Efficacy of incremental loads of cow's milk as a treatment for lactose malabsorption in Japan.

BACKGROUND: Lactose intolerance (LI) is commonly seen in East Asian countries. Several studies showed that lactose or milk loading has been used as a treatment for lactose malabsorption (LM) in Western countries, but there have been no reports regarding this type of treatment in Japan. As lactose or milk loading requires ingestion of large amounts of lactose within a short period, this is considered to be too harsh for Japanese people because of their less habitual milk consumption (175 mL per day in average) than Western people. In this study, we demonstrated lactose tolerance acquisition in a suitable way for Japanese. AIM: To examine the efficacy of lactose (cow's milk) loading treatment in patients with LM. METHODS: Individuals with abdominal symptoms induced by milk or dairy products (LI symptoms) were identified with a questionnaire. A 20 g lactose hydrogen breath test (LHBT) was carried out to confirm LM diagnosis and to evaluate co-existence of small intestinal bacterial overgrowth (SIBO). Respondents diagnosed with LM were selected as study subjects and were treated with incremental loads of cow's milk, starting from 30 mL and increasing up to 200 mL at 4-7 d intervals. After the treatment, changes in symptoms and LM diagnostic value of 20 g LHBT were investigated. Stool samples pre- and post-treatment were examined for changes in intestinal microbiota using 16S rRNA sequencing. Informed consent was obtained prior to each stage of the study. RESULTS: In 46 subjects with LI symptoms (10-68 years old, mean age 34 years old) identified with the questionnaire, 35 (76.1%) were diagnosed with LM by 20 g LHBT, and 6 had co-existing SIBO. The treatment with incremental cow's milk was carried out in 32 subjects diagnosed with LM (14-68 years old, median age 38.5 years old). The mean period of the treatment was 41 ± 8.6 d. Improvement of symptoms was observed in 29 (90.6%; 95% confidence interval: 75.0%-98.0 %) subjects. Although 20 g LHBT indicated that 10 (34.5%) subjects had improved diagnostic value of LM, no change was observed in 16 (55.2%) subjects. Analysis of the fecal intestinal microbiota showed a significant increase in Blautia in 7 subjects who became symptom-free after the treatment (P = 0.0313). CONCLUSION: LM was diagnosed in approximately 75% of the subjects who had LI. Incremental loads of cow's milk is regarded as a useful treatment for LM without affecting everyday life.

Useful manifestations to detect adenovirus in children with upper respiratory infections: A retrospective study.

OBJECTIVE: Approximately 1 million adenovirus immunochromatography (IC) kits are annually used in Japan. However, no practical strategies have been developed regarding their use for detecting adenovirus. The present study aims to verify the usefulness of clinical manifestations in making decisions regarding the use of adenovirus IC kits for children with upper respiratory infections (URI). METHODS: The medical records of 825 pediatric cases tested by IC kits for adenovirus were extracted from clinical laboratory department database over a 3-year period at our hospital. Among them, 585 patients were suspected adenovirus URI, and their clinical manifestations were reviewed. After data cleaning, 10 types of clinical manifestations were statistically analyzed between adenovirus IC kit-positive and -negative groups. Multivariate analysis was performed to select significant clinical manifestations using adenovirus IC kit positivity as the objective variable. RESULTS: Among 585 pediatric patients, the cases of 420 patients, with suitable data for whom no other pathogen was detected, were reviewed. Adenovirus was detected in 86 cases. Multivariate analysis identified a significant difference for three clinical manifestations: (1) fever ≥ 39.0°C, (2) rhinorrhea, and (3) tonsillar exudate. The negativity rate for the IC kit was 90% when none of the three manifestations was observed. CONCLUSIONS: The results suggested that IC kits for adenovirus tend to give negative results in cases that lack all the three above mentioned clinical manifestations.

A case report with functional characterization of a HNF1B mutation (p.Leu168Pro) causing MODY5.

