Publications by authors named "Keisuke Nagasaki"

103 Publications

A Japanese family with a heterozygous novel mutation in the Indian hedgehog gene exhibiting a broad spectrum of clinical features and radiological findings.

Congenit Anom (Kyoto) 2021 Sep 30. Epub 2021 Sep 30.

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

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http://dx.doi.org/10.1111/cga.12445DOI Listing
September 2021

A case of adolescent trichorhinophalangeal syndrome undergoing pelvic osteotomy for bilateral acetabular dysplasia.

J Orthop Sci 2021 Sep 6. Epub 2021 Sep 6.

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

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http://dx.doi.org/10.1016/j.jos.2021.07.021DOI Listing
September 2021

Peripheral precocious puberty in a girl with an intracranial hCG-producing tumor: case report and literature review.

Endocr J 2021 Jul 17. Epub 2021 Jul 17.

Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.

Human chorionic gonadotropin (hCG)-producing tumors cause peripheral precocious puberty (PP) in boys, but generally not in girls. Homology between LH and hCG activates the LH receptor in testicular Leydig cells, increases testosterone production, and causes virilization. However, since FSH action is required for follicle development, hCG action alone does not increase estradiol (E2) production and does not cause feminization. Only a few cases of peripheral PP with hCG tumors in girls have been reported. We describe the case of a 7-year-old Japanese girl with peripheral PP associated with an hCG-producing tumor. She had prolonged vomiting, loss of appetite, and Tanner stage III breast development. Although no apparent increase in growth rate, bone age was advanced at 9.8 years. Serum E2 was slightly elevated and LH and FSH were below the measurement sensitivity, and abdominal ultrasonography and computed tomography images showed no abnormal findings in the uterus or ovaries. Subsequently, she developed visual field disturbance and loss of consciousness, and brain magnetic resonance imaging revealed an intracranial tumor. Based on pathological findings and abnormally high serum hCG-β level (48,800 IU/L), intracranial choriocarcinoma was diagnosed. 2.5 months after the start of chemotherapy, the hCG-β level became almost negative and the breast development disappeared synchronously. Tissue immunostaining of the tumor showed strong positivity for aromatase and hCG, indicating that the choriocarcinoma cells themselves may have produced estrogen via aromatase. This unique case highlights the possibility that hCG-producing tumors can cause peripheral PP in girls as well as boys.
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http://dx.doi.org/10.1507/endocrj.EJ21-0117DOI Listing
July 2021

Two cases of cytochrome P450 oxidoreductase deficiency with severe scoliosis and surgery requirement.

Congenit Anom (Kyoto) 2021 Sep 29;61(5):202-203. Epub 2021 Jun 29.

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

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http://dx.doi.org/10.1111/cga.12434DOI Listing
September 2021

Re-Evaluation of the Prevalence of Permanent Congenital Hypothyroidism in Niigata, Japan: A Retrospective Study.

Int J Neonatal Screen 2021 May 28;7(2). Epub 2021 May 28.

Department of Pediatrics, Nagaoka Institute for Severely Handicapped Children, Nagaoka 940-2135, Japan.

Although newborn screening (NBS) for congenital hypothyroidism (CH) in Japan started more than 40 years ago, the prevalence of CH remains unclear. Prevalence estimations among NBS-positive CH individuals include those with transient hypothyroidism and transient hyperthyrotropinemia, and re-evaluation with increasing age is necessary to clarify the actual incidence. Thus, we re-evaluated the incidence of permanent CH. Of the 106,114 patients who underwent NBS in the Niigata Prefecture, Japan, between April 2002 and March 2006, 116 were examined further due to high thyroid-stimulating hormone levels (>8 mIU/L) and were included in the study. We retrospectively evaluated their levothyroxine sodium (LT4) replacement therapy status from the first visit to 15 years of age. Of the 116 NBS-positive patients, 105 (91%) were initially examined in our department. Of these, 72 (69%) started LT4 replacement therapy on the first visit. Subsequently, 27 patients continued LT4 replacement until 15 years of age after multiple re-evaluations. The prevalence of permanent CH in the Niigata Prefecture during this period was 1 in 2500-3500 children. Ultimately, 62.5% of patients on LT4 replacement discontinued treatment by 15 years of age. This is the first study to clarify the true prevalence of permanent CH in Japan.
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http://dx.doi.org/10.3390/ijns7020027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162320PMC
May 2021

Regulation of Serum Sodium Levels during Chemotherapy Using Selective Arginine Vasopressin V2-Receptor Antagonist Tolvaptan in a Four-Year-Old Girl with a Suprasellar Germ Cell Tumor.

Children (Basel) 2021 Apr 10;8(4). Epub 2021 Apr 10.

Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.

There are limited reports on the use of tolvaptan for syndrome of inappropriate antidiuretic hormone secretion (SIADH) in children. Managing serum sodium levels in SIADH patients during chemotherapy is often difficult because of the need for massive fluid infusions. We report the course of the use of tolvaptan for the treatment of hyponatremia during chemotherapy in a four-year-old girl with a suprasellar germ cell tumor. The patient was a Japanese girl who presented with left ptosis with a mass in the pituitary gland and cavernous sinus. She was diagnosed with an intermediate-grade germ cell tumor and was treated with carboplatin and etoposide combination chemotherapy. She developed hyponatremia due to SIADH caused by intravenous infusion therapy before chemotherapy. Subsequently, tolvaptan (3.25 mg; 0.20 mg/kg/dose) was administered orally to control serum sodium levels. After 4 h of administration, a marked increase in urine volume of up to 15 mL/kg/h was observed, and serum sodium level increased from 126 to 138 mEq/L after 10 h of tolvaptan administration, followed by a decrease in urine volume. The use of tolvaptan in pediatric patients with SIADH who require intravenous hydration during chemotherapy can be useful for the management of serum sodium balance.
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http://dx.doi.org/10.3390/children8040293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070153PMC
April 2021

Investigation of TSH receptor blocking antibodies in childhood-onset atrophic autoimmune thyroiditis.

Clin Pediatr Endocrinol 2021 3;30(2):79-84. Epub 2021 Apr 3.

Department of Pediatrics, Jichi Medical University, Tochigi, Japan.

Atrophic autoimmune thyroiditis (AAT) is a type of autoimmune hypothyroidism without goiter. TSH receptor-blocking antibodies (TSBAb) are involved in its etiology in adults. Reportedly, this disease is extremely rare in children. In this study, we aimed to investigate the prevalence of TSBAb during AAT onset in children using a commercially available cell-based bioassay TSAb kit. We conducted a multicenter retrospective observational study. We collected data of patients with AAT who were < 15 yr old, enrolled in a collaborative research group, and diagnosed since July 2003. AAT was defined as acquired autoimmune hypothyroidism without thyroid enlargement. Eighteen patients (including 15 females) whose TSH receptor antibody (TRAb) or TSBAb levels were measured within a year from the initial visit were included. The median age at diagnosis was 9.3 years, and the estimated time between onset and diagnosis was 2.6 yr. The positive rate for either TSBAb or TRAb was 38.8% (95% confidence interval: 18.3-59.5%). There were no significant differences in age, the estimated time between onset and diagnosis, and FT4 levels at diagnosis between the TSBAb-positive and -negative groups. Unlike previous reports, we showed that the prevalence of TSBAb-positivity in childhood-onset AATs is not rare, as in adults.
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http://dx.doi.org/10.1297/cpe.30.79DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022035PMC
April 2021

Long-term Effect of Aromatase Inhibition in Aromatase Excess Syndrome.

J Clin Endocrinol Metab 2021 04;106(5):1491-1500

Division of Pediatrics, Niigata University Graduate School of Medicine and Dental Science, Niigata, Japan.

Context: Aromatase excess syndrome (AEXS) is a very rare disorder characterized by prepubertal gynecomastia, bone age acceleration, and early growth arrest. Heterozygote submicroscopic rearrangements within the promotor of CYP19A1 result in overexpression of aromatase and enhanced aromatization of androgens.

Objective: The objective was to study long-term treatment effects of an aromatase inhibitor.

Methods: Data from 7 boys with AEXS were retrospectively collected. Genetic analysis revealed upstream of CYP19A1 a 165 901 bp deletion in 4 German cousins, a 198 662 bp deletion in 2 Japanese brothers, and a 387 622 bp tandem duplication in a Japanese boy.

Results: All boys developed prepubertal gynecomastia, at median 9.0 years of age (range: 7.0-11.0). Height was +1.20 standard deviation score (SDS) (-0.24 to +1.98); predicted adult height was -1.29 SDS (-3.29 to +1.09). Four boys were treated with 1.0 mg of anastrozole daily, while 3 reached adult height untreated. Treatment with anastrozole was stopped after 5.6 years (4.0-6.8). Three treated boys exceeded their prognosis by 2.4, 6.9, and 8.1 cm, while 1 untreated boy fell below the prognosis by 8.6 cm. One treated with a low dose and 2 untreated reached their prognosis. Adult heights were -0.91 SDS with anastrozole (-2.86 to -0.29) and -0.15 SDS without (-2.31 to -0.03). Distance to target height was -0.22 SDS with anastrozole (-1.72 to +0.52) and +0.54 SDS without (+0.23 to +1.30).

