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In newborn screening (NBS), it is important to consider the availability of multiplex assays or other tests that can be integrated into existing systems when attempting to implement NBS for new target diseases. Recent developments in innovative testing technology have made it possible to simultaneously screen for severe primary immunodeficiency (PID) and spinal muscular atrophy (SMA) using quantitative real-time polymerase chain reaction (qPCR) assays. We describe our experience of optional NBS for severe PID and SMA in Osaka, Japan. A multiplex TaqMan qPCR assay was used for the optional NBS program. The assay was able to quantify the levels of T-cell receptor excision circles and kappa-deleting recombination excision circles, which is useful for severe combined immunodeficiency and B-cell deficiency screening, and can simultaneously detect the homozygous deletion of SMN1 exon 7, which is useful for NBS for SMA. In total, 105,419 newborns were eligible for the optional NBS program between 1 August 2020 and 31 August 2023. A case each of X-linked agammaglobulinemia and SMA were diagnosed through the optional NBS and treated at early stages (before symptoms appeared). Our results show how multiplex PCR-based NBS can benefit large-scale NBS implementation projects for new target diseases. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests a fat depot-specific relationship with bone mineral density (BMD) in children, particularly in those who are overweight/obese. However, this has not yet been investigated in detail in children with Prader–Willi syndrome (PWS), a genetic syndrome characterized by a decreased lean mass (LM) and increased fat mass (FM). The objective of this study is to investigate the relationships of LM and FM, particularly fat distribution, with bone mineral parameters. This is a retrospective and cross-sectional study. Forty-seven prepubertal Japanese children with PWS (22 males, mean age: 6.86 years) were included. No subjects had type 2 diabetes mellitus or osteoporotic medications. LM, FM, and BMD and bone mineral content in the total body less head and the lumbar spine were measured using dual-energy x-ray absorptiometry, in addition to subcutaneous/visceral adipose tissue (SAT/VAT), and the ratio of VAT to SAT (V/S) by computed tomography at the umbilical level. Bone mineral apparent density was calculated to correct for bone size. LM positively correlated with bone mineral parameters after controlling for age, sex, growth hormone (GH) treatment, and FM. Although FM did not correlate with bone mineral parameters, compartment-specific analysis revealed that SAT positively and V/S negatively correlated with bone mineral parameters after controlling for age, sex, GH treatment and LM. A compartment-specific effect of FM on bone mineral parameters was noted such that SAT was a positive predictor for BMD independent of LM in prepubertal children with PWS. [ABSTRACT FROM AUTHOR]

Objective: Insulin growth factor‐1 (IGF‐1) is used to evaluate growth hormone (GH) sufficiency and is decreased in children with Prader–Willi syndrome (PWS). Although IGF‐1 is negatively affected by body size and nutritional status, both of which are impaired in PWS children, these variables are typically not considered when assessing IGF‐1 levels in these subjects. Here, we compared IGF‐1 levels in PWS children to controls matched for age, sex, anthropometric parameters, and nutritional status. Design/Patients/Measurements: The retrospective analysis included genetically diagnosed PWS subjects (n = 65, median age; 14.0 months) and controls (n = 111, 14.3 months) matched for age, sex, anthropometric parameters (height‐standard deviation score [SDS], weight‐SDS, body mass index‐SDS), and serum albumin levels, a marker for nutritional status. IGF‐1 SDS was compared between PWS subjects and controls after adjustment for confounding variables. The GH provocation test was performed in 29 PWS subjects, and IGF‐1 SDS was compared between GH‐sufficient (n = 20) and GH‐deficient (n = 9) subjects. Spearman's rank correlation coefficient was performed to investigate the association between age and IGF‐1 SDS. None had received GH or levothyroxine treatment. Results: After adjustment for confounding variables, IGF‐1 SDS was significantly lower in PWS subjects than controls (−1.56 vs. −1.01, p =.003), while it was not different between GH‐sufficient and GH‐deficient PWS subjects. Correlation analysis failed to show an association between age and IGF‐1 SDS both in control and PWS groups. Conclusions: IGF‐1 SDS is lower in very young children with PWS independent of anthropometric parameters and nutritional status, suggesting the presence of hypothalamic dysfunction of GH secretion. [ABSTRACT FROM AUTHOR]

Background: Children born small for gestational age (SGA), particularly when associated with an extremely low birthweight (ELBW), have a higher risk of renal dysfunction. Growth hormone (GH) treatment is used to treat short‐statured children born SGA; however, its effects on renal function remain elusive, especially in those born SGA with ELBW. Methods: Short‐statured children born SGA (N = 42) were included. Subjects were subdivided into two groups based on their birthweight: the ELBW group (N = 15) with a birthweight of <1,000 g, and the non‐ELBW group (N = 27) with birthweights ranging between 1,000 and 2,500 g. The creatinine‐based estimated glomerular filtration rates (eGFR) before (pre‐eGFR) and 5 years after GH treatment (post‐eGFR) were compared. Correlations between eGFR, anthropometric, or birth parameters, and cumulative GH dose were evaluated using Spearman's rank correlation coefficient. Results: The ELBW group had a lower pre‐ and post‐eGFR than the non‐ELBW group. Five‐year GH treatment did not significantly reduce eGFR in either group. Post‐eGFR was positively associated with gestational week and birthweight. However, the cumulative GH dose was not correlated with pre‐eGFR, post‐eGFR, or percentage change in eGFR (%ΔeGFR). The change in bodyweight standard deviation score during GH treatment was positively correlated with %ΔeGFR in the ELBW group. Conclusions: The current results indicated that GH treatment was unlikely a risk for the reduction in eGFR in short‐statured children born SGA. However, eGFR should be carefully monitored, especially in those born SGA with ELBW because these subjects had lower eGFR than non‐ELBW subjects. [ABSTRACT FROM AUTHOR]