We previously performed next-generation sequencing-based genetic screening in patients with autoantibody-negative type 1 diabetes, and identified the p.Leu168Pro mutation in HNF1B. Here,we report the clinical course of the patient and the results of functional characterization of this mutation. The proband had bilateral renal hypodysplasia and developed insulin-dependent diabetes during childhood. The pathogenicity of Leu168Pro-HNF1B was evaluated with three-dimensional structure modeling, Western blotting, immunofluorescence analysis and luciferase reporter assays using human embryonic kidney 293 cells. Three-dimensional structure modeling predicted that the Leu168 residue is buried in the DNA-binding Pit-Oct-Unc-specific (POUS) domain and forms a hydrophobic core. Western blotting showed that the protein expression level of Leu168Pro-HNF1B was lower than that of wild-type (WT) HNF1B. Immunofluorescence staining showed that both WT- and Leu168Pro-HNF1B were normally localized in the nucleus. The cells transfected with WT-HNF1B exhibited 5-fold higher luciferase reporter activity than cells transfected with an empty vector. The luciferase activities were comparable between WT-HNF1B/Leu168Pro-HNF1B and WT-HNF1B/empty vector co-transfection. In conclusion, Leu168Pro is a protein-destabilizing HNF1B mutation, and the destabilization is likely due to the structural changes involving the hydrophobic core of POUS. The disease-causing Leu168Pro HNF1B mutation is a loss-of-function mutation without a dominant-negative effect.

Complete remission from post-heart transplant lymphoproliferative disorder: A case report.

We report a case of Burkitt's lymphoma, post-transplant lymphoproliferative disorder (BL-PTLD) that was treated with intensive chemotherapy. The patient was a 4-year-old boy who underwent heart transplantation at 7 months of age for refractory heart failure due to dilated cardiomyopathy. He was admitted to our hospital with a chief complaint of abdominal pain associated with an abdominal mass. Computed tomography was notable for a bulky mass arising from the terminal ileum. Fluorodeoxyglucose-positron emission tomography revealed multiple lesions in brain, bone, and lymph nodes. He was diagnosed with BL-PTLD stage III by pathological and clinical scoring. He was Epstein-Barr virus (EBV)-seronegative with a low EBV viral DNA load. No EBV-encoded small RNAs were in his intra-abdominal lymph nodes by in situ hybridization. On cytogenetic examination, the intra-abdominal lymph nodes revealed both a MYC rearrangement and a t(8;14)(q24;32), t(16;19)(q24;q13.1) translocation. Administration of tacrolimus and mycophenolate mofetil was discontinued; immunosuppression was maintained with everolimus. Intensive chemotherapy based on the modified LMB 96 protocol for BL was initiated, resulting in complete remission achieved. During the intensive chemotherapy and immunosuppressive switching period, cardiac dysfunction and allograft rejection had not been shown. The patient has remained well for two years after the treatment with no evidence of relapse. .

Adiponectin, ALT and family history as critical markers for the development of type 2 diabetes in obese Japanese children.

Aims/Introduction: An association between the pathogenesis of type 2 diabetes mellitus (T2D) and that of metabolic syndrome (MS) in obese children has been suggested. We clarified the critical markers for the development of T2D in obese Japanese children. Methods: One hundred and seven obese children who visited our outpatient clinic were enrolled in this study. The obese subjects were divided into 3 groups: Group A, T2D (n = 19); Group B, MS but not T2D (n = 19); and Group C: non-T2D, non-MS (n = 69). In all the subjects, a biochemical examination was performed and the serum adiponectin and leptin levels were measured. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured using computed tomography images. Results: Group A tended to have higher VAT values and VAT/SAT ratios and lower leptin and adiponectin levels, compared with Groups B and C. In Group A, the alanine aminotransferase (ALT) level was significantly higher and the aspartate aminotransferase (AST)/ALT ratio was significantly lower than in Group C. A receiver operating characteristic (ROC) analysis showed that the optimal cut-off point for adiponectin was 6.4 µg/mL (AUC = 0.859). The cut-off points for ALT, the AST/ALT ratio and VAT were 35 IU/L (AUC = 0.821), 0.85 (AUC = 0.794) and 78 cm2 (AUC = 0.713), respectively. Group A had a significantly higher frequency of a family history of T2D than Group B. Conclusions: Our study revealed that the adiponectin level, ALT level, AST/ALT ratio, VAT value and a family history of T2D may be critical characteristic markers for T2D among obese Japanese children.

Residual endogenous insulin secretion in Japanese children with type 1A diabetes.

