Publications by authors named "Yukihiro Hasegawa"

151 Publications

Role of Liquid-Liquid Separation in Endocrine and Living Cells.

J Endocr Soc 2021 Oct 19;5(10):bvab126. Epub 2021 Jul 19.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 157-8535 Tokyo, Japan.

Context: Recent studies have revealed that every eukaryotic cell contains several membraneless organelles created via liquid-liquid phase separation (LLPS). LLPS is a physical phenomenon that transiently compartmentalizes the subcellular space and thereby facilitates various biological reactions. LLPS is indispensable for cellular functions; however, dysregulated LLPS has the potential to cause irreversible protein aggregation leading to degenerative disorders. To date, there is no systematic review on the role of LLPS in endocrinology.

Evidence Acquisition: We explored previous studies which addressed roles of LLPS in living cells, particularly from the viewpoint of endocrinology. To this end, we screened relevant literature in PubMed published between 2009 and 2021 using LLPS-associated keywords including "membraneless organelle," "phase transition," and "intrinsically disordered," and endocrinological keywords such as "hormone," "ovary," "androgen," and "diabetes." We also referred to the articles in the reference lists of identified papers.

Evidence Synthesis: Based on 67 articles selected from 449 papers, we provided a concise overview of the current understanding of LLPS in living cells. Then, we summarized recent articles documenting the physiological or pathological roles of LLPS in endocrine cells.

Conclusions: The discovery of LLPS in cells has resulted in a paradigm shift in molecular biology. Recent studies indicate that LLPS contributes to male sex development by providing a functional platform for SOX9 and CBX2 in testicular cells. In addition, dysregulated LLPS has been implicated in aberrant protein aggregation in pancreatic β-cells, leading to type 2 diabetes. Still, we are just beginning to understand the significance of LLPS in endocrine cells.
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http://dx.doi.org/10.1210/jendso/bvab126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358989PMC
October 2021

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

Endocr J 2021 Aug 7. Epub 2021 Aug 7.

Department of Gastroenterology and Endocrinology, Osaka Women's and Children's Hospital, Osaka 594-1101, Japan.

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.
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http://dx.doi.org/10.1507/endocrj.EJ21-0292DOI Listing
August 2021

Methylation status of genes escaping from X-chromosome inactivation in patients with X-chromosome rearrangements.

Clin Epigenetics 2021 Jun 30;13(1):134. Epub 2021 Jun 30.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.

Background: X-chromosome inactivation (XCI) is a mechanism in which one of two X chromosomes in females is randomly inactivated in order to compensate for imbalance of gene dosage between sexes. However, about 15% of genes on the inactivated X chromosome (Xi) escape from XCI. The methylation level of the promoter region of the escape gene is lower than that of the inactivated genes. Dxz4 and/or Firre have critical roles for forming the three-dimensional (3D) structure of Xi. In mice, disrupting the 3D structure of Xi by deleting both Dxz4 and Firre genes led to changing of the escape genes list. To estimate the impact for escape genes by X-chromosome rearrangements, including DXZ4 and FIRRE, we examined the methylation status of escape gene promoters in patients with various X-chromosome rearrangements.

Results: To detect the breakpoints, we first performed array-based comparative genomic hybridization and whole-genome sequencing in four patients with X-chromosome rearrangements. Subsequently, we conducted array-based methylation analysis and reduced representation bisulfite sequencing in the four patients with X-chromosome rearrangements and controls. Of genes reported as escape genes by gene expression analysis using human hybrid cells in a previous study, 32 genes showed hypomethylation of the promoter region in both male controls and female controls. Three patients with X-chromosome rearrangements had no escape genes with abnormal methylation of the promoter region. One of four patients with the most complicated rearrangements exhibited abnormal methylation in three escape genes. Furthermore, in the patient with the deletion of the FIRRE gene and the duplication of DXZ4, most escape genes remained hypomethylated.

Conclusion: X-chromosome rearrangements are unlikely to affect the methylation status of the promoter regions of escape genes, except for a specific case with highly complex rearrangements, including the deletion of the FIRRE gene and the duplication of DXZ4.
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http://dx.doi.org/10.1186/s13148-021-01121-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244138PMC
June 2021

A Longitudinal Study of Lumbar Sagittal Change in Middle-Aged Healthy Volunteers.

Spine Surg Relat Res 2021 23;5(3):160-164. Epub 2020 Sep 23.

Department of Orthopedic Surgery, Nagoya University Hospital, Graduate School of Medicine, Aichi, Japan.

Introduction: Recent research has shown that spinal sagittal alignment plays a critical role in health-related quality of life. However, most of these studies were cross-sectional in nature, and longitudinal studies of lumbar lordosis (LL) in healthy subjects were few. This study aims to evaluate the change in lumbar sagittal parameters during a 10-year period.

Methods: The study population included 45 individuals (mean age, 65.7 years; male, n=20; female, n=25) who underwent sagittal lumbar radiography and a basic health checkup during a 10-year period. The radiologic parameters were LL, disc angle, sacral slope angle (SS), and pelvic incidence (PI). The change of LL during the 10-year period was defined as ΔLL. The subjects were divided into the LL maintenance group (n=33) and the LL non-maintenance group (n=12) based on their LL values.

