論文 - 長谷川　奉延

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

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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

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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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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

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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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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

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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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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

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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

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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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Whole-exome analysis of 177 pediatric patients with undiagnosed diseases

Narita K., Muramatsu H., Narumi S., Nakamura Y., Okuno Y., Suzuki K., Hamada M., Yamaguchi N., Suzuki A., Nishio Y., Shiraki A., Yamamori A., Tsumura Y., Sawamura F., Kawaguchi M., Wakamatsu M., Kataoka S., Kato K., Asada H., Kubota T., Muramatsu Y., Kidokoro H., Natsume J., Mizuno S., Nakata T., Inagaki H., Ishihara N., Yonekawa T., Okumura A., Ogi T., Kojima S., Kaname T., Hasegawa T., Saitoh S., Takahashi Y.

Scientific Reports 12 （ 1 ）  2022年12月

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Recently, whole-exome sequencing (WES) has been used for genetic diagnoses of patients who remain otherwise undiagnosed. WES was performed in 177 Japanese patients with undiagnosed conditions who were referred to the Tokai regional branch of the Initiative on Rare and Undiagnosed Diseases (IRUD) (TOKAI-IRUD). This study included only patients who had not previously received genome-wide testing. Review meetings with specialists in various medical fields were held to evaluate the genetic diagnosis in each case, which was based on the guidelines of the American College of Medical Genetics and Genomics. WES identified diagnostic single-nucleotide variants in 66 patients and copy number variants (CNVs) in 11 patients. Additionally, a patient was diagnosed with Angelman syndrome with a complex clinical phenotype upon detection of a paternally derived uniparental disomy (UPD) [upd(15)pat] wherein the patient carried a homozygous DUOX2 p.E520D variant in the UPD region. Functional analysis confirmed that this DUOX2 variant was a loss-of-function missense substitution and the primary cause of congenital hypothyroidism. A significantly higher proportion of genetic diagnoses was achieved compared to previous reports (44%, 78/177 vs. 24–35%, respectively), probably due to detailed discussions and the higher rate of CNV detection.

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Fetal growth restriction and a single umbilical artery are independent predictors of hypospadias during pregnancy

Endo T., Iida M., Ichihashi Y., Oishi M., Ikenoue S., Kasuga Y., Sato T., Hida M., Ishii T., Asanuma H., Hasegawa T., Tanaka M., Ochiai D.

Placenta 130   53 - 59 2022年12月

ISSN  01434004

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Introduction: Little is known about the association between hypospadias and small fetuses, as well as the pathological implications of fetal growth restriction (FGR). Thus, we aimed to investigate the association between hypospadias and small fetuses using a database of fetal ultrasound and obstetric events. Methods: A cohort of male singleton infants delivered after 22 weeks of gestation at Keio University Hospital between 2013 and 2019 was retrospectively reviewed. FGR was defined according to the Delphi criteria. Logistic regression analysis was performed to identify the significant predictors of hypospadias. Placental pathology was reviewed in cases with hypospadias. Results: Of the 2,040 male infants included in the present study, 23 had hypospadias. The prevalences of a single umbilical artery (SUA), small for gestational age, maternal hypertensive disorders of pregnancy, and a small placenta, were significantly higher in infants with hypospadias. Multiple logistic regression analysis revealed that FGR (odds ratio [OR] = 9.39; 95% confidence interval [CI], 2.50–35.3) and the presence of a SUA (OR = 33.4; 95% CI, 8.00–139.5) were independently and significantly associated with hypospadias. When FGR was stratified by the time of onset, its association with hypospadias was significant regardless of the time of onset. Moreover, placental histological findings suggested that fetal vascular malperfusion might play a role in hypospadias. Discussion: FGR and SUAs are independent prenatal predictors of the development of hypospadias, and fetal vascular malperfusion of the placenta may be involved in the etiology of hypospadias.

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A patient with congenital hypothyroidism due to a PAX8 frameshift variant accompanying a urogenital malformation

Tanase-Nakao K., Muroya K., Adachi M., Abe K., Hasegawa T., Narumi S.

Clinical Pediatric Endocrinology 31 （ 4 ） 250 - 255 2022年10月

ISSN  09185739

　概要を見る

PAX8 is a transcription factor that is expressed in the thyroid gland and kidneys. Monoallelic loss-of-function PAX8 variants cause congenital hypothyroidism (CH), and urogenital malformations are infrequent complications seen in less than 10% of PAX8 variant carriers. Herein, we report the case of a 3-yr-old female patient with CH who was diagnosed during newborn screening. She was treated with levothyroxine, and she showed normal growth and development at a minimal dose (0.7 µg/kg/d of levothyroxine at 3 yr of age). At 5 mo of age, she visited an emergency department for fever and was incidentally found to have differently sized kidneys by ultrasonography, which was subsequently diagnosed as unilateral multicystic dysplastic kidney. Her serum creatinine and cystatin C levels were normal. Next-generation sequencing-based genetic analysis revealed that the patient was heterozygous for a PAX8 frameshift variant (p.Thr320ProfsTer106) and a DUOX2 missense variant (p.Arg885Gln). Our patient is the first truncating PAX8 variant carrier to have a urogenital malformation with CH. Genetic analysis for PAX8 should be considered in patients with CH and urogenital malformations.

