研究者詳細 - 長谷川　奉延

論文 - 長谷川　奉延

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GWAS of thyroid dysgenesis identifies a risk locus at 2q33.3 linked to regulation of Wnt signaling

Narumi S., Opitz R., Nagasaki K., Muroya K., Asakura Y., Adachi M., Abe K., Sugisawa C., Kuhnen P., Ishii T., Nothen M.M., Krude H., Hasegawa T.

Human Molecular Genetics 31 （ 23 ） 3967 - 3974 2022年12月

ISSN 09646906

Congenital hypothyroidism due to thyroid dysgenesis (TD), presented as thyroid aplasia, hypoplasia or ectopia, is one of the most prevalent rare diseases with an isolated organ malformation. The pathogenesis of TD is largely unknown, although a genetic predisposition has been suggested. We performed a genome-wide association study (GWAS) with 142 Japanese TD cases and 8380 controls and found a significant locus at 2q33.3 (top single nucleotide polymorphism, rs9789446: P = 4.4 × 10-12), which was replicated in a German patient cohort (P = 0.0056). A subgroup analysis showed that rs9789446 confers a risk for thyroid aplasia (per allele odds ratio = 3.17) and ectopia (3.12) but not for hypoplasia. Comprehensive epigenomic characterization of the 72-kb disease-associated region revealed that it was enriched for active enhancer signatures in human thyroid. Analysis of chromosome conformation capture data showed long-range chromatin interactions of this region with promoters of two genes, FZD5 and CCNYL1, mediating Wnt signaling. Moreover, rs9789446 was found to be a thyroid-specific quantitative trait locus, adding further evidence for a cis-regulatory function of this region in thyroid tissue. Specifically, because the risk rs9789446 allele is associated with increased thyroidal expression of FDZ5 and CCNYL1 and given the recent demonstration of perturbed early thyroid development following overactivation of Wnt signaling in zebrafish embryos, an enhanced Wnt signaling in risk allele carriers provides a biologically plausible TD mechanism. In conclusion, our work found the first risk locus for TD, exemplifying that in rare diseases with relatively low biological complexity, GWAS may provide mechanistic insights even with a small sample size.

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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

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

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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An elderly patient with 17α-hydroxylase deficiency misdiagnosed as primary aldosteronism: a case report

Ishinoda Y., Uto A., Yamada Y., Okazaki M., Asada H., Wakamatsu S., Kurihara I., Shibata H., Ishii T., Hasegawa T., Kumagai H., Kasuga A.

BMC Endocrine Disorders 22 （ 1 ） 2022年12月

Background: 17α-hydroxylase deficiency (17OHD) is a rare autosomal recessive disorder. Aldosterone levels are usually low in patients with 17OHD. However, among the approximately 150 cases of 17OHD reported to date, aldosterone levels were not low in all cases. Therefore, some 17OHD cases may have been misdiagnosed as primary aldosteronism (PA) cases. Often before puberty, 17OHD is diagnosed because of abnormal genital morphology and menstrual irregularities. However, we report a very rare case of 17OHD in an elderly patient with a high aldosterone/renin ratio (ARR) similar to that in PA. Case presentation: A 63-year-old Japanese woman was transferred to our medical facility for the evaluation of bilateral adrenal hypertrophy, which was incidentally discovered during an abdominal examination after cholecystectomy. The patient had hypokalemia and a high aldosterone/renin ratio. Her medical history included hypertension and right intracerebral capsular hemorrhage at the age of 30 years. Additional testing revealed low cortisol, high adrenocorticotropic hormone, and low testosterone and dehydroepiandrosterone sulfate, indicating congenital adrenal hyperplasia. Genetic analysis revealed a mutation in the CYP17A1 gene and a karyotype of 46, XY; hence, she was diagnosed with 17OHD. Conclusion: 17OHD can resemble PA. The combination of a high ARR and low cortisol level should trigger the consideration of 17OHD.

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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

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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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

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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Molecular Basis for Hypochondroplasia in Japan

Ishii T., Takagi M., Nagasaki K., Ohara T., Miyai K., Kosho T., Takada F., Nishimura G., Hasegawa T.

Endocrines 3 （ 3 ） 428 - 432 2022年09月

Hypochondroplasia is an autosomal dominant genetic disorder due to a heterozygous pathogenic variant of the FGFR3 gene. The early diagnosis of hypochondroplasia is necessary, since growth hormone is effective for improving adult height. The genetic test for the FGFR3 gene could help the early diagnosis. The detailed characteristics of FGFR3 genotypes have not been widely investigated in Japan, except for a common pathogenic variant, p.Asn540Lys. This study retrospectively analyzed the FGFR3 genotypes of 35 patients from 30 families with hypochondroplasia (age, range 0–6 years, median 1 year) in Japan. The pathogenic variants of FGFR3 were identified in all the patients: p.Asn540Lys in 23 probands (76.7%), p.Lys650Gln in 2 (6.7%), p.Leu324His in 2 (6.7%), p.Leu324Val, p.Ser351Cys, and p.Lys650Thr in 1 each (3.2%). The median age at diagnosis, height SD score at diagnosis, or the severity of radiologic findings was not significantly different between probands with p.Asn540Lys and those with other variants. Intellectual disability or epilepsy was identified in seven patients with p.Asn540Lys, but none with other variants. The genetic test of FGFR3 can be useful for assessing the potential risk of neurological sequela in children with hypochondroplasia.