The general methods to detect the RNA of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) in clinical diagnostic testing involve reverse transcriptases and thermostable DNA polymerases. In this study, we compared the detection of SARS-CoV-2 by a one-step real-time RT-PCR method using a heat-resistant reverse transcriptase variant MM4 from Moloney murine leukemia virus, two thermostable DNA polymerase variants with reverse transcriptase activity from Thermotoga petrophila K4 and Thermococcus kodakarensis KOD1, or a wild-type DNA polymerase from Thermus thermophilus M1. The highest performance was achieved by combining MM4 with the thermostable DNA polymerase from T. thermophilus M1. These enzymes efficiently amplified specific RNA using uracil-DNA glycosylase (UNG) to remove contamination and human RNase P RNA amplification as an internal control. The standard curve was obtained from 5 to 105 copies of synthetic RNA. The one-step real-time RT-PCR method's sensitivity and specificity were 99.44% and 100%, respectively (n = 213), compared to those of a commercially available diagnostic kit. Therefore, our method will be useful for the accurate detection and quantification of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of early-onset inflammatory bowel disease is increasing in Japan. Objective: This study aimed to analyze the treatment and progress of early-onset inflammatory bowel disease. Methods: This prospective survey evaluated the data of 43 patients aged <8 years who were diagnosed with inflammatory bowel disease (IBD) from the time of diagnosis to 36 months after registration. Results: A total of 12 patients with Crohn's disease (CD), 21 with ulcerative colitis (UC), and 3 with unclassified IBD were enrolled. The mean disease onset age was 3 years and 7 months. Colon and anal lesions were present in 100 and 50% of patients with CD, respectively. Granulomas were detected in 5 patients (41.7%). Dietary elimination including elemental diet was performed in all patients. Eleven patients (91.7%) were in remission by initial induction therapy, and 72.7% maintained remission for 36 months. Three patients (14.3%) with UC had familial history, 71.4% had pancolitis-type UC, and 66.7% exhibited disease of moderate severity. Colectomy was performed in 4 patients (21.1%). Eighteen patients (85.7%) were in remission by initial induction therapy; however, only 15.8% maintained remission for 36 months. Anal complication was more prevalent in infantile-onset IBD than in childhood-onset IBD (p = 0.014). Conclusions: Among Japanese patients aged <8 years who were diagnosed with IBD, colitis-type disease was more common in CD and pancolitis was more common in UC. As the courses of several patients were severe, identifying primary immunodeficiency appears to be necessary to confirm background disease. [ABSTRACT FROM AUTHOR]

Objective: Abnormalities in the hypothalamic‐pituitary‐thyroid (HPT) axis have been implicated in Prader‐Willi syndrome (PWS); however, limited information is currently available on age‐dependent alterations in the HPT axis. We herein investigated age‐dependent differences in thyroid hormone levels in PWS children. Design/Patients/Measurements: Free T4 (FT4), free T3 (FT3) and thyroid‐stimulating hormone (TSH) concentrations were retrospectively compared between genetically confirmed PWS children (N = 43, median age: 11.2 months) and controls (N = 85, median age: 14.5 months) matched for age, sex, body weight‐SD score (SDS), height‐SDS, body mass index‐SDS and serum albumin level, a marker of the nutritional status. Subjects were subdivided into two groups based on their age: an infant group aged between 1 and 11 months (PWS: N = 22, controls: N = 30) and a toddler group aged between 12 and 47 months (PWS: N = 21, controls: N = 55). None of the subjects had ever been treated with growth hormone or levothyroxine. Results: After adjustments for confounding variables, in the infant group, FT4 levels (pmol/L) were significantly lower in PWS (11.24 in PWS vs 14.32 in controls, P =.0002), whereas no significant differences were observed in FT3 or TSH levels. In the toddler group, no significant differences were noted in FT4 (12.23 in PWS vs 15.31 in controls, P =.10), FT3 or TSH levels. The FT3/FT4 ratio was significantly increased in PWS in both groups. FT4 levels were positively correlated with age in PWS. Conclusions: Infants with PWS had lower FT4 levels, but FT3 levels were normal, indicating that the levothyroxine replacement therapy may not need to be routinely performed. [ABSTRACT FROM AUTHOR]

Background: The effectiveness of growth hormone (GH) treatment for height gain in short‐stature children born small for gestational age (SGA) with extremely low birthweight (ELBW; birthweight <1,000 g) remains largely unknown. Methods: In study 1, 35 prepubertal Japanese children born SGA with ELBW were categorized into three groups based on the presence or absence of catch‐up growth by age 3 (CU(+) and CU(−), respectively) and GH treatment (GH(+) and GH(−), respectively). Height standard deviation (SD) scores (HT‐SDS) in the CU−/GH+ group (n = 19) were compared with those in the age‐matched CU+/GH− (n = 9) and CU−/GH‐ groups (n = 7). In study 2, 66 prepubertal Japanese SGA children treated with GH were divided into three groups by birthweight: <1,000 g (n = 19), 1,000–2,000 g (n = 20), and >2,000 g (n = 27). Changes in HT‐SDS during the initial 3 years of GH treatment were compared among the three groups. Results: In study 1, the mean HT‐SDS in the CU−/GH+ group (−1.15 SD) was similar to that in the CU+/GH‐ group (−1.39 SD) but higher than that in the CU−/GH− group (−2.24 SD). In study 2, GH achieved a height gain of +1.62 SD in the ELBW group, which was similar to that in the other groups (1,000–2,000 g: +1.46 SD, >2,000 g: +1.53 SD). Conclusions: Growth hormone treatment in short‐stature children born SGA with ELBW increased HT‐SDS, which was similar to that in SGA children born with a birthweight ≥1,000 g. These results indicate that GH treatment may be an effective approach to promote adequate growth recovery for short‐stature children born SGA with ELBW. [ABSTRACT FROM AUTHOR]