Results: The radiologic baseline/final parameters were as follows: LL, 45/34 degrees (P<0.001); L1/L2 disc angle, 4.5/2.5 degrees; L2/L3 disc angle, 5.5/2.7 degrees; L3/L4 disc angle, 6.2/4.2 degrees; L4/L5 disc angle, 8.1/5.1 degrees; L5/S disc angle, 14.2/12.2 degrees; and SS, 32.0/32.1 degrees. The mean PI (50.5 degrees) was tended to be associated with the final LL (R=0.31, P=0.044) and was correlated with the ΔLL (R=0.43, P<0.01). The data of the LL maintenance/non-maintenance groups were as follows: age, 65.0/67.0; primary LL, 43.2/50.2 degrees (P<0.05); final LL, 36.2/27.8 degrees (P<0.05); and PI, 52.8/43.8 degrees (P<0.01).

Conclusions: During the 10-year study period, the LL in middle-aged and elderly volunteers decreased by 11 degrees. The factor of maintenance of LL was PI.
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http://dx.doi.org/10.22603/ssrr.2020-0123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208952PMC
September 2020

The efficacy of nintedanib in 158 patients with idiopathic pulmonary fibrosis in real-world settings: A multicenter retrospective study.

SAGE Open Med 2021 6;9:20503121211023357. Epub 2021 Jun 6.

Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, Aomori, Japan.

Background: The INPULSIS trials revealed that nintedanib reduced the decline in lung function in patients with idiopathic pulmonary fibrosis. We aimed to evaluate the efficacy and safety of nintedanib in Japanese idiopathic pulmonary fibrosis patients in real-world settings.

Method: Medical records of idiopathic pulmonary fibrosis patients, who received treatment with nintedanib in five institutions between July 2015 and June 2017, were reviewed. Patients with % forced vital capacity ⩾50% and % predicted diffusing capacity of the lung carbon monoxide ⩾30% were classified as the moderate group and those with more impaired lung functions as the severe group.

Result: Among 158 patients analyzed, 132 (84.6%) were classified as the moderate group and 26 (15.4%) as the severe group. In the moderate group, changes in forced vital capacity in 12 months were significantly different between before and after nintedanib administration (-253 ± 163 vs -125 ± 235 mL;  = 0.0027). In contrast, changes in forced vital capacity in 12 months were not significantly changed by nintedanib treatment in the severe group (-353 ± 250 vs -112 ± 341 mL;  = 0.2374). Incidence of acute exacerbation was higher in the severe group than in the moderate group (30.8% vs 18.9%). The overall survival of the moderate and the severe groups was 17.2 and 10.1 months.

Conclusion: In real-world practice, nintedanib showed comparable efficacy to those observed in previous trials. In the severe group, the efficacy of nintedanib might be limited.
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http://dx.doi.org/10.1177/20503121211023357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188975PMC
June 2021

Genome analyses and androgen quantification for an infant with 5α-reductase type 2 deficiency.

J Pediatr Endocrinol Metab 2021 Sep 24;34(9):1191-1195. Epub 2021 Jun 24.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

Objectives: 5α-reductase type 2 deficiency due to biallelic variants is a common form of 46,XY disorders of sex development.

Case Presentation: A Chinese neonate presented with ambiguous genitalia. He carried a homozygous likely_pathogenic variant (c.650C>A, p.A217E). His apparently nonconsanguineous parents were heterozygotes for the variant. The variant has previously been identified in two Chinese patients. Our patient carried 14.2 Mb loss-of-heterogeneity regions distributed in the genome. The variant in this family was invariably coupled with two polymorphisms in exon 1 and intron 1. In the patient, blood testosterone (T)/5α-dihydrotestosterone (5αDHT) ratios were elevated before and during mini puberty, and were higher when measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) than measured by conventional immune assays.

Conclusions: This study provides evidence for the founder effect of an variant. Furthermore, our data indicate that there is a need to establish a new reference value for T/5αDHT ratios using LC-MS/MS.
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http://dx.doi.org/10.1515/jpem-2020-0678DOI Listing
September 2021

Rapid Hypercalciuria Induction With Bone Formation Marker Reduction During Immobilization in Children.

Endocr Pract 2021 Jun 5. Epub 2021 Jun 5.

Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan. Electronic address:

Objective: To prospectively examine the occurrence of hypercalciuria and changes in bone metabolite markers in pediatric patients during immobilization.

Methods: In total, 13 children with an orthopedic disease requiring immobilization longer than 2 weeks were enrolled. Blood samples were collected after breakfast. Urine samples were collected at the second voiding after waking. The urine calcium/creatinine (Ca/Cr) ratio and various bone metabolite parameters were measured before and every 1 to 4 weeks after the start of immobilization.

Results: The median patient age was 7 years with a range of 2 to 13 years. Orthopedic diseases in the patients were dislocated hip joint (N = 7), slipped capital femoral epiphysis (N = 2), etc. The urine Ca/Cr ratio increased significantly within a week after immobilization (P < .01) and continued to increase for 2 more weeks. Once immobilization ended, the urine Ca/Cr ratio gradually decreased and returned to the normal range approximately 6 weeks after mobility was achieved (P < .01). Serum alkaline phosphatase (ALP) and bone-specific ALP significantly decreased after immobilization began (P < .01). After immobilization ended, the serum ALP returned to preimmobilization levels in 2 to 4 weeks (P < .01). Serum N-terminal telopeptides did not change significantly during immobilization.