Conclusion: Spontaneous growth in AEXS varied, even in the same family. Our data suggest that early started, long-term inhibition by anastrozole promotes adult height in boys with AEXS.
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http://dx.doi.org/10.1210/clinem/dgab054DOI Listing
April 2021

Letter to the Editor: Testosterone priming increased growth hormone peak levels in the stimulation test and suppressed gonadotropin secretion in three Japanese adolescent boys.

Clin Pediatr Endocrinol 2020 3;29(4):201. Epub 2020 Oct 3.

Department of Pediatrics, Niigata University Medical and Dental Hospital, Niigata, Japan.

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http://dx.doi.org/10.1297/cpe.29.201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534528PMC
October 2020

A Japanese Family with DICER1 Syndrome Found in Childhood-Onset Multinodular Goitre.

Horm Res Paediatr 2020 20;93(7-8):477-482. Epub 2020 Oct 20.

Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University, Tochigi, Japan.

Introduction: Germline DICER1 mutations have recently been identified in familial multinodular goitre (MNG). The natural history of thyroid nodules in DICER1 carriers in children is unclear. The purpose of this study was to describe the clinical and genetic findings of childhood-onset MNG with DICER1 carrier in a patient who underwent total thyroidectomy.

Case Presentation: The 6-year-old proband had a thyroid nodule, and the number and size of nodules increased over 3 years. A total thyroidectomy was chosen because of the rapid rise in thyroglobulin levels, discomfort when swallowing, and the mother's history of poorly differentiated thyroid cancer (PDTC). Histopathology revealed adenomatous goitre without malignant cells. Her mother, maternal aunt, and maternal grandmother also had thyroid nodules removed during adolescence. Also, her mother had PDTC with lung metastases, and her maternal aunt had an ovarian germ cell tumour. DICER1 mutation analysis identified a heterozygous novel nonsense mutation (c.4509C>G, p.Y1503X) for the patient, her mother, her maternal grandmother, and her asymptomatic elder brother. Y1503X was identified in all resected thyroid tissues, while heterozygous D1709G, D1810V, and E1813K mutations were identified in individual nodules.

Discussion/conclusion: A thyroid nodule was detected in chemotherapy- or radiotherapy-naïve patient with DICER1 carrier aged 6 years, and MNG developed over 3 years. This pedigree highlights the natural history of nodular disease in DICER1 carriers and identifies a possible association between DICER1 and more aggressive malignancies.
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http://dx.doi.org/10.1159/000511140DOI Listing
October 2020

Foetal virilisation caused by overproduction of non-aromatisable 11-oxygenated C19 steroids in maternal adrenal tumour.

Hum Reprod 2020 11;35(11):2609-2612

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-0074, Japan.

It is widely believed that adrenal tumours and ovarian luteomas in pregnant women cause virilisation of female foetuses through overproduction of testosterone and/or androstenedione. However, this notion raises a fundamental question as to how these classic androgens pass through the placenta without being converted by aromatase into oestrogens. Here, we report a case of maternal adrenal tumour, in which overproduction of 11-oxygenated C19 steroids (11ox C19s), newly characterised non-aromatisable androgens in humans, caused foetal virilisation. The female proband presented with severely virilised external genitalia at birth. The mother exhibited hirsutism, hyperglycaemia and hypertension and was diagnosed as having adrenal tumour. The mother was subjected to comprehensive steroid measurement. Serum levels of 11ox C19s were markedly elevated. In contrast, testosterone and androstenedione levels remained within the normal range, and levels of most other steroids in the conventional and backdoor androgenic pathways were normal or only mildly elevated. After tumour removal, levels of 11ox C19s were markedly reduced. These results provide the first evidence that 11ox C19s can be synthesised in adrenal adenomas and, due to their non-aromatisable nature, can pass through the placental barrier to cause foetal virilisation. These findings highlight a unique pathogenic property of these newly specified androgens in humans.
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http://dx.doi.org/10.1093/humrep/deaa221DOI Listing
November 2020

Congenital Hypothyroidism Due to Truncating PAX8 Mutations: A Case Series and Molecular Function Studies.

J Clin Endocrinol Metab 2020 11;105(11)

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

Context: PAX8 is a transcription factor required for thyroid development, and its mutation causes congenital hypothyroidism (CH). More than 20 experimentally verified loss-of-function PAX8 mutations have been described, and all but one were located in the DNA-binding paired domain.

Objective: We report the identification and functional characterization of 3 novel truncating PAX8 mutations located outside the paired domain.

Methods: Three CH probands, diagnosed in the frame of newborn screening, had thyroid hypoplasia and were treated with levothyroxine. Next-generation sequencing-based mutation screening was performed. Functionality of the identified mutations were verified with Western blotting, intracellular localization assays, and transactivation assays with use of HeLa cells. Luciferase complementation assays were used to evaluate the effect of mutations on the interaction between PAX8 and its partner, NKX2-1.