The Japan Pediatric Helicobacter pylori Study Group published the first guidelines on childhood H. pylori infection in 1997. They were later revised by the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (JSPGHAN). The H. pylori eradication rates, when employing triple therapy with amoxicillin and clarithromycin, currently recommended as the first‐line therapy of H. pylori infection in Japan, have substantially decreased, creating an important clinical problem worldwide. In Japanese adults, the "test‐and‐treat" strategy for H. pylori infection is under consideration as an approach for gastric cancer prevention. However, the combined North American and European pediatric guidelines have rejected such a strategy for asymptomatic children. As risk for gastric cancer development is high in Japan, determining whether the "test‐and‐treat" strategy can be recommended in children has become an urgent matter. Accordingly, the JSPGHAN has produced a second revision of the H. pylori guidelines, which includes discussion about the issues mentioned above. They consist of 19 clinical questions and 34 statements. An H. pylori culture from gastric biopsies is recommended, not only as a diagnostic test for active infection but for antimicrobial susceptibility testing to optimize eradication therapy. Based upon antimicrobial susceptibility testing of H. pylori strains (especially involving clarithromycin), an eradication regimen including use of the antibiotics to which H. pylori is susceptible is recommended as the first‐line therapy against H. pylori‐associated diseases. The guidelines recommend against a "test‐and‐treat" strategy for H. pylori infection for asymptomatic children to protect against the development of gastric cancer because there has been no evidence supporting this strategy. [ABSTRACT FROM AUTHOR]

Background: Children born small for gestational age (SGA) with catch‐up growth are at high risk for developing obesity; however, the characteristics of body composition, especially fat distribution, before and after growth hormone (GH) treatment in SGA children without catch‐up growth remains largely unknown. Methods: Anthropometric characteristics, body composition by dual‐energy X‐ray absorption, and fat distribution by computed tomography at the umbilical level were examined in 27 prepubertal short‐stature children born SGA before and 1 year after GH treatment. Results: Before GH treatment, short‐stature SGA children had lean phenotypes, and both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were significantly lower than the age‐ and sex‐matched Japanese reference values. Growth hormone treatment significantly increased height standard deviation scores (SDS), without affecting body mass index SDS. Percentage fat mass decreased with GH treatment; however, fat mass was not altered. Both VAT and SAT were significantly lower than the reference values after GH treatment. The ratio of VAT over SAT significantly increased by GH treatment. Conclusions: Both VAT and SAT were within or below the age‐ and sex‐matched Japanese reference values in short‐stature children born SGA before and after GH treatment, indicating that GH treatment may not have unfavorable effects on adiposity in short‐stature children born SGA, although it may alter fat distribution. [ABSTRACT FROM AUTHOR]

The essential trace element zinc maintains liver functions. Liver diseases can alter overall zinc concentrations, and hypozincemia is associated with various hepatic pathologies. Modulating systemic zinc through dietary supplementation is potentially useful for liver diseases. We evaluated the usefulness of zinc (NPC-02; acetate formulation) supplementation. We conducted two NPC-02 studies on zinc-deficient patients (serum zinc < 70 μg/dL). Study 1: double-blind, randomized, placebo-controlled trial on 57 subjects with chronic liver diseases comparing serum zinc in patients given NPC-02 (NPC-02 group) versus placebo (Placebo group). Study 2: dose adjustment study on 43 subjects with/without liver diseases to determine proportions maintaining serum zinc target (≥ 80 μg/dL but < 200 μg/dL). In study 1, NPC-02 subjects had higher serum zinc concentrations at week 8 than Placebo subjects (83.2 ± 20.2 and 61.3 ± 12.0, respectively; P < 0.0001), and more NPC-02 than Placebo subjects achieved the serum zinc target (15/27 vs. 1/26). In study 2, the NPC-02-induced serum zinc increase was dose-dependent in subjects both with and without liver diseases (r = 0.5143, P = 0.0022 and r = 0.5753, P = 0.0005, respectively). Interestingly, there was a marginally positive correlation between serum zinc and albumin levels in subjects with but not in those without liver diseases (r = 0.4028, P = 0.0631 and r = 0.1360, P = 0.5567, respectively). NPC-02 dose-dependently increases serum zinc in hypozincemic patients, regardless of liver disease. NPC-02 is a potentially effective therapy for liver cirrhosis, in which zinc deficiency is common. Clinical trial registry number: NCT02337569, NCT02321865. [ABSTRACT FROM AUTHOR]

MIRAGE syndrome is a recently identified disorder characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. It is caused by a gain-of-function variant in the SAMD9 gene, but there is limited knowledge regarding the genotype–phenotype correlation. We herein report a Japanese patient with MIRAGE syndrome carrying a novel de novo heterozygous missense variant in the SAMD9 gene (c.4435 G > T; p.Ala1479Ser). [ABSTRACT FROM AUTHOR]

For preterm and very low birthweight infants, the mother's own milk is the best nutrition. Based on the latest information for mothers who give birth to preterm and very low birthweight infants, medical staff should encourage and assist mothers to pump or express and provide their own milk whenever possible.If the supply of maternal milk is insufficient even though they receive adequate support, or the mother's own milk cannot be given to her infant for any reason, donor human milk should be used.Donors who donate their breast milk need to meet the Guideline of the Japan Human Milk Bank Association.Donor human milk should be provided according to the medical needs of preterm and very low birthweight infants, regardless of their family's financial status.In the future, it will be necessary to create a system to supply an exclusive human milk‐based diet (EHMD), consisting of human milk with the addition of a human milk‐derived human milk fortifier, to preterm and very low birthweight infants. [ABSTRACT FROM AUTHOR]