Conclusion: The urine Ca/Cr ratio immediately increased after immobilization. In contrast to adults, bone formation markers in children decreased during immobilization, whereas bone resorption markers did not increase. To our knowledge, this study is the first to examine bone metabolism markers in children during immobilization.
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http://dx.doi.org/10.1016/j.eprac.2021.05.009DOI Listing
June 2021

Randomized phase 2 study comparing irinotecan versus amrubicin as maintenance therapy after first-line induction therapy for extensive disease small cell lung cancer (HOT1401/NJLCG1401).

Thorac Cancer 2021 07 2;12(14):2113-2121. Epub 2021 Jun 2.

Division of Pulmonary Medicine, Allergy, and Rheumatology, Iwate Medical University Faculty of Medicine Graduate School of Medicine Morioka, Iwate, Japan.

Background: A cisplatin plus irinotecan (CPT-11) regimen is used for patients with extensive disease small cell lung cancer (ED-SCLC). Amrubicin (AMR) is primarily used for relapsed SCLC. The HOT1401/NJLCG1401 trial, an open-label randomized phase II trial, was designed to assess the benefit of maintenance therapy in patients with ED-SCLC who responded to induction therapy.

Methods: Patients with histologically- or cytologically-confirmed ED-SCLC were included and were treated with an induction therapy of four cycles of cisplatin (60 mg/m on day 1) plus CPT-11 (60 mg/m on days 1, 8, and 15) every four weeks. After induction therapy, patients who had nonprogressive disease were randomized to receive either maintenance CPT-11 (60 mg/m on days 1 and 8) every three weeks, or AMR (35 mg/m on days 1-3) every three weeks.

Results: A total of 34 patients were enrolled; 20 patients had progressive disease or received incomplete induction chemotherapy. Finally, 14 patients were randomly assigned to receive CPT-11 (n = 7) or AMR (n = 7). This study was terminated prematurely because of low patient accrual. The overall objective response rate was 73%, the median PFS was 5.7 months (95% confidence interval [CI]: 3.6-11.8), and the median overall survival was 20.1 months (95% CI: 13.7-not reached). No statistically significant difference in progression-free survival (PFS) were noted between patients treated with CPT-11 and those treated with AMR. There were no treatment-related deaths in this study.

Conclusions: Maintenance therapy with CPT-11 or AMR after induction therapy might be effective in some patients.
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http://dx.doi.org/10.1111/1759-7714.14048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287008PMC
July 2021

Genetic Analysis of Japanese Children Clinically Diagnosed with Familial Hypercholesterolemia.

J Atheroscler Thromb 2021 May 20. Epub 2021 May 20.

Department of Pediatrics, Showa University School of Medicine.

Aim: This study aimed to elucidate the gene and lipid profiles of children clinically diagnosed with familial hypercholesterolemia (FH).

Methods: A total of 21 dyslipidemia-related Mendelian genes, including FH causative genes (LDLR, APOB, and PCSK9) and LDL-altering genes (APOE, LDLRAP1, and ABCG5/8), were sequenced in 33 Japanese children (mean age, 9.7±4.2 years) with FH from 29 families.

Results: Fifteen children (45.5%) with pathogenic variants in LDLR (eight different heterozygous variants) and one child (3.0%) with the PCSK9 variant were found. Among 17 patients without FH causative gene variants, 3 children had variants in LDL-altering genes, an APOE variant and two ABCG8 variants. The mean serum total cholesterol (280 vs 246 mg/dL), LDL-cholesterol (LDL-C, 217 vs 177 mg/dL), and non-HDL cholesterol (228 vs 188 mg/dL) levels were significantly higher in the pathogenic variant-positive group than in the variant-negative group. In the variant-positive group, 81.3% of patients had LDL-C levels ≥ 180 mg/dL but 35.3% in the variant-negative group. The mean LDL-C level was significantly lower in children with missense variants, especially with the p.Leu568Val variant, than in children with other variants in LDLR, whereas the LDL-altering variants had similar effects on the increase in serum LDL-C to LDLR p.Leu568Val.

Conclusion: Approximately half of the children clinically diagnosed with FH had pathogenic variants in FH causative genes. The serum LDL-C levels tend to be high in FH children with pathogenic variations, and the levels are by the types of variants. Genetic analysis is useful; however, further study on FH without any variants is required.
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http://dx.doi.org/10.5551/jat.62807DOI Listing
May 2021

Starting age of oestrogen-progestin therapy is negatively associated with bone mineral density in young adults with Turner syndrome independent of age and body mass index.

Clin Endocrinol (Oxf) 2021 Jul 3;95(1):84-91. Epub 2021 May 3.

Department of Gastroenterology, Nutrition, and Endocrinology, Osaka Women's and Children's Hospital, Izumi, Japan.

Objective: Osteoporosis is an important health issue in patients with Turner syndrome (TS), and oestrogen sufficiency has been implicated in increased bone mineral density (BMD); however, the impact of the starting age of hormone replacement therapy (HRT) on bone mineral density remains unclear, particularly during young adulthood.

Design: A retrospective study from three tertiary care hospitals in Japan.

Patients: One hundred and three patients with TS aged between 18 and 30 years of age who underwent dual-energy X-ray absorptiometry.

Measurements: Anthropometric parameters, lumbar bone mineral density (L-BMD), including areal BMD (aBMD) and volumetric BMD (vBMD), karyotypes, the presence of spontaneous menarche, the starting ages of oestrogen replacement therapy (ERT) and oestrogen-progestin therapy (EPT), and the duration between starting ages of oestrogen replacement therapy and oestrogen-progestin therapy were investigated. vBMD was calculated based on the Kröger method.

