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.

Co-occurrence of both maternally inherited neurofibromatosis type 1 and Lesch-Nyhan disease in a child with severe neurodevelopmental impairment

Lesch-Nyhan disease (LND) is a rare X-linked recessive inherited purine metabolic disorder that accompanies neurodevelopmental problems. Neurofibromatosis type 1 (NF1) is a relatively common autosomal dominant inherited genetic disorder characterized by tumors in various systems. Some children with NF1 also accompanies neurodevelopmental problems.Here, we describe a 5-year-old boy with a maternally inherited pathogenic variant in NF-1 and hypoxanthine-guanine phosphoribosyltransferase (HPRT ). He was referred for severe neurodevelopmental impairment and hyperuricemia. His mother was diagnosed with NF1 and the patient was also suspected of having NF1 because of cafe au lait macules. He had dystonia, rigidity, cognitive deficit, and speech/language impairment. Serum and urine uric acid concentrations were elevated. He had more severe neurodevelopmental delay than patients with only NF1, so his clinical symptoms could not be fully understood by the disease alone. To find the cause of his neurologic symptoms and hyperuricemia, the patient and his mother underwent a whole-exome sequencing test. As a result, the pathogenic variant c.151C>T (p.Arg51Ter) in HPRT1 was identified as hemizygote in the patient and heterozygote in his mother. The pathogenic variant c.7682C>G (p.Ser2561Ter) in NF-1 was identified as heterozygotes in both of them. Although the clinical symptoms of both diseases were overlapping and complicated, genetic testing was helpful for accurate diagnosis and treatment. Therefore, we suggest to consider preemptive genetic evaluation if there are symptoms not sufficiently explained by known existing diseases. And it is considered valuable to review this rare case to understand the clinical course and possible synergic effects of these diseases.

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

A Neonate Diagnosed with Wolff-Parkinson-White Syndrome Presenting with Cardiogenic Shock

We present the case of a healthy 28-day-old female full-term neonate who was admitted to the neonatal intensive care unit for severe metabolic acidosis, hypoglycemia, and an initial sinus rhythm. The first diagnostic hypothesis was hypovolemic shock, and fluid resuscitation was started immediately. During fluid therapy, cardiovascular collapse occurred with supraventricular tachycardia. The latter was successfully treated with adenosine and beta-blockers. After 8 days, electrocardiography showed ventricular pre-excitation, and Wolff-Parkinson-White syndrome was diagnosed. A novel variant of the MYL2 gene that is related to hypertrophic cardiomyopathy and conduction defect was found after discharge. Cardiogenic shock should be considered, despite being a rare cause of shock in neonates.

A Neonate Diagnosed with Wolff-Parkinson-White Syndrome Presenting with Cardiogenic Shock

We present the case of a healthy 28-day-old female full-term neonate who was admitted to the neonatal intensive care unit for severe metabolic acidosis, hypoglycemia, and an initial sinus rhythm. The first diagnostic hypothesis was hypovolemic shock, and fluid resuscitation was started immediately. During fluid therapy, cardiovascular collapse occurred with supraventricular tachycardia. The latter was successfully treated with adenosine and beta-blockers. After 8 days, electrocardiography showed ventricular pre-excitation, and Wolff-Parkinson-White syndrome was diagnosed. A novel variant of the MYL2 gene that is related to hypertrophic cardiomyopathy and conduction defect was found after discharge. Cardiogenic shock should be considered, despite being a rare cause of shock in neonates.

Molecular characterization in chromosome 11p15.5 related imprinting disorders Beckwith–Wiedemann and Silver–Russell syndromes

Epigenetics deals with modifications in gene expression, without altering the underlying DNA sequence. Genomic imprinting is a complex epigenetic phenomenon that refers to parent-of-origin-specific gene expression. Beckwith–Wiedemann syndrome (BWS) and Silver–Russell syndrome (SRS) are congenital imprinting disorders with mirror opposite alterations at the genomic loci in 11p15.5 and opposite phenotypes. BWS and SRS are important imprinting disorders with the increase of knowledge of genetic and epigenetic mechanisms. Altered expression of the imprinted genes in 11p15.5, especially IGF2 and CDKN1C, affects fetal and postnatal growth. A wide range of imprinting defects at multiple loci, instead of a restricted locus, has been shown in some patients with either BWS or SRS. The development of new high-throughput assays will make it possible to allow accurate diagnosis, personalized therapy, and informative genetic counseling.

