First evaluation of Eyberg Child Behavior Inventory for foster children in Japan.

BACKGROUND: Behavioral problems of foster children are an important issue for the maintenance of the foster care system, but they have not been adequately studied in Japan. We used the Eyberg Child Behavior Inventory (ECBI) to investigate behavioral problems among foster children and to examine associated factors. METHODS: Twenty-nine foster children and their foster parents and 479 non-foster children and parents were recruited for the foster and control groups, respectively. Both groups underwent statistical comparative analyses using data from their ECBI assessments. The ECBI has two scales: the Intensity Scale quantifies the severity of child behavioral problems, and the Problem Scale captures the caregiver's perceived difficulties handling each behavior. We conducted a retrospective investigation of the background of the foster parent-child pairs to explore potential causal relationships with behavioral problems. RESULTS: The mean intensity score for the foster group was significantly higher than that for the control group (p = 0.001). The mean problem scores for the foster group and the control group were not significantly different (p = 0.79). In the foster group, the retrospective investigation revealed two children with neurological or neurodevelopmental disorders, 17 with histories of abuse, and 10 with other issues. CONCLUSION: Intensity scores showed severe behavioral problems among foster children, perhaps caused by neurological disorders, abuse, parental mental health, or economic hardship. Problem scores showed no significant differences between groups. It can therefore be posited that foster parents might exhibit a more lenient parenting style when dealing with children who have a history of abuse by their biological parents.

An Unusual Pediatric Case of an Insidious Thermal Airway Injury Without Initial Signs of Facial or Intraoral Scalding.

Thermal airway injuries, usually accompanied by facial burns, require emergency management. We encountered a pediatric case of a late airway-scalding injury without any initial signs of scalding on the face or inside the oral cavity. A 16-month-old boy was accidentally exposed to boiling water from overhead and developed tachypnea and dyspnea at 8 h after the injury. When he visited our hospital at 12 h after the injury, there were no scalding-related findings on his face or inside his oral cavity; however, severe laryngeal edema was observed, which required emergency intubation. Thermal airway injuries can occur later, even if there is no evidence of facial or oral scalding immediately after the injury. Airway injuries should be considered when a patient has been exposed to hot water from overhead.

Efficacy of parent-child interaction therapy for children born premature.

BACKGROUND: Premature children are known to be at a high risk of developing behavioral problems. This study examined the effectiveness of parent-child interaction therapy (PCIT) in reducing behavioral problems in young children born premature. METHODS: The study included 18 child-parent pairs with children born at less than 35 weeks of gestation (range: 23-34 weeks, median: 31.0 weeks) and aged 27-52 months (median: 38.0 months). They were assigned to either the PCIT group (n = 7) or the non-PCIT group (n = 11) based on maternal desire for treatment. The study was designed to examine the effects of PCIT. Specifically, the Eyberg Child Behavior Inventory (ECBI) intensity score, ECBI problem score, and Parenting Stress Index Short Form (PSI-SF) scores were compared before treatment and after 6 months. RESULTS: In the PCIT group, the mean ECBI intensity score was 135.7 (SD = 13.5; T-score = 64) at baseline and 90.1 (SD = 15.5; T-score = 46) at post-assessment, the mean ECBI problem score was 9.8 (SD = 1.9; T-score = 54) at baseline and 4.4 (SD = 3.1; T-score = 44) at post-assessment, the mean PSI-SF total score was 60.1 (SD = 4.8; 95%tile) at baseline and 49.6 (SD = 5.6; 85%tile) at post-assessment, showing a significant improvement (ECBI intensity scores: p < 0.001, d = 2.03; ECBI problem scores: p < 0.001, d = 1.94; PSI-SF total scores: p = 0.004, d = 0.86). On the other hand, none of the scores showed significant change in the non-PCIT group. CONCLUSIONS: The PCIT can be considered as a potential treatment option for behavioral problems in young children born premature.

