論文 - 長谷川　奉延

An infant with congenital nephrogenic diabetes insipidus presenting with hypercalcemia and hyperphosphatemia

Tao K., Awazu M., Honda M., Shibata H., Mori T., Uchida S., Hasegawa T., Ishii T.

Endocrinology, Diabetes and Metabolism Case Reports 2021 （ 1 ）  2021年04月

　概要を見る

We report a male infant with congenital nephrogenic diabetes insipidus (NDI) who presented with hypercalcemia and hyperphosphatemia since birth. Serum sodium started to increase at 39 days. Although there was no polyuria, urine osmolality was 71 mOsm/kg, when serum osmolality was 296 mOsm/kg with plasma arginine vasopressin 22.5 pg/mL. He was thus diagnosed as NDI. An undetectable level of urine calcium and unsuppressed intact parathyroid hormone suggested hyperparathyroidism including calcium-sensing receptor mutations that could cause hypercalcemia-induced NDI. Polyuria became apparent after the initiation of i.v. infusion for the treatment of hypernatremia. Low calcium and low sodium formula with hypotonic fluid infusion did not correct hypernatremia, hypercalcemia, or hyperphosphatemia. Hydrochlorothiazide and subsequently added celecoxib effectively decreased urine output and corrected electrolytes abnormalities. Normal serum electrolytes were maintained after the discontinuation of low calcium formula. The genetic analysis revealed a large deletion of the arginine vasopressin receptor-2 (AVPR2) gene but no pathogenic variant in the calcium-sensing receptor (CASR) gene. Whether hypercalcemia and hyperphosphatemia were caused by dehydration alone or in combination with other mechanisms remains to be clarified.

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Population-based waist circumference reference values in Japanese children (0-6 years): Comparisons with Dutch, Swedish and Turkish preschool children

Hasegawa T., Inokuchi M., Matsuo N., Takayama J.I.

Journal of Pediatric Endocrinology and Metabolism 34 （ 3 ） 349 - 356 2021年03月

ISSN  0334018X

　概要を見る

Background: During 1978-1981 the Japanese Standards Association conducted a national survey to collect 64 distinct body measurements for Japanese children and adults. During 1978-1981, the prevalence of childhood obesity was relatively low yet the population was well nourished in Japanese children. The aim of this study is to construct waist circumference and waist circumference to stature ratio reference centile curves for Japanese preschool children. Methods: We utilized 1978-1981 national survey data on body sizes. There are 4937 boys and 4758 girls age 0-6 years for waist circumference measurements. Waist circumference was measured at the level of the umbilicus. Using LMS method, centile curves were constructed for waist circumference and waist circumference to stature ratio. These reference values were compared with those of Dutch, Swedish and Turkish children. Results: Centile reference curves were made for clinical and epidemiological use. Japanese children had smaller waist circumference centile values as compared to waist circumference measured at the midpoint of the lowest rib cage and the iliac crest of Dutch, Swedish and Turkish children. However, Japanese children had comparable waist circumference to stature ratio centile values to those of Dutch and Turkish children. Conclusions: This study presents the first age-, sex-, and ethnicity-specific reference values for waist circumference and waist circumference to stature ratio in Japanese preschool children.

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A Case of Luscan-Lumish Syndrome: Possible Involvement of Enhanced GH Signaling

Suda K., Fukuoka H., Iguchi G., Kanie K., Fujita Y., Odake Y., Matsumoto R., Bando H., Ito H., Takahashi M., Chihara K., Nagai H., Narumi S., Hasegawa T., Ogawa W., Takahashi Y.

