NANS-CDG: Expanding clinical insights with a novel patient with novel variants.

N-acetyl-d-neuraminic acid synthase-congenital disorder of glycosylation (NANS-CDG) is a rare autosomal recessive defect in the N-acetyl-neuraminic acid biosynthesis pathway. Herein, we report the first Korean NANS-CDG patient. A 10-year-old boy was referred to our clinic because of incidental radiographic findings indicating spondyloepimetaphyseal dysplasia. The patient had microcephaly, cavum septum pellucidum, and ventriculomegaly at birth, and at 10 years, a very short stature. He had a history of idiopathic chronic immune thrombocytopenia, central adrenal insufficiency, and hypothyroidism since infancy. The first unprovoked seizure occurred at the age of 2 years, and he was subsequently admitted to the hospital frequently because of respiratory infections and intractable seizures. Exome sequencing identified unreported biallelic variants of the NANS gene. Clinical and genetic confirmation of NANS-CDG highlights its expanding phenotypic and genotypic diversity.

The impacts of COVID-19 on childhood obesity: prevalence, contributing factors, and implications for management.

PURPOSE: This study aimed to identify changes in the prevalence of obesity and related diseases among children and adolescents during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This study was conducted using data from the 2016-2021 Korean National Health and Nutrition Examination Survey and included 3,861 children and adolescents aged 10-18 years. The prevalence of obesity and related diseases was adjusted for age, sex, and income. We also analyzed the socioeconomic, nutritional, and physical activity items in the survey. RESULTS: During the COVID-19 pandemic, there was a significant increase in the prevalence of obesity (p=0.02), central obesity (p=0.001), mean body mass index (BMI, p=0.03), and hemoglobin A1c (p=0.005) among children and adolescents aged 10-18 years. The intake of food and calories was significantly reduced in the normal-weight group (p=0.001 and <0.001) but not in the obese group. Incidences of skipping breakfast increased and eating out decreased, regardless of obesity status. However, the changes in health behaviors were not significant. The prevalence of central obesity and increased BMI showed a significant linear association between children and their parents, especially in the 10-12-year-old age group. A clear increase in the proportion of metabolically unhealthy children and adolescents was observed in the obese group, and the frequency of central obesity in parents also increased. CONCLUSION: The number of metabolically unhealthy, obese children and adolescents increased during the COVID-19 pandemic. Age-specific strategies that consider growth, development, and genetic and social factors are required. Health strategies targeting the entire family are required to develop healthier habits.

The first case of novel variants of the FSHR mutation causing primary amenorrhea in 2 siblings in Korea.

Follicle-stimulating hormone receptor (FSHR) mutation is a rare cause of amenorrhea. We report the first case of FSHR mutations in Korea. Two female siblings, aged 16 (patient 1) and 19 (patient 2) years, were referred to the pediatric endocrinology clinic because of primary amenorrhea despite normal breast budding. Gonadotropin-releasing hormone stimulation test showed markedly elevated luteinizing hormone and follicle-stimulating hormone with a relatively low level of estrogen, suggesting hypergonadotropic hypogonadism. Pelvic magnetic resonance imaging revealed a bicornuate uterus in patient 1 and uterine hypoplasia with thinning of the endometrium in patient 2. The progesterone challenge test revealed no withdrawal of bleeding. After two months of administration of combined oral contraceptives, menarche was initiated at regular intervals. To determine the genetic cause of amenorrhea in these patients, whole exome sequencing (WES) was performed, which revealed a compound heterozygous FSHR mutation, c.1364T>G (p.Val455Gly) on exon 10, and c.374T>G (p.Leu125Arg) on exon 4; both of which were novel mutations and were confirmed by Sanger sequencing. The patients maintained regular menstruation and improved bone mineral density while taking combined oral contraceptives, calcium, and vitamin D. Therefore, FSHR mutations can be the cause of amenorrhea in Koreans, and WES facilitates diagnosing the rare cause of amenorrhea.

Pediatric management challenges of hyperglycemic hyperosmolar state: case series of Korean adolescents with type 2 diabetes.

The hyperglycemic hyperosmolar state (HHS) is considered the most fatal complication of type 2 diabetes mellitus (DM). The number of case reports describing pediatric HHS has increased recently in parallel with obesity and the prevalence of type 2 DM in pediatric patients. In this study, we investigated the patient characteristics and outcomes of HHS in 9 adolescents with obesity and type 2 DM. Almost all patients exhibited mixed clinical features of HHS and diabetic ketoacidosis (DKA), including characteristics such as hyperosmolality and ketoacidosis. These features made definitive diagnosis difficult; 5 out of 9 patients were initially diagnosed with DKA and were treated accordingly. Patients who were initially diagnosed with HHS received a more vigorous and appropriate fluid replacement than other patients did. No patients died, although 3 exhibited complications, such as arrhythmia, acute kidney injury requiring renal replacement therapy, rhabdomyolysis, and acute pancreatitis. Hyperosmolality with consequent severe dehydration is considered a significant factor contributing to the outcomes of patients with HHS. Therefore, early recognition of hyperosmolality is crucial for an appropriate diagnosis and adequate fluid rehydration to restore perfusion in the early period of treatment to improve patient outcomes for this rare but serious emerging condition in pediatric patients.