Background: In Japan, prophylactic thyroidectomy involves out-of-pocket expense. The American Thyroid Association (ATA) recommends prophylactic thyroidectomy for medullary thyroid carcinoma (MTC) during early childhood in patients with multiple endocrine neoplasia type 2 (MEN2). The ATA reports a high frequency of postoperative complications in childhood, which also influenced the delay of prophylactic thyroidectomy in Japan. Methods: This retrospective study of multiple medical centers in Japan included individuals aged <20 years diagnosed with germline RET mutations between 1997 and 2017. The onset and onset possibility were defined based on confirmed lesions or calcitonin levels. The definition of risk and prophylactic thyroidectomy were based on the ATA 2015 revised guideline. Results: Twenty-one patients with MEN2 were enrolled (highest risk, n = 5; high risk, n = 5; and moderate risk, n = 11). The cumulative incidence of the onset/onset possibility reached 50% at 5 and 8 years and 100% at 9 years and 17 years in high- and moderate-risk patients, respectively. Of 7 patients with MEN2A, 71% underwent prophylactic thyroidectomy. Only one 5-year-old patient (C634Y) had increased serum calcitonin level after prophylactic thyroidectomy in the MEN2A group. The only permanent complication, which did not occur in patients who underwent total thyroidectomy alone, was hypoparathyroidism (33% of patients). This permanent complication occurred with clinically developed MTC. No permanent postoperative complications occurred in patients aged 5–6 years. Conclusions: Prophylactic thyroidectomy reduces recurrence and postoperative complications in pediatric patients with MEN2. Early thyroidectomy based on only calcitonin level could possibly reduce thyroidectomy delay. [ABSTRACT FROM AUTHOR]

Background: Proton pump inhibitors (PPI) are widely used for the treatment of gastric acid‐related disease, but they are not approved for use in children in Japan. To assess the safety, pharmacokinetics, pharmacodynamics, and efficacy (gastrointestinal symptom improvement) of PPI in Japanese pediatric patients with gastric acid‐related disease, we conducted an 8 week, open‐label, parallel‐group, multicenter, phase I/III study of once‐daily oral esomeprazole use. Methods: Japanese children, aged 1–14 years with gastric acid‐related disease, were stratified by weight and age into five groups (10 patients/group) to receive esomeprazole as granules for suspension (10 mg) or capsules (10 mg or 20 mg) once daily. Results: Esomeprazole was absorbed and eliminated rapidly in all groups, with a median time to reach maximum plasma concentration of 1.47–1.75 h, an arithmetic mean terminal elimination half‐life of 0.80–1.37 h, and a weight‐correlated apparent total body clearance of 0.216–0.343 L/h/kg. Area under the plasma concentration–time curve during a dosage interval and maximum plasma drug concentration were generally higher in groups given a higher dose (20 mg) or with a lower age/weight, but also in patients identified as poor metabolizers on cytochrome P450 2C19 genotype. Most patients who had any upper gastrointestinal symptoms at baseline were asymptomatic at the end of the study. Thirty‐three patients (66%) reported ≥1 adverse events, including three patients who reported serious adverse events not judged to be causally related to esomeprazole. Conclusions: Oral esomeprazole, at 10 mg or 20 mg once daily, had a similar safety, efficacy, and pharmacokinetic profile in Japanese pediatric patients to that previously seen in adults and Caucasian children. [ABSTRACT FROM AUTHOR]

The article focuses on the study of Male assignment in 5a-reductase type 2 deficiency with female external genitalia. Topics discussed include Posterior reversible encephalopathy syndrome (PRES) can occur in diverse situations and is characterized by seizures, impairment of consciousness, headaches, visual abnormalities, nausea, and vomiting; and most cases are caused by systemic hypertension but there are other etiological conditions and entities, including immunosuppressant drug use.

The article presents a case study of a patient with 46,XY disorders of sex development (DSD) who has been presented with Wilms tumor during infancy and later developed late-onset nephrotic syndrome. Regular monitoring for Wilms tumor and nephrotic syndrome is emphasized in 46,XY DSD, especially in cases with pathogenic variants in the WT1 gene. It underscore the importance of long-term monitoring and early genetic testing for predicting clinical outcomes in such cases.

Background: The aim of this study was to investigate consumer perception of ionic beverage consumption by young children as a potential link to their excessive use. Methods: We studied parents' awareness of ionic beverages and the current pattern of use in their young children using a self‐administered questionnaire. Results: A total of 424 responses were recorded. Approximately 25–33% of parents believed that ionic beverages are good for health and rich in nutrients and vitamins, but, only 5.9% of the parents agreed with the statement that ionic beverages are safe to consume in large quantities. Regarding their use, 11 children (2.6%) were drinking ionic beverages every day or several times a week. The parents of these children were classified into the frequent use group. The rates at which parents agreed with statements that ionic beverages are good for health and rich in vitamins were higher in the frequent use group than in controls. Conclusion: Parental awareness of ionic beverages, and current consumption patterns in their young children are generally good. Having a positive opinion about the benefits of ionic beverages was associated with excessive consumption. [ABSTRACT FROM AUTHOR]

Abstract: Background: Shwachman–Diamond syndrome (SDS) is a rare multisystem disorder associated with exocrine pancreatic insufficiency. The present study reports the results of a nationwide survey and a systematic review on SDS to develop consensus guidelines for intractable diarrhea including SDS. Methods: Questionnaires were sent to 616 departments of pediatrics or of pediatric surgery in Japan in a nationwide survey. A second questionnaire was sent to doctors who had treated SDS patients and included questions on clinical information. Additionally, a systematic review was performed using digital literature databases to assess the influence of medical (i.e. non‐surgical) treatment on SDS prognosis. Results: Answers were received from 529 institutions (85.9%), which included information on 24 patients with SDS (median age, 10.4 years; male, n = 15) treated from January 2005 to December 2014. Although 75% of patients received pancreatic enzyme replacement therapy, there was no significant association between treatment and prognosis. Systematic review identified one clinical practice guideline, two case series, eight case reports and 26 reviews. Patient information from those studies was insufficient for meta‐analysis. Conclusions: The rarity of SDS makes it difficult to establish evidence‐based treatment for SDS. According to the limited information from patients and published reports, medical treatment for malabsorption due to SDS should be performed to improve fat absorption and stool condition, but it is not clear whether this treatment improves the prognosis of malabsorption. [ABSTRACT FROM AUTHOR]

