論文 - 長谷川　奉延

Siblings of neonatal hyperbilirubinemia with UGT1A1 double missense variants

Kubota Y., Sato T., Matsuyama M., Maruo Y., Narumi S., Ishii T., Hasegawa T.

Clinical Pediatric Endocrinology 33 （ 3 ） 195 - 198 2024年

ISSN  09185739

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Underweight in young Japanese women over time: a longitudinal retrospective study of the change in body mass index from ages 6 to 20 years

Nagashima Y., Inokuchi M., Sato Y., Hasegawa T.

Annals of Human Biology 51 （ 1 ）  2024年

ISSN  03014460

　概要を見る

Background: The high prevalence of underweight in young women has become a serious health problem in Japan. When and how young women reach a low body mass index (BMI) has not been clarified. Aim: To clarify the characteristics of BMI standard deviation scores (BMI SDS) trajectory of young Japanese women with underweight. Subjects and methods: A total of 601 Japanese female university students aged 20 years were classified into underweight and healthy weight groups. Their school health check-up data were available from the ages of 6 to 20 years. We evaluated the estimated mean values of BMI SDS at each age and differences in BMI SDS (ΔBMI SDS) from 6 years to each age using a mixed-effects model and compared between the two groups at each age. Results: In the underweight group, the BMI SDS at every age (−1.67 to −0.91) and the ΔBMI SDS after 16 years of age (−0.76 to −0.38) were significantly lower than those in the healthy weight group (−0.41 to −0.13, −0.07 to 0.04), respectively. Conclusion: Young Japanese women with underweight have at least two characteristics of BMI SDS trajectory: being constitutionally underweight and shifting their weight status from baseline towards underweight in their late teens.

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Adrenal crisis during a trip in a young child with septo-optic dysplasia

Takahashi M., Sato T., Nakano S., Hamada J., Ishii T., Hasegawa T.

Clinical Pediatric Endocrinology 33 （ 2 ） 101 - 103 2024年

ISSN  09185739

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Pitfalls in estradiol measurement by electrochemiluminescence immunoassay: A case study of a prepubertal girl with a falsely elevated serum estradiol level

Furusawa K., Hachiya R., Shibata H., Uchida N., Sasaki G., Fukushima H., Ishii T., Hasegawa T.

Clinical Pediatric Endocrinology 33 （ 1 ） 35 - 38 2024年

ISSN  09185739

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Potential indication of chemotherapy for hypodipsia and arginine vasopressin deficiency secondary to hypothalamic-pituitary Langerhans cell histiocytosis: a case report and literature review

Ota M., Sato T., Nakano S., Yamazaki F., Ishii T., Hasegawa T.

Clinical Pediatric Endocrinology 33 （ 3 ） 157 - 162 2024年

ISSN  09185739

　概要を見る

Hypothalamic-pituitary Langerhans cell histiocytosis (HP-LCH) is often associated with arginine vasopressin deficiency (AVD). Patients with AVD caused by HP-LCH rarely develop an impaired osmotic threshold for thirst (OTT). Improvement in OTT among such patients has not been reported in the literature. To our knowledge, here we report the first case of AVD due to HP-LCH in which hypodipsia resolved during chemotherapy. A nine-year-old Japanese girl presented with polydipsia, polyuria, anorexia, and hypernatremia (149.8 mEq/L) and was diagnosed with AVD secondary to HP-LCH. Visual analog scale examination showed a reduced OTT following the water deprivation test. During chemotherapy for Langerhans cell histiocytosis (LCH), serum sodium concentrations became stable between 138.9 and 142.9 mEq/L under the replacement of desmopressin. Repeated visual analog scale examinations showed that she experienced a sense of thirst at a serum sodium concentration of 142.3–144.6 mEq/L, at which she did not experience any thirst prior to the initiation of chemotherapy. These data suggest that chemotherapy directly improved the OTT in our patient. Improved mechanical compression or infiltration of the hypothalamus related to OTT may lead to the recovery of the sense of thirst. This report highlights the potential role of chemotherapy for solitary HP-LCH in patients with hypodipsia and AVD.

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Characteristic external genitalia in male neonates with 5α-reductase deficiency

Munenaga T., Ichihashi Y., Nakano S., Shibata H., Sato T., Asanuma H., Homma K., Hasegawa T., Ishii T.