Characteristics of pediatric rhabdomyolysis and the associated risk factors for acute kidney injury: a retrospective multicenter study in Korea.

BACKGROUND: The clinical features of pediatric rhabdomyolysis differ from those of the adults with rhabdomyolysis; however, multicenter studies are lacking. This study aimed to investigate the characteristics of pediatric rhabdomyolysis and reveal the risk factors for acute kidney injury (AKI) in such cases. METHODS: This retrospective study analyzed the medical records of children and adolescents diagnosed with rhabdomyolysis at 23 hospitals in South Korea between January 2007 and December 2016. RESULTS: Among 880 patients, those aged 3 to 5 years old composed the largest subgroup (19.4%), and all age subgroups were predominantly male. The incidence of AKI was 11.3%. Neurological disorders (53.6%) and infection (39.0%) were the most common underlying disorder and cause of rhabdomyolysis, respectively. The median age at diagnosis in the AKI subgroup was older than that in the non-AKI subgroup (12.2 years vs. 8.0 years). There were no significant differences in body mass index, myalgia, dark-colored urine, or the number of causal factors between the two AKI-status subgroups. The multivariate logistic regression model indicated that the following factors were independently associated with AKI: multiorgan failure, presence of an underlying disorder, strong positive urine occult blood, increased aspartate aminotransferase and uric acid levels, and reduced calcium levels. CONCLUSIONS: Our study revealed characteristic clinical and laboratory features of rhabdomyolysis in a Korean pediatric population and highlighted the risk factors for AKI in these cases. Our findings will contribute to a greater understanding of pediatric rhabdomyolysis and may enable early intervention against rhabdomyolysis-induced AKI.

Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature.

BACKGROUND: Large-scale genomic analyses have provided insight into the genetic complexity of short stature (SS); however, only a portion of genetic causes have been identified. In this study, we identified disease-causing mutations in a cohort of Korean patients with suspected syndromic SS by targeted exome sequencing (TES). METHODS: Thirty-four patients in South Korea with suspected syndromic disorders based on abnormal growth and dysmorphic facial features, developmental delay, or accompanying anomalies were enrolled in 2018-2020 and evaluated by TES. RESULTS: For 17 of 34 patients with suspected syndromic SS, a genetic diagnosis was obtained by TES. The mean SDS values for height, IGF-1, and IGFBP-3 for these 17 patients were - 3.27 ± 1.25, - 0.42 ± 1.15, and 0.36 ± 1.31, respectively. Most patients displayed distinct facial features (16/17) and developmental delay or intellectual disability (12/17). In 17 patients, 19 genetic variants were identified, including 13 novel heterozygous variants, associated with 15 different genetic diseases, including many inherited rare skeletal disorders and connective tissue diseases (e.g., cleidocranial dysplasia, Hajdu-Cheney syndrome, Sheldon-Hall, acromesomelic dysplasia Maroteaux type, and microcephalic osteodysplastic primordial dwarfism type II). After re-classification by clinical reassessment, including family member testing and segregation studies, 42.1% of variants were pathogenic, 42.1% were likely pathogenic variant, and 15.7% were variants of uncertain significance. Ultra-rare diseases accounted for 12 out of 15 genetic diseases (80%). CONCLUSIONS: A high positive result from genetic testing suggests that TES may be an effective diagnostic approach for patients with syndromic SS, with implications for genetic counseling. These results expand the mutation spectrum for rare genetic diseases related to SS in Korea.

Non-carbapenem antimicrobial therapy in young infant with urinary tract infections caused by community-acquired extended-spectrum ß-lactamase-producing Escherichia coli.

BACKGROUND: The frequency of urinary tract infections (UTIs) caused by community-acquired extended-spectrum ß-lactamase (CA-ESBL)-producing Enterobacteriaceae is increasing worldwide. Increased carbapenem use may lead to selection of carbapenem-resistant organisms, resulting in dire consequences for hospitals. We compared the outcomes of non-carbapenem antimicrobial therapy on UTIs caused by CA-ESBL-producing and non-producing Escherichia coli (E. coli) in infants younger than 6 months of age. METHODS: We conducted a retrospective chart review, from January 2010 to December 2018, in infants (0-6 months old) with diagnosed UTIs caused by CA-ESBL-producing and non-producing E. coli at the Pusan National University Children's Hospital. Chart reviews were completed for patients whose urine sample had been collected using urinary catheterization. We treated all patients using non-carbapenem antimicrobials. Two weeks after therapy completion, clinical states were evaluated. RESULTS: There were 105 and 582 patients diagnosed with UTIs caused by CA-ESBL-producing and non-producing E. coli, respectively. The mean age at diagnosis in ESBL and non-ESBL groups was 2.7 ± 1.6 and 2.8 ± 1.1 months (P = 0.711), respectively. There were no significant differences between ESBL and non-ESBL groups in the duration of fever (1.2 ± 0.5 and 1.2 ± 0.4 days, respectively, P = 0.761) or clinical cure states post therapy (101/105 and 567/582, respectively, P = 0.513). CONCLUSION: This study found no significant differences in treatment outcomes between ESBL and non-ESBL groups treated with non-carbapenem antimicrobials. Therefore, initially administered non-carbapenem antimicrobials can be continued in patients with UTIs caused by CA-ESBL-producing E. coli who show clinical improvement.