MAGEL2 is the paternally expressed gene within Prader–Willi syndrome critical region at 15q11.2. We encountered three individuals in whom truncating mutations of MAGEL2 were identified. Patients 1 and 2, siblings born to healthy, non‐consanguineous Japanese parents, showed generalized hypotonia, lethargy, severe respiratory difficulty, poor feeding, and multiple anomalies including arthrogryposis soon after birth. We carried out whole‐exome sequencing, which detected a MAGEL2 mutation (c.1912C>T, p.Gln638*, heterozygous). The patients’ father was heterozygous for the mutation. Patient 3 was a female infant, showed respiratory difficulty reflecting pulmonary hypoplasia, generalized hypotonia, feeding difficulty and multiple anomalies soon after birth. Targeted next‐generation sequencing detected a novel heterozygous mutation in MAGEL2 (c.3131C>A, p.Ser1044*). This mutation was not found in the parents. MAGEL2 mutations, first reported to be the cause of the Prader–Willi like syndrome with autism by Schaaf et al. (2013) Nature Genetics, 45: 1405–1408 show the wide range of phenotypic spectrum from lethal arthrogryposis multiplex congenital to autism spectrum disorder (ASD) and mild intellectual disability (ID). Our results indicate that MAGEL2 mutations cause multiple congenital anomalies and intellectual disability accompanied by arthrogryposis multiplex congenita and various endocrinologic abnormalities, supporting that the view that clinical phenotypes of MAGEL2 mutations are variable. [ABSTRACT FROM AUTHOR]

Esophagogastric landmarks are recognizable in the same way both in children and in adults, and palisade-shaped vessels can be observed at the distal position of esophageal mucosa, even in infants. Few studies have been done in respect to Barrett's esophagus ( BE) in children. Incidence of endoscopically suspected BE among all children undergoing esophagogastroduodenoscopy ( EGD) is approximately 0.25-1.4%, but can be up to 9.7% in patients with gastroesophageal reflux disease ( GERD). Some data suggest that BE is an acquired disorder and point to the possibility of a congenital component in combination with severe mucosal injury. Recent reports noted that multilayered epithelium ( ME), which shows morphological and immunocytochemical characteristics of both squamous and columnar epithelium, is associated with goblet cell metaplasia in adult patients with columnar-lined esophagus. The role of ME in the development of intestinal metaplasia in children is uncertain. Furthermore, detailed mechanisms about how short-segment BE ( SSBE) changes to long-segment BE ( LSBE) are not yet well understood. Further studies are required to understand the pathological esophagogastric junction ( EGJ) and BE in children based on reliable epidemiological data and analysis especially in children who have reflux symptoms. Better understanding of the pediatric EGJ and BE may allow improved diagnosis, monitoring, therapy and, therefore, prognosis of GERD-related disorders in adulthood. [ABSTRACT FROM AUTHOR]

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We previously documented a girl with macrothrombocytopenia and developmental delay who carried a de novo mutation in CDC42, which plays pivotal roles in the cell cycle and the formation of the actin cytoskeleton. The phenotype of mice lacking Cdc42 was strikingly similar to that of the reported patient, indicating that the mutation in CDC42 causes a new syndromic form of thrombocytopenia. We, herein, report another unrelated female patient with a similar phenotype and a de novo mutation in the same CDC42. The present observation provides further evidence supporting the notion that a mutation in CDC42 causes a recognizable syndromic form of thrombocytopenia. The cardinal features of this entity include macrothrombocytopenia, developmental delay, lymphedema in the lower extremities, camptodactyly, and distinctive facial features. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background/objective: Approximately 10% of small for gestational age (SGA) infants fail to catch up. The relationship between postnatal growth and placental pathology in SGA infants remains unclear. Our aim was to assess the involvement of placental pathology in postnatal growth of SGA infants.Methods: We retrospectively evaluated placental pathology and postnatal growth in single-pregnancy infants born after 37 gestational weeks in our institution, with both birth weight and length below -2 standard deviation scores (SDS) of the normal weight and length. "Catch-up" was defined as height reaching -2 SDS before the second birthday. Pathology of the placenta was classified into: abnormality due to maternal factors or fatal factors, villitis of unknown etiology (VUE), other abnormalities and no abnormality.Results: Of the 33 084 infants, 142 met our criteria and 49 of them had analyzable data. The overall catch-up rate was 84%. Catch-up growth took place in all infants with no placental abnormality and only 57% of infants with abnormality due to fatal factors. There was no significant relationship between catch-up rate and other factors.Conclusion: Placental pathology is associated with postnatal growth in SGA children born at term. Placental abnormality due to fetal factors is related to poor catch-up rate. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 6-year-old girl has visited the hospital for evaluation of short stature. Topics include the turner syndrome (TS) is a chromosomal disorder with characteristic features, such as short stature and ovarian failure, the TS is typically diagnosed based on 20-cell karyotyping of peripheral blood lymphocytes, with 45, X being the most prevalent, and the TS is phenotypically suspected, despite a lack of evidence for mosaicism by 20-cell karyotyping.

X-linked alpha thalassemia mental retardation ( ATR- X) syndrome is an X-linked recessive disorder that often involves gastrointestinal symptoms. Aspiration pneumonia related to gastroesophageal reflux has been reported as the major cause of death, but gastrointestinal function has not been well investigated. The present report describes a child with ATR- X syndrome who suffered from periodical episodes of refractory vomiting. We investigated the function of upper alimentary tract and found that esophago-gastric dysmotility and severe gastric volvulus were the major causes of gastrointestinal symptoms. This child was surgically treated with anterior gastropexy and jejunal alimentation through gastrostomy, and the symptoms were relieved with good weight gain. This report may provide insight into the gastrointestinal function and nutritional management in children with ATR- X syndrome. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the impact of cow's milk allergy (CMA) on infants with Hirschsprung's disease (HD). Methods: Twenty-four patients, who developed gastrointestinal symptoms before the age of 60 days and underwent surgery for HD in the period between January 2003 and December 2012, were enrolled in this study. They were divided into two groups based on CMA-related findings: stimulation index of lymphocyte stimulation test >300 % and the presence of eosinophilic infiltration in the resected colon. Ten patients were determined specimen as not having CMA (Group A), because they did not satisfy any of the criteria. The remaining 14 were determined as having possible CMA (Group B), because they satisfied either or both findings. Patient background characteristics, pre- and postoperative clinical history, and laboratory data were compared between Groups A and B. Results: Pre- and postoperative enterocolitis did not occur in Group A patients. Postoperative enterocolitis was more frequent in Group B than in Group A ( p = 0.04). Other clinical and laboratory data did not show significant difference between the two groups. Conclusion: CMA is a possible risk factor for postoperative enterocolitis in patients with HD. [ABSTRACT FROM AUTHOR]