Results: aBMD was lower in young adults with TS than in an age-matched reference population. L-BMD positively correlated with weight and body mass index (BMI). L-BMD was higher in subjects with spontaneous menarche (N = 22) than in those without. A dose escalation regimen of oestrogen replacement therapy was used in 84% of subjects without spontaneous menarche (N = 81). The starting age of oestrogen replacement therapy and the duration between the starting ages of oestrogen replacement therapy and oestrogen-progestin therapy negatively and independently correlated with aBMD, but not with vBMD, after adjustment with age and BMI. The starting age of oestrogen-progestin therapy negatively correlated with L-BMD independent of age and BMI.

Conclusions: Early introduction of hormone replacement therapy, particularly oestrogen-progestin therapy, is important to accrue better L-BMD in young adults with TS.
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http://dx.doi.org/10.1111/cen.14484DOI Listing
July 2021

Errata to "Ultra-low-dose estrogen therapy for female hypogonadism".

Clin Pediatr Endocrinol 2021 3;30(2):119. Epub 2021 Apr 3.

Department of Pediatrics, Thomas Jefferson University, Pennsylvania, USA.

[This corrects the article DOI: 10.1297/cpe.29.49.].
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http://dx.doi.org/10.1297/cpe.30.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022039PMC
April 2021

A Phase I/II Study of Biweekly Carboplatin and Nab-paclitaxel With Concurrent Radiotherapy for Patients With Locally Advanced Unresectable Stage III Non-small-cell Lung Cancer.

Clin Lung Cancer 2021 01 14;22(1):42-48. Epub 2020 Oct 14.

Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with locally advanced non-small-cell lung cell cancer (LA-NSCLC). We conducted a phase I/II study of biweekly carboplatin and nab-paclitaxel (nab-PTX) with radiotherapy (RT).

Materials And Methods: In the phase I part, patients with inoperable stage IIIA/IIIB NSCLC were treated with carboplatin (area under the time-concentration curve, 4) and nab-PTX (60-100 mg/m) on days 1, 15, and 29. Thoracic RT was administered from day 1 to a total dose of 60 Gy in 30 fractions. In the phase II part, patients were administered carboplatin and nab-PTX on days 1, 15, and 29 at the recommended dose (RD). The primary endpoint of the phase I part was to determine the maximum tolerated dose and the RD. In the phase II part, the primary endpoint was 2-year overall survival (OS) rate, and secondary endpoints were the objective response rate, progression-free survival, OS, and safety profile.

Results: In the phase I part, although maximum tolerated dose was not obtained, the RD was carboplatin (area under the time-concentration curve, 4) and nab-PTX (100 mg/m). Of the evaluable 28 patients, the rate of 2-year OS was 67.8% (95% confidence interval, 49.3%-82.1%). The objective response rate was 96.4%, and the median follow-up time was 33.2 months. The median progression-free survival was 18.2 months (95% confidence interval, 13.1 months to not reached). The most common toxicities of grade 3 or higher were neutropenia (60.5%), anemia (14.2%), thrombocytopenia (7.2%), and pneumonitis (3.6%).

Conclusions: This study achieved the primary endpoint. Biweekly carboplatin and nab-PTX with concurrent RT was well-tolerated and exerted promising antitumor activity.
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http://dx.doi.org/10.1016/j.cllc.2020.09.016DOI Listing
January 2021

SOX9 is colocalized with paraspeckle protein NONO in cultured murine sertoli cells and features structural characteristics of intrinsically disordered proteins.

Mol Reprod Dev 2020 11 6;87(11):1124-1125. Epub 2020 Oct 6.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

This study provides supporting evidence for the association between SOX9 and liquid-liquid phase separation. We show that SOX9 colocalized with a paraspeckle protein NONO in many, but not all, of the immortalized and primary murine Sertoli cells examined. In addition, we confirmed that SOX9 has structural characteristics of intrinsically disordered proteins.
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http://dx.doi.org/10.1002/mrd.23425DOI Listing
November 2020

Retrospective study of the renal function using estimated glomerular filtration rate and congenital anomalies of the kidney-urinary tract in pediatric Turner syndrome.

Congenit Anom (Kyoto) 2020 Nov 4;60(6):175-179. Epub 2020 Aug 4.

Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Although Turner syndrome (TS) is frequently associated with congenital anomalies of the kidney-urinary tract (CAKUT), which is a major cause of pediatric chronic kidney disease, renal function in TS is usually considered normal. The present study aimed to analyze the frequency of renal dysfunction and CAKUT in pediatric patients with TS. Our study included 122 patients with TS between the ages of 2 and 18 years from 30 hospitals across Japan. Clinical data related to renal function and CAKUT were retrospectively collected. The estimated glomerular filtration rate (eGFR) was calculated using the serum creatinine-based formula recommended by the Japanese Society for Pediatric Nephrology. An eGFR <90 mL/min/1.73 m for two consecutive years was defined as renal dysfunction. Fifteen (13.5%) of 122 patients had CAKUT, and four patients had renal dysfunction (3.2%, 95% confidence interval: 0%-6.7%). Three of the four did not have CAKUT. Of the CAKUT manifestations, horseshoe kidney, renal hypodysplasia, and multicystic dysplastic kidney were seen in nine, two, and one patient, respectively. Eight of the nine patients with horseshoe kidney had a normal renal function; however, the remaining patient with renal hypodysplasia had renal dysfunction. A small percentage of patients with pediatric TS may had an eGFR below 90 mL/min/1.73 m which was not necessarily associated with CAKUT.
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http://dx.doi.org/10.1111/cga.12384DOI Listing
November 2020

A retrospective multicenter study of bone mineral density in adolescents and adults with Turner syndrome in Japan.

