Search

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]

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]

Aim : To show the clinical, physiological and histological characteristics in GER with cow's milk intolerance Methods : Nine children with GERD tess than 6 years old who had at least recurrent vomiting as ther symptom were studied. Endoscopic and histologic diagnosis, gastric scintigraphy and 24 h-pH monitoring, blood tests were done. Results : All children had cow's milk intolerance clinically. Acid reflux in esophagus and delayed gastric emptying were shown. Duodenitis with histamine and substance P and mild esophagitis were present in these children. Conclusions : Duodenitis with chemical mediators secondary to cow's milk intolerance may play an important role for the cause of GER in children. [ABSTRACT FROM AUTHOR]

Aim To characterize cholesterol regulation in the liver of patients with Alagille syndrome (AGS). Methods Serum total cholesterol (TC) and total bile acid (TBA) levels were measured in 23 AGS patients. The expressions of genes involved in cholesterol regulation, including low-density lipoprotein receptor ( LDLR ), scavenger receptor class B type I ( SR-BI ), 3-hydroxy-3-methylglutaryl coenzyme A reductase ( HMGCR ), cholesterol 7α-hydroxylase ( CYP7A1 ), ATP-binding cassette transporter ( ABC) A1 , and ABCG1/5/8 , were measured in liver tissues from five of these patients. Expression of regulators for these genes, including farnesoid X receptor/small heterodimer partner ( SHP ), liver X receptor α ( LXRα ) and mature Sterol regulatory element-binding protein 2 (SREBP2) was measured. The expression of mature SREBP2 protein was also examined. Results Serum TC and TBA levels were correlated in the AGS patients. Liver cholesterol was also increased compared with controls, and correlated with bile acid contents. LDLR , SR-BI , HMGCR , and ABCGs mRNA expression were upregulated, while CYP7A1 mRNA expression was downregulated in AGS livers. SHP and LXRα mRNA expression was also increased, but maturation of SREBP2 was not suppressed in the patients. Conclusions The major upregulators of liver cholesterol might be increased in AGS patients, indicating an impaired negative feedback mechanism and accelerated liver cholesterol accumulation. [ABSTRACT FROM AUTHOR]

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.

Noonan syndrome (NS) is caused by pathogenic variants in genes encoding components of the RAS/MAPK pathway and presents with a number of symptoms, including characteristic facial features, congenital heart diseases, and short stature. Advances in genetic analyses have contributed to the identification of pathogenic genes in NS as well as genotype-phenotype relationships; however, updated evidence for the detection rate of pathogenic genes with the inclusion of newly identified genes is lacking in Japan. Accordingly, we examined the genetic background of 116 individuals clinically diagnosed with NS and the frequency of short stature. We also investigated genotype-phenotype relationships in the context of body mass index (BMI). Genetic testing revealed the responsible variants in 100 individuals (86%), where PTPN11 variants were the most prevalent (43%) and followed by SOS1 (12%) and RIT1 (9%). The frequency of short stature was the lowest in subjects possessing RIT1 variants. No genotype-phenotype relationships in BMI were observed among the genotypes. In conclusion, this study provides evidence for the detection rate of pathogenic genes and genotype-phenotype relationships in Japanese patients with NS, which will be of clinical importance for accelerating our understanding of the genetic backgrounds of Japanese patients with NS., Competing Interests: The authors have no conflicts of interest to disclose., (2024©The Japanese Society for Pediatric Endocrinology.)