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Impact of school closure due to the coronavirus disease 2019 pandemic on body mass index in Japanese children: Retrospective longitudinal study

Nagashima Y., Inokuchi M., Yasui Y., Uchida K., Tokumura M., Hasegawa T.

Journal of Paediatrics and Child Health 58 （ 10 ） 1841 - 1846 2022年10月

ISSN  10344810

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Aim: During the coronavirus disease 2019 pandemic, the governments of many countries responded to high levels of infection with lockdowns. As a result, some children were reported to experience weight gain. The aim of the present study was to examine the impact of school closures on body mass index (BMI) in Japanese children. Methods: This was a retrospective study of students enrolled in the participating schools (6- to 11-year-old elementary school students and 12- to 14-year-old junior high school students) between 2015 and 2020. Using school health check-up data, annual changes in the BMI standard deviation score (ΔBMI-SDS) were calculated. We compared ΔBMI-SDS in 2019–2020 with the corresponding control years. Results: 19 565 children with complete data were included in the analysis. Median ΔBMI-SDS in 2019–2020 were 0.24–0.35 in elementary school boys, 0.10–0.13 in junior high school boys, −0.02 to 0.15 in elementary school girls and −0.14 to −0.10 in junior high school girls. In comparison with every control year, ΔBMI-SDS in 2019–2020 were significantly higher in elementary school boys (control years: −0.07 to 0.14) and junior high school boys (control years: −0.04 to 0.06), and significantly lower in junior high school girls (control years: −0.06 to 0.09). Conclusion: BMI-SDS increased significantly in elementary and junior high school boys, but decreased significantly in junior high school girls. The pandemic appears to have had an impact on Japanese children that was different from other countries.

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High-dose fludrocortisone therapy was transiently required in a female neonate with 21-hydroxylase deficiency

Kawasaki Y., Sato T., Nakano S., Usui T., Narumi S., Ishii T., Hasegawa T.

Clinical Pediatric Endocrinology 31 （ 2 ） 93 - 97 2022年04月

ISSN  09185739

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For salt-wasting 21-hydroxylase deficiency (21OHD), fludrocortisone (FC) is usually supplemented at 0.05–0.2 mg/d dose. To date, no report has described 21OHD neonates requiring > 0.4 mg/d of FC. Our female 21OHD patient was lethargic and experienced weight loss with hyponatremia (133 mEq/L), hyperkalemia (6.5 mEq/L), and elevated active renin concentration (ARC, 1942.2 pg/mL) at 6 days of life. Hydrocortisone and FC replacement were initiated. FC dose was gradually increased to 0.4 mg/d at 21 days of life, but her hyperkalemia (6.4 mEq/L) and high ARC (372.3 pg/mL) persisted. We increased FC to 0.6 mg/d and used a low-potassium and high-sodium formula. Hyperkalemia subsequently improved. At 33 days of life, the ARC decreased to 0.6 pg/mL and FC dosage was gradually decreased. At 3 months of age, the low-potassium and high-sodium formula was discontinued, but the serum potassium level was normal and ARC remained low at 0.1 mg/d of FC. We speculated that severe mineralocorticoid resistance was the reason why her hyperkalemia persisted even with 0.4 mg/d of FC; however, the pathophysiology of transiently severe resistance to FC in this patient is unknown. In conclusion, 21OHD neonates may show severe salt-wasting that transiently require > 0.4 mg/d of FC.

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Destructive thyroiditis without autoantibodies in an infant

Ichikawa Y., Sato T., Ichihashi Y., Ishii T., Hasegawa T.

Pediatrics International 64 （ 1 ）  2022年01月

ISSN  13288067

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Biallelic PROKR2 variants and congenital hypogonadotropic hypogonadism: a case report and a literature review

Sugisawa C., Taniyama M., Sato T., Takahashi Y., Hasegawa T., Narumi S.