Background: 46,XY disorders of sex development (46,XY DSD) are genetically heterogeneous conditions. Recently, a few submicroscopic genomic rearrangements have been reported as novel genetic causes of 46,XY DSD. Methodology/Principal Findings: To clarify the role of cryptic rearrangements in the development of 46,XY DSD, we performed array-based comparative genomic hybridization analysis for 24 genetic males with genital abnormalities. Heterozygous submicroscopic deletions were identified in three cases (cases 1–3). A ∼8.5 Mb terminal deletion at 9p24.1–24.3 was detected in case 1 that presented with complete female-type external genitalia and mental retardation; a ∼2.0 Mb interstitial deletion at 20p13 was identified in case 2 with ambiguous external genitalia and short stature; and a ∼18.0 Mb interstitial deletion at 2q31.1–32 was found in case 3 with ambiguous external genitalia, mental retardation and multiple anomalies. The genital abnormalities of case 1 could be ascribed to gonadal dysgenesis caused by haploinsufficiency of DMRT1, while those of case 3 were possibly associated with perturbed organogenesis due to a deletion of the HOXD cluster. The deletion in case 2 affected 36 genes, none of which have been previously implicated in sex development. Conclusions/Significance: The results indicate that cryptic genomic rearrangements constitute an important part of the molecular bases of 46,XY DSD and that submicroscopic deletions can lead to various types of 46,XY DSD that occur as components of contiguous gene deletion syndromes. Most importantly, our data provide a novel candidate locus for 46,XY DSD at 20p13. [ABSTRACT FROM AUTHOR]

Background and Aim Pediatric inflammatory bowel disease ( IBD) has not been rare in Japan since the 1990s. The present study attempted to define the epidemiological and clinical characteristics of early-childhood IBD in Japan in comparison with results from Western countries. Methods Among children diagnosed as having IBD between January 1998 and December 2008, those showing onset before 8 years of age were investigated retrospectively. A questionnaire survey was carried out at 45 facilities throughout Japan, and 80 cases were reported from 27 facilities. On the basis of the final diagnosis, 24 patients with Crohn's disease ( CD) and 47 patients with ulcerative colitis ( UC) were analyzed. Results Among the patients with CD, the age at onset was less than 1 year in 62.5%. On the basis of the Montreal classification, 87.5% of CD cases involved the colon, and 63.8% of UC cases were pancolitis. Coexisting conditions such as congenital diseases (five cases) and cerebral palsy (four cases) were present before the onset of IBD. Growth failure was more severe ( P < 0.05) at diagnosis in CD patients than in UC patients. Familial occurrence within first-degree relatives was observed in eight families among 45 patients with UC, compared with none among the CD patients ( P < 0.05). Conclusion Our results suggest that, in Japan, the pathogenesis of IBD in infants and children may differ from that in Western countries, and that the characteristics of early childhood-onset IBD are distinct from those of school age-onset IBD. [ABSTRACT FROM AUTHOR]

There is little information available on the efficacy of pegylated interferon (PEG IFN) therapy for children with chronic hepatitis C. The aim of this study was to evaluate the efficacy and tolerability of PEG IFN-α2a monotherapy for children infected by chronic hepatitis C virus (HCV). From 2004-2006, we conducted a prospective, open-label, multicenter study of 22 patients aged 4-18 years, including eight with genotype 1 and 14 with genotype 2. None had previously received IFN. The patients were treated with s.c. PEG IFN-α2a at a dose of 3 µg/kg once a week for 48 weeks. Rapid virological response (RVR) was defined as: undetectable serum HCV RNA at week 4; early viral response (EVR) as a 2 or more log reduction or undetectable serum HCV RNA at week 12; and sustained viral response (SVR) as undetectable serum HCV RNA at 24 weeks after the cessation of treatment. SVR was achieved in 10 (45%) of the 22 patients (three with genotype 1, seven with genotype 2). Retrospectively, the patients with SVR included five with RVR (one with genotype 1, four with genotype 2) and five with EVR (two with genotype 1, three with genotype 2). PEG IFN-α2a monotherapy was well tolerated, except in one patient in whom alanine aminotransferase activity flared (>500 IU/L) during treatment. The efficacy of PEG IFN-α2a monotherapy in children is similar to that for adults, while tolerability seems to be better in children than in adults. [ABSTRACT FROM AUTHOR]

To describe the clinical features of children with ovotesticular disorder of sex development (DSD) and to review cases of ovotesticular DSD in Japan. Medical records of eight children diagnosed with ovotesticular DSD at our institute during the past 17 years were retrospectively evaluated. A review of 165 reported cases of ovotesticular DSD from Japanese institutions was carried out. Mean follow up was 8.2 years for six children, with two children lost to follow up. Mean age at first presentation was 2.4 months. All children were Japanese. The most common initial manifestation was ambiguous genitalia. The female : male ratio as the sex of rearing was 1:1. Gender reassignment, from male to female, was carried out in one child at 4-months-old. Genital surgery was always carried out in early childhood as per family desire. Appropriate gonadal tissue was preserved except for one child. No gonadal tumors were detected during follow up. Spontaneous pubertal development occurred in one boy. In reviewing Japanese data, the frequency of testes was higher than in other ethnicities and this was related to the higher incidence of 46,XY. According to our experience, most families in Japan desire early genital surgery in the case of ovotesticular DSD. Chromosomal and gonadal distributions in patients with ovotesticular DSD differ between Japanese and other ethnic groups. Treatment for these patients needs to be provided after considering the cultural and social backgrounds of DSD in Japan. [ABSTRACT FROM AUTHOR]

The article provides information on a longitudinal study which investigated the effect of birth size on serum adinopectin levels in infants and preschoolers and age-dependent changes in this effect. A review of the related literature is presented. Study population were 83 healthy Japanese children. A linear mixed model for repeated measures was utilized to analyze the effect of sex, gestational age, birth length, birth weight or placental weight on adiponectin. The findings of the study are presented and discussed in detail.