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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

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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Iatrogenic Cushing syndrome due to topical corticosteroids after skin graft surgery for giant nevus: A case report

Katsura M., Sato T., Morita K., Ishii T., Kishi K., Hasegawa T.

Pediatric Dermatology 39 （ 1 ） 147 - 148 2022年01月

ISSN 07368046

Iatrogenic Cushing syndrome (ICS) may be caused by exposure to corticosteroid therapy. We report a case of ICS caused by topical corticosteroids applied to the skin after skin graft surgery. We presume that the development of ICS, in this case, was attributed to a combination of skin barrier disruption, usage of high-potency corticosteroids, broad application area/ large quantity of the corticosteroid, and the extended treatment period. Patients may be at risk for ICS after extensive skin graft surgery if large amounts of very potent topical corticosteroids are applied for an extended period to prevent scar formation or relieve itching.

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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

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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Transient central diabetes insipidus after cranioplasty for craniosynostosis in an infant with septo-optic dysplasia

Fukuyama T., Sato T., Nakano S., Tomita K., Sakamoto Y., Miwa T., Hamada J., Futagawa N., Hasegawa K., Ishii T., Hasegawa T.

Clinical Pediatric Endocrinology 31 （ 1 ） 50 - 53 2022年

ISSN 09185739

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Reference values of inside leg length and inside leg length to stature ratio for Japanese children, 0–12 years of age

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

Annals of Human Biology 49 （ 1 ） 1 - 9 2022年

ISSN 03014460

Background: Large datasets of detailed anthropometric measurements are scarce in children. The Japanese Standard Association 1978–1981 survey provides a rare opportunity to use high quality data from Japanese children. Aim: To construct inside leg length (ILL) and inside leg length to stature ratio (ILL/S) reference centile curves for Japanese children. Subjects and methods: The study sample consisted of 14,825 boys and 14,577 girls age 0–18 years for stature and weight measurements, and 9064 boys and 8796 girls age 0–12 years for ILL measurements, who participated in the 1978–1981 national survey on body sizes. LMS method was used to construct the reference centile curves. The reference centile curves for stature, weight, ILL, and ILL/S were compared to those of British children. Results: The L, M, and S reference values for Japanese children are presented for stature, weight, ILL, and ILL/S. Compared with British children of 0–12 years of age, Japanese children of 0–12 years of age had shorter median stature, shorter median ILL, and shorter median ILL/S. Conclusion: We present the first reference values for ILL and ILL/S in Japanese children. Japanese children had relatively shorter legs compared to British children from infancy.

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Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021

Naruse M., Katabami T., Shibata H., Sone M., Takahashi K., Tanabe A., Izawa S., Ichijo T., Otsuki M., Omura M., Ogawa Y., Oki Y., Kurihara I., Kobayashi H., Sakamoto R., Satoh F., Takeda Y., Tanaka T., Tamura K., Tsuiki M., Hashimoto S., Hasegawa T., Yoshimoto T., Yoneda T., Yamamoto K., Rakugi H., Wada N., Saiki A., Ohno Y., Haze T.

Endocrine Journal 69 （ 4 ） 327 - 359 2022年

ISSN 09188959

Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.

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Demographic characteristics of children with growth hormone deficiency from 1996 to 2015 in Japan: 20 years of data from the foundation for growth science in Japan

Isojima T., Hasegawa T., Yokoya S., Tanaka T.