Molecular characterization in chromosome 11p15.5 related imprinting disorders Beckwith–Wiedemann and Silver–Russell syndromes

Epigenetics deals with modifications in gene expression, without altering the underlying DNA sequence. Genomic imprinting is a complex epigenetic phenomenon that refers to parent-of-origin-specific gene expression. Beckwith–Wiedemann syndrome (BWS) and Silver–Russell syndrome (SRS) are congenital imprinting disorders with mirror opposite alterations at the genomic loci in 11p15.5 and opposite phenotypes. BWS and SRS are important imprinting disorders with the increase of knowledge of genetic and epigenetic mechanisms. Altered expression of the imprinted genes in 11p15.5, especially IGF2 and CDKN1C, affects fetal and postnatal growth. A wide range of imprinting defects at multiple loci, instead of a restricted locus, has been shown in some patients with either BWS or SRS. The development of new high-throughput assays will make it possible to allow accurate diagnosis, personalized therapy, and informative genetic counseling.

Diffuse Intracranial Hemorrhages, Acute Peripheral Neuropathy, and Acute Kidney Injury in a Newly Diagnosed Diabetes Patient with Severe Diabetic Ketoacidosis: A Case Report and Literature Review

Diabetic ketoacidosis (DKA) is a common complication associated with pediatric type 1 diabetes mellitus (DM). Although cerebral edema is the major cause of death in DKA, there is a possibility of the occurrence of other dangerous complications involving multiple systems, thereby contributing to mortality and morbidity. Herein, we report the case of a 13-year-old girl with new-onset type 1 DM and severe DKA. Her condition was further complicated by the occurrence of diffuse intracranial hemorrhages, acute kidney injury requiring hemodialysis, and peripheral neuropathy. Patients with severe acidosis require careful monitoring of kidney function and neurological complications, and these conditions should be treated appropriately.

Diffuse Intracranial Hemorrhages, Acute Peripheral Neuropathy, and Acute Kidney Injury in a Newly Diagnosed Diabetes Patient with Severe Diabetic Ketoacidosis: A Case Report and Literature Review

Diabetic ketoacidosis (DKA) is a common complication associated with pediatric type 1 diabetes mellitus (DM). Although cerebral edema is the major cause of death in DKA, there is a possibility of the occurrence of other dangerous complications involving multiple systems, thereby contributing to mortality and morbidity. Herein, we report the case of a 13-year-old girl with new-onset type 1 DM and severe DKA. Her condition was further complicated by the occurrence of diffuse intracranial hemorrhages, acute kidney injury requiring hemodialysis, and peripheral neuropathy. Patients with severe acidosis require careful monitoring of kidney function and neurological complications, and these conditions should be treated appropriately.

Rare Cases of PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome in a Korean Family Identified by Next Generation Sequencing

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive connective tissue disorder characterized by muscular hypotonia, hyperextensible skin, skin fragility, joint hypermobility, and progressive kyphoscoliosis. The disorder results from a deficiency of the enzyme collagen lysyl hydroxylase 1 due to mutations in the gene PLOD1. We describe the rare cases of kEDS in Korean siblings with two novel compound heterozygous variants, c.926_934del (p.Leu309_Leu311del) and c.2170_2172del (p.Phe724del) in the PLOD1 gene. They had congenital hypotonia, joint laxity, skin hyperextensibility, Marfanoid habitus, high myopia and atrophic scarring. The younger sibling had an early-onset progressive kyphoscoliosis, while the older sibling showed mild scoliosis during childhood. Intrafamilial variability of the clinical severity and age of kyphoscoliosis onset observed in our cases.