Temporal Trend of the SARS-CoV-2 Omicron Variant and RSV in the Nasal Cavity and Accuracy of the Newly Developed Antigen-Detecting Rapid Diagnostic Test.

The aim of this work is to analyze the viral titers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) at the anterior nasal site (ANS) and nasopharyngeal site (NS), evaluate their virological dynamics, and validate the usefulness of a newly developed two-antigen-detecting rapid antigen diagnostic test (Ag-RDT) that simultaneously detects SARS-CoV-2 and RSV using clinical specimens. This study included 195 asymptomatic to severely ill patients. Overall, 668 specimens were collected simultaneously from the ANS and NS. The cycle threshold (Ct) values calculated from real-time polymerase chain reaction were used to analyze temporal changes in viral load and evaluate the sensitivity and specificity of the Ag-RDT. The mean Ct values for SARS-CoV-2-positive, ANS, and NS specimens were 28.8, 28.9, and 28.7, respectively. The mean Ct values for RSV-positive, ANS, and NS specimens were 28.7, 28.8, and 28.6, respectively. SARS-CoV-2 and RSV showed the same trend in viral load, although the viral load of NS was higher than that of ANS. The sensitivity and specificity of the newly developed Ag-RDT were excellent in specimens collected up to 10 days after the onset of SARS-CoV-2 infection and up to 6 days after the onset of RSV infection.

A MinION-based Long-Read Sequencing Application With One-Step PCR for the Genetic Diagnosis of 21-Hydroxylase Deficiency.

CONTEXT: Recently developed long-read sequencing (LRS) technology has been considered an option for CYP21A2 analysis. However, the clinical use of LRS for CYP21A2 analysis is limited. OBJECTIVE: This study's objective is to develop an efficient and low-cost LRS system for CYP21A2 screening. METHODS: A DNA fragment library was prepared in a single polymerase chain reaction (PCR) that covers the entire CYP21A2 gene and all known junctions caused by TNXB gene structural rearrangements, yielding a single 8-kb product of CYP21A2 or CYP21A1P/CYP21A2 chimera. After barcoding, the PCR products were sequenced on a MinION-based platform with Flongle Flow Cell R9.4.1 and R10.4.1. RESULTS: The reference genotypes of 55 patients with 21-hydroxylase deficiency (21OHD) were established using the conventional method with multiplex ligation-dependent probe amplification (MLPA) and nested PCR. LRS using Flongle Flow Cell R9.4.1 yielded consistent results. Additionally, the recently updated LRS "duplex" analysis with Flongle flow cell R10.4.1 was tested to reveal an advantage of accurately sequencing a variant located on the homopolymer region. By introducing a barcode system, the cost was reduced to be comparable to that of conventional analysis. A novel single-nucleotide variation was discovered at the acceptor site of intron 7, c.940-1G > C. We also identified a subtype of the classical chimeric junction CH2, "CH2a," in the region from the latter part of intron 5 to exon 6. CONCLUSION: We successfully established a novel low-cost and highly accurate LRS system for 21OHD genetic analysis. Our study provides insight into the feasibility of LRS for diagnosing 21OHD and other genetic diseases caused by structural rearrangements.

Impact of the omicron phase on a highly advanced medical facility in Japan.