We investigated serum C-peptide immunoreactivity (CPR) levels in registered data from a multi-center collaborative nationwide type 1 diabetes study. The CPR levels were obtained from 576 and 409 children during the early registration (2013/2014) and late observation (2016/2017) periods, respectively. The percentages of children with a CPR < 0.1 or < 0.3 ng/mL increased according to the duration since diagnosis. Among patients with 5 or more years since diagnosis, 69% had a CPR < 0.1 and 95% had a CPR < 0.3 in the early registration period. A significant negative correlation was observed between the HbA1c and the CPR levels, and the HbA1c levels were significantly higher among children with a CPR < 0.1 or < 0.3 than among those with a CPR ≥ 0.6 ng/mL. During the late observation period, the prevalence of a CPR < 0.1 ng/mL was 88% among long-standing patients and 77% among patients aged 18-20 yr. Regarding the characteristics of "Responders" with a sustained CPR ≥ 0.6 ng/mL at 5 or more years since diagnosis, six of the seven were adolescent females; five of the seven had an HLA DR4-DQ4 haplotype. When type 1A diabetes mellitus (T1AD) children transit to adult care centers, most of them may have some difficulty in glycemic control because of the depleted endogenous insulin.

Increasing secular trends in height and obesity in children with type 1 diabetes: JSGIT cohort.

BACKGROUND: Recently, anthropometric indices in children with type 1 diabetes mellitus (T1DM) have begun to change. OBJECTIVE: To examine secular trends in patients' anthropometric indices. SUBJECTS: Japanese children with T1DM from the 1995, 2000, 2008 and 2013 cohorts of The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes. METHODS: We analysed serum haemoglobin A1c (HbA1c) levels, the incidence of severe hypoglycaemic events, the types and doses of insulin, height standard deviation scores (SDS), body mass index (BMI) percentiles compared with healthy Japanese children and obesity prevalence over time. We also stratified the patients according to glycaemic control levels of <58 mmol/mol (optimal), 58-75 mmol/mol (suboptimal) and ≥75 mmol/mol (high-risk). RESULTS: Data for 513-978 patients from each of the cohorts were analysed. The incidence of severe hypoglycaemic events decreased over time (from 21 to 4.8/100 patient-years), while the proportion of insulin analogue doses increased (14.6% to 98.6%). In addition, patient height SDS (-0.22 to +0.17), BMI percentile (52.1 to 58.7) and obesity prevalence (2.1% to 5.1%) increased. Height SDS increased in all of the glycaemic control subgroups, while BMI percentile and obesity prevalence increased in the suboptimal and high-risk groups. CONCLUSIONS: Since 1995, the average height of children with T1DM has increased in parallel with increasing insulin doses. Clinicians should be aware of increased BMI in these patients and the associated risk of developing cardiovascular disease in the future.

Policy statement of enteral nutrition for preterm and very low birthweight infants.

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

Increased diagnosis of autoimmune childhood-onset Japanese type 1 diabetes using a new glutamic acid decarboxylase antibody enzyme-linked immunosorbent assay kit, compared with a previously used glutamic acid decarboxylase antibody radioimmunoassay kit.

AIMS/INTRODUCTION: We compared the results of testing for glutamic acid decarboxylase antibodies (GADAb) using a radioimmunoassay (RIA) and an enzyme-linked immunosorbent assay (ELISA) in individuals with childhood-onset type 1 diabetes mellitus. MATERIALS AND METHODS: Serum specimens were collected from 1,024 Japanese children (426 boys and 598 girls) in 2013. The median age at diagnosis was 7 years (0-18 years). The blood specimens were obtained at a median age of 13 years (2-22 years). RESULTS: Among the 628 children whose serum specimens were collected within 5 years after diagnosis, the rate of GADAb positivity was 47.9% using RIA and 69.4% using ELISA. The participants were divided into four groups according to their RIA and ELISA results for GADAb as follows: group I (RIA+/ELISA+), group II (RIA+/ELISA-), group III (RIA-/ELISA+) and group IV (RIA-/ELISA-). The clinical and genetic characteristics of group I and group III were quite similar in terms of age at diagnosis, male/female ratio, relatively high positive rates for both autoantibody to protein tyrosine phosphatase IA-2 and autoantibody to the cation efflux transporter zinc transporter 8, and human leukocyte antigen genotype. Group II contained just five patients, and was characterized by a younger age at diagnosis, low positive rates for both autoantibody to protein tyrosine phosphatase IA-2 and autoantibody to the cation efflux transporter zinc transporter 8, and a unique human leukocyte antigen genotype. If the positive rates of either autoantibody to protein tyrosine phosphatase IA-2 or autoantibody to the cation efflux transporter zinc transporter 8 or both were added to the GADAb results using RIA, the percentage of autoimmune type 1 diabetes increased from 47.9% to 78.5%. CONCLUSIONS: The diagnosis of autoimmune childhood-onset Japanese type 1 diabetes increased when GADAb results were obtained using a new ELISA method, compared with a previously utilized RIA method.