Journal of Clinical Endocrinology and Metabolism 106 （ 3 ） 718 - 723 2021年03月

ISSN  0021972X

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Context: Luscan-Lumish syndrome (LLS) is characterized by postnatal overgrowth, obesity, Chiari I malformation, seizures, and intellectual disability. SET domain-containing protein 2 (SETD2) is a histone methyltransferase, where mutations in the gene are associated with the development of LLS. However, mechanisms underlying LLS remain unclear. Case Description: A 20-year-old man was referred to our hospital because of tall stature. His body height was 188.2 cm (+3.18 SD) and he showed obesity with a body mass index of 28.4 kg/m2. He exhibited acral overgrowth, jaw malocclusion, and prognathism, but no history of seizures, intellectual disability, or speech delay. Serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), and nadir GH levels after administration of 75 g oral glucose were within normal range. Pituitary magnetic resonance imaging showed no pituitary adenoma, but Chiari I malformation. Whole exome sequencing analysis of the proband revealed a de novo heterozygous germline mutation in SETD2 (c.236T>A, p.L79H). Skin fibroblasts derived from the patient grew faster than those from his father and the control subject. In addition, these cells showed enhanced tyrosine phosphorylation and transcriptional activity of signal transducer and activator of transcription 5b (STAT5b) and increased IGF-1 expression induced by GH. Conclusion: This is a mild case of LLS with a novel mutation in SETD2 without neurological symptoms. LLS should be differentiated in a patient with gigantism without pituitary tumors. Although further investigation is necessary, this is the first study to suggest the involvement of aberrant GH signaling in the development of LLS.

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Oral sodium phenylbutyrate for hyperammonemia associated with congenital portosystemic shunt: A case report

Hasegawa T., Sato T., Ishii T., Oyanagi T., Kato M., Kuroda T., Nakatsuka S.

Journal of Pediatric Endocrinology and Metabolism 34 （ 3 ） 407 - 410 2021年03月

ISSN  0334018X

　概要を見る

Objectives: The efficacy of sodium phenylbutyrate (SPB) for hyperammonemia associated with congenital portosystemic shunt (CPSS) remains unknown. We show the effectiveness of oral SPB. Case presentation: Our patient had CPSS with severe hypoplasia of extrahepatic portal veins. At 9 months of age, to assess the efficacy of oral SPB, we evaluated the 24 h fluctuations of venous ammonia levels. In the first two days without SPB, ammonia levels were above 80 μmol/L for half a day. On the third and fourth days, administration of oral SPB three times a day decreased ammonia to acceptable levels, except at midnight. On the fifth day, another oral SPB administration at 8 pm decreased ammonia at midnight. Low levels of branched-chain amino acids, as well as coagulation disturbances, were observed without apparent symptoms. At 12 months of age, he showed normal psychomotor development. Conclusions: Oral SPB may be effective for hyperammonemia associated with CPSS.

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The progression of salt-wasting and the body weight change during the first 2 weeks of life in classical 21-hydroxylase deficiency patients

Gau M., Konishi K., Takasawa K., Nakagawa R., Tsuji-Hosokawa A., Hashimoto A., Sutani A., Tajima T., Hasegawa T., Morio T., Kashimada K.

Clinical Endocrinology 94 （ 2 ） 229 - 236 2021年02月

ISSN  03000664

　概要を見る

Background: One of the major purposes of newborn screening for 21-hydroxylase deficiency (21OHD) is preventing life-threatening adrenal crisis. However, the details of adrenal crisis in newborns are not precisely documented. Aim: We aimed to clarify the clinical details of salt-wasting in newborn 21OHD patients. Methods: Based on the follow-up survey of the screening in Tokyo from 1989 to 2017, we retrospectively analysed the conditions of classical 21OHD neonates before the initiation of therapy. Results: One hundred classical 21OHD patients (55 male, 45 female) were analysed. The age at the first hospital visit was 0–20 days with sex difference (male: 9.0 ± 3.5 days; female: 6.2 ± 3.9 days). Thirty-seven (37.4%) patients exhibited severe salt-wasting (SSW), that is, Na < 130 mEq/L, K > 7 mEq/L or Na/K ratio < 20; except for one case, SSW developed in or after the second week of life. The serum concentrations of Na, K and Na/K were linearly correlated with age in days (R2 =.38,.25, and.34 respectively), suggesting that the risk of SSW increases linearly without a threshold. The age at which the regression lines reached Na < 130 mEq/L, K > 7 mEq/L and Na/K < 20 was approximately coincided, 11.1, 12.3 and 11.2 days, respectively. All SSW patients exhibited decreased body weight from birth in their second week of life. Conclusion: Our data revealed that the risk of developing SSW increases during the second week of life without a threshold, and for preventing SSW, early intervention, ideally during first week of life, is desirable. An increased body weight in the second week of life indicates the absence of SSW.