Endocrine Journal 69 （ 7 ） 831 - 838 2022年

ISSN  09188959

　概要を見る

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that causes gonadotropin-releasing hormone (GnRH) deficiency and sexual immaturity. CHH may accompany an abnormal sense of smell (Kallmann syndrome, KS) or no such manifestation (normosmic-CHH). This unusual combination of manifestations is explained by the fact that GnRH neurons originate in the olfactory placode and migrate to the forebrain during embryogenesis. We describe the case of a 31-year-old man with normosmic-CHH, who also had obesity, type 2 diabetes and intellectual disability. He was noticed to have sexual immaturity (small testes with no pubic hair) at age 20 years, when diabetic ketoacidosis developed. Basal and GnRH-stimulated levels of LH (1.0→12.0 IU/L) and FSH (1.9→6.1 IU/L) were detectable but low. The results of the T&T olfactometer and the Alinamin test were definitely normal, with an anatomically normal olfactory system on MRI. Sequencing of 22 CHH-related genes was performed, and compound heterozygous PROKR2 variants were identified: one was a previously known loss-of-function variant (p.Trp178Ser) and the other was a nonsense variant (p.Trp212*). Through a literature review, we found 22 patients (including our patient) with CHH due to biallelic PROKR2 variants, which led us to recognize that most of the patients (86%) were diagnosed with KS. Clinical observations in this study indicate that, even though they have CHH, biallelic PROKR2 variant carriers may have a normal olfactory system as well as presumably normal migration of GnRH neurons. This suggests that the PROK2-PROKR2 pathway affects the function of GnRH neurons after their migration.

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Hereditary paraganglioma presenting with atypical symptoms: Case report

Eguchi S., Ono R., Sato T., Yada K., Umehara N., Narumi S., Ichihashi Y., Nozaki T., Kanomata N., Hasegawa T., Ozawa M., Hasegawa D.

Medicine (United States) 100 （ 46 ）  2021年11月

ISSN  00257974

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Rationale:Paraganglioma (PGL), an extra-adrenal pheochromocytoma, is a rare tumor, especially in children. While hypersecretion of catecholamines causes the classic triad of headaches, palpitations, and profuse sweating, prompt diagnosis is still challenging.Patient concerns:For 7 months, an 8-year-old boy complained of polyuria and weight loss, followed by proteinuria and headache for 1 month prior to admission. He was admitted to our hospital due to an afebrile seizure.Diagnosis:His blood pressure remained markedly elevated even after cessation of the convulsion. Magnetic resonance imaging of the brain revealed posterior reversible encephalopathy syndrome. Abdominal computed tomography showed a mass lesion encasing the left renal artery, measuring 41 mm in length along its major axis. The plasma and urine levels of normetanephrine were elevated. Additionally, iodine-123-metaiodobenzylguanidine scintigraphy showed an abnormal uptake in the abdominal mass with no evidence of metastasis. Based on these findings, we tentatively diagnosed him with PGL.Intervention:Substantial alpha-and beta-blocking procedures were performed, followed by a tumor resection and an extended left nephrectomy on day 31 of hospitalization. Pathological findings confirmed the diagnosis of PGL.Outcome:The postoperative course was uneventful, and his blood pressure normalized without the use of antihypertensive agents. Genetic testing revealed a known SDHB germline mutation. The same mutation was also detected on his father and paternal grandfather without any history of hypertension or malignant tumor.Lesson:It remains challenging to diagnose pheochromocytoma/paraganglioma (PPGL) promptly because PPGL can present with a variety of symptoms. Preceding symptoms of the presented case might be caused by PGL. Although PPGL is a rare disease, especially in children, it should be considered in differential diagnosis when various unexplained symptoms persist.

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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

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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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Identification of the first promoter-specific gain-of-function SOX9 missense variant (p.E50K) in a patient with 46,XX ovotesticular disorder of sex development

Ushijima K., Ogawa Y., Terao M., Asakura Y., Muroya K., Hayashi M., Ishii T., Hasegawa T., Sekido R., Fukami M., Takada S., Narumi S.

American Journal of Medical Genetics, Part A 185 （ 4 ） 1067 - 1075 2021年04月

ISSN  15524825

　概要を見る

SOX9, a transcription factor, is expressed in the undifferentiated XX and XY gonads. SRY induces significant upregulation of SOX9 expression in XY gonads. Loss-of-function SOX9 variants cause testicular dysgenesis in 46,XY patients, while duplication of the total gene or the upstream regulatory region results in testicular development in 46,XX patients. However, gain-of-function (GoF) SOX9 variants have not been reported previously. We report the case of a 16-year-old female patient with a 46,XX karyotype who had masculinized external genitalia and unilateral ovotestis. Next-generation sequencing-based genetic screening for disorders of sex development led to the identification of a novel SOX9 variant (p.Glu50Lys), transmitted from the phenotypically normal father. Expression analysis showed that E50K-SOX9 enhanced transactivation of the luciferase reporter containing the testis enhancer sequence core element compared with that containing the wildtype-SOX9. This GoF activity was not observed in the luciferase reporter containing Amh, the gene for anti-Müllerian hormone. We genetically engineered female mice (Sox9E50K/E50K), and they showed no abnormalities in the external genitalia or ovaries. In conclusion, a novel SOX9 variant with a promoter-specific GoF activity was identified in vitro; however, the disease phenotype was not recapitulated by the mouse model. At present, the association between the GoF SOX9 variant and the ovotestis phenotype remains unclear. Future studies are needed to verify the possible association.

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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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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

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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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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

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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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