KLF11 variant in a family clinically diagnosed with early childhood-onset type 1B diabetes.

KLF11 is the causative gene for maturity-onset diabetes of the young 7 (MODY7). KLF11 regulates insulin gene expression through binding to the GC box in the promoter. To date, only two KLF11 mutations have been identified in three families with early-onset type 2 diabetes. Here, we report a novel KLF11 variant associated with early childhood-onset type 1B diabetes. The proband and his younger sister exhibited hyperglycemia at age 1 year, and their mother developed diabetes at age 4 years. These three individuals required insulin injection from the initial phase of the disease. Being negative for islet cell autoantibodies, they were diagnosed with type 1B diabetes. Mutation screening for 30 diabetes-associated genes identified a heterozygous KLF11 variant (p.His418Gln) in the proband and his sister. The variant was also detected in the affected mother, as well as in the allegedly unaffected maternal grandmother. In silico analyses indicated that this variant involves a highly conserved histidine residue in the first C2 H2 zinc finger domain which ligates a zinc ion. In vitro analyses showed that expression levels and intracellular localization of His418Gln-KLF11 were comparable to those of wildtype (WT)-KLF11. Luciferase assays demonstrated that while WT-KLF11 suppressed the activity of a 6 × GC box-containing reporter, His418Gln-KLF11 lacked the suppressive effect. Notably, His418Gln-KLF11 canceled the suppressive effect of co-transfected WT-KLF11. Such a dominant-negative effect was absent in the previously reported Ala347Ser-KLF11 variant. These results indicate that specific variants of KLF11 (MODY7) with a dominant-negative effect underlie early childhood-onset type 1B diabetes with incomplete penetrance. This study documents a novel monogenic mutation associated with diabetes in children.

Metformin monotherapy in children and adolescents with type 2 diabetes mellitus in Japan.

OBJECTIVE: To evaluate the safety and effectiveness of metformin monotherapy for 52 weeks, including 24 weeks of treatment and a 28-week extension period for evaluation of long-term safety, in 37 Japanese pediatric patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: This study design was an open-label, non-randomized, multicenter trial. The primary effectiveness endpoint was the changes from baseline to the final visit at 24 weeks in HbA1c. The secondary endpoints were the rate for achieving the treatment goal, and the changes in glycated albumin, fasting blood glucose, fasting insulin, HOMA-IR, and fasting serum lipids. Metformin was administrated at the dose of 500 mg/day up to a maximum of 2000 mg/day taken in two or three divided doses. RESULTS: The mean change of HbA1c at the final visit at 24 weeks for 20 metformin-naïve patients (Group A) was - 0.66 ± 0.95% and that of 17 already-on metformin patients (Group B) was - 0.98 ± 1.62%. These figures proved the effectiveness of metformin as defined before the study. Secondary effectiveness endpoints were also improved. The improvement of blood glucose, fasting insulin and serum lipid levels proved the effectiveness of metformin without increasing body weight. Adverse effects such as nausea and diarrhea were observed in 35 of the 37 subjects and drug-related adverse events were observed in 19 patients. However, these events were not serious and did not increase with long-term treatment. CONCLUSIONS: Metformin is safe and effective for Japanese pediatric patients with T2DM.

Status and trends in the use of insulin analogs, insulin delivery systems and their association with glycemic control: comparison of the two consecutive recent cohorts of Japanese children and adolescents with type 1 diabetes mellitus.