Endocr J 2020 Oct 18;67(10):1023-1028. Epub 2020 Jun 18.

Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo 183-8561, Japan.

Osteoporosis is one of the clinical features of women with Turner syndrome (TS). The reasons for low bone mineral density (BMD) and increased bone fragility are multifactorial, including estrogen deficiency, X-chromosome abnormalities, and environmental factors. Few, large-scale studies on bone mineral density in either adolescents or adults with TS have been done in Japan. The goal of the present study was to investigate spinal BMD in women with TS, assess its relationship with clinical parameters, especially estrogen replacement therapy, and investigate its longitudinal changes. The spinal BMD and clinical data of 149 Japanese women with TS aged 15 to 49 years who were followed at the four participating hospitals were retrospectively analyzed. The BMD Z-scores of the women with TS ranged from -5.30 to +1.89. Women with TS aged 15-39 years had lower BMD than healthy Japanese women (p < 0.01) while women with spontaneous menstruation had a significantly higher BMD Z-score than those without spontaneous menstruation (-0.73 ± 1.11 vs. -1.67 ± 1.18, p < 0.01). In women without spontaneous menstruation, BMD Z-scores correlated with the duration of their estrogen therapy (r = 0.167, p < 0.01). Women aged 15-39 years with TS had low BMD, which was associated with primary amenorrhea and short estrogen replacement therapy duration.
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http://dx.doi.org/10.1507/endocrj.EJ20-0083DOI Listing
October 2020

Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients.

Clin Epigenetics 2020 06 16;12(1):86. Epub 2020 Jun 16.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.

Background: Silver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features. Major (epi)genetic causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). However, IGF2, CDKN1C, HMGA2, and PLAG1 mutations infrequently cause SRS. In addition, other imprinting disturbances, pathogenic copy number variations (PCNVs), and monogenic disorders sometimes lead to SRS phenotype. This study aimed to clarify the frequency and clinical features of the patients with gene mutations among etiology-unknown patients with SRS phenotype.

Results: Multigene sequencing was performed in 92 out of 336 patients referred to us for genetic testing for SRS. The clinical features of the patients were evaluated based on the Netchine-Harbison clinical scoring system. None of the patients showed 11p15 LOM, upd(7)mat, abnormal methylation levels for six differentially methylated regions (DMRs), namely, PLAGL1:alt-TSS-DMR on chromosome 6, KCNQ1OT1:TSS-DMR on chromosome 11, MEG3/DLK1:IG-DMR on chromosome 14, MEG3:TSS-DMR on chromosome 14, SNURF:TSS-DMR on chromosome 15, and GNAS A/B:TSS-DMR on chromosome 20, PCNVs, or maternal uniparental disomy of chromosome 16. Using next-generation sequencing and Sanger sequencing, we screened four SRS-causative genes and 406 genes related to growth failure and/or skeletal dysplasia. We identified four pathogenic or likely pathogenic variants in responsible genes for SRS (4.3%: IGF2 in two patients, CDKN1C, and PLAG1), and five pathogenic variants in causative genes for known genetic syndromes presenting with growth failure (5.4%: IGF1R abnormality (IGF1R), SHORT syndrome (PIK3R1), Floating-Harbor syndrome (SRCAP), Pitt-Hopkins syndrome (TCF4), and Noonan syndrome (PTPN11)). Functional analysis indicated the pathogenicity of the CDKN1C variant. The variants we detected in CDKN1C and PLAG1 were the second and third variants leading to SRS, respectively. Our patients with CDKN1C and PLAG1 variants showed similar phenotypes to previously reported patients. Furthermore, our data confirmed IGF1R abnormality, SHORT syndrome, and Floating-Harbor syndrome are differential diagnoses of SRS because of the shared phenotypes among these syndromes and SRS. On the other hand, the patients with pathogenic variants in causative genes for Pitt-Hopkins syndrome and Noonan syndrome were atypical of these syndromes and showed partial clinical features of SRS.

Conclusions: We identified nine patients (9.8%) with pathogenic or likely pathogenic variants out of 92 etiology-unknown patients with SRS phenotype. This study expands the molecular spectrum of SRS phenotype.
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http://dx.doi.org/10.1186/s13148-020-00865-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298762PMC
June 2020

Ultra-low-dose estrogen therapy for female hypogonadism.

Clin Pediatr Endocrinol 2020 16;29(2):49-53. Epub 2020 Apr 16.

Department of Pediatrics, Thomas Jefferson University, Pennsylvania, USA.

In females, endogenous estrogen secretion increases gradually before pubertal development. The benefits of low-dose estrogen therapy in patients with Turner syndrome were originally discussed by Ross and Quigley . These seminal studies used ethinyl estradiol (EE2), starting at a dose of 25 ng/kg/d. We hypothesized that the initial dosage of estrogen could be titrated to more closely mimic physiological increments of endogenous estrogen. Therefore, our recent study initiated EE2 treatment at a dosage of 1-2 ng/kg/d, an ultra-low-dose estrogen therapy in pediatric patients with Turner syndrome. The ultra-low-dose estrogen therapy in this syndrome produced a good final height outcome but achieved suboptimal bone mineral density (BMD). In the present review, we have explained our findings to clarify the merits and demerits of this new therapy and to promote further discussion and research. This type of ultra-low-dose estrogen therapy, initiated at an early age, could be ideal for estrogen replacement in female patients with hypogonadism, such as Turner syndrome.
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http://dx.doi.org/10.1297/cpe.29.49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160460PMC
April 2020

MIRAGE syndrome with recurrent pneumonia probably associated with gastroesophageal reflux and achalasia: A case report.