Rare Cases of PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome in a Korean Family Identified by Next Generation Sequencing

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive connective tissue disorder characterized by muscular hypotonia, hyperextensible skin, skin fragility, joint hypermobility, and progressive kyphoscoliosis. The disorder results from a deficiency of the enzyme collagen lysyl hydroxylase 1 due to mutations in the gene PLOD1. We describe the rare cases of kEDS in Korean siblings with two novel compound heterozygous variants, c.926_934del (p.Leu309_Leu311del) and c.2170_2172del (p.Phe724del) in the PLOD1 gene. They had congenital hypotonia, joint laxity, skin hyperextensibility, Marfanoid habitus, high myopia and atrophic scarring. The younger sibling had an early-onset progressive kyphoscoliosis, while the older sibling showed mild scoliosis during childhood. Intrafamilial variability of the clinical severity and age of kyphoscoliosis onset observed in our cases.

Rare Cases of PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome in a Korean Family Identified by Next Generation Sequencing

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive connective tissue disorder characterized by muscular hypotonia, hyperextensible skin, skin fragility, joint hypermobility, and progressive kyphoscoliosis. The disorder results from a deficiency of the enzyme collagen lysyl hydroxylase 1 due to mutations in the gene PLOD1. We describe the rare cases of kEDS in Korean siblings with two novel compound heterozygous variants, c.926_934del (p.Leu309_Leu311del) and c.2170_2172del (p.Phe724del) in the PLOD1 gene. They had congenital hypotonia, joint laxity, skin hyperextensibility, Marfanoid habitus, high myopia and atrophic scarring. The younger sibling had an early-onset progressive kyphoscoliosis, while the older sibling showed mild scoliosis during childhood. Intrafamilial variability of the clinical severity and age of kyphoscoliosis onset observed in our cases.

Correlation between genetic heterogeneity and variability for response to growth hormone in Noonan syndrome / 소아과

No abstract available.

Pediatric thyroid disorders

Thyroid hormones play an important role in normal growth and development throughout infancy, childhood, and adolescence. Abnormalities of thyroid function during the fetal period and infancy result in impaired development of the brain and skeleton. In childhood and adolescence, thyroid disorders can negatively affect normal growth and pubertal development. Therefore, early diagnosis and treatment of thyroid disorders are essential for obtaining excellent outcomes. Because most pediatric patients with thyroid disorders need long-term therapy, and can experience adverse effects or have an unfavorable prognosis, physicians should provide professional treatment and monitoring.

Frequency of Self-Monitoring of Blood Glucose during the School Day Is Associated with the Optimal Glycemic Control among Korean Adolescents with Type 1 Diabetes

BACKGROUND: This study aimed to evaluate the relationship between the frequency of self-monitoring of blood glucose (SMBG) and glycosylated hemoglobin (HbA1c) levels among Korean adolescents with type 1 diabetes mellitus (T1DM). Factors affecting the SMBG frequency were analyzed in order to improve their glycemic control. METHODS: Sixty-one adolescents aged 13 to 18 years with T1DM were included from one tertiary center. Clinical and biochemical variables were recorded. Factors associated with SMBG frequency were assessed using structured self-reported questionnaires. RESULTS: Average total daily SMBG frequency was 3.8±2.1 and frequency during the school day was 1.3±1.2. The mean HbA1c level was 8.6%±1.4%. As the daily SMBG frequency increased, HbA1c levels declined (P=0.001). The adjusted odds of achieving the target HbA1c in participants who performed daily SMBG ≥5 significantly increased 9.87 folds (95% confidence interval [CI], 1.58 to 61.70) compared with those performed SMBG four times a day. In the subjects whose SMBG frequency < 1/day during the school day, an 80% reduction in the adjusted odds ratio 0.2 (95% CI, 0.05 to 0.86) showed compared to the group with performing two SMBG measurements in the school setting. The number of SMBG testing performed at school was significantly high for individuals assisted by their friends (P=0.031) and for those who did SMBG in the classrooms (P=0.039). CONCLUSION: Higher SMBG frequency was significantly associated with lower HbA1c in Korean adolescents with T1DM. It would be necessary to establish the school environments that can facilitate adequate glycemic control, including frequent SMBG.