Background Treatment for type 1 diabetes mellitus (T1DM) has greatly changed by the general use of insulin analogs and continuous subcutaneous insulin infusion (CSII). To investigate whether these advances have been translated into continued improvement in glycemic control in Japanese children and adolescents, we analyzed the registration data of the two consecutive recent cohorts of Japanese childhood-onset T1DM patients. Methods The registration data including hemoglobin A1c (HbA1c), hypoglycemia and insulin regimen were compared between the two cohorts (862 patients in the 2008 cohort and 1090 in the 2013 cohort). Results The proportion of subjects with multiple daily insulin injection therapy (MDI) and CSII significantly increased (p<0.0001) from 67.4% and 9.7% to 71.8% and 23.4%, respectively. In the 2013 cohort, almost all patients were treated with basal-bolus treatment using insulin analogs. The use of CSII increased in all age groups, especially in the age group 0-5 years. The rates of overall, moderate and severe hypoglycemia significantly declined from 10.24, 10.18 and 0.056 events/100 persons/period in the 2008 cohort to 0.66, 0.62 and 0.033 in the 2013 cohort (p<0.0001, <0.0001, 0.04), respectively. Contrarily, there were no significant changes in HbA1c values between the two cohorts. Conclusions The popularization of the basal-bolus treatment using insulin analogs hascontributed to a significant decrease in hypoglycemia. In contrast, the intensive insulin treatment may not be enough for the satisfactory improvement of glycemic control in Japanese children and adolescents with T1DM. Considerable points remain, such as diabetic education and support to motivate patients.

Fulminant type 1 diabetes mellitus in Japanese children and adolescents: multi-institutional joint research of the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes.

Fulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes mellitus characterized by a remarkably abrupt onset. In Japan, FT1DM accounts for approximately 20% of acute-onset adult type 1 diabetes mellitus cases; however, reports of pediatric-onset FT1DM are rare. We aimed to determine the frequency and clinical characteristics of FT1DM in Japanese children and adolescents by conducting a 2-phase questionnaire survey among the members of the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT) regarding their clinical experience with FT1DM. Responses were obtained from 54 of the 79 participating hospitals (68.4%). Of these, 8 hospitals managed a total of 15 pediatric patients with FT1DM (4 patients in each of 2 hospitals, 2 patients in 1 hospital, and 1 patient in each of 5 hospitals). The distribution of patient age was biphasic, with peaks in children younger than 5 years and older than 8 years of age. The clinical characteristics of FT1DM in this population (such as the duration from onset of symptoms to diagnosis, severity of symptoms, preceding flu-like episodes, and abnormal laboratory data) did not differ from those of patients with adult-onset FT1DM. The frequency of pediatric-onset FT1DM is low compared with that of adult-onset FT1DM. The genetic background and susceptibility patterns of pediatric patients with FT1DM may differ from those typical of adults with FT1DM, but both age groups share similar clinical characteristics.

Incidence and Characteristics of Adrenal Crisis in Children Younger than 7 Years with 21-Hydroxylase Deficiency: A Nationwide Survey in Japan.

BACKGROUND/AIMS: We aimed to evaluate the incidence and characteristics of adrenal crisis in Japanese children with 21-hydroxylase deficiency (21-OHD). METHODS: We conducted a retrospective nationwide survey for the councilors of the Japanese Society for Pediatric Endocrinology (JSPE) regarding adrenal crisis in children under 7 years with 21-OHD, admitted to hospitals from 2011 through 2016. We defined adrenal crisis as the acute impairment of general health due to glucocorticoid deficiency with at least two of symptoms, signs, or biochemical abnormalities. RESULTS: The councilors of the JSPE in 83 institutions responded to this survey (response rate, 60.1%). Data analyses of 378 patients with 1,101.4 person-years (PYs) revealed that 67 patients (17.7%) experienced at least 1 episode of hospital admission for adrenal crisis at the median age of 2 years. The incidence of adrenal crisis was calculated as 10.9 per 100 PYs (95% confidence interval [CI] 9.6-12.2). Infections were the most common precipitating factors, while no factor was observed in 12.5%. Hypoglycemia occurred concomitantly in 27.4%. One patient died from severe hypoglycemia, resulting in a mortality rate of 0.09 per 100 PYs (95% CI 0.0-0.2). CONCLUSION: Adrenal crisis is not rare and can be accompanied by disastrous hypoglycemia in children with 21-OHD.

The incidences of and risk factors for severe retinopathy requiring photocoagulation and albuminuria in Japanese patients with childhood-onset type 1 diabetes.