Objective: This study aimed to establish an optional newborn screening program for spinal muscular atrophy (SMA-NBS) in Osaka., Methods: A multiplex TaqMan real-time quantitative polymerase chain reaction assay was used to screen for SMA. Dried blood spot samples obtained for the optional NBS program for severe combined immunodeficiency, which covers about 50% of the newborns in Osaka, were used. To obtain informed consent, participating obstetricians provided information about the optional NBS program to all parents by giving leaflets to prospective parents and uploading the information onto the internet. We prepared a workflow so that babies that were diagnosed with SMA through the NBS could be treated immediately., Results: From 1 February 2021 to 30 September 2021, 22,951 newborns were screened for SMA. All of them tested negative for survival motor neuron (SMN)1 deletion, and there were no false-positives. Based on these results, an SMA-NBS program was established in Osaka and included in the optional NBS programs run in Osaka from 1 October 2021. A positive baby was found by screening, diagnosed with SMA (the baby possessed 3 copies of the SMN2 gene and was pre-symptomatic), and treated immediately., Conclusion: The workflow of the Osaka SMA-NBS program was confirmed to be useful for babies with SMA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The earlier initiation of growth hormone (GH) treatment for patients with Prader-Willi syndrome (PWS) who are younger than 2 years has become more prevalent. Because free thyroxine (FT4) levels are low during this period, GH may induce further reductions; however, limited information is currently available on this issue. Therefore, we herein performed age-dependent and time-course analyses of thyroid hormone levels in GH-treated PWS children. This retrospective analysis included genetically diagnosed PWS patients (N = 37, median age of 26 months). An age-dependent analysis was performed by subdividing subjects based on age [a younger group aged between 1 and 24 months (N = 16) and an older group between 25 and 84 months (N = 21)] and was followed by a multiple regression analysis with adjustments for sex and the cumulative GH dose per bodyweight. A time-course analysis of subjects who had not received levothyroxine during the first 18 months of GH treatment (N = 28) was conducted. A one-month treatment with GH decreased FT4 levels in the older group, but not in the younger group, and this was associated with increases in thyroid-stimulating hormone levels. A positive correlation was noted between age and decreases in FT4 levels independent of the cumulative GH dose per bodyweight. The time-course analysis revealed no changes in FT4 levels in the younger group, while transient decreases were observed in the older group. In conclusion, GH treatment causes age-dependent changes in FT4 levels. This result will help clinicians establish a therapeutic strategy to decide the necessity of levothyroxine supplementation in GH-treated children with PWS.

Obesity is a major complication in children with 21-hydroxylase deficiency (21-OHD). There is evidence to show that higher body mass index (BMI) during infancy and early childhood is associated with an increased risk for the subsequent development of obesity in the general population; however, limited information is currently available on this issue in 21-OHD patients. Additionally, despite the frequent use of supraphysiological dosages of hydrocortisone in 21-OHD, the association between BMI and hydrocortisone dosage during these periods remains largely unclear; therefore, we retrospectively investigated BMI at approximately 1 and 3 years old and its association with hydrocortisone dosage in 56 children with 21-OHD. The median BMI-standard deviation score (SDS) was 0.28 (Interquartile range [IQR]: -0.53 to 1.09) and 0.39 (IQR: -0.44 to 1.14) at approximately 1 and 3 years old, respectively, and no association was observed between hydrocortisone dosage and BMI-SDS at either time-point; however, multivariate analysis revealed that hydrocortisone dosage at approximately 1 year old was positively associated with changes in BMI (β = 0.57, p = 0.013) and BMI-SDS (β = 0.59, p = 0.011) between approximately 1 and 3 years old after adjustment for age, sex, and changes in hydrocortisone dosage during the same period. The average dosage of hydrocortisone between approximately 6 months and 1 year old also showed similar results. These results indicate that a higher dosage of hydrocortisone during late infancy is associated with a higher BMI at approximately 3 years old, which may lead to the development of obesity later in life in children with 21-OHD.

GH treatment has been widely utilized for short-statured children born small for gestational age (SGA). Although SGA children are at a higher risk of renal dysfunction, the effect of GH treatment on renal function is still unclear. We have previously shown that GH treatment is not associated with renal dysfunction during the prepubertal period; however, its effect during the pubertal period has not been investigated. Accordingly, we herein retrospectively investigated creatinine-based estimated glomerular filtration rates (eGFR) in 26 short-statured children born SGA during puberty, defined as the period between the onset of puberty and cessation of GH treatment, and their association with parameters at birth and GH treatment. We found that eGFR did not decrease during the pubertal period; however, gestational week and birth weight were negatively and significantly correlated with percentage decrease in eGFR during the pubertal period. The percentage decrease in eGFR did not correlate with changes in the insulin-like growth factor-1 standard deviation score or average weekly GH dose. In conclusion, GH treatment was not associated with a reduction in eGFR in short-statured SGA children during puberty. Since low birth weight and prematurity were associated with reductions in eGFR during puberty, monitoring for renal function was mandatory regardless of GH treatment in short-statured children born SGA., Competing Interests: The authors have no conflicts of interest to declare., (2023©The Japanese Society for Pediatric Endocrinology.)