McCune-Albright syndrome is characterized by café-au-lait spot, multiple endocrine hyperfunction, and polyostotic fibrous dysplasia. A somatic point mutation of Gsalpha protein leads to an increase in the Gsalpha-associated hormone activity in McCune-Albright syndrome. Because cyclic adenosine 3',5'-monophosphate stimulates the dopamine beta hydroxylase gene, an activating mutation of the Gsalpha protein may cause the hyperproduction of norepinephrine via dopamine. We report on a 9-year-old girl with McCune-Albright syndrome complicated by severe arterial hypertension. The urinary excretion of norepinephrine was 5- to 10-fold higher than in age-matched controls. Meta-iodobenzylguanidine scintigraphy and positron emission tomography/computed tomography (PET/CT) revealed no hot spots. These findings suggest that severe hypertension might be due to an activating mutation of Gsalpha protein in sympathetic ganglia. Because of the reported association of GNAS1 gene polymorphism with hypertension, our patient provides further evidence for a role of Gsalpha protein in hypertension. [ABSTRACT FROM AUTHOR]

Rikkunshito (TJ-43), a herbal medicine consisting of eight herbs, is used to treat chronic dyspepsia. Studies have shown that TJ-43 improves human gastric emptying. This study investigated the effects of TJ-43 on the clinical symptoms and esophageal acid exposure in children with symptomatic gastroesophageal reflux (GER). Eight children, aged from 2 months to 15 years (median age 4 years), were studied. Six of them had neurological impairment. TJ-43 (0.3 g/kg/day) was given orally or via nasogastric tubes in three divided doses before meals for 7 days. Their symptoms were frequent emesis in four, nausea in two, and hematemesis and stridor in one each. Twenty-four-hour esophageal pH monitoring was conducted using multichannel pH electrodes located at the distal esophagus (P1) and 10 cm proximal to P1 (P2). The clinical symptoms and esophageal pH were compared before and after TJ-43 therapy for 1 week. The frequency of emesis decreased in three patients. Other symptoms, including nausea, hematemesis, and stridor, were relieved in the remaining patients. Measured at the distal pH electrode, the percentage time of esophageal pH < 4.0 and the mean duration of reflux decreased significantly (P < 0.05). However, the number of acid reflux per hour did not change significantly, and no pH parameters measured at the proximal electrode differed significantly. The short-term administration of TJ-43 relieved symptoms and reduced the distal esophageal acid exposure through improved esophageal acid clearance. [ABSTRACT FROM AUTHOR]

Background. Although Helicobacter pylori infection is typically acquired in childhood, the role of H. pylori infection in gastroduodenal diseases in childhood remains to be defined. The purpose of this study was to evaluate the prevalence of H. pylori infection in children with gastritis, duodenal ulcer, and gastric ulcer. Methods. This was a retrospective analysis of 283 Japanese children (mean age, 11.5 years) with non-nodular gastritis (n = 73), nodular gastritis (n = 67), duodenal ulcer (n = 100), and gastric ulcer (n = 43). H. pylori status was based on biopsy tests. Clinical symptoms at the time of endoscopy were analyzed with regard to a possible association with the infection. Results. The prevalence of H. pylori in non-nodular gastritis, nodular gastritis, duodenal ulcer, and gastric ulcer was 28.8%, 98.5%, 83.0%, and 44.2%, respectively. H. pylori was significantly linked to duodenal ulcer and gastric ulcers in the age group of 10–16 years, but not in the age group of 9 years and under. In children with H. pylori infection, nodular gastritis was observed in 26.3% of gastric ulcer patients and in 74.7% of duodenal ulcer patients (P < 0.001). H. pylori infection was significantly associated with the prevalence of anemia (P < 0.05). Conclusions. H. pylori is the most important causal factor for the development of duodenal ulcer in childhood. While H. pylori infection appears to be a risk factor in gastric ulcer, other causes are responsible for most cases. Nodular gastritis is the most common type of H. pylori gastritis in childhood. Chronic infection with H. pylori is associated with anemia. [ABSTRACT FROM AUTHOR]

Purpose. Our aim was to evaluate the usefulness of the [sup 13] C-urea breath test (UBT) for the diagnosis of Helicobacter pylori infection, for assessment of the efficacy of eradication therapy, and for post-treatment follow-up in children. Methods. Seventy-two patients who underwent endoscopy for symptoms related to the upper gastrointestinal tract were examined by rapid urease test, histology, and culture. The patients were also studied with serology and UBT. Results. Forty-seven of the 72 patients were diagnosed with H. pylori infection, based on the results of biopsy-based tests and serology. As an initial diagnostic test to detect H. pylori infection, the sensitivity of the UBT was 95%, which was comparable with that of histology (94%), rapid urease test (96%), and serology (91%) and was greater than that of culture (79%). The specificity of the UBT was 100%, which was comparable with that of the other four tests. The efficacy of eradication therapy was assessed by biopsy-based tests and the UBT in 24 H. pylori-positive patients. For this purpose, the sensitivities of UBT and histology were 100%, while the sensitivities of culture and the rapid urease test were 88%. The specificity was 100% for all of these tests. Eleven patients were assessed by biopsy-based tests and UBT after more than 6 months of post-treatment follow-up. There were no discordances between the results of the UBT and those of the biopsy-based tests in any of the patients. Conclusions. The UBT may be useful for detecting H. pylori infection in children with upper gastrointestinal tract symptoms, for assessment of the efficacy of eradication therapy, and for the follow-up evaluation of patients after the therapy. [ABSTRACT FROM AUTHOR]