Background: Eight waves of the coronavirus disease 2019 (COVID-19) epidemic have been observed in Japan. This retrospective study was conducted to clarify the clinical characteristics of pediatric COVID-19 patients. Methods: We studied 121 patients admitted to the Jichi Children's Medical Center Tochigi between April 2020 and March 2023. Incidence of pediatric COVID-19 in Tochigi Prefecture was used to examine hospitalization and severe illness rates. Results: The mean age of the patients was 3 years and 8 months. One hundred and eleven patients (91.7%) were hospitalized after January 2022 (after the 6th wave), when the Omicron strain became endemic in Japan. Convulsions occurred in 30 patients (24.8%), all of whom were admitted after the 6th wave. Twenty-three of the 30 patients had no underlying disease. Eleven patients (9.1%) were diagnosed with acute encephalopathy. One patient died due to hemorrhagic shock and encephalopathy syndrome and two had sequelae after the 6th wave. The patient who died due to encephalopathy had hypercytokinemia. In the Tochigi Prefecture, the number of pediatric COVID-19 patients increased after the 6th wave, but the hospitalization rate declined. The rate of severe illness did not change before the end of 5th and after the 6th wave. Conclusion: Although the rate of severe illness in patients with pediatric COVID-19 did not increase after the 6th wave, some patients had complicated critical illnesses. Systemic inflammatory reaction was considered to have been associated with the severe encephalopathy.

A case of papilledema in Camurati-Engelmann disease treated effectively with prednisolone.

Camurati-Engelmann disease (CED) causes bone pain, muscle weakness, and cranial nerve symptoms due to abnormal thickening of the long bones of the limbs and the cortex of the skull. The pathophysiology of CED is a gain-of-function variant of transforming growth factor beta 1 (TGFB1). The ophthalmological symptoms of CED are usually caused by increased intracranial pressure and optic canal stenosis. Here, we report the case of a patient in whom prednisolone was effective against papilledema caused by CED. In this case, when papilledema was observed in both fundi, the patient showed increased bone pain, fever, and elevated CRP and ALP levels. Brain magnetic resonance imaging (MRI) revealed a high short tau inversion recovery (STIR) signal in both optic nerves, suggesting edematous changes. Prednisolone ameliorated bone pain, fever, and papilledema, resulting in a slight improvement of the visual function of the right eye. Our results suggest that prednisolone may be effective in treating ophthalmologic symptoms in addition to bone pain in patients with CED.

Guidelines for Newborn Screening of Congenital Hypothyroidism (2021 Revision).

Purpose of developing the guidelines: Newborn screening (NBS) for congenital hypothyroidism (CH) was started in 1979 in Japan, and early diagnosis and treatment improved the intelligence prognosis of CH patients. The incidence of CH was once about one in 5,000-8,000 births, but has been increased with diagnosis of subclinical CH. The disease requires continuous treatment and specialized medical facilities should conduct differential diagnosis and treatment in patients who are positive by NBS to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, the guidelines were revised in 2014. Here, we have added minor revisions to the 2014 version to include the most recent findings. Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.

Functional analysis of PAX8 variants identified in patients with congenital hypothyroidism in situ.

Paired box transcription factor 8 (PAX8) is essential for thyroid organogenesis and development. Heterozygous pathogenic variants of PAX8 typically cause congenital hypothyroidism (CH) due to thyroid hypoplasia. Additionally, pathogenic PAX8 variants have been identified in patients with gland in situ (GIS). This study was conducted to analyze the in vitro functional consequences of four PAX8 variants (p.D94N, p.E90del, p.V58I, and p.L186Hfs*22) previously identified in patients with CH and GIS. The transcriptional activity of PAX8 variants on the thyroglobulin (TG) promoter was assessed in a luciferase reporter assay. The levels of transcriptional activity on the TG promoter of p.E90del and p.L186Hfs*22 were significantly reduced, whereas p.D94N and p.V58I showed residual activation. In addition, a dominant negative effect on the wild-type (WT) was not detected in any PAX8 variant using a luciferase reporter assay. Two PAX8 variants (p.E90del and p.L186Hfs*22) may be pathogenic causes of CH with GIS.

The High Relevance of 21-Deoxycortisol, (Androstenedione + 17α-Hydroxyprogesterone)/Cortisol, and 11-Deoxycortisol/17α-Hydroxyprogesterone for Newborn Screening of 21-Hydroxylase Deficiency.