The aim of this study was to clarify the incidences of and the risk factors for severe retinopathy requiring photocoagulation therapy and albuminuria in Japanese patients with childhood-onset type 1 diabetes mellitus. A total of 756 patients from a cohort study by the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes were included in the study. Patients were registered in 1995 or 2000, and HbA1cwas measured every 4 months and analyzed in central hospital for an average of 6 years. The presence of severe retinopathy requiring laser photocoagulation and the presence of albuminuria was checked for during the period 2010-2011. During a median of 18 (range: 15-21) years, 34 out of 756 patients underwent laser photocoagulation and 57 out of 605 patients developed albuminuria. A Cox proportional hazards model showed that the risk of severe retinopathy requiring laser photocoagulation increased by 1.15 (95% confidence interval [CI] 1.03-1.29, p = 0.012) with each increase of a year in the age at onset, by 4.03 (95% CI 1.20-13.5, p = 0.024) in females, and by 2.05 (95% CI 1.69-2.49, p < 0.0001) with each increase of 1% in HbA1c. The risk of albuminuria increased significantly, by 1.09 (95% CI 1.01-1.18 p = 0.037), with each increase of a year in the age at onset and by 2.38 (95% CI 1.93-2.97 p < 0.0001) with each increase of 1% in HbA1c. In Japanese patients with childhood-onset type 1 diabetes, older age at the onset of diabetes, female rather than male gender, and higher HbA1c were found to increase the risk of requiring photocoagulation. No patients with HbA1c < 7.5% developed severe retinopathy requiring photocoagulation therapy. The risk of developing albuminuria increased with age at onset of diabetes and HbA1c. Female gender was a strong risk factor for severe retinopathy requiring photocoagulation, but not for albuminuria.

Comprehensive screening for monogenic diabetes in 89 Japanese children with insulin-requiring antibody-negative type 1 diabetes.

BACKGROUND: Mutations in causative genes for neonatal diabetes or maturity-onset diabetes of the young have been identified in multiple patients with autoantibody-negative type 1 diabetes (T1D). OBJECTIVES: We aimed to clarify the prevalence and phenotypic characteristics of monogenic abnormalities among 89 children with autoantibody-negative insulin-requiring T1D. METHODS: Mutations in 30 genes were screened using next-generation sequencing, and copy-number alterations of 4 major causative genes were examined using multiplex-ligation-dependent probe amplification. We compared the clinical characteristics between mutation carriers and non-carriers. RESULTS: We identified 11 probable pathogenic substitutions (6 in INS , 2 in HNF1A , 2 in HNF4A , and 1 in HNF1B ) in 11 cases, but no copy-number abnormalities. Only 2 mutation carriers had affected parents. De novo occurrence was confirmed for 3 mutations. The non-carrier group, but not the carrier group, was enriched with susceptible HLA alleles. Mutation carriers exhibited comparable phenotypes to those of non-carriers, except for a relatively normal body mass index (BMI) at diagnosis. CONCLUSIONS: This study demonstrated significant genetic overlap between autoantibody-negative T1D and monogenic diabetes. Mutations in INS and HNF genes, but not those in GCK and other monogenic diabetes genes, likely play critical roles in children with insulin-requiring T1D. This study also suggests the relatively high de novo rates of INS and HNF mutations, and the etiological link between autoimmune abnormalities and T1D in the non-carrier group. Carriers of monogenic mutations show non-specific phenotypes among all T1D cases, although they are more likely to have a normal BMI at diagnosis than non-carriers.

Clinical characteristics of septo-optic dysplasia accompanied by congenital central hypothyroidism in Japan.

Septo-optic dysplasia (SOD) is a congenital anomaly in which agenesis of the septum pellucidum and optic nerve hypoplasia are accompanied by hypopituitarism. Typically, the symptoms develop in 3 organs, the brain, eyes, and pituitary, and approximately one third of the patients present with all of the three cardinal features. The diagnostic criteria for SOD were established in Japan in 2015. The purpose of this study is to review clinical features regarding SOD patients with hypopituitarism in Japan. In this study, 21 patients with SOD were identified by a questionnaire survey for congenital central hypothyroidism. All 3 symptoms of SOD, agenesis of the septum pellucidum, optic nerve hypoplasia, and endocrine abnormalities, were noted in 8 of the 21 patients. Various combinations of pituitary hormone deficiencies were observed in patients with SOD, although SOD is a rare, heterogeneous, and phenotypically variable disorder, some patients develop hypoglycemia and convulsions after birth, and early intervention with hormone replacement is necessary in severe cases. In addition, 14 cases were complicated by both developmental delay and epilepsy, and 16 cases involved eye abnormalities. Therefore, in addition to an early endocrinological diagnosis and hormone replacement, consultation with both pediatric neurologists and pediatric ophthalmologists is necessary.

