Comprehensive analyses of neurodevelopmental outcomes and quality of life of children with biliary atresia.

OBJECTIVES: To holistically evaluate neurodevelopmental outcomes and quality of life (QOL) of Japanese patients with biliary atresia (BA) and to investigate the factors associated with the outcomes. METHODS: This study enrolled patients with BA aged 5-18 years who visited Osaka University Hospital in 2021. Neurodevelopmental assessments were performed to evaluate intellectual ability, cognitive functions and adaptive skill levels. Furthermore, emotional and behavioral issues, characteristics of attention deficit hyperactivity disorder, and QOL were concomitantly assessed in the same cohort. Biochemical and social factors associated with the results were examined. RESULTS: Fifty-three patients, with a median age of 11.2 years were included in the analyses. Patients with BA had a significantly lower Full-Scale Intelligence Quotient or developmental quotient (FSIQ/DQ) score and Vineland Adaptive Behavior Scale (VABS) composite score than the general Japanese population. Household education level and short stature were associated with low and borderline FSIQ/DQ and VABS composite scores, respectively. Among patients with low and borderline FSIQ/DQ scores, those with average or high VABS composite scores received significantly less neuroeducational care than those with low and borderline VABS composite scores. Despite the low FSIQ/DQ and VABS composite scores, the total QOL scores were higher than those of the general population. CONCLUSION: Patients with BA had intellectual and behavioral impairments. Notably, patients with intellectual impairments are overlooked and not followed up, especially if adaptive skills are maintained.

Novel gene mutations in three Japanese patients with ARC syndrome associated mild phenotypes: a case series.

BACKGROUND: Arthrogryposis, renal dysfunction, and cholestasis syndrome (ARCS) is a rare autosomal recessive disorder caused by mutations in VPS33B (ARCS1) and VIPAS39 (ARCS2). As per literature, most patients with ARCS died of persistent infections and bleeding by the age of 1 year. We report the first Japanese cases with ARCS1 and ARCS2 who presented with mild phenotypes and were diagnosed via genetic testing. CASE PRESENTATION: Case 1: A 6-year-old boy born to nonconsanguineous Japanese parents presented with jaundice and normal serum gamma-glutamyl transferase (GGT) levels, proteinuria, bilateral nerve deafness, motor delay, failure to thrive, and persistent pruritus. After cochlear implantation for deafness at the age of 2 years, despite a normal platelet count and prothrombin time-international normalized ratio, the patient presented with persistent bleeding that required hematoma removal. Although he did not show any obvious signs of arthrogryposis, he was suspected to have ARCS based on other symptoms. Compound heterozygous mutations in VPS33B were identified using targeted next-generation sequencing (NGS), which resulted in no protein expression. Case 2: A 7-month-old boy, the younger brother of case 1, presented with bilateral deafness, renal tubular dysfunction, failure to thrive, and mild cholestasis. He had the same mutations that were identified in his brother's VPS33B. Case 3: A 24-year-old man born to nonconsanguineous Japanese parents was suspected to have progressive familial intrahepatic cholestasis 1 (PFIC1) in his childhood on the basis of low GGT cholestasis, renal tubular dysfunction, sensory deafness, mental retardation, and persistent itching. A liver biopsy performed at the age of 16 years showed findings that were consistent with PFIC1. He developed anemia owing to intraperitoneal hemorrhage from a peripheral intrahepatic artery the day after the biopsy, and transcatheter arterial embolization was required. ARCS2 was diagnosed using targeted NGS, which identified novel compound heterozygous mutations in VIPAS39. CONCLUSIONS: The first Japanese cases of ARCS1 and ARCS2 diagnosed using genetic tests were reported in this study. These cases are milder than those previously reported. For patients with ARCS, invasive procedures should be performed with meticulous care to prevent bleeding.

Urinary iodine and thyroglobulin are useful markers in infants suspected of congenital hypothyroidism based on newborn screening.

