty liver and family history of T2DM were significantly higher and SPISE level was significantly lower in patients with T2DM than in normoglycemic overweight/obese and prediabetic adolescents (p<0.01). A family history of T2DM, fatty liver, and SPISE value below the cutoff point (4.49) were identified as significant risk factors for T2DM in multiple logistic regression analysis after controlling for age, sex, and body mass index standard deviation score (p<0.01). CONCLUSION: Family history of T2DM, fatty liver, and low SPISE (<4.49) are risk factors that can independently affect the occurrence of T2DM in obese adolescents. Among these risk factors, SPISE is a promising marker for predicting adolescent T2DM; careful monitoring of these individuals is needed to prevent progression to T2DM.