CONTEXT: There are limited reports on the detailed examination of steroid profiles for setting algorithms for 21-hydroxylase deficiency (21OHD) screening by liquid chromatography-tandem mass spectrometry (LC-MS/MS). OBJECTIVE: We aimed to define an algorithm for newborn screening of 21OHD by LC-MS/MS, measuring a total of 2077 dried blood spot samples in Tokyo. METHODS: Five steroids (17α-hydroxyprogesterone [17αOHP], 21-deoxycortisol [21DOF], 11-deoxycortisol [11DOF], androstenedione [4AD], and cortisol [F]) were included in the panel of LC-MS/MS. Samples from 2 cohorts were assayed: Cohort A, 63 "screening positive" neonates who were referred to an endocrinologist (n = 26 with 21OHD; n = 37 false-positive; obtained from 2015 to 2020); and Cohort B, samples (n = 2014) with 17αOHP values in the 97th percentile or above, in the first-tier test with 17αOHP ELISA from 2020 to 2021. RESULTS: Analysis of Cohort A revealed that the 3 indexes 21DOF, 11DOF/17αOHP, and (4AD + 17αOHP)/F had higher area under the curve (AUC) values (0.999, 0.997, 0.989, respectively), while the 17αOHP AUC was lower (0.970). Accordingly, in addition to 17αOHP, the 3 markers were included for defining the screening algorithm. The assay of Cohort B revealed that the new algorithm gave 92% of predicted positive predictive value without false-negative cases. We also determined the reference values for the 5 steroids at 4 to 7 days after birth, according to sex and gestational age (GA), revealing extremely low levels of 21DOF at any GA irrespective of sex differences. CONCLUSION: Our study demonstrated the high relevance of 21DOF, (4AD + 17αOHP)/F, and 11DOF/17αOHP, rather than 17αOHP, for 21OHD screening.

Genetic causes of central precocious puberty.

Central precocious puberty (CPP) is a condition in which the hypothalamus-pituitary-gonadal system is activated earlier than the normal developmental stage. The etiology includes organic lesions in the brain; however, in the case of idiopathic diseases, environmental and/or genetic factors are involved in the development of CPP. A genetic abnormality in KISS1R, that encodes the kisspeptin receptor, was first reported in 2008 as a cause of idiopathic CPP. Furthermore, genetic alterations in KISS1, MKRN3, DLK1, and PROKR2 have been reported in idiopathic and/or familial CPP. Of these, MKRN3 has the highest frequency of pathological variants associated with CPP worldwide; but, abnormalities in MKRN3 are rare in patients in East Asia, including Japan. MKRN3 and DLK1 are maternal imprinting genes; thus, CPP develops when a pathological variant is inherited from the father. The mechanism of CPP due to defects in MKRN3 and DLK1 has not been completely clarified, but it is suggested that both may negatively control the progression of puberty. CPP due to such a single gene abnormality is extremely rare, but it is important to understand the mechanisms of puberty and reproduction. A further development in the genetics of CPP is expected in the future.

Clinical guidelines for the diagnosis and treatment of 21-hydroxylase deficiency (2021 revision).

Congenital adrenal hyperplasia is a category of disorders characterized by impaired adrenocortical steroidogenesis. The most frequent disorder of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which is caused by pathogenic variants of CAY21A2 and is prevalent between 1 in 18,000 and 20,000 in Japan. The clinical guidelines for 21-hydroxylase deficiency in Japan have been revised twice since a diagnostic handbook in Japan was published in 1989. On behalf of the Japanese Society for Pediatric Endocrinology, the Japanese Society for Mass Screening, the Japanese Society for Urology, and the Japan Endocrine Society, the working committee updated the guidelines for the diagnosis and treatment of 21-hydroxylase deficiency published in 2014, based on recent evidence and knowledge related to this disorder. The recommendations in the updated guidelines can be applied in clinical practice considering the risks and benefits to each patient.

Acute Perimyocarditis in an Adolescent Japanese Male after a Booster Dose of the BNT162b2 COVID-19 Vaccine.