Ampicillin-sulbactam monotherapy in infants with febrile urinary tract infections.

BACKGROUND: Cephalosporin is the most commonly used empirical agent for urinary tract infections (UTIs) in children. However, increasing use of cephalosporins can lead to an increase in resistant pathogens. This study therefore aims to investigate the effects of monotherapy with ampicillin-sulbactam as an alternative to cephalosporins. METHODS: All 2- to 24-month-old patients who were hospitalized at Pusan National University Children's Hospital due to a first episode of a febrile UTI during the 2-year period from 2012 to 2014 were included in the study. The subjects were divided into two groups according to their empirical therapy (cefotaxime or ampicillin-sulbactam). We determined the patients' UTI pathogens and their antibiotic susceptibilities and compared the effectiveness and the occurrence of adverse effects of ampicillin-sulbactam and cephalosporin therapy. RESULTS: Forty-six patients were treated with cefotaxime (group A) and 41 patients with ampicillin-sulbactam as the empirical antibiotic (group B). The most common pathogen in both groups was Escherichia coli, and antibiotic susceptibilities of the bacterial strains isolated from both groups were similar in ampicillin-sulbactam and cefotaxime. In addition, there was no significant difference in the duration of fever after treatment between the two groups (group A: 2.0 versus group B: 3.0, P = 0.331). There were no treatment failures and no recurrence in either group, even in patients with resistant pathogens. The most common side effect of the antibiotic agents was diarrhea. CONCLUSIONS: Ampicillin-sulbactam could be an effective alternative to cephalosporin as empiric antibiotic for the treatment of first-episode UTI in patients under 24 months of age.

The first Korean cases of combined oxidative phosphorylation deficiency 35 with two novel TRIT1 mutations in two siblings confirmed by clinical and molecular investigation.

BACKGROUND: Combined oxidative phosphorylation deficiency 35 (COXPD 35) is a very rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the TRIT1 gene on chromosome 1p34. Only six cases of COXPD 35 and six allelic variants of TRIT1 gene mutations have been reported worldwide. CASE DESCRIPTION: We describe two siblings who presented with similar clinical features including severe intellectual disability and epilepsy with onset of symptom in early infancy. RESULTS: The whole exome sequencing results revealed a compound heterozygous novel variant, c.979G > A (p.Glu327Lys) and c.682 + 2 T > C, on TRIT1 exon 8 and intron 5, respectively, which was confirmed by Sanger sequencing. Protein structure analysis revealed that the p.Glu327Lys variant disrupts the conformation and electrostatic charge of the zinc-finger motif in the tRNA isopentenyltransferase (IPT), impairing binding of the mutant IPT to specific DNA sequences. CONCLUSION: This is the first report of two Korean siblings with COXPD 35 with two novel variants in TRIT1. This study will help to understand the various phenotypic spectra in patients with COXPD 35 and to expand knowledge on the mechanisms of the disease based on genetic features.

Delineation of the genetic and clinical spectrum, including candidate genes, of monogenic diabetes: a multicenter study in South Korea.

OBJECTIVES: Monogenic diabetes includes a group of heterogeneous diabetes types. We aimed to identify the frequency, clinical and molecular features of monogenic diabetes in a Korean pediatric cohort. METHODS: A retrospective cohort and multicenter study of Korean children suspected to have monogenic diabetes, managed by four pediatric endocrine centers in the southeast region of South Korea, from February 2016 to February 2020. We recruited 27 pediatric Korean patients suspected to have monogenic diabetes who had at least two of the following three criteria (age at diagnosis, family history, and clinical presentation). Targeted exome sequencing was conducted in these patients. The functional consequences of the variants were predicted by bioinformatics and protein structure analysis. RESULTS: Molecular genetic analysis identified 16 patients (59.3%) with monogenic diabetes. We identified a total of eight unique variants, including five novel variants (HNF4A c.1088C>T, CEL c.1627C>T and c.1421C>T, PAX4 c.538+8G>C, INS c.71C>T). We also identified two potential candidate gene variants for monogenic diabetes, namely c.650T>C in the SLC2A2 gene and c.629G>A in the PTF1A gene. Other variants were identified in the WFS1and NPHP3 genes in two rare genetic disorders. Variant-positive individuals had a lower presence of autoantibody positivity at the time of diagnosis and higher glycosylated hemoglobin levels at last follow-up when compared to variant-negative patients (p<0.001 and p=0.029, respectively). CONCLUSIONS: These results further expand the spectrum of known variants as well as potential candidate gene variants associated with monogenic diabetes in Korea.