OBJECTIVES: Iodine deficiency and excess both cause thyroid dysfunction. Few data describe the relationship between iodine status and outcomes of congenital hypothyroidism (CH) in iodine-sufficient areas. We investigated urinary iodine (UI) concentration and its relationship with the clinical course of CH. METHODS: We reviewed and retrospectively analyzed patients with positive newborn screening (NBS) for CH from January 2012 to June 2019 in Japan, obtaining UI and UI-urine creatinine ratio (UI/Cr), serum TSH, free T4, free T3 and thyroglobulin (Tg) at the first visit, TSH at NBS, levothyroxine (LT4) dose, and subsequent doses. A UI value of 100-299 µg/L was considered adequate. RESULTS: Forty-eight patients were included. Median UI and UI/Cr were 325 µg/L and 3,930 µg/gCr, respectively. UI was high (≥300 µg/L) in 26 (54%) and low (≤99 µg/L) in 11 (23%). LT4 was administered to 34 patients. Iodine status was not related to the need for treatment. We found a U-shaped relationship between Tg and UI/Cr. Patients with high Tg (≥400 ng/mL) and abnormal UI levels required significantly lower LT4 doses (≤20 µg/day) at three years of age. Even if they showed severe hypothyroidism initially, they did not need subsequent dose increments. CONCLUSIONS: Abnormal UI levels with Tg elevation were associated with lower LT4 dose requirements. The evaluation of iodine status and Tg concentrations were considered useful in patients suspected of CH.

Two girls with a neonatal screening-negative 21-hydroxylase deficiency requiring treatment with hydrocortisone for virilization in late childhood.

Herein, we report two girls with a neonatal screening (NS)-negative 21-hydroxylase deficiency (21-OHD) requiring treatment with hydrocortisone due to virilization that developed in late childhood. Patient 1 was born prematurely on the 30th gestational week with normal external genitalia at birth. She passed the NS for 21-OHD. At 6 yr of age, she was referred to a hospital for evaluation of premature pubarche and clitoromegaly. Her diagnosis was central precocious puberty, and GnRH agonist was initiated. However, her symptoms did not improve despite treatment for over 4 years. She was then referred to our hospital where she was diagnosed with 21-OHD. Although she was started on hydrocortisone therapy, her adult height reached only 140 cm (-3.4 SD). Patient 2 was delivered at 37 weeks of gestation and passed the NS for 21-OHD. She was referred to a hospital because of premature pubarche at the age of 6 yr. She was diagnosed with 21-OHD, and hydrocortisone replacement therapy was initiated. Her present height at 13 yr of age is 148 cm (-1.3 SD). These cases reminded us that the possibility of 21-OHD should be considered when patients show premature pubarche or precocious puberty, even if they passed the NS test for 21-OHD.

CYP7A1 expression in hepatocytes is retained with upregulated fibroblast growth factor 19 in pediatric biliary atresia.

AIM: Bile acid biosynthesis is strictly regulated under physiological conditions. The expression of fibroblast growth factor (FGF) 19 is induced when bile acids bind to the farnesoid X receptor in the intestinal epithelium. Fibroblast growth factor 19 is then transported by the portal flow, causing transcriptional inhibition of cytochrome P450, family 7, subfamily A, polypeptide 1 (CYP7A1), a key enzyme in bile acid biosynthesis, through the extracellular signal-regulated kinase (ERK) pathway. However, the regulatory mechanisms of these signaling pathways in hepatocytes under chronic cholestasis remain unclear. We investigated the regulation of these signaling pathways in patients with biliary atresia (BA). METHODS: We analyzed the regulation of molecules in these signaling pathways using liver and serum samples from eight BA children and four non-cholestatic disease controls. RESULTS: CYP7A1 mRNA expression was not inhibited in BA microdissected hepatocyte-enriched tissue (HET) despite high serum bile acid concentrations. The FGF19 protein was synthesized in BA HET, and its serum concentration was elevated. Fibroblast growth factor receptor 4 was phosphorylated in BA livers. However, ERK phosphorylation was significantly reduced. We examined SPRY2 expression to determine how the ERK pathway was inactivated downstream of the FGF receptor; the expression was significantly increased in BA HET. CONCLUSIONS: This is the first study to measure the CYP7A1 mRNA levels in human BA HET. Fibroblast growth factor 19 was increased in BA hepatocytes. By focusing on its regulation in hepatocytes, we showed that the FGF19 pathway did not suppress bile acid synthesis, probably due to an altered mechanism involving upregulated SPRY2 in BA patients.

Total Bile Acid Concentration in Duodenal Fluid Is a Useful Preoperative Screening Marker to Rule Out Biliary Atresia.