Results: Each proband had novel truncating PAX8 mutations that were I160Sfs*52, Q213Efs*27, and F342Rfs*85. Western blotting showed destabilization of the I160fs-PAX8 protein. Q213fs-PAX8 and F342fs-PAX8 showed normal protein expression levels and normal nuclear localization, but showed loss of transactivation of the luciferase reporter. By luciferase complementation assays, we showed that PAX8-NKX2-1 interaction was defective in Q213fs-PAX8. We also characterized the recombinant PAX8 proteins, and found that the protein sequence corresponding to exon 10 (363-400 aa residues) was essential for the PAX8-NKX2-1 interaction.

Conclusions: Clinical and molecular findings of 3 novel truncating PAX8 mutations located outside the paired domain were reported. Experiments using cultured cells and recombinant proteins showed that the C-terminal portion (ie, 363-400 aa) of PAX8 is required for the PAX8-NKX2-1 interaction.
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http://dx.doi.org/10.1210/clinem/dgaa584DOI Listing
November 2020

Timing of hyponatremia development in patients with salt-wasting-type 21-hydroxylase deficiency.

Clin Pediatr Endocrinol 2020 11;29(3):105-110. Epub 2020 Jul 11.

Department of Pediatrics, Niigata University Medical and Dental Hospital, Niigata, Japan.

Newborn screening (NBS) can detect 21-hydroxylase deficiency (21-OHD), allowing for early treatment initiation. However, many patients present with adrenal crises or hyponatremia at their first visit. Age (in days) of hyponatremia development in infants with salt-wasting (SW)-type 21-OHD remains unclear. Therefore, we determined the earliest age of hyponatremia diagnosis in this retrospective observational study using medical records of 40 patients with classic 21-OHD in Niigata Prefecture, Japan, from April 1989 to March 2019. We determined the earliest diagnosis of hyponatremia (serum sodium levels < 130 mEq/L) and created a sodium decrease rate model to estimate hyponatremia development age. Of 23 patients with SW-type 21-OHD, 10 (43.5%) were identified during NBS; the earliest case to present with hyponatremia was at day 7. Serum sodium levels were significantly and negatively correlated with age in days, and hyponatremia was estimated to develop at 6.6 d after birth. Genotype or serum 17-hydroxyprogesterone levels were not associated with sodium decrease rate. Thus, hyponatremia development age is earlier (within 7 d) than the previously described time-point (10-14 d) in infants with SW-type 21-OHD. Efforts to reduce the time lag from obtaining results to consultation may be required in patients with high 17-hydroxyprogesterone levels on NBS.
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http://dx.doi.org/10.1297/cpe.29.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348630PMC
July 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

Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency.

Sci Rep 2020 07 3;10(1):10985. Epub 2020 Jul 3.

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

Isolated hypogonadotropic hypogonadism (IHH), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) constitute a disease spectrum whose etiology remains largely unknown. This study aimed to clarify whether mutations in SMCHD1, an epigenetic regulator gene, might underlie this disease spectrum. SMCHD1 is a causative gene for Bosma arhinia microphthalmia syndrome characterized by arhinia, microphthalmia and IHH. We performed mutation screening of SMCHD1 in patients with etiology-unknown IHH (n = 31) or CPHD (n = 43, 19 of whom also satisfied the SOD diagnostic criteria). Rare variants were subjected to in silico analyses and classified according to the American College of Medical Genetics and Genomics guidelines. Consequently, a rare likely pathogenic variant, p.Asp398Asn, was identified in one patient. The patient with p.Asp398Asn exhibited CPHD, optic nerve hypoplasia, and a thin retinal nerve fiber layer, and therefore satisfied the criteria of SOD. This patient showed a relatively low DNA methylation level of the 52 SMCHD1-target CpG sites at the D4Z4 locus. Exome sequencing for the patient excluded additional variants in other IHH/CPHD-causative genes. In vitro assays suggested functional impairment of the p.Asp398Asn variant. These results provide the first indication that SMCHD1 mutations represent a rare genetic cause of the HH-related disease spectrum.
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http://dx.doi.org/10.1038/s41598-020-67715-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335161PMC
July 2020

Degeneration of dopaminergic neurons and impaired intracellular trafficking in Atp13a2 deficient zebrafish.

IBRO Rep 2020 Dec 1;9:1-8. Epub 2020 Jun 1.