Pediatric thyroid disorders

Thyroid hormones play an important role in normal growth and development throughout infancy, childhood, and adolescence. Abnormalities of thyroid function during the fetal period and infancy result in impaired development of the brain and skeleton. In childhood and adolescence, thyroid disorders can negatively affect normal growth and pubertal development. Therefore, early diagnosis and treatment of thyroid disorders are essential for obtaining excellent outcomes. Because most pediatric patients with thyroid disorders need long-term therapy, and can experience adverse effects or have an unfavorable prognosis, physicians should provide professional treatment and monitoring.

Measles outbreaks in the Kyeongin area of the Republic of Korea, 2013-2014: A single-center experience in a country of measles elimination

OBJECTIVE@#To identify the source of infection and determine the clinical features and laboratory finding of measles infection.@*METHODS@#In 27 measles patients, except for 3 adult patients, the rest of 24 pediatric measles cases were analyzed with regard to age, sex, immunization status, transmission routes and molecular genotyping of measles virus. Eighteen measles patients who admitted in isolation ward were set apart to investigate clinical findings and its correlation with laboratory characteristics. Retrospective analysis of cases was conducted in this study.@*RESULTS@#Of the 24 pediatric patients, 23 (95.8%) had not received any measles-containing vaccine (MCV). Sixteen of the patients (66.7%) were aged <12 months. The suspicious index case of a girl aged 34 months was not vaccinated with MCV1 and got measles after a trip to Philippines, and molecular genotype was revealed as B3. Measles outbreaks in the community such as a restaurant were followed by this one imported case. According to analysis of 18 patients admitted in isolation ward, the median level of C-reactive protein (CRP) was 0.38 mg/dL and that of lactate dehydrogenase (LDH) was 1200 IU/L. All of the 18 patients had LDH levels above the normal range. Age correlated with CRP (ρ = 0.528, P = 0.024) and LDH (ρ = 0.501, P = 0.034). The duration of fever was correlated with the duration of fever before rash (ρ = 0.898, P < 0.01). The duration of hospitalization was correlated with CRP (ρ = 0.586, P = 0.011). The white blood cell counts were correlated with the levels of LDH (ρ = 0.505, P = 0.033), aspartate aminotransferase (ρ = 0.507, P = 0.032), and alanine aminotransferase (ρ = 0.481, P = 0.043).@*CONCLUSIONS@#Early weaning of maternally derived measles antibodies therefore vaccination of MCV1 at a young age from 9 months to 12 months should be considered in situations of early exposure. Furthermore, there is a call for consideration of scheduling an earlier age for the first dose of MMR vaccine in Europe. It is necessary for Korea to investigate the duration of the presence and quantitative analysis of maternal measles antibodies in infants and to reconsider the timing of MCV1.

Measles outbreaks in the Kyeongin area of the Republic of Korea, 2013–2014: A single-center experience in a country of measles elimination