Endocrine Journal 71 （ 10 ） 973 - 978 2024年

ISSN  09188959

　概要を見る

There have been no reports comparing neonatal external genitalia of 5α-reductase deficiency (5αRD) with those of other 46,XY differences of sex differentiation (DSD). This study enrolled 31 Japanese cases of 46,XY DSD whose external genitalia was examined during the neonatal period; four were diagnosed as 5αRD and 15 were defined as non-5αRD by genetic analysis of SRD5A2 or urinary steroid metabolites. We compared the following characteristics between 5αRD and non-5αRD groups, adjusting the severity of undermasculinization of the external genitalia: stretched penile length (SPL), glans width, location of the external urethral opening, and proportion of undescended testis. The external genitalia of all the 5αRD cases were Quigley classification grade 2 or 3. We compared the phenotypes between the four 5αRD cases and 11 non-5αRD cases with grade 2 or 3. The median (range) of SPL in the 5αRD group (14 mm [11-16]) was significantly lower than that in the non-5αRD group (22 mm [15-29]) (p = 0.003). An SPL cut-off value of <15 mm yielded a sensitivity of 50% (95% confidence interval [CI]; 7–93%) and specificity of 100% (95% CI, 72–100%) for discriminating between the groups. The median glans width, location of the external urethral opening, and proportion of undescended testis were not significantly different between the groups. The SPL of 5αRD in Quigley classification grade 2 or 3 was significantly shorter than that of other 46,XY DSDs with the equivalent grade.

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Sequential imaging of hyperplastic callus formation in Osteogenesis Imperfecta type V: A case report and review of the literature

Yung D., Arai M., Matsumoto S., Sato T., Hirozane T., Yamaguchi S., Asano N., Hasegawa T., Nakayama R.

Journal of Orthopaedic Science 28 （ 6 ） 1430 - 1435 2023年11月

ISSN  09492658

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Fibroblast growth factor 23 levels in cord and peripheral blood during early neonatal period as possible predictors of affected offspring of X-linked hypophosphatemic rickets: Report of three female cases from two pedigrees

Nabeshima Y., Sato T., Zukeran H., Komatsu R., Nakano S., Ichihashi Y., Tominaga T., Miwa M., Amano N., Ishii T., Hasegawa T.

Journal of Pediatric Endocrinology and Metabolism 36 （ 8 ） 786 - 790 2023年08月

ISSN  0334018X

　概要を見る

Objectives: The role of serum fibroblast growth factor 23 (FGF23) level in early neonatal period on the diagnosis of X-linked hypophosphatemic rickets (XLH) remains unclear. Case presentation: Two female patients from the first pedigree had an affected mother, and the other female from the second pedigree had an affected father. In all three cases, FGF23 levels were high in cord blood and peripheral blood at day 4-5. Additionally, the FGF23 levels considerably increased from birth to day 4-5. We identified a PHEX pathogenic variant and initiated treatment during infancy in each case. Conclusions: In neonates with a parent diagnosed as PHEX-associated XLH, FGF23 in cord blood and peripheral blood at day 4-5 may be useful markers for predicting the presence of XLH.

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Intracranial germinoma in the lateral ventricle with polydipsia and polyuria: a case report and literature review

Kuranari Y., Miwa T., Kono M., Shibata H., Ishii T., Hasegawa T.

Child's Nervous System 39 （ 4 ） 1065 - 1069 2023年04月

ISSN  02567040

　概要を見る

Central nervous system germ cell tumors (CNSGCTs) are rare neoplasms which usually develop in the midline structures. They are occasionally involved in off-midline structures of the brain. Here, we report an extremely rare case of an intracranial germinoma in the lateral ventricle. The patient was a 10-year-old boy with a 1-year history of polydipsia and polyuria. Brain magnetic resonance imaging (MRI) showed a relatively homogeneously enhancing lesion in the lateral ventricle, and the posterior pituitary gland was not hyperintense on T1-weighted imaging. Subependymoma was suspected, and tumor removal operation was performed; however, because the intraoperative pathological investigation revealed germinoma, we could only perform partial removal of the tumor. Postoperative histology also confirmed germinoma. Then, the patient received chemotherapy, followed by radiation therapy. MRI showed no recurrence for 6 years after treatment. Intracranial germinoma in the lateral ventricle is extremely rare. The diagnosis is occasionally challenging, especially when the tumors are located in atypical locations. This paper presents a literature review of previously described CNSGCTs of the lateral ventricle to improve awareness of CNSGCTs in atypical locations. We also consider the relationship between imaging findings and clinical manifestations.