OBJECTIVES: Duodenal tube test (DTT) is used as a preoperative screening to rule out biliary atresia (BA). In previous reports, DTT was assessed by the color of the duodenal fluid, but there were no quantitative criteria. The aim of this study was to examine the efficacy of DTT based on the total bile acid (TBA) concentration in duodenal fluid. METHODS: This is a single-center retrospective study of infants with cholestasis who underwent DTT from 2008 to 2016 at the Osaka University Hospital. The cut-off values of maximum TBA in duodenal fluid (dTBA), dTBA/serum TBA ratio (sTBA), and dTBA/serum gamma-glutamyl transpeptidase (sGGT) ratio were assessed for the accuracy in excluding BA. RESULTS: A total of 37 infants were included in this study; 16 infants with BA and 21 infants with other causes of intrahepatic cholestasis. dTBA demonstrated sensitivity of 100% and specificity of 90.5% with the cut-off value of 16.8 µmol/L. Specificity was further improved to 95.2% with dTBA/sTBA ratio (cut-off value: 0.088) and 100% with dTBA/sGGT ratio (cut-off value: 0.076 µmol/U). DTT could be performed 0.8 ±â€Š1.4 days after admission. Hypoglycemia was developed in 1 infant. CONCLUSIONS: DTT evaluated by dTBA, dTBA/sTBA ratio, and dTBA/sGGT ratio had high accuracy to rule out BA and could avoid unnecessary surgery in some infants.

Myocardial bridging is associated with exercise-induced ventricular arrhythmia and increases in QT dispersion.

BACKGROUND: A myocardial bridge (MB) has been associated with ventricular arrhythmia and sudden death during exercise. QT dispersion (QTd) is a measure of abnormal repolarization and may predict ventricular arrhythmia. We investigated the frequency of ventricular arrhythmias during exercise and the QTd at rest and after exercise, in patients with an MB compared to a normal cohort. METHODS: We studied the rest and stress ECG tracings of patients with an MB suspected by focal septal buckling on exercise echocardiography (EE) (Echo-MB group, N = 510), those with an MB confirmed by another examination (MB group, N = 110), and healthy controls (Control group, N = 198). RESULTS: The frequency of exercise-induced premature ventricular contractions (PVCs) was significantly higher in the Echo-MB and MB groups compared with the Control group (both p < .001). In all, 25 patients (4.9%) in the Echo-MB group, seven patients (6.4%) in the MB group and no patients in the Control group had exercise-induced non-sustained ventricular tachycardia (NSVT). There was no difference in the baseline QTd between the groups. In the Echo-MB and MB groups, QTd postexercise increased significantly when compared with baseline (both p < .001). Patients with NSVT had a higher frequency of male gender and an even greater increase in QTd with exercise compared with the non-NSVT group. DISCUSSION: There is an increased frequency of exercise-induced PVCs and NSVT in patients with MBs. Exercise significantly increases QTd in MB patients, with an even greater increase in QTd in MB patients with NSVT. Exercise in MB patients results in ventricular arrhythmias and abnormalities in repolarization.

Relationship between dose of antithyroid drugs and adverse events in pediatric patients with Graves' disease.

Graves' disease (GD) accounts for a large proportion of pediatric hyperthyroidism, and the first-line treatment is antithyroid drug (ATD) therapy. Methimazole (MMI) is effective in most patients but is associated with significant adverse events (AEs). We reviewed the medical records of GD patients (n = 56) with onset age of <15 yr and investigated the relationship between MMI dose and AEs. The study population comprised 11 male and 45 female patients and the median age at diagnosis was 11 yr. All patients were initially treated with ATDs. Among the 52 patients initially treated with MMI, 20 received a low dose, and 32 received a high dose of MMI (< 0.7 vs ≥ 0.7 mg/kg/day, respectively). AEs occurred in 20% of the patients in the low-dose MMI group, and in 50% patients in the high-dose MMI group (p = 0.031). A greater variety of AEs was observed in the high-dose group. Neutropenia and rash were observed in both groups. With treatment transition to low-dose MMI according to the Japanese Society for Pediatric Endocrinology guidelines, we expect a decrease in the incidence of AEs in future. However, we should be careful as neutropenia and rash can occur independently of the MMI dose.

Longitudinal observation of serum anti-Müllerian hormone in three girls after cancer treatment.

Gonadal dysfunction and infertility are major endocrinological late effects among childhood cancer survivors. Chemotherapy and radiation have gonadotoxic effects and diminish the ovarian reserve. The serum concentration of anti-Müllerian hormone (AMH) is a useful marker of ovarian reserve in survivors. We conducted a longitudinal study to investigate the variations of AMH in evaluating the acute and chronic effects of cancer therapy on the ovary. Three young female patients with different hematological diseases were registered, and their medical records were reviewed. Patient 1 with myelodysplastic syndrome received reduced-intensity hematopoietic stem cell transplantation (HSCT) at 10 yr of age. Breast development and menarche occurred spontaneously after HSCT; however, AMH level became undetectable and gonadotropin did not increase. Patient 2 with acute lymphoblastic leukemia had been receiving chemotherapy since 11 yr of age. AMH level became undetectable but increased after chemotherapy and was associated with regular menstruation. Patient 3 with acute myeloid leukemia received chemotherapy at 13 yr of age and myeloablative HSCT at 14 yr of age. AMH level became undetectable after HSCT, and the patient developed amenorrhea. These different patterns in the recovery phase demonstrated that the AMH level immediately after the end of cancer therapy is inappropriate for the evaluation of the ovarian reserve.