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Case Report: Prenatal Genetic Counseling to Parents of Fetuses Suspected of Having Ambiguous Genitalia

Sato T., Ishii T., Yamaguchi Y., Ichihashi Y., Ochiai D., Asanuma H., Kuroda T., Hasegawa T.

Frontiers in Pediatrics 8 2021年01月

　概要を見る

The occurrence of fetuses suspected of having ambiguous genitalia will likely increase in the future. Currently, the impact of prenatal genetic counseling on parents' understanding and psychological preparedness has not been addressed. We provided prenatal genetic counseling to parents of two fetuses suspected of ambiguous genitalia. Case 1: At 22 weeks of gestation, swelling of the labia majora, and a clitoris-like structure were noted despite 46,XY detected in amniotic fluid cells. Case 2: At 28 weeks of gestation, bladder exstrophy and a scrotum-like structure were noted. At 32 weeks (Case 1) and 37 weeks (Case 2) of gestation, we shared information with parents regarding the possible difficulty of legal sex assignment at birth, and a scenario for registration of the birth certificate. At birth, both babies presented with ambiguous genitalia. For both cases, the parents remained calm on seeing their baby's genitalia for the first time. After a month, we shared medical information with parents, including karyotype, testosterone production capacity, and surgical schedule. In both cases parents assigned their respective baby's legal sex as male. Several months later, parents were questioned on prenatal genetic counseling. Case 1: Mother, “I was prepared to address our baby's genitalia calmly.” Father, “I understood the procedure of legal sex assignment.” Case 2: Mother, “Without counseling, I would have been more upset and worried.” Father, “We were assured that multidisciplinary experts would support us.” Prenatal genetic counseling provides reassurance to parents, who remain informed and emotionally secure throughout the legal sex assignment of their child.

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Inactivation of a Frameshift TSH Receptor Variant Val711Phefs∗18 is Due to Acquisition of a Hydrophobic Degron

Sugisawa C., Ono M., Kashimada K., Hasegawa T., Narumi S.

Journal of Clinical Endocrinology and Metabolism 106 （ 1 ） E265 - E272 2021年01月

ISSN  0021972X

　概要を見る

Context: Inactivating variants of thyrotropin (thyroid-stimulating hormone; TSH) receptor (TSHR) cause congenital hypothyroidism. More than 60 such variants have been reported so far, most of which were located in the extracellular or transmembrane domain. Objective: We report the identification and characterization of a frameshift TSHR variant in the intracytoplasmic C-tail region. Methods: Sequencing of TSHR was performed in a patient with congenital hypothyroidism. The functionality of the identified variants was assessed by expressing TSHR in HEK293 cells and measuring TSH-dependent activation of the cAMP-response element-luciferase reporter. A series of systematic mutagenesis experiments were performed to characterize the frameshifted amino acid sequence. Results: The proband was heterozygous for a known TSHR variant (p.Arg519His) and a novel frameshift TSHR variant (p.Val711Phefs∗18), which removed 54 C-terminal residues and added a 17-amino acid frameshifted sequence. The loss of function of Val711Phefs∗18-TSHR was confirmed in vitro, but the function of Val711∗-TSHR was found to be normal. Western blotting showed the low protein expression of Val711Phefs∗18-TSHR. Fusion of the frameshift sequence to green fluorescent protein or luciferase induced inactivation of them, indicating that the sequence acted as a degron. A systematic mutagenesis study revealed that the density of hydrophobic residues in the frameshift sequence determined the stability. Eight additional frameshift TSHR variants that covered all possible shifted frames in C-tail were created, and another frameshift variant (Thr748Profs∗27) with similar effect was found. Conclusions: We characterized a naturally occurring frameshift TSHR variant located in C-tail, and provided a unique evidence that hydrophobicity in the C-terminal region of the receptor affects protein stability.