Molecular and clinical features of KATP -channel neonatal diabetes mellitus in Japan.

BACKGROUND: There are few reports pertaining to Asian patients with neonatal diabetes mellitus (NDM) caused by activating mutations in the ATP-sensitive potassium channel genes (KATP-NDM). OBJECTIVES: To elucidate the characteristics of Japanese patients with KATP-NDM. METHODS: By the amplification and direct sequencing of all exons and exon-intron boundaries of the KCNJ11 and ABCC8 genes, 25 patients with KATP-NDM were identified from a total of 70 patients with NDM. Clinical data were collected from the medical charts. RESULTS: Sixteen patients had mutations in KCNJ11 and nine in ABCC8. Eight novel mutations were identified; two in KCNJ11 (V64M, R201G) and six in ABCC8 (R216C, G832C, F1176L, A1263V, I196N, T229N). Interestingly, V64M caused DEND (developmental delay, epilepsy, neonatal diabetes) syndrome in our patient, while mutation of the same residue (V64G) had been reported to cause congenital hyperinsulinism. Mutations in ABCC8 were associated with TNDM (4/9) or isolated PNDM (5/9), whereas those in KCNJ11 were associated with more severe phenotypes, including DEND (3/16), iDEND (intermediate DEND, 4/16), or isolated PNDM (6/16). Switching from insulin to glibenclamide monotherapy was successful in 87.5% of the patients. Neurological improvement was observed in two patients, one with DEND (T293N) and one with iDEND (R50P) syndrome. Three others with iDEND mutations (R201C, G53D, and V59M) remained neurologically normal at 5, 1, and 4 years of age, respectively, with early introduction of sulfonylurea. CONCLUSION: Overall, clinical presentation of KATP-NDM in Japanese patients was similar to those of other populations. Early introduction of sulfonylurea appeared beneficial in ameliorating neurological symptoms.

Improvement in glycemic control through changes in insulin regimens: findings from a Japanese cohort of children and adolescents with type 1 diabetes.

OBJECTIVE: Although insulin analogs have dramatically changed diabetes treatment, scarce evidence is available on those effects. We aimed to explore whether glycemic control had improved, the use of insulin analogs had been increased, and hypoglycemic events had decreased over time in Japanese pediatric patients with type 1 diabetes (T1D). METHODS: Glycated hemoglobin A1c (HbA1c) values, proportion of insulin regimens, incidence of severe hypoglycemic events, and pubertal increase in HbA1c were compared in three cohorts of childhood-onset Japanese T1D patients (567 subjects in the 1995 cohort, 754 subjects in the 2000 cohort, and 806 subjects in the 2008 cohort). RESULTS: Mean HbA1c values tended to decrease [78.5 mmol/mol (9.33%) in the 1995 cohort, 68.2 mmol/mol (8.39%) in the 2000 cohort, and 61.2 mmol/mol (7.75%) in the 2008 cohort; P < .0001]. The proportion of patients who received basal-bolus treatment tended to increase with statistical significance, as did the proportion on insulin analogs. The incidence of severe hypoglycemic events (events/100 patients/y) had decreased (19.1 in the 2000 cohort and 8.7 in the 2008 cohort; P = .02). The pubertal increase in HbA1c tended to decrease [males, 12.0 mmol/mol (1.10%) in 1995, 9.4 mmol/mol (0.85%) in 2008, and 9.4 mmol/mol (0.86%) in 2008; P = .55; females, 14.0 mmol/mol (1.28%) in 1995, 10.3 mmol/mol (0.94%) in 2000, and 4.2 mmol/mol (0.38%) in 2008; P = .0003]. CONCLUSIONS: Glycemic control and incidence of severe hypoglycemic events were chronologically improved, especially in female adolescents.