Endocrine Journal 69 （ 8 ） 927 - 939 2022年

ISSN 09188959

Growth hormone (GH) deficiency (GHD) in children is a heterogeneous condition that includes several entities of various severities. GH treatment has been affected by various factors. Because comprehensive analyses for Japanese children with GHD over time are scarce, we investigated the baseline characteristics of patients with GHD at the start of GH treatment between 1996 and 2015 using data from the Foundation for Growth Science in Japan. During the registration period, 19,717 subjects were determined to be eligible for GH treatment as GHD. Overall analyses revealed that there were twice the number of male patients as female patients, and the etiology was idiopathic in 91.1%, central nervous system (CNS) tumor at the hypothalamus–pituitary area in 1.7%, CNS tumor distant from the hypothalamus–pituitary area in 0.68%, other tumors in 0.91%, congenital CNS malformations in 0.83%, and other diseases in 1.1% with their specific characteristics. The latest average age, height standard deviation score (SDS), insulin-like growth factor–1 SDS, and proportion of severe GHD at GH treatment initiation were 8.8 years, –2.76, –1.42, and 19.5%, respectively. The proportions of breech delivery and asphyxia gradually decreased, whereas that of caesarean section gradually increased during the registration period with the latest values of 2.2%, 4.9%, and 14.0%, respectively (all analyses: p < 0.0001). In contrast, the proportion of idiopathic GHD with breech delivery seemed to reach the lowest level among those with a birth year before 2000. This study identified the characteristics and changes of patients with GHD over 20 years.

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Current status of transition medicine for 21-hydroxylase deficiency in Japan: from the perspective of pediatric endocrinologists

Takasawa K., Nakamura-Utsunomiya A., Amano N., Ishii T., Hasegawa T., Hasegawa Y., Tajima T., Ida S.

Endocrine Journal 69 （ 1 ） 75 - 83 2022年

ISSN 09188959

To manage of 21-hydroxylase deficiency (21-OHD), transition medicine from pediatric to adult health care is an important process and requires individually optimized approaches. We sent cross-sectional questionnaire surveys on the current status of transition from pediatric to adult health care in 21-OHD patients to all councillors of the Japanese Society for Pediatric Endocrinology. Many pediatric departments (42.2%) experienced adult 21-OHD patients, and 115 patients (53 males, mean age of 26) in 46 institutions were identified. Whereas almost two-thirds of pediatric endocrinologists regarded the problems of counterparts and cooperation as hindrance of transition medicine, the major reason for continuing to be treated in pediatrics was the patient’s own request. The prevalence of long-term complications including obesity, osteoporosis, infertility, menstrual disorder, gender dysphoria, and testicular adrenal rest tumor were 27.5%, 8.8%, 11.1%, 26.3%, 7.1%, 12.5%, respectively, which is comparable to those of other cohorts previously reported. However, several items, especially infertility and osteoporosis were not checked well enough in adult 21-OHD patients treated in pediatrics. Though 44 of 62 female patients had genital reconstructive surgery, more than half of them were not followed up by gynecologists or pediatric urologists. Quite a few adult 21-OHD patients had been followed up in pediatrics even after coming of age; however, surveillance by pediatric endocrinologists of gynecological, reproductive, and mental problems may be insufficient. Therefore, multidisciplinary approaches should be required in transition medicine for 21-OHD and prerequisite for graduation of pediatrics. Pediatric endocrinologists will need to play a leading role in the development of transition systems.

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Novel STAR gene variant in a patient with classic lipoid congenital adrenal hyperplasia and combined pituitary hormone deficiency

Higa M., Zaha A., Takushi A., Morishima N., Majikina T., Touma T., Shimabukuro M., Masuzaki H., Honda M., Hasegawa T.

Human Genome Variation 8 （ 1 ） 2021年12月

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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

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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Two girls with a neonatal screening-negative 21-hydroxylase deficiency requiring treatment with hydrocortisone for virilization in late childhood

Onuma S., Fukuoka T., Miyoshi Y., Fukui M., Satomura Y., Yasuda K., Kimura T., Tachibana M., Bessho K., Yamamoto T., Tanaka H., Katsumata N., Fukami M., Hasegawa T., Ozono K.

Clinical Pediatric Endocrinology 30 （ 3 ） 143 - 148 2021年07月

ISSN 09185739

Herein, we report two girls with a neonatal screening (NS)-negative 21-hydroxylase deficiency (21-OHD) requiring treatment with hydrocortisone due to virilization that developed in late childhood. Patient 1 was born prematurely on the 30th gestational week with normal external genitalia at birth. She passed the NS for 21-OHD. At 6 yr of age, she was referred to a hospital for evaluation of premature pubarche and clitoromegaly. Her diagnosis was central precocious puberty, and GnRH agonist was initiated. However, her symptoms did not improve despite treatment for over 4 years. She was then referred to our hospital where she was diagnosed with 21-OHD. Although she was started on hydrocortisone therapy, her adult height reached only 140 cm (−3.4 SD). Patient 2 was delivered at 37 weeks of gestation and passed the NS for 21-OHD. She was referred to a hospital because of premature pubarche at the age of 6 yr. She was diagnosed with 21-OHD, and hydrocortisone replacement therapy was initiated. Her present height at 13 yr of age is 148 cm (−1.3 SD). These cases reminded us that the possibility of 21-OHD should be considered when patients show premature pubarche or precocious puberty, even if they passed the NS test for 21-OHD.

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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

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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長谷川 奉延

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長谷川　奉延

論文 - 長谷川　奉延