Department of Neuroscience of Disease, Center for Transdisciplinary Research, Niigata University, Niigata, Japan.

is the autosomal recessive causative gene for juvenile-onset Parkinson's disease (PARK9, Parkinson's disease 9), also known as Kufor-Rakeb syndrome. The disease is characterized by levodopa-responsive Parkinsonism, supranuclear gaze palsy, spasticity, and dementia. Previously, we have reported that Atp13a2 deficient medaka fish showed dopaminergic neurodegeneration and lysosomal dysfunction, indicating that lysosome-autophagy impairment might be one of the key pathogeneses of Parkinson's disease. Here, we established Atp13a2 deficient zebrafish using CRISPR/Cas9 gene editing. We found that the number of TH + neurons in the posterior tuberculum and the locus coeruleus significantly reduced (dopaminergic neurons, 64 % at 4 months and 37 % at 12 months, < 0.001 and < 0.05, respectively; norepinephrine neurons, 52 % at 4 months and 40 % at 12 months, < 0.001 and < 0.05, respectively) in Atp13a2 deficient zebrafish, proving the degeneration of dopaminergic neurons. In addition, we found the reduction (60 %, < 0.05) of cathepsin D protein expression in Atp13a2 deficient zebrafish using immunoblot. Transmission electron microscopy analysis using middle diencephalon samples from Atp13a2 deficient zebrafish showed lysosome-like bodies with vesicle accumulation and fingerprint-like structures, suggesting lysosomal dysfunction. Furthermore, a significant reduction ( < 0.001) in protein expression annotated with vesicle fusion with Golgi apparatus in Atp13a2 deficient zebrafish by liquid-chromatography tandem mass spectrometry suggested intracellular trafficking impairment. Therefore, we concluded that Atp13a2 deficient zebrafish exhibited degeneration of dopaminergic neurons, lysosomal dysfunction and the possibility of intracellular trafficking impairment, which would be the key pathogenic mechanism underlying Parkinson's disease.
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http://dx.doi.org/10.1016/j.ibror.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283103PMC
December 2020

Clinical characteristics of cytochrome P450 oxidoreductase deficiency: a nationwide survey in Japan.

Endocr J 2020 Aug 21;67(8):853-857. Epub 2020 Apr 21.

Department of Pediatrics, Jichi Medical University, Tochigi 329-0498, Japan.

Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis that causes various symptoms such as skeletal malformations, disorders of sex development, and adrenal insufficiency. The aim of this study was to elucidate the clinical characteristics, especially age at diagnosis and treatment, of PORD from the perinatal period to adulthood in Japan. The first questionnaire was sent to 183 council members of the Japanese Society for Pediatric Endocrinology on 1 September 2018. The response rate was 65%, and a total of 39 patients with PORD were examined at 20 hospitals. The second questionnaire was sent in November 2018 to the council members examining these 39 patients with PORD. The response rate was 77%, and we received clinical information on 30 of the 39 patients. The two novel clinical findings were the age at diagnosis and the treatment of Japanese patients with PORD. In many cases, PORD can be diagnosed at <3 months of age. Hydrocortisone as the primary treatment during infancy can be used daily or in stressful situations; however, because patients with PORD generally have mild to moderate adrenal insufficiency, some might be able to avoid hydrocortisone treatment. Patients with PORD should be carefully followed up, and treatment should be optimized as for patients with other types of adrenal insufficiency. Other characteristics in the present study were similar to those described in previous reports.
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http://dx.doi.org/10.1507/endocrj.EJ20-0011DOI Listing
August 2020

A nationwide questionnaire survey targeting Japanese pediatric endocrinologists regarding transitional care in childhood, adolescent, and young adult cancer survivors.

Clin Pediatr Endocrinol 2020 16;29(2):55-62. Epub 2020 Apr 16.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Existing guidelines recommend long-term follow-up of childhood cancer survivors (CCS). However, in Japan, transitional care for CCS has not been established. To ascertain the current status in Japan, and to cultivate a better understanding, a questionnaire survey was conducted on transitional care in CCS, and adolescent and young adult (AYA) cancer survivors. Questionnaires were distributed to 183 councilors (137 institutions) of the Japanese Society for Pediatric Endocrinology. A total of 131 responses, representative of 174 councilors, were obtained. The response rate was 95%. Among the respondents, 91% had experience in medical care for cancer patients, while 63% had experience in transitional care; however, the number of patients referred to adult clinics was small. Further, 89% acknowledged the availability of adult endocrinologists who were willing to accept these patients; although their numbers were insufficient. Pediatric endocrinologists highlighted difficulties in medical examinations concerning infertility, obesity, pregnancy/delivery, and gonadal dysfunction, in that order. Staff and time shortages were listed as some of the challenges faced by medical staff, while multisystem morbidity was listed for patients. This nationwide questionnaire survey revealed that Japanese pediatric endocrinologists require cooperation between related departments and collaborative infrastructure to develop transitional care for cancer survivors.
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http://dx.doi.org/10.1297/cpe.29.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160455PMC
April 2020

Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy.