Abstract Alagille syndrome (AGS) is a congenital anomaly syndrome that affects liver, heart, pulmonary artery, eyes, face, and skeleton. Recently, mutations of the JAG1 gene, which encodes a ligand for the Notch receptor, have been identified in AGS patients. We investigated the JAG1 gene for genetic alterations in eight Japanese AGS patients, using fluorescence in situ hybridization (FISH), single strand conformation polymorphism (SSCP) analysis, and direct sequencing. Subtle genetic alterations were identified in six of the eight patients, including three frameshift mutations, two splice donor mutations, and one nonsense mutation. All alleles with identified mutations can be expected to produce non-functional truncated proteins without a transmembrane domain. There was no apparent correlation between the genotypes of the patients and their affected organs, although the phenotypes of the patients with mutations at the splice donor site were found to be less severe. [ABSTRACT FROM AUTHOR]

Recently, it has been reported that boys with severe hypospadias are at increased risk for acquired cryptorchidism. The reports suggested that prenatal and postnatal androgen disruption might be correlated with this condition. We experienced a case of ovotesticular disorder of sex development (DSD), which was ultimately diagnosed at surgery for acquired cryptorchidism. Ascent of the scrotal contents of the left side was detected in a 7-yr-old boy with the 46, XX karyotype, who had a history of perineal hypospadias repair. Intraoperative findings revealed the left gonad consisted of 2 segments, and this was histologically diagnosed as ovotestis by biopsy specimen. Resection of the ovarian segment was performed simultaneously. Exploration of the contralateral gonad showed the same findings. This is the first report of acquired cryptorchidism observed in a patient with DSD presenting with ambiguous genitalia. [ABSTRACT FROM AUTHOR]

In the pathophysiology of inflammatory bowel diseases (IBD), interaction between mucosal immune system and commensal enteric bacteria plays an important role. In this study, we performed terminal restriction fragment length polymorphism (T-RFLP) analyses of fecal microbiota from five siblings, which included two subjects with ulcerative colitis (UC). Fecal microbiota in the two siblings with UC were clearly different from those obtained from the healthy siblings. The mother’s pattern was a cross between the UC and the healthy siblings. Predicted bacteria based on a BslI-digested T-RFLP database showed a tendency of increases in Clostridium cluster IX and decreases in Clostridium cluster XIVa in the UC siblings. These data indicate that fecal microbial communities differed between UC subjects and healthy individuals under conditions where environmental effects on fecal microbiota may be minimized. [ABSTRACT FROM AUTHOR]

The authors present a neonatal case of allergic colitis, which manifested the difficulty of spontaneous defecation and irregular narrowing of distal rectum in contrast enema. Rectal suction biopsy showed positive acetylcholinesterase activity. These clinical, radiological and histological findings were indistinguishable from Hirschsprung's disease. Gastrointestinal symptoms were improved by the cessation of cow's milk formula. The present findings may impact on the less recognizable gastrointestinal manifestation of allergic colitis. [ABSTRACT FROM AUTHOR]

Summary: Context: Cryptorchidism is common in Prader‐Willi syndrome (PWS) males, but the testicular histology in childhood remains uncertain. The association between testicular histology and long‐term gonadal function in PWS males is also unknown. Objectives: To evaluate the relationship between testicular histology in childhood and long‐term gonadal function in PWS males. Patients and Methods: Forty men with PWS were assessed longitudinally at our institute over the past 24 years. Clinical examinations and blood tests for LH, FSH and testosterone levels were compared with normal reference values. Tissue specimens were collected during orchiopexy and analyzed based on Nistal categories. Results: Of nine testes available for pathological assessments, two showed favourable histology (Nistal I) and seven showed unfavourable histology (Nistal II or III). Of five postpubertal males with histology available, four reached puberty spontaneously, but only one reached Tanner stage 5. In a male with favourable histology, LH and FSH were high, but testosterone was normal, though below the average of the reference range. In three males with unfavourable histology, LH was normal, but FSH was highly elevated, and testosterone was at the lower limit of normal. One patient took hCG treatment to induce puberty; this patient showed favourable histology, but LH, FSH and testosterone were not elevated in adolescence. Conclusions: Testicular histology of PWS men in childhood varies from normal to Sertoli Cell‐Only Syndrome. Regardless of the testicular histology in childhood, hypogonadism in PWS adults arises as a consequence of primary testicular dysfunction with highly elevated FSH and insufficient testosterone levels. Cryptorchidism is common in Prader‐Willi syndrome (PWS) males, but the testicular histology in childhood remains uncertain. The association between testicular histology and long‐term gonadal function in PWS males is also unknown. [ABSTRACT FROM AUTHOR]

Background: The aim of our study was to clarify the attitudes of pediatricians toward children's consumption of ionic beverages.Methods: A questionnaire survey of pediatric practitioners' attitudes toward the consumption of ionic beverages was administered to 537 doctors under 60 years of age who were members of the Japanese Pediatric Society.Results: We received 215 valid responses from 182 board-certified pediatric specialists and 31 non-specialists. Approximately 60% of respondents recommended ionic beverages either often or sometimes. About half of all respondents cautioned patients about excessive consumption. About 40% had experienced at least one instance of excessive consumption characterized by acute symptoms including vomiting, diarrhea, and pyrexia. Specialists were more likely to recommend ionic beverages for oral rehydration than did non-specialists. Non-specialists more often recommended ionic beverages to patients with pyrexia.Conclusions: Pediatricians' attitudes toward children's consumption of ionic beverages were generally appropriate. Pediatric specialists' attitudes were more appropriate than were those of non-specialists. [ABSTRACT FROM AUTHOR]