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Complete androgen insensitivity syndrome with accelerated onset of puberty due to a sertoli cell tumor

Izawa M., Hisamatsu E., Yoshino K., Yoshida M., Sato T., Narumi S., Hasegawa T., Hamajima T.

Clinical Pediatric Endocrinology 30 （ 2 ） 99 - 104 2021年

ISSN  09185739

　概要を見る

Complete androgen insensitivity syndrome (CAIS) is caused by mutations in the androgen receptor gene. Patients with this syndrome have a 46,XY karyotype, male gonads, and normal female external genitalia. While the pre-pubertal risk of developing gonadal tumors is low in these patients, it increases with age. Most gonadal tumors arise from germ cells; stromal cell tumors are uncommon. Herein, we report a CAIS patient with a feminizing Sertoli cell tumor. The patient presented at 8 yr of age with breast enlargement and growth acceleration, concomitant with elevated serum estradiol levels and suppressed serum gonadotropin levels; these findings were inconsistent with CAIS. The patient underwent gonadectomy at 10 yr of age, and histology demonstrated presence of a non-malignant Sertoli cell tumor in the right gonad. We conclude that this is the first reported case of CAIS with accelerated onset of puberty resulting from a Sertoli cell tumor.

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The first survey about women doctors in the japanese society for pediatric endocrinology (Jspe)

Murashita M., Ito J., Hasegawa T.

Clinical Pediatric Endocrinology 30 （ 3 ） 121 - 126 2021年

ISSN  09185739

　概要を見る

The Career Development for Women Pediatric Endocrinologists and Work-Life Balance Committee and Support Team for Women Doctors in Education and Training Committee investigated the current situation of women doctors in the Japanese Society for Pediatric Endocrinology (JSPE). The proportion of women doctors (PWD) was as follows. 1) Members of JSPE: 40.2% in fiscal 2018, versus 33.3% in fiscal 2010; 2) councilors: 21.6% from fiscal 2014 to 2017, versus 6.3% from fiscal 2008 to 2010; 3) board members: 13.6% from fiscal 2014 to 2017, versus 0% from fiscal 2008 to 2010; 4) board-certified endocrinologists (Pediatrics) and certified endocrine educators (Pediatrics): 31.7% and 25.4% in fiscal 2018, versus 22.4% and 15.3% in fiscal 2010, respectively; and 5) average value of first presenters and chairpersons in the Annual Scientific Meeting of JSPE was 41.4% and 22.3% from 2010 to 2019. These PWD figures for JSPE were higher than those of the Japan Pediatric Society and the Japan Endocrine Society, indicating a reducing gender gap in JSPE, although increases in the PWD of decision-making posts remains insufficient.

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The current status of 492 adult women with turner syndrome: A questionnaire survey by the foundation for growth science

Hanew K., Tanaka T., Horikawa R., Hasegawa T., Yokoya S.

Endocrine Journal 68 （ 9 ） 1081 - 1089 2021年

ISSN  09188959

　概要を見る

Current status and its background of Adult Turner Syndrome (TS) are not clarified well. Via a questionnaire survey of 492 adult women with TS, this study investigated the association between menstruation, Kaufmann therapy (menstrual induction therapy), social status (education, employment & marriage), complications, transition from pediatric to adult care, and sex chromosome karyotype using statistical methods. Spontaneous menarche occurred in 22.0% and more frequently among patients with the 45,X/46,XX karyotype. Over 60% of these subjects, menstruation did not persist regularly. Kauffmann therapy was performed in 69.4%; the most common formulation was a conjugated estrogen and progesterone combination. Marriage and higher education advancement rates were low in adults with TS, whereas their employment rate was similar to that of the age-matched general female population. Patients receiving Kauffmann therapy had higher complication rates, greater education length, and higher employment rates. The higher-education advancement rate was observed among patients with 45,X/46,X,Xi and 46,X,Xi karyotypes. Transition from pediatrician to adult specialist was not smooth, subjects were treated in pediatric departments (60.7%), gynecological department (21.4%), internal medicine departments (13.3%), and others. While reason is not clear, the largest number of TS patients are treated in general pediatrics and the percentage of receiving Kauffmann therapy and having complication were significantly lower than in pediatric and adult department of endocrinology (& metabolism). This Study revealed many novel findings of adult TS.