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POU1F1/Pou1f1 c.143-83A &gt; G Variant Disrupts the Branch Site in Pre-mRNA and Leads to Dwarfism

Akiba K., Hasegawa Y., Katoh-Fukui Y., Terao M., Takada S., Hasegawa T., Fukami M., Narumi S.

Endocrinology (United States) 164 （ 2 ）  2023年02月

ISSN  00137227

　概要を見る

POU Class 1 Homeobox1 (POU1F1/Pou1f1) is a well-established pituitary-specific transcription factor, and causes, when mutated, combined pituitary hormone deficiency in humans and mice. POU1F1/Pou1f1 has 2 isoforms: the alpha and beta isoforms. Recently, pathogenic variants in the unique coding region of the beta isoform (beta domain) and the intron near the exon-intron boundary for the beta domain were reported, although their functional consequences remain obscure. In this study, we generated mice carrying the Pou1f1 c.143-83A>G substitution that recapitulates the human intronic variant near the exon-intron boundary for the beta domain. Homozygous mice showed postnatal growth failure, with an average body weight that was 35% of wild-type littermates at 12 weeks, which was accompanied by anterior pituitary hypoplasia and deficiency of circulating insulin-like growth factor 1 and thyroxine. The results of RNA-seq analysis of the pituitary gland were consistent with reduction of somatotrophs, and this was confirmed immunohistochemically. Reverse transcription polymerase chain reaction of pituitary Pou1f1 mRNA showed abnormal splicing in homozygous mice, with a decrease in the alpha isoform, an increase in the beta isoform, and the emergence of the exon-skipped transcript. We further characterized artificial variants in or near the beta domain, which were candidate positions of the branch site in pre-mRNA, using cultured cell-basis analysis and found that only c.143-83A>G produced transcripts similar to the mice model. Our report is the first to show that the c.143-83A>G variant leads to splicing disruption and causes morphological and functional abnormalities in the pituitary gland. Furthermore, our mice will contribute understanding the role of POU1F1/Pou1f1 transcripts in pituitary development.

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Fluorodeoxyglucose-positron emission tomography as a potential alternative tool for functional diagnosis of glycogen storage disease type I

Sato T., Inokuchi M., Nakano S., Iwabuchi Y., Hayashida T., Ishii T., Hasegawa T.

Radiology Case Reports 18 （ 1 ） 91 - 93 2023年01月

　概要を見る

A 43-year-old woman with genetically confirmed glycogen storage disease type Ib was suspected to have left breast cancer. Fluorodeoxyglucose-positron emission tomography showed high fluorodeoxyglucose accumulation in the whole liver as well as left mammary gland. We consider that high fluorodeoxyglucose accumulation in the liver of patients with glycogen storage disease type I is caused by impaired glucose-6-phosphate metabolism due to the congenital deficiency of glucose-6-phosphatase activities in hepatocytes. This study describes fluorodeoxyglucose-positron emission tomography as a potential alternative tool to diagnose glycogen storage disease type I functionally.

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Clinical features of non-classical 21-hydroxylase deficiency after normal newborn mass screening

Takahashi F., Adachi S., Sakurai N., Mori T., Fujikura K., Usui T., Hasegawa T.

Pediatrics International 65 （ 1 ）  2023年01月

ISSN  13288067

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A girl with type 1A diabetes mellitus and extrahepatic portal vein obstruction

Kameyama M., Sato T., Nakano S., Maeda Y., Yamada Y., Ishii T., Hasegawa T.

Pediatrics International 65 （ 1 ）  2023年01月

ISSN  13288067

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Potential benefit of rapid genetic testing for Pallister–Hall syndrome

Maeda-Usui A., Sato T., Nakano S., Kusakawa M., Kin T., Takahashi N., Motojima Y., Asanuma H., Hida M., Ishii T., Kuroda T., Hasegawa T.