Clin Pediatr Endocrinol 2019 19;28(4):147-153. Epub 2019 Oct 19.

Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

Aspiration pneumonia is a common complication of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE) syndrome. However, the detailed clinical course of aspiration pneumonia in neonates and infants diagnosed with this disorder remains unclear. We report a case of a 2-yr-old girl diagnosed with MIRAGE syndrome during the early neonatal period. The patient developed 3 episodes of aspiration pneumonia until 4 mo of age, and this complication was attributed to esophageal hypoperistalsis secondary to achalasia and gastroesophageal reflux. Enteral feeding via a duodenal tube effectively prevented further episodes of aspiration pneumonia in this patient.
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http://dx.doi.org/10.1297/cpe.28.147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801359PMC
October 2019

Uterus in mixed gonadal dysgenesis was detected by continuous irregular vaginal bleeding.

Clin Pediatr Endocrinol 2019 19;28(4):135-138. Epub 2019 Oct 19.

Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

Disorders of sex development (DSD) are a group of congenital conditions presenting with differences in the chromosomal, gonadal, or anatomic sex development. Evaluating the chromosomes, gonads, and internal and external genitalia of the patients is important for understanding DSD. Furthermore, confirming the presence of a uterus is essential for the assessment of the internal genitalia status. Although the uterus can be identified by ultrasonography, magnetic resonance imaging, or laparoscopy, it may be easily overlooked. Here, we report the case of a patient with mixed gonadal dysgenesis, in whom the presence of a uterus could not be confirmed before the initiation of estrogen replacement therapy despite the performance of various tests. The detection of the uterus was prompted by an atypical genital bleeding. This case implies that physicians may have difficulties identifying the uterus in female patients with DSD before the initiation of estrogen treatment.
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http://dx.doi.org/10.1297/cpe.28.135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801358PMC
October 2019

Levothyroxine dosages less than 2.4 μg/kg/day at 1 year and 1.3 μg/kg/day at 3 years of age may predict transient congenital hypothyroidism.

Clin Pediatr Endocrinol 2019 19;28(4):127-133. Epub 2019 Oct 19.

Department of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

Significant differences in levothyroxine (LT4) dosages for congenital hypothyroidism (CH), which can be permanent (P-CH) or transient (T-CH), and their respective cutoff values have been reported. In Japanese children, however, these values are unknown, and were thus determined in this retrospective single-center study, which included 34 patients- 19 with P-CH and 15 with T-CH. The LT4 dosages of the two groups at ages 1 and 3 yr were compared, and receiver operating characteristic (ROC) analysis was performed to identify the cutoff dosages. The results showed that the LT4 dosages of the P-CH and T-CH groups differed significantly at both ages. When LT4 dosage cutoff at 1 yr of age was set at 2.4 μg/kg/d, the sensitivity and specificity were 93% and 74%, respectively, and when it was set at 1.3 μg/kg/d at 3 yr of age, they were 80% and 84%, respectively, suggesting that when LT4 dosages are ≤2.4 μg/kg/d at 1 yr and ≤1.3 μg/kg/d at 3 yr of age, T-CH should be suspected.
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http://dx.doi.org/10.1297/cpe.28.127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801356PMC
October 2019

Levothyroxine Dosage as Predictor of Permanent and Transient Congenital Hypothyroidism: A Multicenter Retrospective Study in Japan.

Horm Res Paediatr 2019 25;92(1):45-51. Epub 2019 Sep 25.

Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

Background: Congenital hypothyroidism (CH) can be divided into 2 types, transient CH (T-CH) and permanent CH (P-CH), depending on the requirement of levothyroxine (LT4) for life-long treatment. Several studies have recently reported that the LT4 dosage is useful for predicting the LT4 requirement, but none of the studies followed their patients to puberty.

Objective: To determine the cutoff value for the LT4 dosage as a predictor of the LT4 requirement after puberty in patients with CH.

Methods: The LT4 dosage and clinical data on 99 patients with CH who were followed at the participating hospitals from the neonatal period to 15 years of age or older were retrospectively analyzed. Based on their LT4 requirement at their last hospital visit, the participants were divided into the P-CH group (n = 75), who were treated with LT4, and the T-CH group (n = 24), who were not.

Results: At age 1 year, a higher LT4 dosage was required for the P-CH group (median 3.75 vs. 2.88 µg/kg/day; p < 0.001). When the LT4 dosage cutoff value at age 1 year was set at 4.79 and 1.74 µg/kg/day, the specificity of P-CH and T-CH (for denying T-CH and P-CH, respectively) was 100 and 97%, respectively.

Conclusions: An LT4 dosage above 4.7 µg/kg/day and below 1.8 µg/kg/day at age 1 year may help predict P-CH and T-CH, respectively.
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http://dx.doi.org/10.1159/000502418DOI Listing
April 2020

Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective.

Horm Res Paediatr 2019 12;92(1):1-14. Epub 2019 Sep 12.

University Children´s Hospital, Tübingen, Germany.