Perimyocarditis is a rare and serious cardiac complication following COVID-19 vaccination. Young males are most at risk after the second dose. With the introduction of the booster (third) dose, some reports have focused on the risk of perimyocarditis after a booster dose. However, no currently available report in Japan has comprehensively described this phenomenon. A healthy 14-year-old Japanese male, who had completed a two-dose primary series of the BNT162b2 (Pfizer-BioNTech) vaccine six months prior, developed fever and chest pain within 24 hours after a homologous booster dose. He was transferred to our institute because of worsening chest pain. A multiplex PCR test showed no evidence of active viral infections, including SARS-CoV-2. Electrocardiography revealed ST-segment elevation in almost all leads, suggesting pericarditis. Echocardiography showed normal systolic function. Laboratory data demonstrated C-reactive protein levels of 8.8 mg/dL and elevated cardiac damage markers (troponin T, 1.9 ng/mL; creatine phosphokinase, 1527 U/L; MB isoenzyme, 120 U/L), suggesting myocarditis. He was diagnosed with perimyocarditis associated with the booster dose, which was confirmed by cardiac magnetic resonance imaging four days after initial symptoms. Chest pain improved spontaneously along with a resolution of electrocardiographic findings and laboratory data within several days. He was discharged eight days after admission. Perimyocarditis is less frequent after a booster dose than after primary doses. In this case, the patient with booster-dose-associated perimyocarditis showed favorable clinical course without severe sequelae. The patient's clinical course was consistent with findings on previous large-scale reports on primary-dose-associated perimyocarditis and case series on booster-dose-associated perimyocarditis.

An Adolescent Patient with Sick Sinus Syndrome Complicated by Hypothyroidism Carrying an SCN5A Variant.

Previous studies have reported that hypothyroidism can lead to sick sinus syndrome (SSS) or other rhythm disturbances. Variants in the alpha subunit of the cardiac sodium channel (SCN5A) are known to be among the genetic causes of SSS. We encountered an adolescent patient with SSS and hypothyroidism who also harbored an SCN5A variant. The patient was a 13-year-old girl who was referred to our hospital because of bradycardia identified during a school electrocardiography screening. Clinical examination revealed severe hypothyroidism due to Hashimoto thyroiditis and SSS. After levothyroxine supplementation, her symptoms of hypothyroidism improved; however, the SSS did not. Genetic testing revealed a heterozygous variant (c.1066 G>A, p.Asp356Asn) in SCN5A. This is the first report of the coexistence of SSS due to an SCN5A variant and severe hypothyroidism in an adolescent patient. While patients with SCN5A variants exhibit phenotypic heterogeneity due to the presence of various modifiers, the presence of severe hypothyroidism may affect the development of SSS. This case highlights the importance of genetic analysis, including testing for SCN5A variants, in patients with hypothyroidism complicated by SSS or cardiac conduction disorders.

Newborn Screening in Japan-2021.

Japan's Newborn Mass Screening (NBS) was started in 1977 for amino acid metabolism disorders (phenylketonuria (PKU), homocystinuria, maple syrup urine, histidineemia (discontinued in 1993)) and galactosemia at the national level as a national project [...].

Current status of transition medicine for 21-hydroxylase deficiency in Japan: from the perspective of pediatric endocrinologists.