Placental examination: prognosis after delivery of the growth-restricted fetus.

PURPOSE OF REVIEW: This article describes the role of placental examination in the prognostic evaluation of fetal growth restriction (FGR) infants. RECENT FINDINGS: A new comprehensive placental classification system was reported. Maternal underperfusion, fetal thrombotic vasculopathy (FTV), villitis (including villitis of unknown etiology and infectious villitis), inflammation, and immature/dysmature villi are important factors affecting FGR prognosis, whereas genomic imprinting is a key factor affecting growth and diseases, as well as placental abnormality. SUMMARY: We discuss the role of placental examination in determining FGR prognosis. Maternal underperfusion, fetal thrombotic vasculopathy, and villitis (including villitis of unknown etiology and infectious villitis) are the most important findings affecting FGR prognosis. Although limited, data have suggested an association of inflammation and immature/dysmature villi with postnatal growth in FGR infants. Placental size also contributes postnatally through fetal programming. In addition, placental imprinting can be a key of pre and postnatal growth and diseases, including imprinting disorders, as well as placental abnormalities such as placental mesenchymal dysplasia.

Serum NT-proCNP levels increased after initiation of GH treatment in patients with achondroplasia/hypochondroplasia.

OBJECTIVE: Serum amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) levels have been proposed as a biomarker of linear growth in healthy children. The usefulness of NT-proCNP in patients with achondroplasia (ACH)/hypochondroplasia (HCH) remains to be elucidated. The objective was to study whether serum NT-proCNP level is a good biomarker for growth in ACH/HCH and other patients of short stature. DESIGN: This was a longitudinal cohort study. PATIENTS: Sixteen children with ACH (aged 0·4-4·3 years), six children with HCH (2·7-6·3 years), 23 children with idiopathic short stature (ISS) (2·2-9·0 years), eight short children with GH deficiency (GHD) (2·9-6·8 years) and five short children born small for gestational age (SGA) (2·0-6·6 years). Patients with ACH/HCH received GH treatment for 1 year. MEASUREMENTS: Serum NT-proCNP levels and height were measured. RESULTS: NT-proCNP levels positively correlated with height velocity in these short children (P < 0·05, r = 0·27). NT-proCNP levels inversely correlated with age in children with ISS alone (P < 0·01, r = -0·55). Serum NT-proCNP levels in patients with ACH/HCH were increased 3 months following the initiation of GH treatment (P < 0·05). Height SDS gain during GH treatment for 1 year was positively correlated with the changes in NT-proCNP levels after the initiation of GH (P < 0·01, r = 0·72). CONCLUSION: Serum NT-proCNP levels may be a good biomarker to indicate the effect of GH treatment on growth in patients with ACH/HCH at least in the first year and height velocity in short stature patients.

Pathological examination of the placenta in small for gestational age (SGA) children with or without postnatal catch-up growth.

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.

Prevalence and Clinical Determinants of Left Atrial Appendage Thrombus in Patients With Atrial Fibrillation Before Pulmonary Vein Isolation.

The CHADS2 score is considered a reliable predictor of stroke/thromboembolism risk in patients with atrial fibrillation (AF). However, thromboembolism can occasionally occur even in patients with AF with low CHADS2 score (CHADS2 score = 0 or 1). To investigate the incidence and predictors of left atrial appendage (LAA) thrombus (LAAT) formation in patients with AF, we studied consecutive 543 Japanese patients with AF who underwent transesophageal echocardiography before pulmonary vein isolation from 2008 to 2012. All patients were treated with anticoagulation therapy with warfarin, and their clinical and echocardiographic characteristics were evaluated. LAATs were observed in 35 (6.4%) of 543 patients, and the prevalence was clearly correlated with the patient's CHADS2 scores. Of 338 patients with low CHADS2 score, LAATs were observed in 7 patients (2.1%). By multivariate analysis, increased left atrial volume (≥50 ml), decreased ejection fraction (<56%), and increased brain natriuretic peptide level (>75 pg/ml) were significantly associated with increased prevalence of LAATs, even in patients with low CHADS2 score. Accordingly, we proposed a new scoring system to predict LAAT (left atrial volume ≥50 ml: score 2; ejection fraction <56%: score 1; brain natriuretic peptide >75 pg/ml: score 1). Patients with a score ≥2 have a greater risk of LAAT, whereas all patients with score ≤1 have no LAATs. Our scoring system is useful for evaluation of the risk of LAAT in patients with AF even with low CHADS2 score.