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Adenocorical cartinoma characterized by gynecomastia: A case report.

Takeuchi T, Yoto Y, Ishii A, Tsugawa T, Yamamoto M, Hori T, Kamasaki H, Nogami K, Oda T, Nui A, Kimura S, Yamagishi T, Homma K, Hasegawa T, Fukami M, Watanabe Y, Sasamoto H, Tsutsumi H.

Clin Pediatr Endocrinol  27   9-18 2018年

研究論文（学術雑誌）, 共著, 査読有り

Comparison of serum 25-hydroxyvitamin D levels between radioimmunoassay and liquid chromatography tandem mass spectrometry in infants and postpartum women.

Hara K, Ikeda K, Hasegawa T.

J Pediatr Endocrinol Metab 2018年

研究論文（学術雑誌）, 共著, 査読有り

Rapid Growth and Early Metastasis of Papillary Thyroid Carcinoma in an Adolescent Girl with Graves’ Disease.

Shimura K, Shibata H, Mizuno Y, Amano N, Hoshino K, Kuroda T, Kameyama K, Matsuse M, Mitsutake N, Sugino K, Noh JY, Hasegawa T, Ishii T.

Hor Res Paediatr 2018年

研究論文（学術雑誌）, 共著, 査読有り

A novel truncating mutation in MYH3 causes spondylocarpotarsal synostosis syndrome with basilar invagination.

Takagi M, Shimomura S, Fukuzawa R, Narumi S, Nishimura G, Hasegawa T.

J Hum Genet  2018年

研究論文（学術雑誌）, 共著, 査読有り

A Novel Mutation in NKX2.1 Shows Dominant-Negative Effects Only in the Presence of PAX8

Shinohara H, Takagi M, Ito K, Shimizu E, Fukuzawa R, Hasegawa T.

28   1071-1073 2018年

研究論文（学術雑誌）, 共著, 査読有り

Methylome analysis of thyroid ectopy showed no disease-specific DNA methylation signature.

Narumi S, Matsubara K, Ishii T, Hasegawa T.

Clin Pediatr Endocrinol  2018年

研究論文（学術雑誌）, 共著, 査読有り

A familial case of spondyloepiphyseal dysplasia tarda caused by a novel splice site mutation in TRAPPC2.

Fukuma M, Takagi M, Shimazu T, Imamura H, Yagi H, Nishimura G, Hasegawa T.

Clin Pediatr Endocrinol  27   193-196 2018年

研究論文（学術雑誌）, 共著, 査読有り

A novel truncating mutation in MYH3 causes spondylocarpotarsal synostosis syndrome with basilar invagination.

Takagi M, Shimomura S, Fukuzawa R, Narumi S, Nishimura G, Hasegawa T.

J Hum Genet 2018年

研究論文（学術雑誌）, 共著, 査読有り

An Association with hypopituitarism and 9q subtelomere deletion syndrome.

Higuchi S, Takagi M, Takeda R, Yoshihashi H, Narumi S, Hasegawa T.

Clinical Case Reports 2018年

研究論文（学術雑誌）, 共著, 査読有り

Two novel mutations of COMP in Japanese boys with pseudoachondroplasia.

Ichihashi Y, Takagi M, Ishii T, Watanabe K, Nishimura G, Hasegawa T.

Hum Genome Variation 5   12 2018年

研究論文（学術雑誌）, 共著, 査読有り