Orphanet J Rare Dis 2019 12 2;14(1):277. Epub 2019 Dec 2.

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan.

Background: Schaaf-Yang syndrome (SYS) is a newly recognized imprinting related syndrome, which is caused by a truncating variant in maternally imprinted MAGEL2 located in 15q11-q13. Yet, precise pathomechanism remains to be solved. We sequenced MAGEL2 in patients suspected Prader-Willi syndrome (PWS) to delineate clinical presentation of SYS. We examined 105 patients with clinically suspected PWS but without a specific PWS genetic alteration. Sanger sequencing of the entire MAGEL2 gene and methylation-specific restriction enzyme treatment to detect the parent of origin were performed. Clinical presentation was retrospectively assessed in detail.

Results: Truncating variants in MAGEL2 were detected in six patients (5.7%), including a pair of siblings. All truncating variants in affected patients were on the paternally derived chromosome, while the healthy father of the affected siblings inherited the variant from his mother. Patients with MAGEL2 variants shared several features with PWS, such as neonatal hypotonia, poor suck, and obesity; however, there were also unique features, including arthrogryposis and a failure to acquire meaningful words. Additionally, an episode of neurological deterioration following febrile illness was confirmed in four of the six patients, which caused severe neurological sequalae.

Conclusions: SYS can be present in infants suspected with PWS but some unique features, such as arthrogryposis, can help discriminate between the two syndromes. An episode of neurological deterioration following febrile illness should be recognized as an important complication.
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http://dx.doi.org/10.1186/s13023-019-1249-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888944PMC
December 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

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

J Hum Genet 2019 Dec 17;64(12):1173-1186. Epub 2019 Sep 17.

Asahikawa-Kosei General Hospital, Hokkaido, Japan.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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http://dx.doi.org/10.1038/s10038-019-0667-4DOI Listing
December 2019

Present status of prophylactic thyroidectomy in pediatric multiple endocrine neoplasia 2: a nationwide survey in Japan 1997-2017.

J Pediatr Endocrinol Metab 2019 Jun;32(6):585-595

Department of Pediatrics, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara-shi, Chiba 299-0111, Japan.

Background In Japan, prophylactic thyroidectomy involves out-of-pocket expense. The American Thyroid Association (ATA) recommends prophylactic thyroidectomy for medullary thyroid carcinoma (MTC) during early childhood in patients with multiple endocrine neoplasia type 2 (MEN2). The ATA reports a high frequency of postoperative complications in childhood, which also influenced the delay of prophylactic thyroidectomy in Japan. Methods This retrospective study of multiple medical centers in Japan included individuals aged <20 years diagnosed with germline RET mutations between 1997 and 2017. The onset and onset possibility were defined based on confirmed lesions or calcitonin levels. The definition of risk and prophylactic thyroidectomy were based on the ATA 2015 revised guideline. Results Twenty-one patients with MEN2 were enrolled (highest risk, n = 5; high risk, n = 5; and moderate risk, n = 11). The cumulative incidence of the onset/onset possibility reached 50% at 5 and 8 years and 100% at 9 years and 17 years in high- and moderate-risk patients, respectively. Of 7 patients with MEN2A, 71% underwent prophylactic thyroidectomy. Only one 5-year-old patient (C634Y) had increased serum calcitonin level after prophylactic thyroidectomy in the MEN2A group. The only permanent complication, which did not occur in patients who underwent total thyroidectomy alone, was hypoparathyroidism (33% of patients). This permanent complication occurred with clinically developed MTC. No permanent postoperative complications occurred in patients aged 5-6 years. Conclusions Prophylactic thyroidectomy reduces recurrence and postoperative complications in pediatric patients with MEN2. Early thyroidectomy based on only calcitonin level could possibly reduce thyroidectomy delay.
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http://dx.doi.org/10.1515/jpem-2018-0444DOI Listing
June 2019

Germline-Derived Gain-of-Function Variants of Gs-Coding Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis.

J Am Soc Nephrol 2019 05 8;30(5):877-889. Epub 2019 Apr 8.

Departments of Molecular Endocrinology,

Background: The stimulatory G-protein -subunit encoded by exons 1-13 (-Gs) mediates signal transduction of multiple G protein-coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function -Gs variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function -Gs variants have been detected in McCune-Albright syndrome and may result in phosphate wasting. However, no germline-derived gain-of-function variant has been identified, implying that such a variant causes embryonic lethality.

Methods: We performed whole-exome sequencing in two families with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD) as a salient phenotype after excluding a gain-of-function variant of and functional studies for identified variants.