Objective To identify the source of infection and determine the clinical features and laboratory finding of measles infection. Methods In 27 measles patients, except for 3 adult patients, the rest of 24 pediatric measles cases were analyzed with regard to age, sex, immunization status, transmission routes and molecular genotyping of measles virus. Eighteen measles patients who admitted in isolation ward were set apart to investigate clinical findings and its correlation with laboratory characteristics. Retrospective analysis of cases was conducted in this study. Results Of the 24 pediatric patients, 23 (95.8%) had not received any measles-containing vaccine (MCV). Sixteen of the patients (66.7%) were aged <12 months. The suspicious index case of a girl aged 34 months was not vaccinated with MCV1 and got measles after a trip to Philippines, and molecular genotype was revealed as B3. Measles outbreaks in the community such as a restaurant were followed by this one imported case. According to analysis of 18 patients admitted in isolation ward, the median level of C-reactive protein (CRP) was 0.38 mg/dL and that of lactate dehydrogenase (LDH) was 1200 IU/L. All of the 18 patients had LDH levels above the normal range. Age correlated with CRP (ρ = 0.528, P = 0.024) and LDH (ρ = 0.501, P = 0.034). The duration of fever was correlated with the duration of fever before rash (ρ = 0.898, P < 0.01). The duration of hospitalization was correlated with CRP (ρ = 0.586, P = 0.011). The white blood cell counts were correlated with the levels of LDH (ρ = 0.505, P = 0.033), aspartate aminotransferase (ρ = 0.507, P = 0.032), and alanine aminotransferase (ρ = 0.481, P = 0.043). Conclusions Early weaning of maternally derived measles antibodies therefore vaccination of MCV1 at a young age from 9 months to 12 months should be considered in situations of early exposure. Furthermore, there is a call for consideration of scheduling an earlier age for the first dose of MMR vaccine in Europe. It is necessary for Korea to investigate the duration of the presence and quantitative analysis of maternal measles antibodies in infants and to reconsider the timing of MCV1.

Evaluation of Eating Behavior and Nutritional Status Using the Nutrition Quotient in Obese Children

BACKGROUND: The increasing incidence of pediatric obesity has recently emerged as a social problem, and children's eating behaviors and nutritional statuses directly affect health. Obesity prevention and treatment must involve dietary life management. Despite the importance of specialized, accurate eating behavior and nutritional status evaluations of obese children, available study tools in Korea are lack. METHODS: Obesity index, blood parameters, and nutrient intake were evaluated in 64 obese children (29 boys, 35 girls) at a university hospital childhood and adolescent obesity clinic; eating behaviors and nutritional statuses were evaluated using a recently developed and validated Korean nutrient quotient (NQ) for children. RESULTS: The subjects' mean age was 9.7±1.8 years, and the mean obesity index was 132.8%±17.2%. Moderate or severe obesity (P<0.001) was significantly more frequent among girls. Nutrient intake analyses revealed insufficient intakes of fiber, calcium, potassium, vitamin A, and folic acid relative to recommendation. Protein and carbohydrate intakes were significantly elevated among boys and girls, respectively (P=0.001 and 0.004, respectively). The overall mean nutrition quotient score was 59.6±15.3. Diversity and practice scores were below average, and girls had significantly higher scores only in regularity (P=0.037). Severely obese children had significantly lower moderation (P=0.032), practice (P=0.005), and mean total scores (P=0.019) relative to normal weight children. CONCLUSION: Specialized nutrition evaluation and mediation are essential for child obesity management. The nutrition quotient might allow more efficient evaluation of obese children.

A novel FBN1 gene mutation associated with early-onset pneumothorax in Marfan syndrome

Marfan syndrome (MFS) is an inherited connective tissue disorder with a mutation in the fibrillin-1 (FBN1) gene. Fibrillin is a major building block of microfibrils, which constitute the structural component of the connective tissues. A 10-year-old girl visited our hospital with the chief complaint of precocious puberty. According to her medical history, she had a pulmonary wedge resection for a pneumothorax at 9 years of age. There was no family history of MFS. Mid parental height was 161.5 cm. The patient's height was 162 cm (>97th percentile), and her weight was 40 kg (75th-90th percentile). At the time of initial presentation, her bone age was approximately 11 years. From the ophthalmologic examination, there were no abnormal findings except myopia. There was no wrist sign. At the age of 14 years, she revisited the hospital with the chief complaint of scoliosis. Her height and weight were 170 cm and 50 kg, respectively, and she had arachnodactyly and wrist sign. We performed an echocardiograph and a test for the FBN1 gene mutation with direct sequencing of 65 coding exons, suspecting MFS. There were no cardiac abnormalities including mitral valve prolapse. A cytosine residue deletion in exon 7 (c.660delC) was detected. This is a novel mutation causing a frameshift in protein synthesis and predicted to create a premature stop codon. We report the case of a patient with MFS with a novel FBN1 gene missense mutation and a history of pneumothorax at a young age without cardiac abnormalities during her teenage years.