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.

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.

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)., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) 2020.)

Objective: To clarify clinical and genetic features of Japanese children with congenital chloride diarrhea (CCD)., Study Design: This was a multi-institutional, retrospective survey of 616 pediatric centers in Japan with identified patients with CCD between 2014 and 2018. Mutations involving SLC26A3 were detected by Sanger sequencing., Results: Thirteen patients met all entry criteria including mutations in SLC26A3, and 14 patients satisfied clinical diagnostic criteria. Homozygous or compound heterozygous mutations in SLC26A3, including 6 novel mutations, were identified in 13 of these 14 patients (93%). The most common (detected in 7 of 13) was c.2063-1g>t. Median age at diagnosis was 1 day. Nine of the patients meeting all criteria were diagnosed as neonates (69%). Median follow-up duration was 10 years. When studied, 8 patients had <5 stools daily (62%), and all had fewer than in infancy. Only 1 patient had nephrocalcinosis, and 3 (23%) had mild chronic kidney disease. Neurodevelopment was generally good; only 1 patient required special education. Five patients (38%) received long-term sodium, potassium, and chloride supplementation., Conclusions: Early fetal ultrasound diagnosis and prompt long-term sodium, potassium, and chloride supplementation were common management features. Genetic analysis of SLC26A3 provided definitive diagnosis of CCD. In contrast with previously reported localities, c.2063-1g>t might be a founder mutation in East Asia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Congenital hyperinsulinism is a rare condition, and following recent advances in diagnosis and treatment, it was considered necessary to formulate evidence-based clinical practice guidelines reflecting the most recent progress, to guide the practice of neonatologists, pediatric endocrinologists, general pediatricians, and pediatric surgeons. These guidelines cover a range of aspects, including general features of congenital hyperinsulinism, diagnostic criteria and tools for diagnosis, first- and second-line medical treatment, criteria for and details of surgical treatment, and future perspectives. These guidelines were generated as a collaborative effort between The Japanese Society for Pediatric Endocrinology and The Japanese Society of Pediatric Surgeons, and followed the official procedures of guideline generation to identify important clinical questions, perform a systematic literature review (April 2016), assess the evidence level of each paper, formulate the guidelines, and obtain public comments.

Background/purpose: A nationwide survey was conducted to identify the clinical presentation of pediatric chronic intestinal pseudo-obstruction (CIPO) in Japan., Methods: Data were collected via a questionnaire, ensuring patient anonymity, from facilities that treat pediatric gastrointestinal diseases in Japan., Results: Ninety-two responses were collected from forty-seven facilities. Sixty-two patients (28 males, 34 females) met formal diagnostic criteria for CIPO. The estimated pediatric prevalence was 3.7 in 1 million individuals. More than half the children (56.5%) developed CIPO in the neonatal period. Full-thickness intestinal specimens were available for histopathology assessment in forty-five patients (72.6%). Forty-one (91.1%) had no pathological abnormalities and were considered to be idiopathic. Patients were treated according to the local protocol of each facility. Forty-one patients (66.1%) had restricted oral intake of ordinary diets, and twenty-nine (46.8%) depended on parenteral nutrition. No therapeutic intervention, including medication and surgery, successfully improved oral food intake or obstructive symptoms. Only three patients (4.8%) died from enteritis or sepsis., Conclusions: In Japan, pediatric CIPO is a rare, serious, and intractable disease. The prognosis with respect to survival is good, but unsatisfactory because of the need for prolonged parenteral nutrition and associated potential for restricted quality of life., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The authors analyzed serum selenium levels of 95 children and adolescents with intestinal dysfunction and/or neurological disabilities [age range: 7 months-20 years; mean±standard deviation (SD): 8.0±5.3 years] who received parenteral nutrition (PN) and/or enteral nutrition (EN) with either reduced or no selenium doses for more than 3 months. Twenty-eight patients (29%) showed serum selenium levels below 4.0μg/dL. Five patients whose serum selenium levels were below 2μg/dL presented various clinical manifestations, including hair browning (n=5), macrocythemia (n=4), nail whitening (n=3) and cardiac dysfunction (n=1). None of these 5 patients were nourished through ordinary diets. Three of these patients were nourished through selenium-free enteral nutritional products, 1 through selenium-deficient PN and 1 through PN and a formula with reduced selenium. After selenium supplement therapy for 1 year, all 5 patients exhibited improvement in their serum selenium levels and clinical features of selenium deficiency. It is important to be cautious about secondary selenium deficiency in children and adolescents nourished only through EN/PN without an adequate dose of selenium., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