Results: Whole-exome sequencing revealed two -Gs candidate variants for NSIAD: -Gs p.(F68_G70del) in one family and -Gs p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, -Gs alone was involved in AVPR2 signaling and shared by the families. Protein structural analyses revealed a gain-of-function-compatible conformational property for p.M255V-Gs, although such assessment was not possible for p.F68_G70del-Gs. Both variants had gain-of-function effects that were significantly milder than those of McCune-Albright syndrome-specific somatic Gs variants. Model mice for p.F68_G70del-Gs showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gs exhibited severe failure to thrive.

Conclusions: This study shows that germline-derived gain-of-function rare variants of -Gs exist and cause NSIAD as a novel Gs-mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to -Gs's gain-of-function effects.
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http://dx.doi.org/10.1681/ASN.2018121268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493982PMC
May 2019

Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.

Hum Genet 2019 Jan 27;138(1):21-35. Epub 2018 Oct 27.

Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.

RASopathies are a group of developmental disorders caused by mutations in genes that regulate the RAS/MAPK pathway and include Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome and other related disorders. Whole exome sequencing studies recently identified LZTR1, PPP1CB and MRAS as new causative genes in RASopathies. However, information on the phenotypes of LZTR1 mutation-positive patients and functional properties of the mutations are limited. To identify variants of LZTR1, PPP1CB, and MRAS, we performed a targeted next-generation sequencing and reexamined previously analyzed exome data in 166 patients with suspected RASopathies. We identified eight LZTR1 variants, including a de novo variant, in seven probands who were suspicious for NS and one known de novo PPP1CB variant in a patient with NS. One of the seven probands had two compound heterozygous LZTR1 variants, suggesting autosomal recessive inheritance. All probands with LZTR1 variants had cardiac defects, including hypertrophic cardiomyopathy and atrial septal defect. Five of the seven probands had short stature or intellectual disabilities. Immunoprecipitation of endogenous LZTR1 followed by western blotting showed that LZTR1 bound to the RAF1-PPP1CB complex. Cells transfected with a small interfering RNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at Ser259. These are the first results to demonstrate LZTR1 in association with the RAF1-PPP1CB complex as a component of the RAS/MAPK pathway.
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http://dx.doi.org/10.1007/s00439-018-1951-7DOI Listing
January 2019

Polysomnography as an indicator for cervicomedullary decompression to treat foramen magnum stenosis in achondroplasia.

Childs Nerv Syst 2018 11 29;34(11):2275-2281. Epub 2018 Jun 29.

Department of Neurosurgery, Brain Research Institute, University of Niigata, 1-757, Asahimachi-dori, Chuo-ku,, Niigata City, Niigata, 951-8585, Japan.

Objective: Management of cervicomedullary compression due to foramen magnum stenosis in achondroplasia remains controversial, especially for patients with no symptoms or mild symptoms. We examined the effectiveness of polysomnography (PSG) as an indicator for cervicomedullary decompression treatment.

Methods: We retrospectively reviewed nine achondroplasia cases (mean age 1 year and 9 months) treated from 2008 to 2015. All patients were examined by PSG, magnetic resonance imaging (MRI), and otolaryngeal fibroscopy. We analyzed demographic data, clinical presentation, degree and type of respiratory impairment, severity of foramen magnum stenosis and concomitant cervicomedullary compression, treatment (conservative or surgical), and clinical outcome.

Results: Eight of nine patients presented with no severe symptoms in the daytime. However, MRI revealed four severe, four moderate, and one mild case of cervicomedullary compression, and PSG demonstrated severe sleep apnea in four cases and moderate sleep apnea in five cases. All sleep apnea cases were obstructive or obstructive-dominant. Fibroscopy revealed no upper airway stenosis in six cases and mild stenosis in three cases. Four patients who had severe sleep-related respiratory disturbance on PSG and severe or moderate cervicomedullary compression were treated by cervicomedullary decompression. Three of these patients demonstrated improved sleep respiration soon after surgery, while one required temporary tracheostomy due to bilateral vocal cord paralysis caused by compression during intratracheal intubation.

Conclusion: Polysomnography can be a useful indicator for cervicomedullary decompression surgery, especially in cases of seemingly asymptomatic achondroplasia with severe foramen magnum stenosis.
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http://dx.doi.org/10.1007/s00381-018-3880-0DOI Listing
November 2018

Clinical characteristics of adolescent cases with Type A insulin resistance syndrome caused by heterozygous mutations in the β-subunit of the insulin receptor (INSR) gene.

J Diabetes 2019 Jan 4;11(1):46-54. Epub 2018 Jul 4.