Clinical Pediatric Endocrinology 32 （ 2 ） 119 - 122 2023年

ISSN  09185739

　概要を見る

Pallister–Hall syndrome (PHS) is defined as a group of characteristic manifestations caused by a monoallelic GLI3 pathogenic variant. A two-month-old infant was referred to our institution because of undetermined sex. The infant had atypical genitalia with postaxial polysyndactyly, a hypothalamic mass, and an imperforate anus. We identified a known pathogenic variant of the GLI3 gene within one week and diagnosed the infant with PHS. The parents assigned the infant as male, considering the 46,XY karyotype, normal testosterone secretion, possible male identity, and the natural history of PHS. In infants with atypical genitalia and other malformations, such as polydactyly, a hypothalamic mass, or an imperforate anus, rapid GLI3 testing may provide information for planning lifelong management, including sex assignment.

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Pubertal induction in Turner syndrome without gonadal function: A possibility of earlier, lower-dose estrogen therapy

Hasegawa Y., Hasegawa T., Satoh M., Ikegawa K., Itonaga T., Mitani-Konno M., Kawai M.

Frontiers in Endocrinology 14 2023年

　概要を見る

Delayed and absent puberty and infertility in Turner syndrome (TS) are caused by primary hypogonadism. A majority of patients with TS who are followed at hospitals during childhood will not experience regular menstruation. In fact, almost all patients with TS need estrogen replacement therapy (ERT) before they are young adults. ERT in TS is administered empirically. However, some practical issues concerning puberty induction in TS require clarification, such as how early to start ERT. The present monograph aims to review current pubertal induction therapies for TS without endogenous estrogen production and suggests a new therapeutic approach using a transdermal estradiol patch that mimics incremental increases in circulating, physiological estradiol. Although evidence supporting this approach is still scarce, pubertal induction with earlier, lower-dose estrogen therapy more closely approximates endogenous estradiol secretion.

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Potential risk of inguinal hernia in complete androgen insensitivity syndrome

Kimizuka Y., Sato T., Nakano S., Ishii T., Hasegawa T.

Clinical Pediatric Endocrinology 32 （ 1 ） 76 - 78 2023年

ISSN  09185739

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A case of 46,XY complete gonadal dysgenesis with a novel missense variant in SRY

Narita C., Takubo N., Sammori M., Matsumura Y., Shimura K., Ozaki R., Haruna H., Narumi S., Ishii T., Hasegawa T., Shimizu T.

Clinical Pediatric Endocrinology 32 （ 4 ） 235 - 238 2023年

ISSN  09185739

　概要を見る

Disorders of sex development (DSD) with mild external genital abnormalities may be diagnosed after puberty. Here, we report a case of 46,XY complete gonadal dysgenesis with a novel missense variant in sex-determining region Y (SRY), diagnosed after primary amenorrhea. A 15-yr-old patient presented to our gynecology department with a chief complaint of amenorrhea. The patient was diagnosed with a 46,XY karyotype, and SRY gene positivity. Gonadotropin levels were high, whereas testosterone levels were low. A pelvic magnetic resonance imaging (MRI) revealed a hypoplastic uterus; however, no gonads could be identified. Laparoscopy revealed bilateral streak gonads, fallopian tube-like structures, and the uterus. The gonads were removed based on the risk of gonadal malignancy. Comprehensive genetic analysis of DSD revealed a previously unreported SRY variant, c.271A>T, p.Ser91Cys, and in silico analysis predicted the variant to be pathogenic. The patient was diagnosed with 46,XY complete gonadal dysgenesis with a novel missense variant in SRY. The patient continued female hormone replacement therapy and experienced breast enlargement and cyclic menstruation. Determining the etiology of DSD can be difficult, causing anxiety in patients and their families. In addition to surgical scrutiny, genetic analysis is important to aid in diagnosis and reassure patients and their families.

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Less-Invasive Diagnostic Approaches for Infants with Suspected Differences of Sex Development: A Case Report of a 297-g Neonate with Ambiguous Genitalia

Sato T., Nakano S., Ichihashi Y., Kobayashi H., Hida M., Ishii T., Hasegawa T.