It has long been recognized that hepatic steatosis (fatty liver) occurs in obese children as in adults. Steatosis of any etiology can be associated with the development of necro-inflammation and fibrosis, so called steatohepatitis, and even cirrhosis. Nonalcoholic steatohepatitis (NASH) has been proposed as a component of insulin resistant syndrome and exists in pediatric population. The other etiology of NASH in children has not been clearly understood. In addition to obesity, adipose tissue distribution also appears to influence metabolic complications. Subjects with visceral fat adiposity appear to be at risk for fatty liver because of their ability to transport free fatty acids directly into the portal vein for conversion to triglycerides within the liver. A stronger relationship of serum ALT to visceral adiposity than BMI was demonstrated. Many metabolic diseases such as Wilson's disease, NICCD, OTC deficiency, carnitine deficiency have steatohepatitis and cirrhosis. It may play the important role to reveal the mechanism of progress to NASH.

Barrett's esophagus (BE) is a condition of esophageal dysplasia in which the tubular esophagus is lined with columnar instead of squamous mucosa--not with just any type of columnar mucosa, but with a specialized type with goblet cells. It is considered to be an acquired phenomenon secondary to acid exposure from gastro-esophageal reflux (GER). This report shows a review of BE of children and our data about BE from the study of 19 handicapped children with GER. 3 had intestinal dysplasia with goblet cells (BE). The % time of pH under 4 on 24-hour pH monitoring was significantly lower in the patients with esophagitis including BE than in them with normal esophagus. BE of our study seemed to be reversible after the surgery and anti-acid therapy. It is suggested that BE is not a rare condition even in children and biopsy specimens should be taken to establish the diagnosis.

Gastroesophageal reflux (GER), defined as passage of gastric contents into esophagus, and GER disease (GERD), defined as symptoms or complications of GER, are common pediatric problems encountered by both primary and specialty medical providers. Clinical manifestations of GERD in children include vomiting, poor weight gain, dysphagia, abdominal or substernal pain, esophagitis and respiratory disorders. On the other hand, recurrent vomiting is the symptom of hydronephrosis, brain tumor, food allergy, uremia, other metabolic disease, obstruction of intestine etc. It is very important for clinicians dealing with children and infants to understand GERD. The evaluation and treatment of gastroesophageal reflux in infants and children were reviewed here.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by short stature, an insatiable appetite resulting in progressive obesity, hypotonia, and hypogonadism. Many of these symptoms suggest a hypothalamic dysfunction. In fact, reduced growth hormone (GH) secretion and low insulin-like growth factor (IGF- I) are shown in PWS resembling the GH deficient state. The GH treatment of patients with PWS are effective on growth and body composition with decreasing in body fat mass and increasing in body muscle mass, resulting in improvement of respiratory function and bone mineral density. The important advance effects reported during GH treatment of patients with PWS are diabetes mellitus and respiratory dysfunction was recently reported. It is very important that GH should be used with another treatment such as diet therapy, and with only this way GH can play an important role among the overall treatments of PWS.

A comparative study of MRI and pathology was performed on a case of cryptococcal meningoencephalitis. An 11-year-old female presented with confusion and vomiting. On admission, CSF examination revealed spherical fungal cells with mild pleocytosis, decreased glucose and elevated protein level. MRI showed multiple punctate lesions in the basal ganglia with high intensity on T2-weighted image, while enhanced MRI revealed diffuse meningeal involvement. Post-mortem examination disclosed that the T2-weighted lesions found in the basal ganglia were aggregated small cystic lesions consisting of a cryptococcal invasion of Virchow-Robin spaces, termed "soap bubble lesions", characteristic findings of cryptococcal meningoencephalitis. Thus MRI findings of the basal ganglia and meninges may help to diagnose cryptococcal meningoencephalitis.