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

Background: Type A insulin resistance (IR) is a rare form of severe congenital IR that is frequently caused by heterozygous mutations in the insulin receptor (INSR) gene. Although Type A IR requires appropriate intervention from the early stages of diabetes, proper diagnosis of this disease is challenging, and accumulation of cases with detailed clinical profiles and genotypes is required.

Methods: Herein we report on six peripubertal patients with clinically diagnosed Type A IR, including four patients with an identified INSR mutation. To clarify the clinical features of Type A IR due to INSR mutation, we validated the clinical characteristics of Type A IR patients with identified INSR mutations by comparing them with mutation-negative patients.

Results: Four heterozygous missense mutations within the β-subunit of INSR were detected: Gly1146Arg, Arg1158Trp, Arg1201Trp, and one novel Arg1201Pro mutation. There were no obvious differences in clinical phenotypes, except for normal lipid metabolism and autosomal dominant inheritance, between Type A IR due to INSR mutations and Type A IR due to other factors. However, our analysis revealed that the extent of growth retardation during the fetal period is correlated with the severity of insulin signaling impairment.

Conclusions: The present study details the clinical features of four patients with genetically proven Type A IR. Further accumulation of genetically proven cases and long-term treatment prognoses following early diagnosis are required to further elucidate the dynamics of this disease.
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http://dx.doi.org/10.1111/1753-0407.12797DOI Listing
January 2019

Incidence rate and characteristics of symptomatic vitamin D deficiency in children: a nationwide survey in Japan.

Endocr J 2018 Jun 10;65(6):593-599. Epub 2018 Mar 10.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

There is concern that vitamin D deficiency is prevalent among children in Japan as well as worldwide. We conducted a nationwide epidemiologic survey of symptomatic vitamin D deficiency to observe its incidence rate among Japanese children. A questionnaire inquiring the number of new patients with vitamin D deficiency rickets and/or hypocalcemia for 3 years was sent to 855 randomly selected hospitals with a pediatrics department in Japan. In this survey, we found that 250 children were diagnosed with symptomatic vitamin D deficiency. The estimated number of patients with symptomatic vitamin D deficiency per year was 183 (95% confidence interval (CI): 145-222). The overall annual incidence rate among children under 15 years of age was 1.1 per 100,000 population (95% CI: 0.9-1.4). The second survey has provided detailed information on 89 patients with symptomatic vitamin D deficiency under 5 years of age in hospitals in the current research group. The nationwide and second surveys estimated the overall annual incidence rate of symptomatic vitamin D deficiency in children under 5 years of age to be 3.5 (2.7-4.2) per 100,000 population. The second survey revealed 83% had bowed legs, 88% had exclusive breastfeeding, 49% had a restricted and/or unbalanced diet and 31% had insufficient sun exposure among the 89 patients. This is the first nationwide survey on definitive clinical vitamin D deficiency in children in Japan. Elucidating the frequency and characteristics of symptomatic vitamin D deficiency among children is useful to develop preventative public health strategies.
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http://dx.doi.org/10.1507/endocrj.EJ18-0008DOI Listing
June 2018

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

Horm Res Paediatr 2018 16;89(3):166-171. Epub 2018 Feb 16.

The Committee on Mass Screening, Japanese Society for Pediatric Endocrinology, Kyoto, 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.
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http://dx.doi.org/10.1159/000486393DOI Listing
September 2018

Entropy-Driven Diastereoselectivity Improvement in the Paternò-Büchi Reaction of 1-Naphthyl Aryl Ethenes with a Chiral Cyanobenzoate through Remote Alkylation.

Angew Chem Int Ed Engl 2018 04 27;57(18):4880-4885. Epub 2018 Feb 27.

Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, 565-0871, Japan.

The precise stereocontrol of photocycloaddition reactions is still a significant challenge owing to their mechanistic complexity and the involvement of highly reactive and short-lived intermediates. Attempts have hitherto been made through structural modifications, mostly by introducing steric conflicts, to increase the difference between the enthalpic barriers. Herein, we show that entropy plays a crucial role in influencing the diastereoselectivity of a Paternò-Büchi reaction. Remote meta alkylation of the donor caused nominal changes in its photophysical properties as well as those of the exciplexes derived thereof. Nevertheless, the diastereomeric excess of the oxetane product was greatly improved by about 40 %. This enhancement, which is not accompanied by any significant changes in the photophysical properties, is difficult to rationalize by conventional enthalpic control concepts based on repulsive steric and/or attractive intermolecular interactions as well as electronic perturbations. Differential activation parameters and compensatory enthalpy-entropy relationships revealed that the diastereoselectivity enhancement is not simply enthalpic but also entropic in origin.
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http://dx.doi.org/10.1002/anie.201801330DOI Listing
April 2018
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