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.
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http://dx.doi.org/10.1159/000502231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979443PMC
April 2020

Real-world study of afatinib in first-line or re-challenge settings for patients with EGFR mutant non-small cell lung cancer.

Med Oncol 2019 May 14;36(6):57. Epub 2019 May 14.

Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5, Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.

Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC), was approved in Japan in 2014. This study evaluated clinical outcomes of afatinib in real-world practice. Medical records of patients who received afatinib for advanced EGFR-mutant NSCLC were retrospectively reviewed. In total, 128 patients were analyzed. Seventy-six patients received afatinib as the first-line setting and 52 as the re-challenge setting (i.e., after failure of prior first-generation TKI). There was no difference in patient characteristics, such as age, sex, and PS, between the first-line and the re-challenge settings. In the first-line setting, the median progression-free survival (PFS) was 17.8 months (95% confidence interval [CI] 13.7-21.5 months). The overall survival (OS) was 39.5 months (95% CI 34.4- not reached). The response rate (RR) was 64.4%. Subset analysis indicated that patients with dose reduction showed longer PFS than those without dose reduction (18.5 months versus 7.9 months) (P = 0.016). In the re-challenge setting, the median PFS was 8.0 months (95% CI 4.9-9.5 months). The RR was 25%. Most common adverse events leading to dose modification or treatment discontinuation included diarrhea, paronychia, and oral mucositis in both settings. Interstitial lung disease occurred in 5.4% (7/128). In the real-world practice in Japan, afatinib showed comparable or better efficacy compared with that shown in previous clinical trials in both the first-line and the re-challenge settings.
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http://dx.doi.org/10.1007/s12032-019-1278-9DOI Listing
May 2019

Frequent and prolonged administration of glucocorticoid for acute adrenal insufficiency treatment can cause diabetes mellitus: A case of holoprosencephaly.

Clin Pediatr Endocrinol 2019 24;28(2):31-36. Epub 2019 Apr 24.

Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

Glucocorticoid (GC)-induced diabetes mellitus (DM) is theoretically unlikely to occur in patients with adrenal insufficiency if adequate physiological replacement doses of GC are given. Herein we report a patient with holoprosencephaly who developed GC-induced DM due to frequent and prolonged administration of high-dose GC for suspected adrenal crisis (AC). GC treatment should be started whenever AC cannot be ruled out. However, the initial and subsequent doses should be adjusted to the severity of AC and to the pace of clinical recovery with treatment, respectively.
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http://dx.doi.org/10.1297/cpe.28.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476947PMC
April 2019

Treatment of adrenal crisis in patients with primary hypoadrenalism can lead to hypertension.

Clin Pediatr Endocrinol 2019 24;28(2):25-30. Epub 2019 Apr 24.

Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

Hypertension is one of the most serious side effects of glucocorticoid therapy. We retrospectively investigated the frequency of hypertension during treatment of adrenal crisis and analyzed the factors associated with its development. Patients who were admitted for primary hypoadrenalism due to diagnosed or suspected adrenal crisis were included. In the analysis, the subjects were divided into two groups: the hypertensive group (group H) and non-hypertensive group (group Non-H). The primary endpoint was the difference in the hourly therapeutic hydrocortisone (HDC) dosage between the two groups. The hourly therapeutic HDC dose in the two groups was defined as the hourly HDC dose from the start of HDC infusion until the development of hypertension in group H or until the last blood pressure measurement in group Non-H. Nine of 19 crises led to hypertension. There was no significant difference in the therapeutic HDC dosage between the groups (p = 0.108). In conclusion, hypertension developed in some patients during treatment for adrenal crisis. There was no significant difference in the therapeutic HDC dosage between groups H and Non-H.
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http://dx.doi.org/10.1297/cpe.28.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476948PMC
April 2019

The efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer harboring driver mutations.

Mol Clin Oncol 2019 Jun 3;10(6):610-614. Epub 2019 Apr 3.

Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.

The present retrospective study was conducted to evaluate the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC) harboring driver mutations. Patients with NSCLC harboring driver mutations who received ICIs (nivolumab or pembrolizumab) were reviewed in Hirosaki University and Aomori Prefectural Central Hospital. There were 139 patients who received molecular targeted drugs, including 24 patients treated with ICIs. Patient characteristics were as follows: Male/female, 5/19; median age 68 (range 39-82); smoking/non-smoking, 6/18; PS 0-1/2, 20/4; driver mutation status, EGFR/ALK/RET/ROS1: 21/1/1/1. The overall response rate was 16.7% [95% confidence interval (CI), 7.0-37.1%] and the disease control rate was 33.4% (95% CI, 18.9-55.1%). The median progression-free survival (PFS) time was 62 days (95% CI 52-81 days). In the patients who had been treated by the preceding tyrosine kinase inhibitor (TKI) for >1 year, the PFS time was 110 days. On the other hand, in the patients who had received a TKI for less than a year, the PFS time was 56 days, which was significantly shorter (P=0.012). To conclude, some of the patients with NSCLC harboring driver mutation could benefit from ICIs, and the duration of previous TKI treatment may be associated with the efficacy.
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http://dx.doi.org/10.3892/mco.2019.1838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482391PMC
June 2019

First-in-Asian Phase I Study of the Anti-Fibroblast Growth Factor 23 Monoclonal Antibody, Burosumab: Safety and Pharmacodynamics in Adults With X-linked Hypophosphatemia.

JBMR Plus 2019 Feb 14;3(2):e10074. Epub 2018 Sep 14.