Neonatology 119 （ 6 ） 785 - 789 2022年12月

ISSN  16617800

　概要を見る

Less-invasive diagnostic approaches for low-birthweight preterm neonates with suspected differences of sex development have not been established. Herein, we describe our diagnostic approaches for a 297-g neonate with ambiguous genitalia. Using a fiberscope, the external genitalia were inspected in an incubator to minimize the risk of hypothermia and infection. Endotracheal aspirate, collected during routine care, was used for genetic testing to avoid anemia and vital signs fluctuations caused by peripheral blood sampling. Array comparative genomic hybridization indicated a 46,XY karyotype. No pathogenic variants of AR and SRD5A2 were found. Endocrinological data could not be evaluated owing to the absence of reference data. Identification and structural evaluation of the internal genitalia and gonads were difficult. On postnatal day 42, the parents assigned their baby's sex as male. Our less-invasive diagnostic approaches of inspection and genetic testing are useful for management, including sex assignment in extremely low-birthweight preterm neonates with ambiguous genitalia.

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Continuous glucose monitoring in an infant with panhypopituitarism having hypoglycemia on growth hormone therapy

Kiuchi K., Sato T., Nakano S., Ishii T., Hasegawa T.

Journal of Pediatric Endocrinology and Metabolism 35 （ 12 ） 1556 - 1559 2022年12月

ISSN  0334018X

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Objectives: The usefulness of continuous glucose monitoring (CGM) in infants with panhypopituitarism (PH) having hypoglycemia is yet to be explored. The potential adverse effects of growth hormone (GH) replacement therapy, such as hyperglycemia, cannot be comprehensively evaluated using the conventional measurement. Case presentation: A 2-month-old infant with PH, including severe GH deficiency, had hypoglycemia despite frequent feeding. Glucose levels were monitored using CGM before and after GH replacement therapy. The proportion of time for hypoglycemia decreased from 4.9 to 0% (p<0.017). Hyperglycemia did not increase. The CGM method did not contribute to any adverse events requiring intervention. Our patient only experienced minor bleeding and no episode of cellulitis. Conclusions: CGM is useful in controlling glucose levels in infants with hypoglycemia and PH.

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The High Relevance of 21-Deoxycortisol, (Androstenedione + 17α-Hydroxyprogesterone)/Cortisol, and 11-Deoxycortisol/17α-Hydroxyprogesterone for Newborn Screening of 21-Hydroxylase Deficiency

Watanabe K., Tsuji-Hosokawa A., Hashimoto A., Konishi K., Ishige N., Yajima H., Sutani A., Nakatani H., Gau M., Takasawa K., Tajima T., Hasegawa T., Morio T., Kashimada K.

Journal of Clinical Endocrinology and Metabolism 107 （ 12 ） 3341 - 3352 2022年12月

ISSN  0021972X

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Context: There are limited reports on the detailed examination of steroid profiles for setting algorithms for 21-hydroxylase deficiency (21OHD) screening by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Objective: We aimed to define an algorithm for newborn screening of 21OHD by LC-MS/MS, measuring a total of 2077 dried blood spot samples in Tokyo. Methods: Five steroids (17α-hydroxyprogesterone [17αOHP], 21-deoxycortisol [21DOF], 11-deoxycortisol [11DOF], androstenedione [4AD], and cortisol [F]) were included in the panel of LC-MS/MS. Samples from 2 cohorts were assayed: Cohort A, 63 "screening positive"neonates who were referred to an endocrinologist (n = 26 with 21OHD; n = 37 false-positive; obtained from 2015 to 2020); and Cohort B, samples (n = 2014) with 17αOHP values in the 97th percentile or above, in the first-tier test with 17αOHP ELISA from 2020 to 2021. Results: Analysis of Cohort A revealed that the 3 indexes 21DOF, 11DOF/17αOHP, and (4AD + 17αOHP)/F had higher area under the curve (AUC) values (0.999, 0.997, 0.989, respectively), while the 17αOHP AUC was lower (0.970). Accordingly, in addition to 17αOHP, the 3 markers were included for defining the screening algorithm. The assay of Cohort B revealed that the new algorithm gave 92% of predicted positive predictive value without false-negative cases. We also determined the reference values for the 5 steroids at 4 to 7 days after birth, according to sex and gestational age (GA), revealing extremely low levels of 21DOF at any GA irrespective of sex differences. Conclusion: Our study demonstrated the high relevance of 21DOF, (4AD + 17αOHP)/F, and 11DOF/17αOHP, rather than 17αOHP, for 21OHD screening.

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