Low serum concentrations of anti-Müllerian hormone are common in 53 female childhood cancer survivors.

BACKGROUND/AIMS: Gonadal dysfunction is one of the major endocrinological late effects among childhood cancer survivors (CCSs). Periodic screening evaluation of gonadotropins and sex steroids has been recommended, although it remains difficult to predict gonadal function and reproductive capacity in childhood. We evaluated the effects of cancer treatments on the ovarian function of Japanese female CCSs by measuring serum levels of anti-Müllerian hormone (AMH) and gonadotropin. METHODS: This was a retrospective, cross-sectional study at a single hospital. RESULTS: Among 53 female CCSs, 28 (53%) had a decreased AMH level, while only 16 (30%) had an increased follicle-stimulating hormone (FSH) level. AMH was low in all patients with high FSH, while FSH was not elevated in 43% of patients with a low AMH level. AMH was low in 8 of 9 patients with no breast development, 11 of 14 patients with no spontaneous menstruation, and 3 of 22 patients with regular menstrual cycles. CONCLUSION: Measurement of AMH concentration is useful as a marker of ovarian reserve in female CCSs for detecting primary gonadal deficiency, particularly among patients without increased gonadotropin levels.

Humoral immunity is involved in the development of pericentral fibrosis after pediatric live donor liver transplantation.

Although LT can be successful for treating end-stage liver disease in children, some patients develop fibrosis around the central vein area (PCF). This raises the possibility that PCF could lead to later cirrhosis and graft failure. Here, we report a retrospective immunohistochemical study of 28 patients who received a live donor liver transplant. We assessed the incidence and etiology of PCF using CD3, CD20, HLA-DR, and C4d-specific antibodies. Histological evidence of PCF was found in 13 cases (46.4%), of which 11 (84.6%) had experienced ACR and/or CP events post-transplant. Immunohistochemical evaluation revealed significantly stronger staining with these antibodies in the central vein area in PCF, especially for CD20 and C4d. This implies humoral immunopathology and suggests involvement of humoral immunity in the development of PCF. These results further imply that suppression of cellular immunity alone is insufficient to prevent PCF. We therefore suggest that suppression of both humoral and cellular immunity in combination would be required for prevention of PCF.

Clinical aspects and adrenal functions in eleven Japanese children with X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a genetic disease associated with demyelination of the central nervous system, adrenocortical insufficiency and accumulation of very long chain fatty acids. It is a clinically heterogeneous disorder ranging from a severe childhood cerebral form to an asymptomatic form. The incidence in Japan is estimated to be between 1:30,000 and 1:50,000 boys as determined by a nationwide retrospective survey between 1990 and 1999, which found no cases with Addison's form. We reviewed the medical records of eleven Japanese boys with X-ALD from 1990 to 2010 in our institute. Eight patients were detected by neuropsychological abnormalities, whereas a higher prevalence of unrecognized adrenocortical insufficiency (5/11: 45%) was observed than previously recognized. While no neurological abnormalities were demonstrated in two brothers, the elder brother had moderate Addison's disease at diagnosis and the presymptomatic younger brother progressed to Addison's disease six months after the diagnosis of X-ALD. Early detection of impaired adrenal function as well as early identification of neurologically presymptomatic patients by genetic analysis is essential for better prognosis. Addison's form might be overlooked in Japan; therefore, X-ALD should be suspected in patients with adrenocortical insufficiency.

A case of pediatric virilizing adrenocortical tumor resulting in hypothalamic-pituitary activation and central precocious puberty following surgical removal.

We present a 6-year-old boy with a virilizing adrenocortical tumor who initially presented with peripheral precocious puberty. Development of facial acne, pubic hair and a growth spurt were noted at the age of five. A low-pitched voice as well as maturation of external genitalia was noted at the age of six. Both serum and urinary levels of adrenal androgens were elevated. Abdominal computed tomography revealed a large right suprarenal mass and he underwent surgical resection without any complications. The histological diagnosis was adrenocortical carcinoma according to the criteria of Weiss. Following surgical removal of the androgen-producing tumor, the patient subsequently developed hypothalamic-pituitary activation and demonstrated central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist in order to delay further pubertal progression. Clinical follow-up of potential secondary effects of excess hormone secretion after removal is important in some pediatric patients with virilizing adrenocortical tumor.