Department of Pediatrics Osaka Hospital Japan Community Healthcare Organization (JCHO) Osaka Japan.

X-linked hypophosphatemia (XLH) is a disease caused by abnormally elevated FGF23 levels, which cause persistent hypophosphatemia accompanied by subsequent reduction in bone mineralization that presents as rickets or osteomalacia. Burosumab is a fully human monoclonal antibody targeting FGF23 that is under development for the treatment of FGF23-related hypophosphatemia including XLH. The safety, tolerability, and proof of concept of burosumab have been evaluated in patients with XLH in previous studies conducted in countries outside of Asia. The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and expression of anti-drug antibodies in Japanese and Korean adults with XLH. This was a multicenter, sequential dose-escalation, open-label, single-dose study. This study began with cohort 1 (s.c. dose of burosumab 0.3 mg/kg), after which the dose was escalated sequentially in cohort 2 (s.c. dose of burosumab 0.6 mg/kg) and cohort 3 (s.c. dose of burosumab 1.0 mg/kg). The PK of burosumab were linear within the dose range of 0.3 to 1.0 mg/kg. The PD effects such as serum phosphorus concentration, serum 1,25[OH]D concentration, and ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) were elevated after a single s.c. administration. The area under the receiver-operating characteristic curve from 0 to (AUC) values calculated using the change from baseline values of serum phosphorus, serum 1,25(OH)D, and TmP/GFR were correlated with the AUC of burosumab. Furthermore, no serious adverse events (AEs), deaths, remarkable increase or decrease in the corrected calcium or intact PTH levels, or signs of nephrocalcinosis or its worsening were observed after treatment. Some AEs and drug-related AEs were observed; however, there were no clinically meaningful tendencies. The positive effects and acceptable safety profile seen in this study are encouraging for Japanese and Korean patients with XLH.
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http://dx.doi.org/10.1002/jbm4.10074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383703PMC
February 2019

A Japanese case of familial hypercholesterolemia with a novel mutation in the gene.

Clin Pediatr Endocrinol 2019 31;28(1):19-22. Epub 2019 Jan 31.

Department of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

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http://dx.doi.org/10.1297/cpe.28.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356093PMC
January 2019

Language delay and developmental catch-up would be a clinical feature of pseudohypoparathyroidism type 1A during childhood.

Endocr J 2019 Mar 23;66(3):215-221. Epub 2019 Jan 23.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.

Pseudohypoparathyroidism type 1A (PHP1A) is characterized by resistance to multiple hormones, the Albright Hereditary Osteodystrophy phenotype, obesity, and developmental delay. Developmental delay usually appears prior to hypocalcemia due to parathyroid hormone resistance and could be a clinically important feature for early diagnosis of PHP1A. To date, however, the details have not been documented. With regard to developmental delays, we conducted a multicenter retrospective study of 22 PHP1A patients from 18 families who were diagnosed clinically or genetically from 2005 to 2015. For quantitative analysis of their development, we calculated the ratios of the milestone ages of the patients to those in normal reference data. The ratio of the ages with respect to speech development, i.e., speaking a first meaningful word (median: 1.67), was significantly higher than that for gross motor development, walking unassisted (median: 1.34). The ratio of age at stringing a two-word sentence (median: 1.32) was significantly lower than that of saying a first word (median: 1.84). Ten out of 11 (91%) patients exhibited two or three of the following clinical phenotypes: developmental delay, obesity, and hyperthyrotropinemia. These results suggest two possible clinical features of developmental delays in PHP1A patients: developmental delay is more obvious in speech acquisition than in gross motor skills, and speech delays could be attenuated during later childhood. Further, the presence of multiple of three clinical symptoms could be an important indicator to differentiate the diagnosis of PHP1A during early childhood.
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http://dx.doi.org/10.1507/endocrj.EJ18-0326DOI Listing
March 2019

Hypoglycemia in type 1A diabetes can develop before insulin therapy: A retrospective cohort study.

Diabetes Res Clin Pract 2019 Jan 24;147:87-92. Epub 2018 Nov 24.

Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo 183-8561, Japan. Electronic address:

Aims: There are as yet no cohort studies of hypoglycemia in type 1 diabetes before starting insulin therapy. Our aim was to determine the frequency and clinical features of hypoglycemia in patients with type 1A diabetes prior to commencing insulin therapy.

Methods: Eighty-seven patients with type 1A diabetes were enrolled, and a retrospective chart review of the patients was conducted.

Results: Hypoglycemia before insulin therapy occurred in six of 87 patients (6.9%). The HbA1c levels at the diagnosis of type 1A diabetes in the hypoglycemia group were lower than in the non-hypoglycemia group (median: 7.3% (56 mmol/mol) vs. 11.9% (106 mmol/mol), p < 0.0001). Similarly, the 24-hour urinary C-peptide (UCPR) levels of the former group were higher than those of the latter group (16.5 μg/day/m vs. 7.0 μg/day/m, p = 0.0075). Hypoglycemic episodes occurred mostly in the postprandial period and gradually disappeared with a decrease in insulin secretion.

Conclusions: We demonstrated that some patients with type 1A diabetes experience hypoglycemic episodes before insulin therapy. Patients with early-stage type 1A diabetes with relatively low HbA1c or high UCPR have a risk of hypoglycemia. These findings may impact when and how insulin is introduced in the treatment of early-stage type 1A diabetes.
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http://dx.doi.org/10.1016/j.diabres.2018.11.011DOI Listing
January 2019
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