To manage of 21-hydroxylase deficiency (21-OHD), transition medicine from pediatric to adult health care is an important process and requires individually optimized approaches. We sent cross-sectional questionnaire surveys on the current status of transition from pediatric to adult health care in 21-OHD patients to all councillors of the Japanese Society for Pediatric Endocrinology. Many pediatric departments (42.2%) experienced adult 21-OHD patients, and 115 patients (53 males, mean age of 26) in 46 institutions were identified. Whereas almost two-thirds of pediatric endocrinologists regarded the problems of counterparts and cooperation as hindrance of transition medicine, the major reason for continuing to be treated in pediatrics was the patient's own request. The prevalence of long-term complications including obesity, osteoporosis, infertility, menstrual disorder, gender dysphoria, and testicular adrenal rest tumor were 27.5%, 8.8%, 11.1%, 26.3%, 7.1%, 12.5%, respectively, which is comparable to those of other cohorts previously reported. However, several items, especially infertility and osteoporosis were not checked well enough in adult 21-OHD patients treated in pediatrics. Though 44 of 62 female patients had genital reconstructive surgery, more than half of them were not followed up by gynecologists or pediatric urologists. Quite a few adult 21-OHD patients had been followed up in pediatrics even after coming of age; however, surveillance by pediatric endocrinologists of gynecological, reproductive, and mental problems may be insufficient. Therefore, multidisciplinary approaches should be required in transition medicine for 21-OHD and prerequisite for graduation of pediatrics. Pediatric endocrinologists will need to play a leading role in the development of transition systems.

Investigation of TSH receptor blocking antibodies in childhood-onset atrophic autoimmune thyroiditis.

Atrophic autoimmune thyroiditis (AAT) is a type of autoimmune hypothyroidism without goiter. TSH receptor-blocking antibodies (TSBAb) are involved in its etiology in adults. Reportedly, this disease is extremely rare in children. In this study, we aimed to investigate the prevalence of TSBAb during AAT onset in children using a commercially available cell-based bioassay TSAb kit. We conducted a multicenter retrospective observational study. We collected data of patients with AAT who were < 15 yr old, enrolled in a collaborative research group, and diagnosed since July 2003. AAT was defined as acquired autoimmune hypothyroidism without thyroid enlargement. Eighteen patients (including 15 females) whose TSH receptor antibody (TRAb) or TSBAb levels were measured within a year from the initial visit were included. The median age at diagnosis was 9.3 years, and the estimated time between onset and diagnosis was 2.6 yr. The positive rate for either TSBAb or TRAb was 38.8% (95% confidence interval: 18.3-59.5%). There were no significant differences in age, the estimated time between onset and diagnosis, and FT4 levels at diagnosis between the TSBAb-positive and -negative groups. Unlike previous reports, we showed that the prevalence of TSBAb-positivity in childhood-onset AATs is not rare, as in adults.

The progression of salt-wasting and the body weight change during the first 2 weeks of life in classical 21-hydroxylase deficiency patients.

BACKGROUND: One of the major purposes of newborn screening for 21-hydroxylase deficiency (21OHD) is preventing life-threatening adrenal crisis. However, the details of adrenal crisis in newborns are not precisely documented. AIM: We aimed to clarify the clinical details of salt-wasting in newborn 21OHD patients. METHODS: Based on the follow-up survey of the screening in Tokyo from 1989 to 2017, we retrospectively analysed the conditions of classical 21OHD neonates before the initiation of therapy. RESULTS: One hundred classical 21OHD patients (55 male, 45 female) were analysed. The age at the first hospital visit was 0-20 days with sex difference (male: 9.0 ± 3.5 days; female: 6.2 ± 3.9 days). Thirty-seven (37.4%) patients exhibited severe salt-wasting (SSW), that is, Na < 130 mEq/L, K > 7 mEq/L or Na/K ratio < 20; except for one case, SSW developed in or after the second week of life. The serum concentrations of Na, K and Na/K were linearly correlated with age in days (R2  = .38, .25, and .34 respectively), suggesting that the risk of SSW increases linearly without a threshold. The age at which the regression lines reached Na < 130 mEq/L, K > 7 mEq/L and Na/K < 20 was approximately coincided, 11.1, 12.3 and 11.2 days, respectively. All SSW patients exhibited decreased body weight from birth in their second week of life. CONCLUSION: Our data revealed that the risk of developing SSW increases during the second week of life without a threshold, and for preventing SSW, early intervention, ideally during first week of life, is desirable. An increased body weight in the second week of life indicates the absence of SSW.